Methods of Treating Nuclear Factor-Kappa B Mediated Disease and Disorders

专利摘要:
The present invention provides a method of treating a disease or disorder responsive to the inhibition of nuclear factor-κB transcription factors comprising administering a sulfonylaminocarbonyl derivative, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. The method of the present invention includes, for example, rheumatoid arthritis, osteoarthritis, autoimmune diseases, psoriasis, asthma, cardiovascular disease, acute coronary syndrome, congestive heart failure, Alzheimer's disease, multiple sclerosis, cancer, type 2 diabetes, metabolic syndrome Useful for the treatment of X, or inflammatory bowel disease.
公开号:KR20020067011A
申请号:KR1020020007716
申请日:2002-02-09
公开日:2002-08-21
发明作者:조셉 안소니 코니셀리；소티리오스 콘스탄티노우 카라타나시스
申请人:워너-램버트 캄파니；
IPC主号:

专利说明:

Methods of Treating Nuclear Factor-Kappa B Mediated Disease and Disorders
[1] FIELD OF THE INVENTION
[2] The present invention provides a method for treating a disease or condition responsive to the inhibition of nuclear factor-κB transcription factors comprising administering a sulfonylaminocarbonyl derivative, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. .
[3] Background technology
[4] Inhibiting nuclear factor-kappa B (“NF-κB”) transcription factor mediated activity may provide a useful method of treating a disease or condition suffered by millions of people around the world. This is because NF-κB mediates the transcription of many genes involved in the production of pro-inflammatory cytokines and other biological molecules that are closely involved in the pathogenesis of many diseases and disorders in which there is no fully effective treatment. . Notable among the diseases and disorders considered to be responsive to the inhibition of NF-κB include rheumatoid arthritis and osteoarthritis, autoimmune diseases, psoriasis, asthma, cardiovascular diseases such as atherosclerosis, myocardial infarction and unstable angina Including acute coronary syndromes, and congestive heart failure, Alzheimer's disease, multiple sclerosis, cancer, type 2 diabetes, metabolic syndrome X, and inflammatory bowel disease (“IBD”). These diseases and disorders are among the most prevalent in modern society and cause innumerable damage and death.
[5] They typically require the removal of surgical modifications or involvement of a part of the human body or the use of agents to stop the symptoms or ideally treat the symptoms without reversing the underlying disease process. Not satisfactory at present. For example, there are many commercially available agents that modify risk factors for atherosclerosis (eg, reduction of plasma lipids and antihypertensives), but there are no treatments that directly modify the atherosclerosis process itself. In addition, more than 60% of patients with coronary arteries cannot be explained based solely on traditional risk factors.
[6] One explanation for the unsuccessful current therapies for the aforementioned diseases is that multiple gene products are likely to be involved in each disease or disorder. Common therapeutic drugs are those that target only one of these gene products. In addition, many of the drugs currently used to treat these diseases and disorders exhibit undesirable side effects such as, for example, gastric ulcers observed in many nonsteroidal anti-inflammatory drugs ("NSAIDs") used to treat arthritis. Disadvantages of surgical methods of treating these diseases and disorders include the use of very invasive methods of causing pain, scar formation and sometimes infection.
[7] In contrast, inhibition of NF-κB is potentially possible to stop and reverse the progression of the basic diseases and disorders mentioned above. Inhibition of NF-κB is effective because it has the ability to prevent, block and stop common critical steps in the activity of genes involved in the production of multiple mediators of these diseases and disorders. In other words, NF-κB inhibition acts upstream to inhibit the production of complex pro-inflammatory mediators, while traditional drug therapy regimens are less likely because they act downstream and typically target only one of these mediators. effective.
[8] Nuclear Factor-κB is a heterologous protein dimer family that acts as a sequence specific transcription factor in the activation of many genes in response to inflammation of gene expression, viral or bacterial infections, or other biological diseases requiring reprogramming. NF-κB is commonly found sequestered in the cytoplasm in an inactive form attached to an inhibitory protein (ie, an inhibitor of κB (“IκB”). Thus, IκB binds to NF-κB to form an NF-κB-IκB complex. However, NF-κB is rapidly converted into active form through the present signaling process.
[9] NF-κB is found in virtually all cell types, including T-lymphocytes, monocytes, macrophages, endothelial cells and smooth muscle cells. For example, in response to stimuli such as inflammatory cytokines, reactive oxygen intermediates or lipopolysaccharides derived from microorganisms, the IκB component of the NF-κB-IκB complex may be subjected to sequential phosphorylation, polyubiquitinylation and degradation steps. It is cut by a process comprising a. Degradation of the modified IκB protein exposes the nuclear confinement sequence to NF-κB, which causes NF-κB to be translocated into the nucleus of the cell. Here, NF-κB binds to a target gene to initiate transcription.
[10] Among genes to which nF-κB binds to initiate transcription are genes that express pro-inflammatory cytokines. These pro-inflammatory cytokines include tumor necrosis factor-alpha ("TNF-α"), interleukin-1 ("IL-1"), IL-6, IL-8, intracellular adhesion molecule-1 ("ICAM-1"). "), Vascular cell adhesion molecule-1 (" VCAM-1 "), E-selectin, monocyte chemotactic protein-1 (" MCP-1 "), inducible nitric oxide synthase, tissue factor and cyclooxygenase- 2 ("COX-2"). The result of transcriptional activation of genes expressing pro-inflammatory cytokines is the local production of these cytokines and the onset or exacerbation of inflammatory processes in affected tissues.
[11] The present invention provides methods of using sulfonylaminocarbonyl derivatives or pharmaceutically acceptable salts thereof, and methods of treating diseases and disorders known to be responsive to the inhibition of NF-κB.
[12] The following US patent discloses the use of certain sulfonylaminocarbonyl derivatives as inhibitors of the enzyme acyl-coenzyme A: cholesterol acyltransferase (ACAT) for the treatment of hypercholesterolemia and atherosclerosis. Is starting.
[13] U.S. Patent No. 5,245,068 and its division Nos. 5,384,328;
[14] U.S. Patent No. 5,214,206 and Subdivision 5,288,757;
[15] U.S. Patent No. 5,254,715 and Division Nos. 5,336,690;
[16] U.S. Patent 5,198,466 and its divisions 5,364,882;
[17] U.S. Patent 5,491,172 and its split 5,633,287; And
[18] US Patent No. 6,093,744 and its continuing 5,981,595.
[19] US Pat. No. 6,093,744 discloses certain sulfonyls with ACAT inhibitors to regulate plasma cholesterol levels, lower serum or plasma Lp (a) levels, and to treat hypercholesterolemia, atherosclerosis, peripheral vascular disease and restenosis. A method of using aminocarbonyl derivatives is disclosed.
[20] US Pat. No. 6,117,909 describes a method for using certain sulfonylaminocarbonyl derivatives as ACAT inhibitors to lower serum or plasma Lp (a) levels and to treat cerebrovascular disease, peripheral vascular disease and restenosis, including stroke. Initiate.
[21] U.S. Pat.Nos. 6,124,309 and its subdivided patents 6,143,755 and 6,093,719 include improving endothelial normal relaxing ability, including vascular relaxation, reducing the properties of vascular cell wall attachment, and reducing platelet coagulation To restore endothelial vascular endothelial dependent activity, and acute ischemic syndrome, coronary vascular disease, hypertension, cerebrovascular accident, including myocardial infarction and angina, transient ischemic attack, chronic obstructive pulmonary disease, chronic hypoxia Sulfonylaminocarbonyl derivatives are used as ACAT inhibitors in combination with HMG-CoA reductase inhibitors to treat pulmonary disease, pulmonary hypertension, nephrotic hypertension, chronic kidney disease, microvascular complications of diabetes mellitus, and vascular obstructive complications of acinar cell anemia. Discuss how to use.
[22] Since NF-κB is involved in the initiation and progression of inflammatory diseases, screening assays that provide a method of rapidly screening multiple compounds in vitro for their ability to inhibit NF-κB mediated gene transcription may be valuable tools. Such screening assays can be an important step in obtaining compounds that treat diseases that are responsive to the inhibition of NF-κB.
[23] We have found the ability of certain sulfonylaminocarbonyl derivatives to inhibit NF-κB mediated transcription. Accordingly, the present invention provides a method for the treatment of a disease or disorder responsive to the inhibition of nF-κB comprising administering to the patient a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof. What is required to practice the present invention is rheumatoid arthritis, osteoarthritis, autoimmune diseases, psoriasis, asthma cardiovascular diseases such as atherosclerosis, acute coronary syndromes (including myocardial infarction and unstable angina) and congestive heart failure, For the treatment of Alzheimer's disease, multiple sclerosis, cancer, type 2 diabetes mellitus, metabolic syndrome X and inflammatory bowel disease, the patient is administered 1 to 6 times daily with a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof. It is within the skill of one of ordinary skill in the pharmaceutical and medical arts to determine suitable dosages and dosage forms of the sulfonylaminocarbonyl derivatives or pharmaceutically acceptable salts thereof for use in the methods of the invention.
[24] Summary of the Invention
[25] The present invention provides a method of treating a disease or disorder responsive to the inhibition of nuclear factor-κB transcription factors comprising administering a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof to a subject in need thereof.
[26] Sulfonylaminocarbonyl derivatives are disclosed in US Pat. No. 5,491,172 and its subdivisions 5,633,287, all of which are incorporated herein by reference and are useful in the present invention. Accordingly, one embodiment of the invention is responsive to the inhibition of nuclear factor-κB transcription factors comprising administering to a subject in need thereof a sulfonylaminocarbonyl derivative of Formula 1 or a pharmaceutically acceptable salt thereof: Method of treatment of a disease or disorder.
[27]
[28] Where
[29] X and Y are oxygen, sulfur and (CR'R ") _n , where n is an integer from 1 to 4, R 'and R" are each independently hydrogen, alkyl, alkoxy, halogen, hydroxy, acyloxy, Cycloalkyl, optionally substituted phenyl, or R 'and R "together form spirocycloalkyl or carbonyl;
[30] Provided that when at least one of X and Y is-(CR'R ") _n -and X and Y together are (CR'R") _n, then R 'and R "are hydrogen, n is 1, and R ₁ And R ₂ is aryl;
[31] R is hydrogen, straight or branched chain alkyl of 1 to 8 carbon atoms, or benzyl;
[32] R ₁ and R ₂ are each independently selected from the following (a) to (e):
[33] (a) phenyl, an alkyl group having 1 to 6 carbon atoms and straight or branched chain, an alkoxy group having 1 to 6 carbon atoms and straight or branched chain, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, Trifluoromethyl, —COOH, —COOalkyl having 1 to 4 carbon atoms and straight or branched chain alkyl, and — (CH ₂ ) _p NR ₃ R ₄ where p is 0 or 1 and R ₃ And R _{4 is} each phenyl or phenoxy unsubstituted or substituted with 1 to 5 substituents selected from hydrogen or a straight or branched chain alkyl group having 1 to 4 carbon atoms;
[34] (b) phenyl, an alkyl group having 1 to 6 carbon atoms and straight or branched chain, an alkoxy group having 1 to 6 carbon atoms and straight or branched chain, hydroxy, phenoxy, fluorine, chlorine, bromine, nitro, Trifluoromethyl, -COOH, -COOalkyl having 1 to 4 carbon atoms and straight or branched chain alkyl, and-(CH ₂ ) _p NR ₃ R ₄ , wherein p, R ₃ and R ₄ are 1- or 2-naphthyl unsubstituted or substituted with one to three substituents selected from: (as defined);
[35] (c) arylalkyl;
[36] (d) straight or branched chain alkyl having 1 to 20 carbon atoms and saturated or comprising 1 to 3 double bonds;
[37] (e) an adamantyl or cycloalkyl group in which the cycloalkyl moiety has 3 to 6 carbon atoms;
[38] only,
[39] (i) if X is (CH ₂ ) n, Y is oxygen and R ₁ is substituted phenyl, then R ₂ is substituted phenyl,
[40] (ii) when Y is oxygen, X is (CH ₂ ) _n and R ₂ is phenyl or naphthyl, then R ₁ is not straight or branched alkyl,
[41] (iii) subject to the exclusion of:
[42]
[43] Sulfamic acid [1-oxo-3- [2,4,6-tris (1-methylethyl) phenyl] propyl] -2,6-bis (1-methylethyl) phenyl ester,
[44] Sulfamic acid [fluoro [2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester, and
[45] Further condition is the exclusion of compounds selected from the group consisting of sulfamic acid [[2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (phenyl) phenyl ester.
[46] Preferably in a method of treating a disease or disorder responsive to the inhibition of nuclear factor-κB transcription factor comprising administering to a subject in need thereof a sulfonylaminocarbonyl derivative of Formula 1 or a pharmaceutically acceptable salt thereof,
[47] R ₁ is phenyl or phenyl substituted at the 2,6-position;
[48] R ₂ is phenyl or phenyl substituted at the 2,6-position;
[49] R ₁ and R ₂ are each phenyl;
[50] R ₁ is 2,6-position di-substituted phenyl, R ₂ is 2,4,6-position tri-substituted phenyl;
[51] R ₁ is 2,6-bis (1-methylethyl) phenyl, R ₂ is 2,6-bis (1-methylethyl) phenyl or 2,4,6-tris (1-methylethyl) phenyl; or
[52] One of R ₁ and R ₂
[53] Gigi,
[54] t is 0 or 1 to 4; w is 0 or 1 to 4, provided that the sum of t and w is 5 or less, and R ₅ and R ₆ are each independently selected from hydrogen or alkyl having 1 to 6 carbon atoms, or when R ₅ is hydrogen R ₆ may be selected from the group defined for R ₇ ; R ₇ is phenyl or a straight or branched chain alkyl group having 1 to 6 carbon atoms, a straight or branched chain alkoxy group having 1 to 6 carbon atoms, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluor Chloromethyl, -COOH, -COOalkyl, where alkyl has 1 to 4 carbon atoms or-(CH ₂ ) _p NR ₃ R ₄ , wherein P, R3 and R4 have the meanings defined above .
[55] Preferably in a method of treating a disease or disorder responsive to the inhibition of nuclear factor-κB transcription factor comprising administering to a subject in need thereof a sulfonylaminocarbonyl derivative of Formula 1 or a pharmaceutically acceptable salt thereof,
[56] X is oxygen, sulfur or (CP'R ") _n ;
[57] Y is oxygen, sulfur or (CP'R ") _n , provided that at least one of X or Y is (CP'R") _n , where n is an integer from 1 to 4, and R 'and R "are each independently Hydrogen, 1 to 6 straight or branched chain alkyl, optionally substituted phenyl, halogen, hydroxy, alkoxy, acyloxy, cycloalkyl, or R 'and R "together are carbonyl or 3 to 10 spiro To form a cycloalkyl group;
[58] R is hydrogen;
[59] R ₁ is optionally substituted phenyl, straight or branched chain alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms;
[60] R ₂ is optionally substituted phenyl, straight or branched chain alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, optionally substituted phenyl, provided that R ₁ is only when X is (CR′R ″) _n May be optionally substituted with phenoxy, R ₂ may be optionally substituted with phenolic only if Y is (CR'R ") _n , and at least one of R ₁ and R ₂ is optionally substituted phenyl or phenoxy Subject to seam.
[61] Preferably in a method of treating a disease or disorder responsive to the inhibition of nuclear factor-κB transcription factor comprising administering to a subject in need thereof a sulfonylaminocarbonyl derivative of Formula 1 or a pharmaceutically acceptable salt thereof,
[62] X is oxygen;
[63] Y is (CR'R ") n, where n is an integer from 1 to 2;
[64] R is hydrogen;
[65] R ₁ is optionally substituted phenyl;
[66] R ₂ is optionally substituted phenyl or phenoxy, straight or branched chain alkyl of 1 to 10 carbons or cycloalkyl of 3 to 10 carbons;
[67] R 'and R "are each independently hydrogen, straight or branched chain alkyl of 1 to 6 carbons, optionally substituted phenyl, halogen, hydroxy, alkoxy, acyloxy, cycloalkyl, or R' and R" together Forms carbonyl or spirocycloalkyl.
[68] Preferably, in a method of treating a disease or disorder responsive to the inhibition of nuclear factor-κB transcription factors, comprising administering a sulfonylaminocarbonyl derivative of formula 1 to a subject in need thereof, R ₁ and R ₂ One is phenyl; More preferably one of R ₁ and R ₂ is substituted phenyl; Even more preferably, one of R ₁ and R ₂ is phenyl di-substituted at 2,6-position.
[69] More preferably in a method of treating a disease or disorder responsive to the inhibition of nuclear factor-κB transcription factors comprising a method of administering a sulfonylaminocarbonyl derivative of formula 1 to a subject in need thereof, R ₁ and R ₂ Are all 2,6-substituted phenyl.
[70] In another more preferred embodiment, the process comprises a sulfonylaminocarbonyl derivative of formula 1 wherein R ₁ is 2,6-position di-substituted phenyl and R ₂ is 2,4,6-position trisubstituted phenyl; or Its pharmaceutically acceptable salts are used.
[71] Preferably in a method of treating a disease or disorder responsive to the inhibition of nuclear factor-κB transcription factor comprising a method of administering to a subject in need thereof a sulfonylaminocarbonyl derivative of Formula 1 or a pharmaceutically acceptable salt thereof , Compounds of formula (1) are selected from the following compounds:
[72] (1,2,3,4-tetrahydro-naphthalene-2-carbonyl) -sulfamic acid 2,6-diisopropyl-phenyl ester;
[73] [Bis- (4-chloro-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-phenyl ester;
[74] (Bromo-phenyl-acetyl) -sulfamic acid 2,6-diisopropyl-phenyl ester;
[75] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4-hydroxy-2,6-diisopropyl-phenyl ester;
[76] Methyl-[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-phenyl ester;
[77] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-4-nitro-phenyl ester;
[78] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4-fluoro-2,6-diisopropyl-phenyl ester;
[79] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-dimethoxy-phenyl ester;
[80] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-amino-2,6-diisopropyl-phenyl ester;
[81] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,4,6-trimethoxy-phenyl ester;
[82] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-tert-butyl-2,6-diisopropyl-phenyl ester;
[83] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-acetyl-2-isopropyl-phenyl ester;
[84] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-4-methoxy-phenyl ester;
[85] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-dichloro-phenyl ester;
[86] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid dodecyl ester;
[87] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4-bromo-2,6-diisopropyl-phenyl ester;
[88] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-4-methyl-phenyl ester;
[89] [1- (4-Dimethylamino-phenyl) -cyclopentanecarbonyl] -sulfamic acid 2,6-diisopropyl-phenyl ester;
[90] [1- (4-Nitro-phenyl) -cyclopentanecarbonyl] -sulfamic acid 2,6-diisopropyl-phenyl ester;
[91] 3,5-diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -benzoic acid methyl ester;
[92] Sulfamic acid (phenylacetyl) -2,6-bis (1-methylethyl) phenyl ester;
[93] Sulfamic acid [[2,4,6-tris (1-methylethyl) phenyl] acetyl-2,6-bis (1-methylethyl) phenyl ester,
[94] Sulfamic acid [[2,6-bis (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester;
[95] Sulfamic acid [[2,4,6-tris (1-methylethyl) phenyl] acetyl-2,4,6-tris (1-methylethyl) phenyl ester;
[96] Sulfamic acid [[2,6-bis (1-methylethyl) phenyl] acetyl] -2,4,6-tris (1-methylethyl) phenyl ester;
[97] Sulfamic acid [adamantaneacetyl] -2,6-bis (1-methylethyl) phenyl ester;
[98] Sulfamic acid [[2,6-bis (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester-sodium salt;
[99] Sulfamic acid [[2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester-sodium salt;
[100] Sulfamic acid (decanoyl) -2,6-bis- (1-methylethyl) phenyl ester;
[101] Sulfamic acid (dodecanoyl) -2,6-bis- (1-methylethyl) phenyl ester;
[102] 2,6-bis (1-methylethyl) -N-[[[2,4,6-tris (1-methylethyl) phenyl] -methyl] sulfonyl] benzeneacetamide;
[103] 2,6-bis (1-methylethyl) -N-[[[2,4,6-tris (1-methylethyl) phenyl] -methyl] -sulfonyl] benzeneacetamide-sodium salt;
[104] 2,6-bis (1-methylethyl) phenyl [[[[2,4,6-tris (1-methylethyl) phenyl] -methyl] sulfonyl] carbamate;
[105] 2,6-bis (1-methylethyl) phenyl [[[2,4,6-tris (1-methylethyl) phenyl] -methyl] sulfonyl] carbamate-sodium salt;
[106] Sulfamic acid (1-oxo-3,3-diphenylpropyl) -2,6-bis (1-methylethyl) phenyl ester;
[107] Sulfamic acid [2,6-dichlorophenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
[108] Sulfamic acid [2,6-dichlorophenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester sodium salt;
[109] Sulfamic acid trans-[(2-phenylcyclopropyl) carbonyl] -2,6-bis (1-methylethyl) phenyl ester;
[110] Sulfamic acid [2,5-dimethoxyphenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
[111] Sulfamic acid [2,4,6-trimethoxyphenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
[112] Sulfamic acid [2,4,6-trimethylphenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
[113] Sulfamic acid [2-thiophenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
[114] Sulfamic acid [3-thiophenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
[115] Sulfamic acid [2-methoxyphenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
[116] Sulfamic acid (oxophenylacetyl) -2,6-bis (1-methylethyl) phenyl ester;
[117] Sulfamic acid [2-trifluoromethylphenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
[118] Sulfamic acid (1-oxo-2-phenylpropyl) -2,6-bis (1-methylethyl) phenyl ester;
[119] Sulfamic acid (cyclopentylphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester;
[120] Sulfamic acid (cyclohexylacetyl) -2,6-bis (1-methylethyl) phenyl ester;
[121] Sulfamic acid (diphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester;
[122] Sulfamic acid (triphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester;
[123] Sulfamic acid [(1-phenylcyclopentyl) carbonyl] -2,6-bis (1-methylethyl) phenyl ester;
[124] Sulfamic acid (3-methyl-1-oxo-2-phenylpentyl) -2,6-bis (1-methylethyl) phenyl ester;
[125] Sulfamic acid (1-oxo-2-phenylbutyl) -2,6-bis (1-methylethyl) phenyl ester;
[126] Sulfamic acid (cyclohexylphenyl-acetyl) -2,6-bis (1-methylethyl) phenyl ester;
[127] Sulfamic acid (1-oxo-2,2-diphenylpropyl) -2,6-bis (1-methylethyl) phenyl ester;
[128] Sulfamic acid [(9H-fluoren-9-yl) carbonyl] -2,6-bis (1-methylethyl) phenyl ester;
[129] Sulfamic acid (1-oxo-3-phenylpropyl) -2,6-bis (1-methylethyl) phenyl ester;
[130] Sulfamic acid [1-oxo-3- [2,4,6-tris (1-methylethyl) phenyl] -2-propenyl] -2,6-bis (1-methylethyl) phenyl ester;
[131] Sulfamic acid [(acetyloxy) [2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester;
[132] Sulfamic acid [hydroxy [2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester;
[133] Sulfamic acid (3-methyl-1-oxo-2-phenylpentyl) -2,6-bis (1-methylethyl) phenyl ester sodium salt;
[134] Sulfamic acid [[2,4,6-tris (1-methylethyl) phenoxy] acetyl] -2,6-bis (1-methylethyl) phenyl ester; And
[135] Sulfamic acid [[2,6-bis (1-methylethyl) phenoxy] acetyl] -2,6-bis (1-methylethyl) phenyl ester.
[136] More preferred are sulfonylaminocarbonyl derivatives of formula 1 of sulfamic acid [[2,4,6-tris (1-methylethyl) phenyl] acetyl-2,6-bis (1-methylethyl) phenyl ester or pharmaceuticals thereof Is a method of treating a disease or disorder responsive to nuclear factor-κB transcription factor inhibition comprising administering an acceptable salt to a subject in need thereof.
[137] Even more preferred is the sulfonylaminocarbonyl derivative of formula 1 of sulfamic acid [[2,4,6-tris (1-methylethyl) phenyl] acetyl-2,6-bis (1-methylethyl) phenyl ester or a pharmaceutical thereof Is a method of treating a disease or disorder responsive to nuclear factor-κB transcription factor inhibition comprising administering an acceptable salt to a subject in need thereof.
[138] Sulfonylaminocarbonyl derivatives disclosed in US Pat. No. 6,093,744, which is incorporated herein by reference in its entirety, are also useful in the present invention. Accordingly, another embodiment of the invention is a disease reactive to the inhibition of nuclear factor-κB transcription factors comprising administering a sulfonyl aminocarbonyl derivative of Formula 2 or a pharmaceutically acceptable salt thereof to a subject in need thereof Or treatment of disorders.
[139]
[140] Where
[141] R ¹ is hydrogen, alkyl or alkoxy;
[142] R ² to R ⁵ are alkyl, alkoxy, or unsubstituted or substituted phenyl;
[143] R ⁶ is —CN, — (CH ₂ ) _0-1 —NR ⁷ R ⁸ , —O— (CH ₂ ) _1-10 —Z, wherein Z is —NR ⁹ R ¹⁰ , OR ¹ or CO ₂ R ¹ -OC (= O) R ¹¹ , -SR ¹¹ , -SCN, -S (CH ₂ ) _1-10 Z, -S (O) _1-2 R ¹² , wherein R ¹² is hydroxy, alkoxy , Alkyl, (CH ₂ ) _1-10 Z or NR ⁷ R ⁸ , -C (= 0) XR ¹¹ , or -CH ₂ -R ¹³ , wherein R ¹³ is (CH ₂ ) _0-5 -Y — (CH ₂ ) _0-5 Z or 1-20 carbons having 1 to 3 double bonds, wherein alkyl is selected from —CN, NO ₂ , halogen, OR ¹ , NR ⁹ R ¹⁰ and CO ₂ R ¹ Optionally substituted with one or more residues)
[144] Wherein R ⁷ and R ⁸ are each independently at least one of R ⁷ and R ⁸ is hydrogen other than hydrogen, — (CH ₂ ) _1-10 Z {where Z is as defined above and R ⁹ and R ¹⁰ is each independently hydrogen, alkyl and unsubstituted or substituted phenyl, or R ⁹ and R ¹⁰ together with the nitrogen attached thereto
[145]
[146] Form a ring selected from: wherein R ¹⁴ , R ¹⁵ and R ¹⁶ are each independently hydrogen, alkyl and unsubstituted or substituted phenyl; and, -C (= Q) XR ¹¹ , wherein X is a bond Or NH, Q is O or S and R ¹¹ is hydrogen, alkyl, unsubstituted or substituted phenyl,-(CH ₂ ) _0-5 -Y- (CH ₂ ) _0-5 Z, wherein Z is As defined above, Y is phenyl or a bond), -C (= 0) -CR ¹⁷ R ¹⁸ Z, -C (= 0) NHCR ¹⁷ R ¹⁸ Z, wherein R ¹⁷ and R ¹⁸ are each Independently hydrogen, alkyl, phenyl, substituted phenyl or side chains of naturally occurring amino acids, -S (O) _1-2 R ¹⁹ , wherein R ¹⁹ is alkyl, unsubstituted or substituted phenyl, naphthyl or heteroaromatic Ring or NR ⁹ R ¹⁰ ), or
[147] R ⁷ and R ⁸ together with the attached nitrogen
[148]
[149] To form a ring selected from wherein R ¹⁴ , R ¹⁵ and R ¹⁷ are as above;
[150] Provided that [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-formyl-2,6-diisopropyl-phenyl ester;
[151] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2-cyano-vinyl) -2,6-diisopropyl-phenyl ester;
[152] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4- (4-methyl-piperazin-1-ylmethyl) -phenyl ester, dihydrochloride ;
[153] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [bis- (2-hydroxy-ethyl) -amino] -2,6-diisopropyl-phenyl ester;
[154] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4- (3-phenyl-thioureido] -phenyl ester; and
[155] Excludes compounds selected from [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4-sulfamoyl-phenyl ester.
[156] Preferably in a method of treating a disease or disorder responsive to the inhibition of nuclear factor-κB transcription factor comprising administering a sulfonylaminocarbonyl derivative of Formula 2 or a pharmaceutically acceptable salt thereof to a subject in need thereof,
[157] R ¹ is hydrogen or alkyl of 1 to 4 carbon atoms;
[158] R ² to R ⁵ are each alkyl of 1 to 4 carbon atoms;
[159] R ⁶ is —NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are each independently hydrogen (at least one of R ⁷ and R ⁸ is not hydrogen), — (CH ₂ ) _1-10 Z, —C (= Q) XR ¹¹ or -S (O) _1-2 R ¹⁹ is selected.
[160] More preferably in a method of treating a disease or disorder responsive to the inhibition of nuclear factor-κB transcription factors comprising administering a sulfonylaminocarbonyl derivative of Formula 2 or a pharmaceutically acceptable salt thereof to a subject in need thereof ,
[161] R ⁷ is hydrogen,
[162] R ⁸ is —C (═O) CR ¹⁷ R ¹⁸ Z, wherein Z is NH ₂ , one of R ¹⁷ and R ¹⁸ is a side chain of naturally occurring amino acid and the other is hydrogen.
[163] Also preferred is a method of treating a disease or disorder responsive to inhibition of nuclear factor-κB transcription factors comprising administering a sulfonylaminocarbonyl derivative of Formula 2 or a pharmaceutically acceptable salt thereof to a subject in need thereof,
[164] R ¹ is hydrogen or alkyl of 1 to 4 carbon atoms;
[165] R ² to R ⁵ are each alkyl of 1 to 4 carbon atoms;
[166] R ⁶ is NR ⁷ R ⁸ and R ⁷ and R ⁸ together with the attached nitrogen
[167] ,
[168] ,
[169] Wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen, alkyl and phenyl; And
[170] Wherein R ¹⁶ is hydrogen, alkyl or phenyl.
[171] Also preferred is a method of treating a disease or disorder responsive to inhibition of nuclear factor-κB transcription factors comprising administering a sulfonylaminocarbonyl derivative of Formula 2 or a pharmaceutically acceptable salt thereof to a subject in need thereof,
[172] R ¹ is hydrogen or alkyl of 1 to 4 carbon atoms;
[173] R ² to R ⁵ are each alkyl of 1 to 4 carbon atoms;
[174] R ⁶ is NR ⁷ R ⁸ , wherein one of R ⁷ and R ⁸ is hydrogen and the other is S (O) _1-2 R ¹⁹ , wherein R ¹⁹ is alkyl, unsubstituted or substituted phenyl, Naphthyl or heteroaromatic ring).
[175] More preferred method of the present invention
[176] R ¹ is hydrogen or alkyl of 1 to 4 carbons;
[177] R ² to R ⁵ are alkyl of 1 to 4 carbons;
[178] R ⁶ is -C (= 0) XR ¹¹ or -CH ₂ R ¹³ , wherein X, R ¹¹ and R ¹³ are as defined for Formula 2 above, using Formula 2 or a pharmaceutically acceptable salt thereof That's how.
[179] Also preferably in a method of treating a disease or disorder responsive to inhibition of nuclear factor-κB transcription factors comprising administering a sulfonylaminocarbonyl derivative of Formula 2 or a pharmaceutically acceptable salt thereof to a subject in need thereof ,
[180] R ¹ is hydrogen or alkyl of 1 to 4 carbon atoms;
[181] R ² to R ⁵ are alkyl of 1 to 4 carbon atoms;
[182] R ⁶ is -O- (CH ₂ ) _1-10 Z, -OC (= O) R ¹¹ , -SH, -SCN, -S (CH ₂ ) _1-10 Z or -S (O) _1-2 R ¹² , wherein Z, R ¹¹ and R ¹² are as defined above for Formula 2.
[183] Also preferred is a method of treating a disease or disorder responsive to inhibition of nuclear factor-κB transcription factors comprising administering a sulfonylaminocarbonyl derivative of Formula 2 or a pharmaceutically acceptable salt thereof to a subject in need thereof,
[184] R ¹ is hydrogen or alkyl of 1 to 4 carbon atoms;
[185] R ² to R ⁵ are alkyl of 1 to 4 carbon atoms;
[186] R ⁶ is O (CH ₂ ) _1-10 NR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ are as defined above for Formula 2.
[187] Particularly preferred are diseases responsive to the inhibition of nuclear factor-κB transcription factors comprising administering to a subject in need thereof a sulfonylaminocarbonyl derivative of formula (2) or a pharmaceutically acceptable salt thereof selected from the following compounds: Treatment of the disorder is:
[188] 6- (3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -phenyl) -hexanoic acid ethyl ester;
[189] 3- [3- (3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -phenyl) -ureido] -propionic acid ethyl ester;
[190] {[4- (1-hydroxy-1-methyl-ethyl) -2,6-diisopropyl-phenyl] -acetyl} -sulfonic acid 2,6-diisopropyl-phenyl ester;
[191] [2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-((S) -2-amino-4-methyl-pentanoylamino) -2,6-diisopropyl- Phenyl esters; Compound with trifluoroacetic acid;
[192] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (3-tert-butyl-ureido) -2,6-diisopropyl-phenyl ester;
[193] [2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (3-amino-propionylamino) -2,6-diisopropyl-phenyl ester; Compounds with trifluoro acetic acid;
[194] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2-cyano-vinyl) -2,6-diisopropyl-phenyl ester;
[195] [2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfonic acid 4-((S) -2-amino-3-hydroxy-propionylamino) -2,6-diisopropyl -Phenyl esters; Compounds with trifluoro acetic acid;
[196] [2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-((S) -2-amino-4-carbamoyl-butyrylamino) -2,6-diiso Propyl-phenyl esters; Compounds with trifluoro acetic acid;
[197] [2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-((S) -2-amino-3-methyl-butyrylamino) -2,6-diisopropyl- Phenyl esters; Compounds with trifluoro acetic acid;
[198] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [3- (3,5-dichloro-phenyl) -thioureido] -2,6-diisopropyl-phenyl ester;
[199] (S)-[5-tert-butoxycarbonylamino-5- (3,5-diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -Phenylcarbamoyl) -pentyl] -carbamic acid tert-butyl ester;
[200] (S)-[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2,6-diamino-hexanoylamino) -2,6-diisopropyl-phenyl ester di Hydrochloride;
[201] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2-t-butoxycarbonylamino-acetylamino) -2,6-diisopropyl-phenyl ester;
[202] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-amino-acetylamino) -2,6-diisopropyl-phenyl ester;
[203] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-t-butoxycarbonylamino-4-methylsulfanyl-butyrylamino) -2,6-diiso Propyl-phenyl esters;
[204] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-amino-4-methylsulfanyl-butyrylamino) -2,6-diisopropyl-phenyl ester trifluor Low acetate;
[205] 3- [3- (3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -phenyl) -ureido] -propionic acid ethyl ester;
[206] 3- [3- (3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -phenyl) -ureido] -propionic acid;
[207] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [2-amino-3- (1H-indol-3-yl) -propionylamino] -2,6-diiso Propyl-phenyl esters;
[208] [(2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (5-amino-pentanoylamino) -2,6-diisopropyl-phenyl ester trifluoroacetate (1: 1 ) (Salts);
[209] (D)-[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2-amino-propionylamino) -2,6-diisopropyl-phenyl ester trifluoroacetate (1; 1) (salt);
[210] (L)-[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2-amino-propionylamino) -2,6-diisopropyl-phenyl ester;
[211] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2-amino-2-methyl-propionylamino) -2,6-diisopropyl-phenyl ester;
[212] [(2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (3-dimethylamino-propoxy) -2,6-diisopropyl-phenyl ester;
[213] [(2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (3-dimethylamino-propoxy) -2,6-diisopropyl-phenyl ester hydrochloride salt;
[214] [(2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (3-amino-propoxy) -2,6-diisopropyl-phenyl ester hydrochloride salt;
[215] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4-thiocyanato-phenyl ester;
[216] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-cyano-2,6-diisopropyl-phenyl ester;
[217] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4-[(2-amino-acetylamino) -methyl] -2,6-diisopropyl-phenyl ester;
[218] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (benzylamino-methyl) -2,6-diisopropyl-phenyl ester mono hydrochloride;
[219] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfame acid 4-carbamoyl-2,6-diisopropyl-phenyl ester;
[220] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-hydroxymethyl-2,6-diisopropyl-phenyl ester;
[221] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-acetylamino-2,6-diisopropyl-phenyl ester;
[222] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2-hydroxy-ethylamino) -2,6-diisopropyl-phenyl ester;
[223] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [3- (2,6-diisopropyl-phenyl) -ureido] -2,6-diisopropyl-phenyl ester;
[224] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4- (3-phenyl-ureido] -phenyl ester;
[225] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4- (thiophene-2-sulfonylamino) -phenyl ester;
[226] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (5-dimethylamino-naphthalene-1-sulfonylamino) -2,6-diisopropyl-phenyl ester;
[227] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4-methanesulfonylamino-phenyl ester;
[228] 6- (3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl-acetyl] sulfamoyloxy} -phenyl) -hexanoic acid ethyl ester; and
[229] (6- (3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl-acetyl] sulfamoyloxy} -phenyl) -hexanoic acid.
[230] Also preferred is a method of treating a disease or disorder responsive to the inhibition of nuclear factor-κB transcription factors comprising administering a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof to a subject in need thereof. :
[231] (9H-Xanthene-9-carbonyl) -sulfamic acid 2,6-diisopropyl-phenyl ester;
[232] ((E) -2-methyl-3-phenyl-acryloyl) -sulfamic acid 2,6-diisopropyl-phenyl ester, and
[233] (2-oxo-2H-chromen-3-carbonyl) -sulfamic acid 2,6-diisopropyl-phenyl ester.
[234] Sulfonylaminocarbonyl derivatives disclosed in US Pat. No. 5,254,715 and its split 5,336,690, all of which are incorporated herein by reference, are also useful in the present invention. Accordingly, another embodiment of the invention is a disease responsive to the inhibition of nuclear factor-κB transcription factors comprising administering to a subject in need thereof a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof selected from: Or a method of treating a disorder:
[235] Carbamic acid, [(phenylamino) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
[236] Carbamic acid, [(phenylamino) sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-hydroxyphenyl ester;
[237] Carbamic acid, [(phenylamino) sulfonyl]-, 2,6-bis (1,1-dimethylethyl) phenyl ester;
[238] Carbamic acid, [(didecylamino) sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester;
[239] Carbamic acid, [[bis (1-methylethyl) amino] sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
[240] Carbamic acid, [(dipentylamino) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
[241] Carbamic acid, [[(diphenylmethyl) amino] sulfonyl] methyl-, 2,6-bis (1,1-dimethylethyl) phenyl ester;
[242] DL-tryptophan, α-methyl-N-[[[((tricyclo [3.3.1.1 ^3,7 ] dec-2-yloxy) carbonyl] amino] sulfonyl]-, methyl ester;
[243] Carbamic acid, sulfonylbis-, bis [2,6-bis (1-methylethyl) phenyl] ester;
[244] Carbamic acid, [[[2- (phenylmethyl) phenyl] amino] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) phenyl ester;
[245] Methyl [[2,6-bis (1-methylethyl) phenyl amino] sulfonyl] carbamate;
[246] Dodecyl [[2,6-bis (1-methylethyl) phenyl] amino] sulfonyl] carbamate;
[247] 2,6-bis (1,1-dimethylethyl) -4-methoxyphenyl [[(2,2-diphenylethyl) -amino] sulfonyl] carbamate;
[248] 2,6-bis (1,1-dimethylethyl) -4-methoxy phenyl [[[2,6-bis (1-methylethyl) phenyl] amino] sulfonyl] carbamate;
[249] 2,6-bis (1,1-dimethylethyl) phenyl-[[(diphenylmethyl) amino] -sulfonyl] carbamate;
[250] 2,6-bis (1,1-dimethylethyl) phenyl [[[2,6-bis (1-methylethyl) phenyl] -amino] sulfonyl] carbamate;
[251] 2,6-bis (1,1-dimethylethyl) phenyl [[(2,2-diphenylethyl) amino] -sulfonyl] carbamate;
[252] 2,6-bis (1,1-dimethylethyl) phenyl [[bis (phenylmethyl) amino] -sulfonyl] carbamate;
[253] 2,6-bis (1-methylethyl) phenyl [(diphenyl-amino) sulfonyl] carbamate;
[254] 2,6-bis (1-methylethyl) phenyl [(dibutyl-amino) sulfonyl] carbamate;
[255] 2,6-bis (1-methylethyl) phenyl [[bis (phenyl-methyl) amino] sulfonyl] -carbamate;
[256] 2,6-bis (1-methylethyl) phenyl [(1H-benzimidazol-2-ylamino) -sulfonyl] carbamate;
[257] 2,6-bis (1-methylethyl) phenyl [[(2,2-diphenylethylamino] sulfonyl] -carbamate;
[258] 2,6-bis (1-methylethyl) phenyl [[[2,6-bis (1-methylethyl) phenyl] -amino] sulfonyl] carbamate;
[259] 2,6-bis (1-methylethyl) phenyl [[(diphenyl-methyl) amino] sulfonyl] -carbamate;
[260] 2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[(diphenylmethyl) -amino] sulfonyl]] carbamate;
[261] 2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[[bis (2,6-bis (1-methylethyl) phenyl] amino] sulfonyl] carbamate;
[262] 2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[(2,2-diphenylethyl) -amino] sulfonyl] -carbamate;
[263] 2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [(dibutylamino) -sulfonyl] carbamate;
[264] 2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [(dipentylamino) -sulfonyl] carbamate;
[265] 2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[bis (1-methylethyl) amino] sulfonyl] carbamate;
[266] 2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [(dihexylamino) -sulfonyl] carbamate;
[267] 2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [(hexylamino) -sulfonyl] carbamate;
[268] 2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[methyl (2-phenylethyl) amino] sulfonyl] carbamate;
[269] 2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[[bis-3- (dimethylamino) -propyl] amino] -sulfonyl] carbamate;
[270] 2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [(methyl octyl amino) -sulfonyl] carbamate;
[271] 2,6-bis (1,1-dimethylethyl) -4-methyl-[[bis (tetrahydro-2-furanyl) methyl] amino] sulfonyl] carbamate;
[272] 2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [(dioctylamino) -sulfonyl] carbamate;
[273] 2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[[methyl 2- (2-pyridinyl) ethyl] amino] sulfonyl] carbamate, hydrochloride salt;
[274] 2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[[methyl 2- (2-pyridinyl) ethyl] amino] -sulfonyl] carbamate, sodium salt;
[275] 2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [(dodecylamino) -sulfonyl] carbamate;
[276] 2,6-bis (1-methylethyl) phenyl [[bis (1-methylethyl) amino] sulfonyl] -carbamate;
[277] 2,6-bis (1-methylethyl) phenyl [[(1-methylethyl) phenylmethyl-amino] sulfonyl] carbamate;
[278] 2,6-bis (1-methylethyl) phenyl [(hexyl-amino) sulfonyl] carbamate;
[279] 2,6-bis (1-methylethyl) phenyl [(dioctyl-amino) sulfonyl] carbamate;
[280] 2,6-bis (1-methylethyl) phenyl [[cyclo-hexyl (1-methylethyl) amino] -sulfonyl] -carbamate;
[281] 2,6-bis (1-methylethyl) phenyl [(methyl-octylamino) sulfonyl] -carbamate;
[282] 2,6-bis (1-methylethyl) phenyl [(dihexyl-amino) sulfonyl] carbamate;
[283] Dodecyl [[((2,4,6-trimethoxyphenyl) amino] -sulfonyl] carbamate;
[284] 2,6-bis (1-methylethyl) phenyl ester (4-morpholinylsulfonyl) -carbamic acid;
[285] 2,6-bis (1-methylethyl) phenyl ester (1-piperidinylsulfonyl) carbamic acid;
[286] 2,6-bis (1-methylethyl) phenyl ester (1-pyrrolidinylsulfonyl) -carbamic acid;
[287] 2,6-bis (1-methylethyl) phenyl ester [(2,3-dihydro-1H-indol-1-yl) sulfonyl] carbamic acid;
[288] 2,6-bis (1-methylethyl) phenyl [(dibutylamino) sulfonyl] carbamate monosodium salt; And
[289] 2,6-bis (1,1-dimethylethyl) phenyl [[(diphenylmethyl) amino] sulfonyl] methyl carbamate.
[290] Sulfonylaminocarbonyl derivatives disclosed in U.S. Pat. No. 5,214,206 and its split 5,288,757, all of which are incorporated herein by reference, are also useful in the present invention. Accordingly, another embodiment of the invention is a disease responsive to the inhibition of nuclear factor-κB transcription factors comprising administering to a subject in need thereof a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof selected from: Or a method of treating a disorder:
[291] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dipropylamino) -sulfonyl]-;
[292] Urea, N- (2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl) -N '-[[(tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) Amino] sulfonyl]-, (4S-cis)-;
[293] Urea, N- (2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl) -N '-[[(2,2-dimethyl-4-phenyl-1,3-dioxane- 5-yl) amino] sulfonyl-, stereoisomer;
[294] N- [2,6-bis (1-methylethyl) phenyl] -N '-[[bis (1-methylethyl) amino] -sulfonyl] urea;
[295] N- [2,6-bis (1-methylethyl) phenyl] -N '-[[(diphenylmethyl) amino] -sulfonyl] urea;
[296] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(diphenylamino) -sulfonyl] urea;
[297] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dibutylamino) sulfonyl] urea;
[298] N-[[[2,6-bis (1-methylethyl) phenyl] amino] -sulfonyl] -N '-(diphenylmethyl) urea;
[299] N- [2,6-bis (1-methylethyl) phenyl] -N '-[[[2,6-bis (1-methylethyl) -phenyl] amino] sulfonyl] urea;
[300] N- [2,6-bis (1-methylethyl) phenyl] -N '-[[(2,2-diphenylethyl) -amino] sulfonyl] urea;
[301] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(9H-fluorene-9-ylamino] -sulfonyl] urea;
[302] N- [2,6-bis (1-methylethyl) phenyl] -N '-[[bis (phenylmethyl) amino] -sulfonyl] urea;
[303] N- [2,6-bis (1-methylethyl) phenyl] -N '-[[(1-methylethyl)-(phenylmethyl) amino] sulfonyl] urea;
[304] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dioctylamino) sulfonyl] urea;
[305] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(4-phenyl-1-piperidinyl) -sulfonyl] urea;
[306] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dihexylamino) sulfonyl] -urea;
[307] N-[[bis [3- (dimethylamino) propyl] amino] -sulfonyl] -N '-[2,6-bis (1-methylethyl) phenyl] urea;
[308] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(hexylamino) sulfonyl] urea;
[309] N- [2,6-bis (1-methylethyl) phenyl] -N '-[[bis-[(tetrahydro-2-furanyl) methyl] amino] sulfonyl] -urea;
[310] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(diethylamino) sulfonyl] urea;
[311] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(methyloctylamino) sulfonyl] urea;
[312] N- [2,6-bis (1-methylethyl) phenyl] -N '-[[cyclohexyl (1-methylethyl) amino] sulfonyl] urea;
[313] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dipentylamino) sulfonyl] -urea;
[314] N- [2,6-bis (1-methylethyl) phenyl] -N '-[[bis (2-methylpropyl) amino] -sulfonyl] urea;
[315] N- [2,6-bis (1-methylethyl) phenyl] -N '-[[ethyl (2-propenyl) amino] -sulfonyl] urea;
[316] N-[[bis (3-methylbutyl) amino] sulfonyl] -N '-[2,6-bis (1-methylethyl) -phenyl] urea;
[317] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(didecylamino) sulfonyl] urea;
[318] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(didodecylamino) -sulfamoyl] urea;
[319] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(diisopropylamino) -sulfonyl] urea;
[320] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dicyclohexylamino) -sulfonyl] urea;
[321] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(methyloctadecylamino) -sulfonyl] urea;
[322] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(di-2-propenylamino) -sulfonyl] urea;
[323] N- [2,6-bis (1-methylethyl) phenyl] -N '-[[(1,1-dimethylethyl) (1-methylethyl) amino] sulfonyl] -urea;
[324] N- [2,6-bis (1-methylethyl) phenyl] -N '-[[bis (1-methylpropyl) amino] -sulfonyl] urea;
[325] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(methyltetradecylamino) -sulfonyl] urea;
[326] N- [2,6-bis (1-methylethyl) phenyl] -N '-(1-pyrrolidinylsulfonyl) urea;
[327] N- [2,6-bis (1-methylethyl) phenyl] -N '-(1-piperidinylsulfonyl) urea;
[328] N '-[[[2,6-bis (1-methylethyl) phenyl] amino] sulfonyl] -N, N-bis (phenylmethyl) urea;
[329] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dibutylamino) sulfonyl] urea, monosodium salt; And
[330] N '-[2,6-bis (1-methylethyl) phenyl] -N-methyl-[(dibutyl-amino) sulfonyl] urea.
[331] Sulfonylaminocarbonyl derivatives disclosed in U.S. Patent 5,198,466 and its split 5,364,882, all of which are incorporated herein by reference, are also useful in the present invention. Accordingly, another embodiment of the invention is a disease responsive to the inhibition of nuclear factor-κB transcription factors comprising administering to a subject in need thereof a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof selected from: Or a method of treating a disorder:
[332] Sulfamic acid, [[[2,4,6-tris (1-methylethyl) phenyl] amino] -carbonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
[333] Sulfamic acid, [[[[1- [4- (dimethylamino) phenyl] cyclopentyl] -methyl] amino] carbonyl], 2,6-bis (1-methylethyl) phenyl ester;
[334] (2,3-dihydro-indole-1-carbonyl) -sulfamic acid 2,6-diisopropyl phenyl ester;
[335] Sulfamic acid, [[(triphenylmethyl) amino] carbonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
[336] Octadecyl [[[2,6-bis (1-methylethyl) phenyl] -amino] carbonyl] -sulfate;
[337] Dodecyl-N-[[[2,6-bis (1-methylethyl) phenyl] -amino] carbonyl] -sulfate;
[338] Decyl [[[2,6-bis (1-methylethyl) phenyl] amino] carbonyl] sulfate;
[339] (±) 1-methylheptyl [[[2; 6-bis (1-methylethyl) phenyl] amino] -carbonyl] sulfate;
[340] 2,6-bis (1-methylethyl) phenyl [[[2; 6-bis (1-methylethyl) -phenyl] amino] carbonyl] sulfate;
[341] (±) 1-methylundecyl [[[2; 6-bis (1-methylethyl) phenyl] amino] -carbonyl] sulfate; And
[342] Dodecyl [[[2; 6-bis (1-methylethyl) phenyl] amino] carbonyl] -sulfate; Sodium salt.
[343] Sulfonylaminocarbonyl derivatives disclosed in U.S. Pat.No. 5,245,068 and its split 5,384,328, all of which are incorporated herein by reference, are also useful in the present invention. Accordingly, another embodiment of the invention is a disease responsive to the inhibition of nuclear factor-κB transcription factors comprising administering to a subject in need thereof a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof selected from: Or a method of treating a disorder:
[344] Carbamic acid, [(dodecyloxy) sulfonyl]-, dodecyl ester;
[345] Carbamic acid, [(dodecyloxy) sulfonyl]-, [1,1 ': 3', 1 "-terphenyl] -2'-yl ester;
[346] Carbamothioic acid, [(dodecyloxy) sulfonyl]-, S- [2,6-bis (1-methylethyl) -phenyl] ester;
[347] Carbamic acid, (phenoxysulfonyl)-, 2,6-bis (1-methylethyl) phenyl ester;
[348] Carbamic acid, [(2,6-dimethylphenoxy) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
[349] Carbamic acid, [[2,6-bis (1,1-dimethylethyl) phenoxy] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) phenyl ester,
[350] Carbamic acid, [[2,6-bis (1,1-dimethylethyl) phenoxy] sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
[351] Carbamic acid, [(2,6-difluorophenoxy) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
[352] Carbamic acid, [(hexadecyloxy) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
[353] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-dimethoxyphenyl ester;
[354] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 1-methylheptyl ester;
[355] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl-, 2,6-bis (1-methylethyl) -4-nitrophenyl ester;
[356] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 1,2-ethanediyl ester;
[357] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 1,2,3-propanetriyl ester;
[358] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-bromo-2,6-bis (1-methylethyl) phenyl ester;
[359] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, [1,1 ': 3', 1 "-terphenyl] -2'-yl ester;
[360] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methoxyphenyl ester;
[361] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-fluoro-2,3,5,6-tetrakis (1-methylethyl) phenyl ester;
[362] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-chloro-2,6-bis- (1-methylethyl) phenyl ester;
[363] Stigmaster-5,22-dien-3-ol, [[2,6-bis (1-methylethyl) phenoxy] -sulfonyl] -carbamate, (3α)-;
[364] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester;
[365] Stigmastan-3-ol, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl] -carbamate, (3α)-;
[366] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-methoxy-2,6-bis (1-methylethyl) phenyl ester;
[367] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,4,6-tris (1-methylethyl) phenyl ester;
[368] Carbamic acid, [[2,4,6-tris (1-methylethyl) phenoxy] sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
[369] Carbamic acid, [[2,4,6-tris (1-methylethyl) phenoxy] sulfonyl]-, 2,4,6-tris (1-methylethyl) phenyl ester;
[370] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,4,6-tris (1,1, -dimethylethyl) phenyl ester;
[371] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] dithio ] -2,6-bis (1,1-dimethylethyl) phenyl ester;
[372] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,4-bis (1-methylethyl) phenyl ester;
[373] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-[(dimethylamino) methyl] -2,6-bis (1-methylethyl) phenyl ester;
[374] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, tricyclo [3.3.1.1 ^3,7 ] dec-2-yl ester;
[375] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-hydroxy-2,6-bis (1-methylethyl) phenyl ester;
[376] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, cyclohexyl ester;
[377] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 3,3 ', 5,5'-tetrakis (1-methylethyl) [1,1'-biphenyl ] -4,4'-diyl ester;
[378] Carbamic acid, [[4-hydroxy-2,6-bis (1-methylethyl) phenoxy] -sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
[379] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, tricyclo [3.3.1.1 ^3,7 ] dec-1-yl ester;
[380] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2- (1,1-dimethylethyl) -6-methylphenyl ester;
[381] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl] -5-methyl-2- (1-methylethyl) cyclohexyl ester;
[382] Carbamothioic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, S- [2,6-bis (1-methylethyl) phenyl] ester;
[383] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, (2,6-diethylphenyl) methyl ester;
[384] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, (2S, 6S) -2,6-bis (1-methylethyl) cyclohexyl ester;
[385] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4- (1,1-dimethylethyl) -2,6-bis (1-methylethyl) phenyl ester;
[386] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-fluorophenyl ester;
[387] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,4-difluorophenyl ester;
[388] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, pentafluorophenyl ester;
[389] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-difluorophenyl ester;
[390] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, (2R, 6S) -2,6-bis (1-methylethyl) cyclohexyl ester;
[391] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,3,5,6-tetramethylphenyl ester;
[392] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 3-pyridinyl ester;
[393] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-dimethylphenyl ester;
[394] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-acetyl-2,6-bis (1-methylethyl) phenyl ester;
[395] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-fluoro-2,6-bis (1-methylethyl) phenyl ester;
[396] 2,6-bis (1-methylethyl) phenyl [[2,6-bis (1-methylethyl) phenoxy] -sulfonyl] carbamate;
[397] 2,6-bis (1; 1-dimethylethyl) -4-methylphenyl (phenoxysulfonyl) -carbamate;
[398] 2,6-bis (1,1-dimethylethyl) -4-methylphenyl [(hexyloxy) -sulfonyl] carbamate;
[399] 2,6-bis (1,1-dimethylethyl) -4-methylphenyl [(dodecyloxy) -sulfonyl] carbamate;
[400] Dodecyl [[2,6-bis (1-methylethyl) phenoxy] -sulfonyl] carbamate;
[401] Methyl [[2,6-bis (1-methylethyl) phenoxy] -sulfonyl] carbamate;
[402] 2,6-bis (1-methylethyl) phenyl [(hexyloxy) -sulfonyl] carbamate;
[403] 2,6-bis (1-methylethyl) phenyl] (dodecyloxy) -sulfonyl] carbamate; And
[404] 2,6-bis (1,1-dimethylethyl) phenyl [[2,6-bis (1-methylethyl) -phenoxy] sulfonyl] carbamate,
[405] Sulfonylaminocarbonyl derivatives disclosed in U.S. Patent No. 5,254,589 and Subdivision 5,981,595, all of which are incorporated herein by reference, are also useful in the present invention. Accordingly, another embodiment of the invention is a disease responsive to the inhibition of nuclear factor-κB transcription factors comprising administering to a subject in need thereof a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof selected from: Or a method of treating a disorder:
[406] N- [2,6-bis (1-methylethyl) phenyl] -N '-(6-ethoxy-2-benzothiazolyl) -sulfonyl] -urea;
[407] N- [2,6-bis (1-methylethyl) phenyl] -N '-(2-octadecylsulfonyl) urea;
[408] N- [2,4,6-trimethoxyphenyl] -N '-(2-octadecylsulfonyl) urea;
[409] N- [2,6-bis (1-methylethyl) phenyl] -N '-(tetradecylsulfonyl) urea;
[410] N- [2,6-bis (1-methylethyl) phenyl] -N '-(dodecylsulfonyl) urea;
[411] N- [2,6-bis (1-methylethyl) phenyl] -N '-(hexadecylsulfonyl) urea;
[412] N- [2,6-bis (1-methylethyl) phenyl] -N'-methyl-N '-(dodecylsulfonyl) urea;
[413] N- [2,6-bis (1-methylethyl) phenyl] -N '-(tridecylsulfonyl) urea;
[414] N- [2,4,6-trimethoxyphenyl] -N '-(hexadecylsulfonyl) urea;
[415] N- [2,6-bis (1-methylethyl) phenyl] -N '-(2-methyl-2-pentadedecylsulfonyl) urea;
[416] N- [2,6-bis (1-methylethyl) phenyl] -N '-(1-phenyl-1-tetradecylsulfonyl) urea;
[417] N-2,6-bis (1-methylethyl) phenyl-N '-(dodecylsulfonyl) urea;
[418] N- [2,6-bis (1-methylethyl) phenyl] -N '-(1-phenyl-1-nonylsulfonyl) urea; And
[419] N- [2,6-bis (1-methylethyl) phenyl] -N '-(2-decylsulfonyl) urea.
[420] The following sulfonylaminocarbonyl derivatives are excluded from those used in the process of the present invention:
[421] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dimethylamino) sulfonyl]-;
[422] Sulfamic acid, [[[2,6-bis (1-methylethyl) phenyl] amino] carbonyl]-, hexyl ester;
[423] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[[methyl (2-phenylethyl) -amino] sulfonyl] =;
[424] Carbamic acid, [(4-methyl-1-piperazinyl) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester, monohydrochloride;
[425] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[(butylmethylamino) sulfonyl]-;
[426] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[[(1-methylethyl) amino] -sulfonyl]-;
[427] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[(butylethylamino) sulfonyl]-;
[428] Carbamic acid, [[[2,6-bis (1-methylethyl) phenyl] amino] sulfonyl]-, [1,1 ': 3', 1 "-terphenyl] -2'yl ester;
[429] Carbamic acid, [(2,6-dimethoxyphenoxy) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
[430] Carbamic acid, [(2,4-difluorophenoxy) sulfonyl]-, 2,6-bis (1-methylethyl) -phenyl ester;
[431] Carbamic acid, [(2,4,6-trimethoxyphenoxy) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
[432] Carbamic acid, [(2,6-dimethoxyphenoxy) sulfonyl]-, 2,6-dimethoxyphenyl ester;
[433] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl] methyl]-, 2,6-bis (1-methylethyl) phenyl ester;
[434] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, ethyl ester, sodium salt;
[435] [3- (2,4,6-Triisopropyl-phenyl) -propionyl] -sulfonic acid 2,6-diisopropyl-phenyl ester;
[436] [Fluoro- (2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-phenyl ester;
[437] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid [1,1 '; 3', 1 "] terphenyl-2'-yl ester;
[438] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-chlorophenyl ester;
[439] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, (3-pyridinyl) methyl ester;
[440] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-chloro-2,6-diisopropyl-phenyl ester;
[441] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-4- (3-phenyl-thioureido) -phenyl ester;
[442] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfame acid 4-formyl-2,6-diisopropyl-phenyl ester;
[443] [2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-((R) -2-amino-4-methyl-pentanoylamino) -2,6-diisopropyl- Phenyl esters; Compounds with trifluoro acetic acid;
[444] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [bis- (2-hydroxy-ethyl) -amino] -2,6-diisopropyl-phenyl ester;
[445] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4-sulfamoyl-phenyl ester;
[446] Benzeneacetamide, N-[[[2,6-bis (1-methylethyl) phenyl] amino] sulfonyl] -2,4,6-tris (1-methylethyl)-;
[447] [2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4- (4-methyl-piperazin-1-ylmethyl) -phenyl ester; Compounds with general inorganic acid neutral components;
[448] [2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfonic acid 4-aminomethyl-2,6-diisopropyl-phenyl ester; Compounds with general inorganic neutral components;
[449] [2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-((S) -2-amino-3-phenyl-propionylamino) -2,6-diisopropyl- Phenyl esters; Fluoride with trifluoroacetic acid;
[450] [2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-((S) -2-amino-3-methyl-pentanoylamino) -2,6-diisopropyl- Phenyl esters; Compounds with trifluoro acetic acid;
[451] (2,3-diphenyl-acryloyl) -sulfamic acid 3,4-dichloro-phenyl ester;
[452] (4-phenyl-but-3-enoyl) -sulfamic acid 2,6-diisopropyl-phenyl ester;
[453] N- [2,6-bis (1-methylethyl) phenyl] -N'-phenylmethyl-N '-(tetradecylsulfonyl) urea;
[454] N- [2,6-bis (1-methylethyl) phenyl] -N '-(octylsulfonyl) urea;
[455] N- (2,4-difluorophenyl) -N '-(tetradecylsulfonyl) urea;
[456] N- [2,6-bis (1-methylethyl) phenyl] -N '-(2-pentadedecylsulfonyl) urea;
[457] N- [2,6-bis (1-methylethyl) phenyl] -N '-[[6- (2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl) hexyl] Sulfonyl] urea;
[458] N-[[[2,6-bis (1-methylethyl) pentyl] amino-carbonyl] -14-heptacosansulfonamide; And
[459] N- [2,4,6-trimethoxyphenyl] -N '-(tetradecylsulfonyl) urea.
[460] Another embodiment of the present invention is a method of inhibiting NF-κB transcription inhibitory factor in an animal comprising administering to the animal an amount of NF-κB inhibitory sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof.
[461] Another embodiment of the invention is the use of sulfonylaminocarbonyl derivatives or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of a disease or disorder responsive to the inhibition of nuclear factor-κB transcription factors.
[462] Another embodiment of the invention is a pharmaceutical composition comprising a nuclear factor-κB transcription factor inhibitory amount of a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof.
[463] Another embodiment of the invention is a disease or disorder being treated for rheumatoid arthritis, osteoarthritis, autoimmune disease, psoriasis, asthma, cardiovascular disease, acute coronary syndrome, congestive heart failure, Alzheimer's disease, multiple sclerosis, cancer, type 2 diabetes Treating a disease or disorder responsive to nuclear factor-κB transcription factor inhibition comprising administering a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof to a subject in need thereof, which is metabolic syndrome X or inflammatory bowel disease It is a way.
[464] Preferably the disease or disorder being treated is rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, Graves' disease, myasthenia gravis, insulin resistance, autoimmune hemolytic anemia, scleroderma with anti-collagen antibodies (Abs), pernicious anemia, diabetes, psoriasis Sulfonylaminocarbonyl to subjects in need of treatment, asthma, atherosclerosis, myocardial infarction, unstable angina, congestive heart failure, Alzheimer's disease, multiple sclerosis, cancer, type 2 diabetes, metabolic syndrome X or inflammatory bowel disease A method of treating a disease or disorder responsive to nuclear factor-κB transcription factor inhibition comprising administering a derivative or a pharmaceutically acceptable salt thereof.
[465] More preferably, the disease is responsive to nuclear factor-κB transcription factor inhibition comprising administering a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the disease or disorder being treated is rheumatoid arthritis or It is a method of treatment of disorder.
[466] Also more preferred is a disease or disorder responsive to nuclear factor-κB transcription factor inhibition comprising administering a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the disease or disorder being treated is osteoarthritis. Method of treatment.
[467] Also more preferably, a disease responsive to nuclear factor-κB transcription factor inhibition comprising administering a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the disease or disorder being treated is insulin resistant. Or a method of treating a disorder.
[468] Also more preferred is a disease or disorder responsive to nuclear factor-κB transcription factor inhibition comprising administering a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the disease or disorder being treated is asthma. Method of treatment.
[469] Also more preferred is a disease responsive to nuclear factor-κB transcription factor inhibition comprising administering a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the disease or disorder being treated is atherosclerosis or It is a method of treatment of disorder.
[470] Also more preferred is a disease responsive to inhibiting nuclear factor-κB transcription factor comprising administering a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the disease or disorder being treated is myocardial infarction or It is a method of treatment of disorder.
[471] Also more preferred is a disease responsive to nuclear factor-κB transcription factor inhibition comprising administering a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the disease or disorder being treated is unstable angina. Or a method of treating a disorder.
[472] Also more preferred is a disease responsive to nuclear factor-κB transcription factor inhibition comprising administering a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the disease or disorder being treated is congestive heart failure. Or a method of treating a disorder.
[473] Also more preferred is a disease or disorder responsive to inhibiting nuclear factor-κB transcription factor comprising administering a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the disease or disorder being treated is Alzheimer's disease. Method of treatment.
[474] Also more preferred are those diseases or disorders that are responsive to nuclear factor-κB transcription factor inhibition comprising administering a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the disease or disorder being treated is cancer. It is a treatment method.
[475] Also more preferred is a disease responsive to inhibiting nuclear factor-κB transcription factor comprising administering a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the disease or disorder being treated is an inflammatory bowel disease. Or a method of treating a disorder.
[476] Also more preferred is a disease responsive to nuclear factor-κB transcription factor inhibition comprising administering a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the disease or disorder being treated is multiple sclerosis or It is a method of treatment of disorder.
[477] Also more preferred is responsive to nuclear factor-κB transcription factor inhibition comprising administering a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the disease or disorder being treated is type 2 diabetes. Method of treatment of a disease or disorder.
[478] Also more preferred is a disease responsive to nuclear factor-κB transcription factor inhibition comprising administering a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the disease or disorder being treated is metabolic syndrome X. Or a method of treating a disorder.
[479] Another embodiment of the present invention is a method for screening a compound for inhibiting NF-κB mediated transcription of a gene in vitro, comprising analyzing the assay mixture containing stimulated NF-κB using fluorescence detection.
[480] Preferred is a method for screening the ability of a compound to inhibit NF-κB mediated transcription of a gene in vitro, comprising analyzing the assay mixture containing stimulated NF-κB using fluorescence detection, wherein the assay is a cell based assay.
[481] Also preferred is analyzing the assay mixture containing stimulated NF-κB using fluorescence detection wherein the assay is a cell based assay and is performed in a high throughput screening mode. A method of screening the inhibitory ability of mediated transcription.
[482] More preferably, the assay comprises analyzing the assay mixture containing stimulated NF-κB using fluorescence detection wherein the assay comprises the following steps: The screening method is:
[483] a) for an enzyme capable of cleaving a non-fluorescent substrate to produce a fluorescent cleavage product, an enzyme capable of cleaving a fluorescent substrate to produce a non-fluorescent cleavage product or an enzyme capable of cleaving a fluorescent substrate to produce a fluorescent cleavage product stably transfecting the plasmid vector containing the cDNA and the NF-κB binding site into the cell;
[484] b) plating the cells of step a) in the medium;
[485] c) incubating the mixture of plated cells of step b);
[486] d) stimulating the cells of step c) with a cytokine or a compound tested for cytokine and NF-κB inhibition;
[487] e) adding a fluorescence initiating reagent to the stimulated cells of step d); And
[488] f) analyzing the mixture of step e) by fluorescence detection.
[489] Even more desirable is black
[490] a) for an enzyme capable of cleaving a non-fluorescent substrate to produce a fluorescent cleavage product, an enzyme capable of cleaving a fluorescent substrate to produce a non-fluorescent cleavage product or an enzyme capable of cleaving a fluorescent substrate to produce a fluorescent cleavage product stably transfecting the plasmid vector containing the cDNA and the NF-κB binding site into the cell;
[491] b) plating the cells of step a) in the medium;
[492] c) incubating the mixture of plated cells of step b);
[493] d) stimulating the cells of step c) with a cytokine or a compound tested for cytokine and NF-κB inhibition;
[494] e) adding a fluorescence initiating reagent to the stimulated cells of step d); And
[495] f) analyzing the assay mixture containing stimulated NF-κB using fluorescence detection, comprising analyzing the mixture of step e) by fluorescence detection. In the method of screening the inhibitory ability of mediated transcription,
[496] The cell undergoing transfection in step a) is an ECV-304 cell;
[497] The cDNA transfected in step a) is encoding β-lactamase;
[498] The NF-κB binding site transfected in step a) is an HIV NF-κB binding site;
[499] The cytokine used in step c) is TNF-α or IL-1β; or
[500] The fluorescent starting reagent used in step e) is a CCF2 dye.
[501] Detailed description of the invention
[502] As discussed above, the present invention provides a method of treating a disease or disorder that is responsive to inhibition of nuclear factor-κB transcription factors comprising administering a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof to a subject in need thereof. To provide.
[503] Some of the sulfonylaminocarbonyl derivatives used in the methods of the present invention as discussed above are also inhibitors of the enzyme ACAT, thus demonstrating serum and plasma cholesterol and Lp (a) regulatory activity in vitro, while these activities and NF There is no association between the ability of sulfonylaminocarbonyl derivatives to inhibit -κB mediated transcription and thereby treat diseases and disorders that are responsive to the inhibition of NF-κB.
[504] In Formula 1, examples of the straight or branched chain saturated hydrocarbon having 1 to 20 carbon atoms include methyl, ethyl n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl , n-hexyl, n-heptyl, n-octyl, n-undecyl, n-dodecyl, n-hexadecyl, 2,2-dimethyldodecyl, 2-tetradecyl and n-octadecyl groups .
[505] Examples of straight or branched chain hydrocarbons having 1 to 20 carbon atoms and 1 to 3 double bonds are ethenyl, 2-propenyl, 2-butenyl, 3-pentenyl, 2-octenyl, 5-nonenyl , 4-undecenyl, 5-heptadecenyl, 3-octadecenyl, 9-octadecetyl, 2,2-dimethyl-11-eicosenyl, 9,12-octadecadienyl and hexadecenyl have.
[506] Straight or branched chain alkoxy groups having 1 to 6 carbon atoms include, for example, methoxy, ethoxy, n-propoxy, t-butoxy and pentyloxy.
[507] Examples of straight or branched chain alkyl groups having 1 to 6 carbon atoms used in the formula (1) include methyl, ethyl, n-propyl, isopropyl, n-pentyl, n-butyl and tert-butyl.
[508] Examples of the cycloalkyl group used in the formula (1) include cyclopentyl, cyclohexyl, cyclooctyl, tetrahydronaphthyl and 1- or 2-adamantyl.
[509] Spirocycloalkyl groups are, for example, spirocyclopropyl, spirocyclobutyl, spirocyclopentyl and spirocyclohexyl.
[510] Examples of arylalkyl groups include benzyl, phenethyl, 3-phenylpropyl, 2-phenylpropyl, 4-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, benzhydryl, 2,2-diphenylethyl and 3,3- Diphenylpropyl.
[511] Examples of straight or branched carbon having 1 to 10 carbon atoms in the formula (2) is methyl, ethyl n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n- Hexyl, n-heptyl and n-octyl.
[512] Alkoxy refers to straight or branched chain groups having 1 to 6 carbon atoms and include, for example, methoxy, ethoxy, n-propoxy, t-butoxy and pentyloxy.
[513] Natural (essential) amino acids are valine, leucine, isoleucine, threonine, methionine, phenylalanine, tryptophan, lysine, alanine, arginine, aspartic acid, cysteine, glutamic acid, glycine, histidine, proline, serine, tyrosine, asparagine and glutamine.
[514] Preferred natural amino acids are valine, leucine, isoleucine, threonine, lysine, alanine, glycine, serine, asparactb and glutamine.
[515] Phenyl, naphthyl or heteroaromatic rings are substituted or substituted by 1 to 5 substituents selected from 1 to 6 carbon atoms of alkyl, alkoxy, halogen, nitro, cyano, carboxylic acid and alkyl esters, amino and hydroxy It doesn't work.
[516] Heteroaromatic rings are, for example, 2-, 3- or 4-pyridinyl; 2-, 4- or 5-pyrimidinyl; 2- or 3-thienyl; Isoquinoline, quinoline, pyrrole, indole and thiazole.
[517] The phrase "sulfonylaminocarbonyl derivative" means a compound having one of the following structural motifs:
[518] Motif character motif structure
[519]
[520]
[521] U.S. Patent 5,245,715 and its split 5,336,690 describe sulfonylaminocarbonyl derivatives having the structural motif A.
[522] U.S. Patent 5,214,206 and its split 5,288,757 describe sulfonylaminocarbonyl derivatives having the structural motif B.
[523] US Pat. No. 5,198,466 and its splitting 5,364,882 describe sulfonylaminocarbonyl derivatives having the structural motif C.
[524] US Pat. No. 5,245,068 and its splitting 5,384,328 describe sulfonylaminocarbonyl derivatives having the structural motif D.
[525] U.S. Pat. No. 5,491,172 and its split 5,633,287 describe sulfonylaminocarbonyl derivatives having the structural motif E.
[526] US Pat. No. 5,254,589 and its splitting 5,981,595 describe sulfonylaminocarbonyl derivatives having the structural motif F.
[527] The phrase "NF-κB inhibitory amount" refers to an amount of sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof sufficient to inhibit NF-κB transcription factor in a particular animal or animal population. For example, the amount of NF-κB inhibition in humans or other mammals can be determined experimentally in laboratory settings by measuring in vitro NF-κB activity according to the methods described below. Alternatively, NF-κB inhibition can be measured in vivo in the animal to be treated by measuring the effects of disease-changed changes in conventional methods. In clinical settings, the amount of NF-κB inhibition may be determined according to the criteria of the US Food and Drug Administration or equivalent foreign authority for the particular inhibited NF-κB transcription factor and the patient being treated.
[528] The term "autoimmune disease" means a disease classified as "likely" or "possible". Table 20, "PUTATIVE AUTOIMMUNE DISORDERS," by The Merck Manual of Diagnosis and Therapy, 16th edition, Robert Berkow ed., Merck Research Laboratories, Rahway, New Jersey, 1992. See -3. Diseases classified as likely include, for example, systemic lupus erythematosus, Graves' disease, myasthenia gravis, insulin resistance and autoimmune hemolytic anemia. Diseases classified as possible include, to some extent, rheumatoid arthritis, scleroderma with anti-collagen antibodies (Abs), some cases of pernicious anemia and diabetes.
[529] Examples of cardiovascular diseases include, but are not limited to atherosclerosis and acute coronary syndromes.
[530] Examples of acute coronary syndromes include, but are not limited to, myocardial infarction and unstable angina.
[531] The term "subject" means a mammal, including humans, cats, dogs, sheep, pigs, horses, and cattle.
[532] The term "animal" refers to a mammal including humans, cats, dogs, sheep, cows, horses, pigs, mice, mice, guinea pigs, rabbits, monkeys and transgenic variants thereof.
[533] The term "comprising", which is synonymous with the term "containing" or "characterizing," is inclusive or open, and does not exclude additional unlisted elements or method steps from the scope of the invention that follows.
[534] The phrase “consisting of” is closed and excludes all elements, steps or components not specified in the description of the invention that follows.
[535] The phrase “essentially made” constrains the scope of the invention which follows hereafter to defined elements or steps and further elements or steps that do not substantially affect the basic and novel nature of the invention.
[536] Some compounds useful in the present invention may have a chiral center, in which case all stereoisomers, individual stereoisomers and mixtures of enantiomers or diastereomers are included within the scope of the sulfonylaminocarbonyl derivatives used in the present invention. do.
[537] Some compounds useful in the present invention may further form nontoxic pharmaceutically acceptable acid additions and / or base salts. All of these forms are within the scope of compounds useful in the present invention.
[538] For example, pharmaceutically acceptable acid addition salts of the compounds useful in the present invention are aliphatic as well as non-toxic salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Salts derived from organic acids such as mono- and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Thus, the salts may be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphate metaphosphates, pyrophosphates, chlorides, bromide, iodides, acetates , Trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suverate, sebacate, fumarate, malate, mandelate, benzoate, chlorobenzoate, methylbenzo Ate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate and the like. Also budgeted are salts of amino acids such as arginate and the like, and glucuronate, galacturonate (see, eg, Berge SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977; 66 : 1-19].
[539] Acid addition salts of compounds useful in the present invention containing a basic functional group are prepared by contacting a sulfonylaminocarbonyl derivative in free base form with a sufficient amount of the desired acid, the amount of which is usually 1 molar equivalent, in a conventional manner. It is produced by producing.
[540] Pharmaceutically acceptable base addition salts of compounds useful in the present invention are formed with metal cations (eg alkali and alkaline earth metal cations) or amines (eg organic amines). Examples of metals used as cations are sodium, potassium, magnesium, calcium and the like. Examples of suitable amines are N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaine (e.g. , 1977).
[541] Base salts of compounds useful in the present invention containing an acid functional group are prepared by contacting the salt with a sufficient amount of the desired base, typically 1 molar equivalent, of the sulfonylaminocarbonyl derivative in free acid form. By producing.
[542] Certain compounds useful in the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. Generally, solvated conditions, including hydrated forms, are equivalent to unsolvated forms and are included within the scope of compounds useful in the present invention.
[543] Examples of sulfonylaminocarbonyl derivatives useful in the present invention are described below. This embodiment is for illustrative purposes and is not intended to limit the scope of the invention in any relationship.
[544] <Example 1>
[545] Carbamic acid, [[(diphenylmethyl) amino] sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester
[546] <Example 2>
[547] Carbamic acid, [[(diphenylmethyl) amino] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) phenyl ester
[548] <Example 3>
[549] Carbamic acid, [[(diphenylmethyl) amino] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester
[550] <Example 4>
[551] Carbamic acid, [[[2,6-bis (1-methylethyl) phenyl] amino] sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester
[552] Example 5
[553] Carbamic acid, [[[2,6-bis (1-methylethyl) phenyl] amino] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) phenyl ester
[554] <Example 6>
[555] Carbamic acid, [[[2,6-bis (1-methylethyl) phenyl] amino] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester
[556] <Example 7>
[557] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[[[2,6-bis (1-methylethyl) phenyl] -amino] sulfonyl]-
[558] <Example 8>
[559] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[[(diphenylmethyl) amino] -sulfonyl]-
[560] <Example 9>
[561] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[[(2,2-diphenylethyl) amino] -sulfonyl]-
[562] <Example 10>
[563] Carbamic acid, [[(2,2-diphenylethyl) amino] sulfonyl]-, 2,6-bis (1-methylethyl) -phenyl ester
[564] <Example 11>
[565] Carbamic acid, [[(2,2-diphenylethyl) amino] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -phenyl ester
[566] <Example 12>
[567] Carbamic acid, [[(2,2-diphenylethyl) amino] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester
[568] Example 13
[569] Carbamic acid, [(phenylamino) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester
[570] <Example 14>
[571] Carbamic acid, [(phenylamino) sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-hydroxyphenyl ester
[572] <Example 15>
[573] Carbamic acid, [(phenylamino) sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -phenyl ester
[574] <Example 16>
[575] Carbamic acid, [(1H-benzimidazol-2-ylamino) sulfonyl]-, 2,6-bis (1-methylethyl) -phenyl ester
[576] <Example 17>
[577] N- [2,6-bis (1-methylethyl) phenyl] -N '-[[bis (phenylmethyl) amino] -sulfonyl] -urea
[578] Example 18
[579] N-[[[2,6-bis (1-methylethyl) phenyl] amino] sulfonyl] -N '-(diphenylmethyl) -urea
[580] Example 19
[581] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(9H-fluorene-9-ylamino) -sulfonyl] -urea
[582] Example 20
[583] N- [2,6-bis (1-methylethyl) phenyl-N '-[[bis (1-methylethyl) amino] -sulfonyl] -urea
[584] Example 21
[585] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dibutylamino) sulfonyl] -urea
[586] <Example 22>
[587] N- [2,6-bis (1-methylethyl) phenyl] -N '-[[(1-methylethyl)-(phenylmethyl) amino] -sulfonyl] -urea
[588] <Example 23>
[589] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dioctylamino) sulfonyl] -urea
[590] <Example 24>
[591] Carbamic acid, [[bis (phenylmethyl) amino] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -phenyl ester
[592] <Example 25>
[593] Carbamic acid, [[bis (phenylmethyl) amino] sulfonyl]-, 2,6-bis (1-methylethyl) -phenyl ester
[594] Example 26
[595] Carbamic acid, [(diphenylamino) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester
[596] Example 27
[597] Carbamic acid, [(dibutylamino) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester
[598] <Example 28>
[599] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester
[600] <Example 29>
[601] N '-[[[2,6-bis (1-methylethyl) phenyl] amino] sulfonyl] -N, N-bis (phenylmethyl) -urea
[602] <Example 30>
[603] Carbamic acid, [(dibutylamino) sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester
[604] <Example 31>
[605] Carbamic acid, [(dipentylamino) sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester
[606] <Example 32>
[607] Carbamic acid, [[bis (1-methylethyl) amino] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester
[608] <Example 33>
[609] Carbamic acid, [(dihexylamino) sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenylester
[610] <Example 34>
[611] Carbamic acid, [(hexylamino) sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester
[612] <Example 35>
[613] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(4-phenyl-1-piperidinyl) -sulfonyl] -urea
[614] <Example 36>
[615] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dihexylamino) sulfonyl] -urea
[616] <Example 37>
[617] N-[[bis [3- (dimethylamino) propyl] amino] sulfonyl] -N '-[2,6-bis (1-methylethyl) phenyl] -urea
[618] <Example 38>
[619] Carbamic acid, [[methyl (2-phenylethyl) amino] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester
[620] <Example 39>
[621] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(hexylamino) sulfonyl] -urea
[622] <Example 40>
[623] Carbamic acid, [[bis [3- (dimethylamino) propyl] amino] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester
[624] <Example 41>
[625] N- [2,6-bis (1-methylethyl) phenyl] -N '-[[bis [(tetrahydro-2-furanyl) methyl] amino] sulfonyl] -urea, (= + /)-
[626] <Example 42>
[627] Carbamic acid, [[methyl [2- (2-pyridinyl) ethyl] amino] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester, monohydrochloride
[628] <Example 43>
[629] Carbamic acid, [(methyloctylamino) sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester
[630] 44
[631] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[(diethylamino) sulfonyl]-
[632] <Example 45>
[633] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[(methyloctylamino) sulfonyl]-
[634] <Example 46>
[635] Carbamic acid, [(dioctylamino) sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester
[636] <Example 47>
[637] Carbamic acid, [[(2,2-diphenylethyl) amino] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methoxyphenyl ester
[638] <Example 48>
[639] Carbamic acid, (phenoxysulfonyl)-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester
[640] <Example 49>
[641] Carbamic acid, [(hexyloxy} sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester
[642] <Example 50>
[643] Carbamic acid, [[[2,6-bis (1-methylethyl) phenyl] amino] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methoxyphenyl ester
[644] <Example 51>
[645] Carbamic acid, [(dodecyloxy) sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester
[646] <Example 52>
[647] Carbamic acid, [(didecylamino) sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester
[648] <Example 53>
[649] Carbamic acid, [[[2,6-bis (1-methylethyl) phenyl] amino] sulfonyl]-, dodecyl ester
[650] <Example 54>
[651] Carbamic acid, [[[2,6-bis (1-methylethyl) phenyl] amino] sulfonyl]-, methyl ester
[652] <Example 55>
[653] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, dodecyl ester
[654] <Example 56>
[655] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, methyl ester
[656] <Example 57>
[657] Carbamic acid, [(hexyloxy) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester
[658] <Example 58>
[659] Carbamic acid, (4-morpholinylsulfonyl)-, 2,6-bis (1-methylethyl) phenyl ester
[660] <Example 59>
[661] Carbamic acid, (1-piperidinylsulfonyl)-, 2,6-bis (1-methylethyl) phenyl ester
[662] <60 times of implementation>
[663] Sulfamic acid, [[[2,6-bis (1-methylethyl) phenyl] amino] carbonyl]-, octadecyl ester
[664] <Example 61>
[665] Carbamic acid, [(dodecyloxy) sulfonyl]-, dodecyl ester
[666] <Example 62>
[667] Carbamic acid, [[bis (1-methylethyl) amino] sulfonyl]-, 2,6-bis (1-methylethyl) -phenyl ester
[668] <Example 63>
[669] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[[cyclohexyl (1-methylethyl) amino] -sulfonyl]-
[670] <Example 64>
[671] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dipentylamino) sulfonyl]-
[672] <Example 65>
[673] Carbamic acid, [[(1-methylethyl) phenylmethyl) amino] sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester
[674] Example 66
[675] Carbamic acid, (1-pyrrolidinylsulfonyl)-, 2,6-bis (1-methylethyl) phenyl ester
[676] <Example 67>
[677] Carbamic acid, [(hexylamino) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester
[678] <Example 68>
[679] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[[bis (2-methylpropyl) amino] -sulfonyl]-
[680] <69 in the embodiment>
[681] Sulfamic acid, [[[2,6-bis (1-methylethyl) phenyl] amino] carbonyl]-, dodecyl ester
[682] <Example 70>
[683] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-(1-pyrrolidinylsulfonyl)-
[684] <Example 71>
[685] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-(1-piperidinylsulfonyl)-
[686] <Example 72>
[687] Carbamic acid, [(2,3-dihydro-1H-indol-1-yl) sulfonyl]-, 2,6-bis (1-methylethyl) -phenyl ester
[688] <Example 73>
[689] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[[ethyl (2-propenyl) amino] -sulfonyl]-
[690] <74 in the embodiment>
[691] Urea, N-[[bis (3-methylbutyl) amino] sulfonyl] -N '-[2,6-bis (1-methylethyl) phenyl]-
[692] <75 in embodiment>
[693] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[(didecylamino) sulfonyl]-
[694] <Example 76>
[695] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[(didodecylamino) sulfonyl]-
[696] <77 times of implementation>
[697] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dipropylamino) sulfonyl]-
[698] <Example 78>
[699] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dicyclohexylamino) -sulfonyl]-
[700] <Example 79>
[701] Carbamic acid, [[(2,4,6-trimethoxyphenyl) amino] sulfonyl]-, dodecyl ester
[702] <80 in practice>
[703] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[(methyloctadecylamino) -sulfonyl]-
[704] <81 embodiment>
[705] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[(di-2-propenylamino) -sulfonyl]-
[706] <Example 82>
[707] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[[(1,1-dimethylethyl) (1-methylethyl) -amino] sulfonyl]-
[708] <Example 83>
[709] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[[bis (1-methylpropyl) -amino] -sulfonyl]-
[710] <Example 84>
[711] Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[(methyltetradecylamino) -sulfonyl]-
[712] <Example 85>
[713] Carbamic acid, [(dioctylamino) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester
[714] <Example 86>
[715] Carbamic acid, [[cyclohexyl (1-methylethyl) amino] sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester
[716] <Example 87>
[717] Carbamic acid, [(methyloctylami) sulfonyl]-, 2,6-bis (1-methylethyl) -phenyl ester
[718] <Example 88>
[719] Carbamic acid, [(dihexylamino) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester
[720] 89
[721] Carbamic acid, [(diphenylamino) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester
[722] <Example 90>
[723] Sulfamic acid, [[[2,6-bis (1-methylethyl) phenyl] amino] carbonyl]-, decyl ester
[724] <Example 91>
[725] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) phenyl ester
[726] <Example 92>
[727] Carbamic acid, [(dodecyloxy) sulfonyl]-, [1,1 ': 3', 1 "-terphenyl] -2'-yl ester
[728] <Example 93>
[729] Carbamothioic acid, [(dodecyloxy) sulfonyl]-, S- [2,6-bis (1-methylethyl) phenyl] ester
[730] <Example 94>
[731] Sulfamic acid, [[[2,6-bis (1-methylethyl) phenyl] amino] carbonyl]-, 1-methylheptyl ester, (= + /)-
[732] <Example 95>
[733] Sulfamic acid, [[[2,6-bis (1-methylethyl) phenyl] amino] carbonyl]-, 2,6-bis (1-methylethyl) phenyl ester
[734] <Example 96>
[735] Carbamic acid, [[(diphenylmethyl) amino] sulfonyl] methyl-, 2,6-bis (1,1-dimethylethyl) phenyl ester
[736] <Example 97>
[737] Carbamic acid, (phenoxysulfonyl)-, 2,6-bis (1-methylethyl) phenyl ester
[738] <Example 98>
[739] Carbamic acid, [(2,6-dimethylphenoxy) sulfonyl]-, 2,6-bis (1-methylethyl) -phenyl ester
[740] <Example 99>
[741] Urea, N '-[2,6-bis (1-methylethyl) phenyl] -N'-[(dibutylamino) sulfonyl] -N-methyl-
[742] <Example 100>
[743] Carbamic acid, [[2,6-bis (1,1-dimethylethyl) phenoxy] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) phenyl ester
[744] <101>
[745] DL-Tryptophan, α-methyl-N-[[[((tricyclo [3.3.1.1 ^3,7 ] dec-2-yloxy) -carbonyl] amino] sulfonyl]-, methyl ester
[746] <Example 102>
[747] Carbamic acid, [[2,6-bis (1,1-dimethylethyl) phenoxy] sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester
[748] <Example 103>
[749] Carbamic acid, [(2,6-difluorophenoxy) sulfonyl]-, 2,6-bis (1-methylethyl) -phenyl ester
[750] <Example 104>
[751] Urea, N- (2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl) -N '-[[(tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) Amino] sulfonyl]-, (4S-cis)-
[752] <Example 105>
[753] Urea, N- (2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl) -N '-[[(2,2-dimethyl-4-phenyl-1,3-dioxane- 5-yl) amino] sulfonyl]-, stereoisomer
[754] <Example 106>
[755] Sulfamic acid, (1-oxodecyl)-, 2,6-bis (1-methylethyl) phenyl ester
[756] <Example 107>
[757] Carbamic acid, [(hexadecyloxy) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester
[758] <108>
[759] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-dimethoxyphenyl ester
[760] <Example 109>
[761] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 1-methylheptyl ester
[762] <Example 110>
[763] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-bis (1-methylethyl) -4-nitrophenyl ester
[764] <Example 111>
[765] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 1,2-ethanediyl ester
[766] <Example 112>
[767] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 1,2,3-propanetriyl ester
[768] <Example 113>
[769] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-bromo-2,6-bis (1-methylethyl) phenyl ester
[770] <Example 114>
[771] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, [1,1 ': 3', 1 "-terphenyl] -2'-yl ester
[772] <Example 115>
[773] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methoxyphenyl ester
[774] <Example 116>
[775] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-fluoro-2,3,5,6-tetrakis (1-methylethyl) phenyl ester
[776] <Example 117>
[777] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-chloro-2,6-bis- (1-methylethyl) phenyl ester
[778] <Example 118>
[779] Stigmaster-5,22-diene-3-ol, [[2,6-bis (1-methylethyl) phenoxy] -sulfonyl] -carbamate, (3α)-
[780] <Example 119>
[781] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester
[782] <Example 120>
[783] Sulfamic acid, [[2,4,6-tris (1-methylethyl) phenyl] acetyl]-, 2,6-bis (1-methylethyl) phenyl ester
[784] <Example 121>
[785] Stigmastan-3-ol, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl] -carbamate, (3α)-
[786] <Example 122>
[787] Sulfamic acid, [[2,6-bis (1-methylethyl) phenyl] acetyl]-, 2,6-bis (1-methylethyl) -phenyl ester
[788] <Example 123>
[789] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-methoxy-2,6-bis (1-methylethyl) phenyl ester
[790] <Example 124>
[791] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,4,6-tris (1-methylethyl) phenyl ester
[792] <Example 125>
[793] Carbamic acid, [[2,4,6-tris (1-methylethyl) phenoxy] sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester
[794] <Example 126>
[795] Carbamic acid, [[2,4,6-tris (1-methylethyl) phenoxy] sulfonyl]-, 2,4,6-tris (1-methylethyl) phenyl ester
[796] <Example 127>
[797] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,4,6-tris (1,1, -dimethylethyl) phenyl ester
[798] <Example 128>
[799] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] dithio ] -2,6-bis (1,1-dimethylethyl) phenyl ester
[800] <Example 129>
[801] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,4-bis (1-methylethyl) phenyl ester
[802] <Example 130>
[803] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-[(dimethylamino) methyl] -2,6-bis (1-methylethyl) phenyl ester
[804] <Example 131>
[805] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, tricyclo [3.3.1.1 ^3,7 ] dec-2-yl ester
[806] <Example 132>
[807] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-hydroxy-2,6-bis (1-methylethyl) phenyl ester
[808] <Example 133>
[809] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, cyclohexyl ester
[810] <Example 134>
[811] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 3,3 ', 5,5'-tetrakis (1-methylethyl) [1,1'-biphenyl ] -4,4'-diyl ester
[812] <Example 135>
[813] Carbamic acid, [[4-hydroxy-2,6-bis (1-methylethyl) phenoxy] -sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester
[814] <136 on implementation>
[815] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, tricyclo [3.3.1.1 ^3,7 ] dec-1-yl ester
[816] <Example 137>
[817] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2- (1,1-dimethylethyl) -6-methylphenyl ester
[818] Example 138
[819] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl] -5-methyl-2- (1-methylethyl) cyclohexyl ester
[820] <Example 139>
[821] Carbamothioic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, S- [2,6-bis (1-methylethyl) phenyl] ester
[822] <Example 140>
[823] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, (2,6-diethylphenyl) methyl ester
[824] <Example 141>
[825] Carbamic acid, sulfonylbis-, bis [2,6-bis (1-methylethyl) phenyl] ester
[826] <Example 142>
[827] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, (2S, 6S) -2,6-bis (1-methylethyl) cyclohexyl ester
[828] <Example 143>
[829] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4- (1,1-dimethylethyl) -2,6-bis (1-methylethyl) phenyl ester
[830] <Example 144>
[831] (2-phenyl-cyclopropanecarbonyl) -sulfamic acid 2,6-diisopropyl phenyl ester
[832] <Example 145>
[833] [(2,5-Dimethoxy-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-phenyl ester
[834] <Example 146>
[835] [(2,4,6-trimethyl-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-phenyl ester
[836] <147 embodiment>
[837] [(2,4,6-trimethoxy-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-phenyl ester
[838] <Example 148>
[839] (Thiophen-2-yl-acetyl) -sulfamic acid 2,6-diisopropyl-phenyl ester
[840] <Example 149>
[841] (Thiophen-3-yl-acetyl) -sulfamic acid 2,6-diisopropyl-phenyl ester
[842] <Example 150>
[843] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-fluorophenyl ester
[844] <Sillisume 151>
[845] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,4-difluorophenyl ester
[846] <Example 152>
[847] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, pentafluorophenyl ester
[848] 153
[849] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-difluorophenyl ester
[850] <Example 154>
[851] Acetic acid 2- (2,6-diisopropyl-phenoxysulfonylamino) -2-oxo-1- (2,4,6-triisopropyl-phenyl) -ethyl ester
[852] <Example 155>
[853] Cyclohexylacetyl-sulfamic acid 2,6-diisopropyl-phenyl ester
[854] <Example 156>
[855] [(2-methoxy-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-phenyl ester
[856] <Embodiment 157>
[857] (Oxo-phenyl-acetyl) -sulfamic acid 2,6-diisopropyl-phenyl ester
[858] <Example 158>
[859] [(2-Trifluoromethyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-phenyl ester
[860] <Example 159>
[861] (2-phenyl-propionyl) -sulfamic acid 2,6-diisopropyl-phenyl ester
[862] <Example 160>
[863] Diphenylacetyl-sulfamic acid 2,6-diisopropyl-phenyl ester
[864] <Example 161>
[865] (Cyclopentyl-phenyl-acetyl) -sulfamic acid 2,6-diisopropyl-phenyl ester
[866] <Example 162>
[867] [Hydroxy- (2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-phenyl ester
[868] <Example 163>
[869] Triphenylacetyl-sulfamic acid 2,6-diisopropyl-phenyl ester
[870] <Example 164>
[871] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, (2R, 6S) -2,6-bis (1-methylethyl) cyclohexyl ester
[872] <Example 165>
[873] (1,2,3,4-tetrahydro-naphthalene-2-carbonyl) -sulfamic acid 2,6-diisopropyl-phenyl ester
[874] <Example 166>
[875] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,3,5,6-tetramethylphenyl ester
[876] <167 in the embodiment>
[877] (3-Methyl-2-phenyl-pentanoyl) -sulfamic acid 2,6-diisopropyl-phenyl ester
[878] <Example 168>
[879] (1-phenyl-cyclopentanecarbonyl) -sulfamic acid 2,6-diisopropyl-phenyl ester
[880] <Example 169>
[881] (2-phenyl-butyryl) -sulfamic acid 2,6-diisopropyl-phenyl ester
[882] <Embodiment 170>
[883] (Cyclohexyl-phenyl-acetyl) -sulfamic acid 2,6-diisopropyl-phenyl ester
[884] Example 171
[885] (2,2-Diphenyl-propionyl) -sulfamic acid 2,6-diisopropyl-phenyl ester
[886] <Example 172>
[887] [Bis- (4-chloro-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-phenyl ester
[888] Example 173
[889] (9H-Xanthene-9-carbonyl) -sulfamic acid 2,6-diisopropyl-phenyl ester
[890] <Example 174>
[891] (9H-Fluorene-9-carbonyl) -sulfamic acid-2,6-diosopropyl-phenyl ester
[892] <Example 175>
[893] (Bromo-phenyl-acetyl) -sulfamic acid 2,6-diisopropyl-phenyl ester
[894] <Example 176>
[895] (3-phenyl-propionyl) -sulfamic acid 2,6-diisopropyl-phenyl ester
[896] <Example 177>
[897] Sulfamic acid, [[[2,4,6-tris (1-methylethyl) phenyl] amino] carbonyl]-, 2,6-bis (1-methylethyl) phenyl ester
[898] <178 in the embodiment>
[899] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 3-pyridinyl ester
[900] Example 179
[901] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-dimethylphenyl ester
[902] <Example 180>
[903] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-hydroxy-2,6-diisopropyl-phenyl ester
[904] <Example 181>
[905] Methyl-[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-phenyl ester
[906] <182 in the embodiment>
[907] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-4-nitro-phenyl ester
[908] <Example 183>
[909] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-acetyl-2,6-bis (1-methylethyl) phenyl ester
[910] <Example 184>
[911] Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-fluoro-2,6-bis (1-methylethyl) phenyl ester
[912] <Example 185>
[913] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-fluoro-2,6-diisopropyl-phenyl ester
[914] <Example 186>
[915] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-dimethoxy-phenyl ester
[916] <187 in practice>
[917] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-amino-2,6-diisopropyl-phenyl ester
[918] Example 188
[919] 6- (3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -phenyl) -hexanoic acid ethyl ester
[920] 189
[921] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,4,6-trimethoxy-phenyl ester
[922] Example 190
[923] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-tert-butyl-2,6-diisopropyl-phenyl ester
[924] Example 191
[925] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4-acetyl-2-isopropyl-phenyl ester
[926] <Example 192>
[927] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-4-methoxy-phenyl ester
[928] <193 to the embodiment>
[929] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-dichloro-phenyl ester
[930] Example 194
[931] 3- [3- (3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamoyloxy} -phenyl) -ureido] -propionic acid ethyl ester
[932] <Example 195>
[933] [5-tert-butoxycarbonylamino-5- (3,5-diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -phenylcarba Moyl) -pentyl] -carbamic acid tert-butyl ester
[934] 196 to the embodiment
[935] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4-acetylamino-2,6-diisopropyl-phenyl ester
[936] <Example 197>
[937] [2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfonic acid 4-((S) -2,6-diamino-hexanoylamino) -2,6-diisopropyl-phenyl ester; Compound with general inorganic neutral component
[938] Example 198
[939] [(3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -phenylcarbamoyl) -methyl] -carbamic acid tert-butyl ester
[940] <Example 199>
[941] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid dodecyl ester
[942] <Example 200>
[943] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-amino-acetylamino) -2,6-diisopropyl-phenyl ester
[944] <Example 201>
[945] [2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-((S) -2-amino-4-methylsulfanyl-butyrylamino) -2,6-diiso Propyl-phenyl ester
[946] <Example 202>
[947] {[4- (1-hydroxy-1-methyl-ethyl) -2,6-diisopropyl-phenyl] -acetyl} -sulfonic acid 2,6-diisopropyl-phenyl ester
[948] <Example 203>
[949] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4-bromo-2,6-diisopropyl-phenyl ester
[950] <Example 204>
[951] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [2-amino-3- (1H-indol-3-yl) -propionylamino] -2,6-diiso Propyl-phenyl ester
[952] <Example 205>
[953] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (3-dimethylamino-propoxy) -2,6-diisopropyl-phenyl ester
[954] <Example 206>
[955] [2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfonic acid 4-((R) -2-amino-propionylamino) -2,6-diisopropyl-phenyl ester; Compound with trifluoro acetic acid
[956] <Example 207>
[957] [(2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-amino-2-methyl-propionylamino) -2,6-diisopropyl-phenyl ester
[958] Example 208
[959] [2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (3-amino-propoxy) -2,6-diisopropyl-phenyl ester
[960] <Example 209>
[961] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4-thiocyanato-phenyl ester
[962] <Example 210>
[963] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-4-methyl-phenyl ester
[964] Example 211
[965] [1- (4-Dimethylamino-phenyl) -cyclopentanecarbonyl] -sulfamic acid 2,6-diisopropyl-phenyl ester
[966] Example 212
[967] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-cyano-2,6-diisopropyl-phenyl ester
[968] <Example 213>
[969] [1- (4-Nitro-phenyl) -cyclopentanecarbonyl] -sulfamic acid 2,6-diisopropyl-phenyl ester
[970] <Example 214>
[971] [1- (3,5-Diisopropyl-4-[[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamoyloxy} -phenylcarbamoyl) -3-methylsufanyl- Propyl] -carbamic acid tert-butyl ester
[972] <Example 215>
[973] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [3- (2,6-diisopropyl-phenyl) -ureido] -2,6-diisopropyl-phenyl ester
[974] <Example 216>
[975] [2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-((S) -2-amino-4-methyl-pentanoylamino) -2,6-diisopropyl- Phenyl esters; Compound with trifluoro acetic acid
[976] <Example 217>
[977] Sulfamic acid, [[[[1- [4- (dimethylamino) phenyl] cyclopentyl] methyl] -amino] carbonyl] -2,6-bis (1-methylethyl) phenyl ester
[978] Example 218
[979] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4- (3-phenyl-ureido) -phenyl ester
[980] <Example 219>
[981] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (3-tert-butyl ureido) -2,6-diisopropyl-phenyl ester
[982] <Example 220>
[983] [2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (3-amino-propionylamino) -2,6-diisopropyl-phenyl ester; Salt with trifluoro acetic acid
[984] <Example 221>
[985] Carbamic acid, [[[2- (phenylmethyl) phenyl] amino] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) phenyl ester
[986] <Example 222>
[987] (2,3-Dihydro-indole-1-carbonyl) -sulfamic acid 2,6-diisopropyl-phenyl ester
[988] <Example 223>
[989] Sulfamic acid, [[(triphenylmethyl) amino] carbonyl]-, 2,6-bis (1-methylethyl) phenyl ester
[990] <Example 224>
[991] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-cyano-vinyl) -2,6-diisopropyl-phenyl ester
[992] <Example 225>
[993] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-4- (thiophene-2-sulfonylamino) -phenyl ester
[994] <Example 226>
[995] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (5-dimethylamino-naphthalene-1-sulfonylamino) -2,6-diisopropyl-phenyl ester
[996] <Example 227>
[997] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4-methanesulfonylamino-phenyl ester
[998] Example 228
[999] 3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -benzoic acid methyl ester
[1000] <Example 229>
[1001] [2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (benzylamino-methyl) -2,6-diisopropyl-phenyl ester; Compound with general inorganic neutral component
[1002] <Example 230>
[1003] [2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfonic acid 4-((S) -2-amino-3-hydroxy-propionylamino) -2,6-diisopropyl -Phenyl esters; Compound with trifluoro acetic acid
[1004] <Example 231>
[1005] [2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-((S) -2-amino-4-carbamoyl-butyrylamino) -2,6-diiso Propyl-phenyl esters; Compound with trifluoro acetic acid
[1006] Example 232
[1007] [2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-((S) -2-amino-3-methyl-butyrylamino) -2,6-diisopropyl- Phenyl esters; Compound with trifluoro acetic acid
[1008] <Example 233>
[1009] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-hydroxymethyl-2,6-diisopropyl-phenyl ester
[1010] <Example 234>
[1011] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4-carbamoyl-2,6-diisopropyl-phenyl ester
[1012] <Example 235>
[1013] [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [3- (3,5-dichloro-phenyl) -thioureido] -2,6-diisopropyl-phenyl ester
[1014] <Example 236>
[1015] ((E) -2-methyl-3-phenyl-acryloyl) -sulfamic acid 2,6-diisopropyl-phenyl ester
[1016] <Example 237>
[1017] (2-oxo-2H-chromen-3-carbonyl) -sulfamic acid 2,6-diisopropyl-phenyl ester
[1018] <Example 238>
[1019] N- [2,6-bis (1-methylethyl) phenyl] -N '-(hexadecylsulfonyl) -urea
[1020] <Example 239>
[1021] N- [2,6-bis (1-methylethyl) phenyl] -N '-[(6-ethoxy-2-benzothiazolyl) sulfonyl) -urea
[1022] <Example 240>
[1023] N- [2,6-bis (1-methylethyl) phenyl] -N '-(tetradecylsulfonyl) -urea
[1024] <Example 241>
[1025] N '-[2,6-bis (1-methylethyl) phenyl] -N-methyl-N- (tetradecylsulfonyl) -urea
[1026] <Example 242>
[1027] N- [2,6-bis (1-methylethyl) phenyl] -N '-(tridecylsulfonyl) urea
[1028] <Example 243>
[1029] N- [2,6-bis (1-methylethyl) phenyl] -N '-(1-phenyl-1-nonylsulfonyl) urea
[1030] <Example 244>
[1031] N- [2,6-bis (1-methylethyl) phenyl] -N '-(2-decylsulfonyl) urea
[1032] <Example 245>
[1033] N- [2,6-bis (1-methylethyl) phenyl] -N '-(1-phenyl-1-tetradecylsulfonyl) urea
[1034] <Example 246>
[1035] N- [2,6-bis (1-methylethyl) phenyl] -N '-(2-octadecylsulfonyl) urea
[1036] <Example 247>
[1037] N- [2,4,6-trimethoxyphenyl] -N '-(2-octadecylsulfonyl) urea
[1038] <Example 248>
[1039] N- [2,6-bis (1-methylethyl) phenyl] -N '-(2-methyl-2-pentadedecylsulfonyl) urea
[1040] <Example 249>
[1041] N- [2,4,6-trimethoxyphenyl] -N '-(2-methyl-2-pentadedecylsulfonyl) urea
[1042] <Example 250>
[1043] Carbamic acid, [[[2,6-bis (1-methylethyl) phenyl] amino] sulfonyl]-, dodecyl ester
[1044] Sulfonylaminocarbonyl derivatives useful in the present invention can be identified using the methods described below.
[1045] Biological method
[1046] Introduction: Described below is an in vitro, cell based, high throughput screening assay that can reliably identify inhibitors of NF-κB mediated transcription. Although the assays described below used inhibitors that are sulfonylaminocarbonyl derivatives useful in the present invention, this assay can be used for screening for all NF-κB mediated transcriptional inhibitors.
[1047] This assay took advantage of AURORA (Aurora Bioscience Corporation, La Jolla, California) fluorescence technology. Endothelial cell vein-304 (ECV-304), an endothelial like endothelial cell type, is a human immunodeficiency virus-1 (HIV-1) NF-κB binding site 5 replica and enzyme β-lactamase (baseline Under the control of the promoter, it can be stably transfected with plasmid vectors containing cDNA against Stratagene pNF-κB-luc vector). ECV-304 cells are described in Takahashi K, et al., Spontaneous Transformation and Immobilizatin of Human Endothelial Cells, In Vitro Cell. Dev. Biol. 1990; 25: 265-274. Activation of NF-κB in ECV-304 by cytokines such as TNF-α or interleukin-1 beta (IL-1β) results in the production of β-lactamase, which is a green fluorescent substrate (excitation / emission wavelength 395 nm). / 530 nm) is cut to give a blue fluorescent product (excitation / emission wavelength 395 nm / 460 nm). Visibly, the uncleaved green fluorescent substrate is sequestered intracellularly and emits green fluorescence, while the cleaved product emits blue fluorescence. Fluorescence is quantified by spectrophotometer and the spectral intensity of blue fluorescence versus green fluorescence can be used to calculate the extent of NF-κB activation.
[1048] The assay was performed as outlined herein and is described below. 2% of ECV-304 cells (ECV-304 NF-κB.βlaZ) permanently transfected with the β-lactamase gene injected with ENF-κB. Plate in clean bottom assay 96-well plates in Medium-199 (M-199) containing Fetal Bovine Serum (FBS) (1.25 × 10 ⁴ cells / well). After about 18 hours cells were stimulated with 10 ng / ml TNF-α or 100 pg / ml IL-1β and incubated for 6 hours at 37 ° C. in the presence or absence of a compound useful in the present invention. Subsequently, AURORA fluorescence initiation reagent was added. After an additional hour, the plates were read by fluorometer at blue 395 nm / 460 nm (excitation / emission) and green 395 nm / 530 nm wavelengths. The blue / green release ratio was then calculated. Inhibition Under Maximum Stimulated Conditions with TNF-α or IL-1β The percent inhibition was calculated by comparing the fluorescence in the presence of sulfonylaminocarbonyl derivatives useful in the present invention with the fluorescence in the absence of the sulfonylaminocarbonyl derivatives. . IC ₅₀ for the sulfonylaminocarbonyl derivatives was determined from the dose-response curve. This assay was planned to run arbitrarily in high or low throughput screening mode.
[1049] Substances: ECV-304 cells were obtained from the American Type Culture Collection (ATCC). Cytokines TNF-α and IL-1β were obtained from the R & D system. Lipofectamine, M199 and penicillin / streptomycin 1000U (P / S) were obtained from GIBCO-BRL. Reagents A, B and C are proprietary reagents of Aurora Technologies. FBS was obtained from Summit Technologies. CCF2 dye was obtained from Aurora Bioscience, La Jolla, Calif., USA.
[1050] Way:
[1051] (i) ECV-304 NF-κB.βlaZ cell line:
[1052] Five copies of the HIV-1 NF-κB binding site (5'-TGGGGACTTTCCGC-3 ') were inserted with the TATA box into the EcorRI / BamHI site of plasmid pMCRBlaZ to create plasmid p5xKBBlaZ, the process described in Scheme 1 below. I will.
[1053]
[1054] The parental plasmid pMCRBlaZ contains multiple cloning sites upstream of the β-lactamase gene as well as the Zeocin antibiotic resistance gene.
[1055] Plasmid p5xKBBlaZ was transfected into ECV-304 cells using known standard conditions found in lipofectamine and package inserts. Cells were selected for antibiotic resistance with keosin for about 2 weeks. After the stable population had expanded to a significant number of cells, it was stimulated with IL-1β and stained with AURORA CCF2 dye, a fluorescent substrate trapped in membrane osmotic cells. Subsequently, cells fluoresced with blue in the stimuli / stained population (indicated by the positive response of the NF-κB / β-lactamase reporter to stimulation by IL-1β) were pooled into the flow cytometer. Classified by. Pools were expanded, stained with CCF2 and then cells showing green fluorescence from the non-polar population (representing the low background of the NF-κB / β-lactamase reporter construct) in a 96-well plate per well. Cells were added and cloned by flow cytometry. The clones were allowed to expand. Each clone cell line was then stimulated with IL-1β using the CCF2 reporter assay and then examined for overlapping stimulation, which was compared to unstimulated cells. Maximal overlap induced cloned cell line (Plate 1, E column, cell 8 or 1E8) was selected for further assay development. This clone consistently showed high fluorescence signal to noise ratio when stimulated with TNF-α or IL-1β.
[1056] (ii) Assay Development: The assays described herein were first developed for high throughput screening purposes. As such, a number of factors were considered in the process. Assays were developed to minimize handling (ie, media changes, washes, etc.). Conditions were set to optimize the incubation period for 4 to 6 hours for logical reasons. The assay also optimized its capacity to allow concentrations of dimethylsulfoxide (DMSO) that could be used without the presence or presence of serum and indirect fluorescence resulting from activation of NF-κB. Cytokine stability and optimal cell density were also optimized. In addition, no differences were found in NF-κB stimulation in ECV-304 cells lined by 20 passages (5 and 25 passages).
[1057] (iii) reagents:
[1058] Cell: ECV-304 NF-κB β-lactamase clone 1E8
[1059] Complete medium: M199, 10% FBS (non-heat activated), 1% P / S, 200 μg / ml zeocin;
[1060] Assay medium: M199, 2% FBS, no antibiotics
[1061] Cell culture: 0.5 × 10 6 cells / T 150 culture flask, 30 ml complete medium, supplied daily; Collected on day 7, yields approximately 1.1 (107 / flask)
[1062] Assay Seed Density: 1.78 × 10 5 / ml, 70 μl / well-96-well plate, (12,500 cells / well)
[1063] Quality Control: Proteosome inhibitors MG132, MG262 and clastolactacystin β-lactone, which are irreversible inhibitors of proteosome degradation of IκB, can be used (McCormicack et al., Journal of Biological Chemistry, 1997; 272 (42): 26103-26109 and Craui et al., Journal of Biological Chemistry, 1997; 272 (20): 13437-13445).
[1064] Inhibitor: preparing a stock solution of aminosulfonyl derivative at 10 mM concentration in DMSO;
[1065] Dilute the stock solution in a 96-well dilution plate as follows:
[1066] a) 20 μl of stock solution is added to 180 μl M199 = A,
[1067] b) 20 μl A is added to 180 μl M199 = B,
[1068] c) 10 μl of B is added to appropriate wells in the assay plate (final concentration of drug is 10 μM),
[1069] d) Dilute further for IC ₅₀ measurements.
[1070] Cytokine TNF-α and IL-1β Activation:
[1071] Stock of TNF-α: 10 μg of R & D system 210-TA was diluted with 2 ml of phosphate buffered saline (PBS) containing 0.1% bovine serum albumin (BSA) (concentration of TNF-α = 5 μg / ml);
[1072] TNF-α stock diluted 1: 100: 90 μl of TNF-α stock was diluted into 9.0 ml of M199 medium (concentration of TNF-α = 50 ng / ml);
[1073] To all wells except reagent control wells and cell control wells 20 μl of a solution of TNF-α was added (final concentration of TNF-α in wells = 10 ng / ml).
[1074] Stock Solution of IL-1β: R & D System 203-LB, 5 μg, was diluted into 1 ml PBS containing 0.1% BSA (concentration of IL-1β = 5 μg / ml);
[1075] Il-1β stock diluted 1: 1000: 20 μl of IL-1β stock was diluted into 20 ml of M199 (concentration of IL-1β = 5 ng / ml);
[1076] 5 ng / ml IL-1β solution diluted 1:10: 0.5 ml of 5 ng / ml IL-1β solution was diluted with 5.0 ml of M199 (concentration of IL-1β = 500 pg / ml);
[1077] 20 μl of a solution of 500 pg / ml IL-1β was added to all wells except the reagent control and cell control wells (final concentration of IL-1β in the well = 100 pg / ml).
[1078] (iv) High Throughput Screening Assay Procedures:
[1079] TABLE 1
[1080]
[1081] Column 1 = USC, unstimulated cell control wells.
[1082] Column 2 A-F = T, maximum active control wells.
[1083] Column 2 G-H = MG, MG132 quality control.
[1084] Column 12 = B, reagent background wells.
[1085] Column 3-11 = O, triple sulfonylaminocarbonyl derivatives of various concentrations for 10 μM concentration (for screening purposes) or for dose response studies (IC ₅₀ ).
[1086] Plates for HTS are placed in a separate format.
[1087] Day PM: Cells were planted at 70 μl / ml, 0.178 × 10 ⁶ / ml in assay medium.
[1088] Day 2 AM:
[1089] a) DMSO control: 10 μl of a 1% DMSO solution in M199 was added to the following wells (final concentration of DMSO in wells = 0,1%): B wells (reagent control: assay medium, no cytokines, no cells), USC wells (non-stimulatory cell control: cells, assay media, no activating cytokines), and T wells (maximum activity: cells, assay media, cytokines).
[1090] b) Inhibitors: 10 μl of sulfonylaminocarbonyl derivative was added to the following wells 10 times the desired final concentration: all O wells (unknown: cells, assay medium, cytokines) and MG wells (quality control: cells, Assay medium, cytokine). Inhibitors should not be added to USC wells, B wells or T wells.
[1091] c) Activating cytokines: 50 ng / ml solution of TNF-α (final concentration of TNF-α = 10 ng / ml) or 20 μl of IL-1β in all T wells, O wells and MG wells pg / ml solution (final concentration of IL-1β = 100 pg / ml) was added.
[1092] d) Cells were stimulated with activated cytokines in the presence or absence of sulfonylaminocarbonyl derivatives and incubated for 6 hours at 37 ° C., 5% CO ₂ atmosphere.
[1093] e) Preparation of AURORA CCF2 Fluorescence Initiating Substrate Solution:
[1094] Four separate solutions of 2 ml each were prepared for each plate using the amounts described in Table 2 below following the procedure below.
[1095] Reagent A was added to a 50 ml tube first, followed by Reagent B. Mix, Reagent C was added and mixed again.
[1096] TABLE 2
[1097] Substrate Formulation Directive
[1098] (Reagent A + Reagent B)+ Reagent C 6 μl60 μl1 ml 24 μl240 μl4 ml 48 μl480 μl8 ml 60 μl600 μl10 ml
[1099] 2 ml / plate, 20 μl / plate; Additional 2 ml prepared
[1100] Incubation at dark, room temperature for 1 hour after addition of AURORA CCF fluorescence initiation solution.
[1101] Spectrophotometer Analysis: The CYTOFLUOR (Millipore Corporation, Bedford, Massachusetts) 2 device used wavelengths of excitation 395 nm / emission 460 nm (blue) and excitation 395 nm / emission 530 nm (green).
[1102] (v) data calculation
[1103] BKG Blue (BB)= Average reagent background blue emission BKG Green (BG)= Average reagent background green emission Calibrated blue (CB)= Subtract BB from all blue readings on the plate Calibrated green (CG)= Subtract BG from all green readings on the plate Blue / Green Rain (BGR)= Dividing CB by CG (CB / CG) BGRF= BGR divided by BGR of USC wells Max activeAverage of BGRF of stimulated cells (TNF-α max or IL-1β max) T maximum activity inhibition(100- (BGRF mean / TNF-α or IL-β max of unknown (cell + inhibitor)) x 100
[1104] Representative sulfonyl aminocarbonyl derivatives useful in the present invention were tested for their ability to inhibit NF-κB mediated transcription at the concentration of 10 μM using the methods described below, and the results are shown in Table 3 below, “Inhibition at 10 μM. Percentages ".
[1105] TABLE 3
[1106]
[1107]
[1108]
[1109]
[1110]
[1111]
[1112]
[1113]
[1114]
[1115] As indicated by cell based assay data, the sulfonylaminocarbonyl derivatives in Table 3 are inhibitors of NF-κB mediated transcription that can cross cell membranes and reach targets of the NF-κB signaling pathway. Thus, sulfonylaminocarbonyl derivatives are used herein to include acute, including, for example, rheumatoid arthritis and osteoarthritis, autoimmune diseases, psoriasis, asthma, cardiovascular diseases such as atherosclerosis, unstable angina and myocardial infarction. It is useful for the treatment of diseases or disorders that are responsive to inhibition of NF-κB such as coronary syndrome and congestive heart failure, Alzheimer's disease, multiple sclerosis, cancer, type 2 diabetes, metabolic syndrome X and inflammatory bowel disease.
[1116] In carrying out a method of treating a disease or disorder responsive to NF-κB inhibition of the present invention, sulfonylaminocarbonyl derivatives useful in the present invention may be administered in a number of pharmaceutically acceptable oral and parenteral forms. Thus, sulfonylaminocarbonyl derivatives can be administered by injection, ie intravenous, intramuscular, intradermal, subcutaneous, duodenum or intraperitoneal injection. In addition, sulfonylaminocarbonyl derivatives can be administered by inhalation (eg, nasal inhalation). In addition, sulfonylaminocarbonyl derivatives may be administered transdermally. The following dosage forms may comprise a compound of formula 1 or formula 2 or another sulfonylaminocarbonyl derivative or pharmaceutically acceptable salt thereof useful in the present invention as an active ingredient.
[1117] Pharmaceutically acceptable carriers for the preparation of pharmaceutical compositions from the compounds of the invention may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier can be one or more substances that can act as diluents, flavors, binders, preservatives, tablet disintegrants or encapsulating materials.
[1118] In powders the carrier is a finely divided solid mixed with the finely divided active ingredient.
[1119] In tablets the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
[1120] Powders and tablets preferably comprise 5 or 10 to about 70% of the active compound. Preferred carriers are magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like. The term "preparation" is intended to include formulations of the active compound with the encapsulating material as a carrier which is surrounded by an active ingredient with or without other carriers and thus provides a capsule associated therewith. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used in solid dosage forms suitable for oral administration.
[1121] To prepare suppositories, low melting waxes such as fatty acid glycerides or cocoa butter are first melted, and the active ingredients are uniformly dispersed therein by stirring or the like. The molten homogeneous mixture is then poured into a mold of convenient size, cooled and solidified thereby.
[1122] Liquid formulations include solutions, suspensions and emulsions, such as water or water propylene glycol solutions. Liquid preparations for parenteral injection may be formulated in solution in aqueous polyethylene glycol solution.
[1123] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers and thickeners as desired.
[1124] Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous substances such as natural or synthetic rubbers, resins, methylcellulose, sodium carboxymethylcellulose and other known suspending agents.
[1125] Also included are solid preparations which are intended to be converted, shortly before use, to liquid preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These formulations may include, in addition to the active ingredient, colorants, flavors, stabilizers, buffering agents, artificial and natural sweeteners, dispersants, thickeners, solubilizers and the like.
[1126] Pharmaceutical formulations are preferably in unit dosage form. Such formulation forms are divided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be a packaged formulation comprising a formulation in a dispersion such as tablets, capsules or powders packaged in vials or ampoules. In addition, the unit dosage form may be a capsule, tablet, cachet or lozenge itself, or may be any suitable number of any of these in packaged form.
[1127] The amount of active ingredient in a unit dose formulation can vary or be adjusted from 0.1 mg to 100 mg, preferably 0.5 mg to 100 mg, depending on the particular application and the potency of the active ingredient. The composition may also include other miscible therapeutics if desired.
[1128] In therapeutic use as an agent for the treatment of antagonists or diseases, the compounds used in the present invention are administered at an initial dose of about 0.01 mg to about 100 mg / kg daily. A daily dose range of about 0.01 mg to about 10 mg / kg is preferred. However, the dosage may vary depending on the needs of the patient, the severity of the disease being treated and the compound used. It is within the skill of the art to determine the appropriate dose for a particular situation. In general, treatment begins with small doses that are below the optimal dose of the compound. Thereafter, the dose is increased in small increments until the optimum effect is reached under the circumstances. Conveniently, the total daily dose may be administered in portions, if desired, in one day.
[1129] Examples of pharmaceutical formulations of sulfonylaminocarbonyl derivatives useful in the present invention are described below. Such agents can be administered to patients, including humans, one to six times daily for the treatment of diseases and disorders that are responsive to the inhibition of NF-κB mediated transcription.
[1130] Preparation Example 1
[1131] Tablet formulations:
[1132] ingredientVolume (mg) Compound of Example 19925 Lactose50 Corn Starch (For Mix)10 Oxo Water Starch (paste)10 Magnesium Stearate (1%)5 Total amount100
[1133] The compound of Example 199, lactose and corn starch (for mix) were uniformly blended. Corn starch (for paste) was suspended in 200 ml of water and heated with stirring to form a paste. The paste was used to granulate the mixed powder. The wet granules were passed through No. 8 screen and dried at 80 ° C. Dry granules were lubricated with 1% magnesium stearate and compressed into tablets.
[1134] <Formulation Example 2>
[1135] Coated tablet :
[1136] The tablets of Formulation Example 1 were coated in a conventional manner with sucrose, potato starch, talc, tragacanta and colorant coatings.
[1137] Preparation Example 3
[1138] Injection Vials :
[1139] The pH of the volume of 5 g of disodium hydrogen phosphate and 500 g of the compound of Example 3 was adjusted to pH 6.5 in 3 L double dilution using 2 M hydrochloric acid. The solution was sterile filtered and the filtrate was filled into injection vials, lyophilized under sterile conditions and sealed aseptically. Each injection vial contains 25 mg of the compound of Example 3.
[1140] Preparation Example 4
[1141] Suppository :
[1142] A mixture of 25 g of the compound of Example 31, 100 g of soy lecithin and 1400 g of cocoa butter were combined, poured into a mold and cooled. Each suppository contains 25 mg of the compound of Example 31.
[1143] Preparation Example 5
[1144] Solution :
[1145] The solution was prepared from 1 g of the compound of Example 55, 9.38 g of NaH ₂ PO ₄ .2H ₂ O, 28.48 g of Na ₂ HPO ₄ .12H ₂ O and 0.1 g of benzalkonium chloride in 940 ml of 2-fold dilution water Prepared. The pH of the solution was adjusted to pH 6.8 using 2 M hydrochloric acid. The solution was diluted to 1.0 L with 2-fold dilution water and sterilized by irradiation. 25 mL of the solution included 25 mg of the compound of Example 55.
[1146] Preparation Example 6
[1147] Ointment :
[1148] 500 mg of the compound of Example 199 was mixed with 99.5 g of petroleum jelly under aseptic conditions. 5 g of ointment comprises 25 mg of the compound of Example 119.
[1149] Preparation Example 7
[1150] Capsules :
[1151] 2 kg of the compound of Example 180 were filled into hard gelatin capsules in a conventional manner such that each capsule contains 25 mg of the compound of the present invention.
[1152] Preparation Example 8
[1153] Ampule :
[1154] A solution of 2.5 kg of the compound of Example 231 was dissolved in 60 L 2-fold dilution water. The solution was sterile filtered and the filtrate was filled in ampoules. The ampoules were lyophilized under sterile conditions and sealed aseptically. Each ampoule contains 25 mg of the compound of Example 231.
[1155] The method of the present invention includes, for example, rheumatoid arthritis, osteoarthritis, autoimmune diseases, psoriasis, asthma, cardiovascular disease, acute coronary syndrome, congestive heart failure, Alzheimer's disease, multiple sclerosis, cancer, type 2 diabetes, metabolic syndrome Useful for the treatment of X, or inflammatory bowel disease.
[1156] Although the method of the present invention has been described above, embodiments of the present invention are claimed below.

权利要求:
Claims (22)
[1" claim-type="Currently amended] A pharmaceutical composition for treating a disease or disorder responsive to the inhibition of nuclear factor κB (NF-κB) transcription factors, including sulfonylaminocarbonyl derivatives or pharmaceutically acceptable salts thereof.
[2" claim-type="Currently amended] The composition of claim 1, wherein the sulfonylaminocarbonyl derivative is a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
<Formula 1>

Where
X and Y are oxygen, sulfur and (CR'R ") _n , where n is an integer from 1 to 4, R 'and R" are each independently hydrogen, alkyl, alkoxy, halogen, hydroxy, acyloxy, Cycloalkyl, optionally substituted phenyl, or R 'and R "together form spirocycloalkyl or carbonyl;
Provided that when at least one of X and Y is-(CR'R ") _n -and X and Y together are (CR'R") _n, then R 'and R "are hydrogen, n is 1, and R ₁ And R ₂ is aryl;
R is hydrogen, straight or branched chain alkyl of 1 to 8 carbon atoms, or benzyl;
R ₁ and R ₂ are each independently selected from the following (a) to (e):
(a) phenyl, an alkyl group having 1 to 6 carbon atoms and straight or branched chain, an alkoxy group having 1 to 6 carbon atoms and straight or branched chain, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, Trifluoromethyl, —COOH, —COOalkyl having 1 to 4 carbon atoms and straight or branched chain alkyl, and — (CH ₂ ) _p NR ₃ R ₄ where p is 0 or 1 and R ₃ And R _{4 is} each phenyl or phenoxy unsubstituted or substituted with 1 to 5 substituents selected from hydrogen or a straight or branched chain alkyl group having 1 to 4 carbon atoms;
(b) phenyl, an alkyl group having 1 to 6 carbon atoms and straight or branched chain, an alkoxy group having 1 to 6 carbon atoms and straight or branched chain, hydroxy, phenoxy, fluorine, chlorine, bromine, nitro, Trifluoromethyl, -COOH, -COOalkyl having 1 to 4 carbon atoms and straight or branched chain alkyl, and-(CH ₂ ) _p NR ₃ R ₄ , wherein p, R ₃ and R ₄ are 1- or 2-naphthyl unsubstituted or substituted with one to three substituents selected from: (as defined);
(c) arylalkyl;
(d) straight or branched chain alkyl having 1 to 20 carbon atoms and saturated or comprising 1 to 3 double bonds;
(e) an adamantyl or cycloalkyl group in which the cycloalkyl moiety has 3 to 6 carbon atoms;
only,
(i) if X is (CH ₂ ) n, Y is oxygen and R ₁ is substituted phenyl, then R ₂ is substituted phenyl,
(ii) when Y is oxygen, X is (CH ₂ ) _n and R ₂ is phenyl or naphthyl, then R ₁ is not straight or branched alkyl,
(iii) subject to the exclusion of:

Sulfamic acid [1-oxo-3- [2,4,6-tris (1-methylethyl) phenyl] propyl] -2,6-bis (1-methylethyl) phenyl ester,
Sulfamic acid [fluoro [2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester, and
Further condition is the exclusion of compounds selected from the group consisting of sulfamic acid [[2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (phenyl) phenyl ester.
[3" claim-type="Currently amended] The method of claim 2, wherein the sulfonylaminocarbonyl derivative is
(1,2,3,4-tetrahydro-naphthalene-2-carbonyl) -sulfamic acid 2,6-diisopropyl-phenyl ester;
[Bis- (4-chloro-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-phenyl ester;
(Bromo-phenyl-acetyl) -sulfamic acid 2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4-hydroxy-2,6-diisopropyl-phenyl ester;
Methyl-[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-4-nitro-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4-fluoro-2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-dimethoxy-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-amino-2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,4,6-trimethoxy-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-tert-butyl-2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-acetyl-2-isopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-4-methoxy-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-dichloro-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid dodecyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4-bromo-2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-4-methyl-phenyl ester;
[1- (4-Dimethylamino-phenyl) -cyclopentanecarbonyl] -sulfamic acid 2,6-diisopropyl-phenyl ester;
[1- (4-Nitro-phenyl) -cyclopentanecarbonyl] -sulfamic acid 2,6-diisopropyl-phenyl ester;
3,5-diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -benzoic acid methyl ester;
Sulfamic acid (phenylacetyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [[2,4,6-tris (1-methylethyl) phenyl] acetyl-2,6-bis (1-methylethyl) phenyl ester,
Sulfamic acid [[2,6-bis (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [[2,4,6-tris (1-methylethyl) phenyl] acetyl-2,4,6-tris (1-methylethyl) phenyl ester;
Sulfamic acid [[2,6-bis (1-methylethyl) phenyl] acetyl] -2,4,6-tris (1-methylethyl) phenyl ester;
Sulfamic acid [adamantaneacetyl] -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [[2,6-bis (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester-sodium salt;
Sulfamic acid [[2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester-sodium salt;
Sulfamic acid (decanoyl) -2,6-bis- (1-methylethyl) phenyl ester;
Sulfamic acid (dodecanoyl) -2,6-bis- (1-methylethyl) phenyl ester;
2,6-bis (1-methylethyl) -N-[[[2,4,6-tris (1-methylethyl) phenyl] -methyl] sulfonyl] benzeneacetamide;
2,6-bis (1-methylethyl) -N-[[[2,4,6-tris (1-methylethyl) phenyl] -methyl] -sulfonyl] benzeneacetamide-sodium salt;
2,6-bis (1-methylethyl) phenyl [[[[2,4,6-tris (1-methylethyl) phenyl] -methyl] sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [[[2,4,6-tris (1-methylethyl) phenyl] -methyl] sulfonyl] carbamate-sodium salt;
Sulfamic acid (1-oxo-3,3-diphenylpropyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [2,6-dichlorophenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [2,6-dichlorophenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester sodium salt;
Sulfamic acid trans-[(2-phenylcyclopropyl) carbonyl] -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [2,5-dimethoxyphenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [2,4,6-trimethoxyphenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [2,4,6-trimethylphenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [2-thiophenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [3-thiophenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [2-methoxyphenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (oxophenylacetyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [2-trifluoromethylphenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (1-oxo-2-phenylpropyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (cyclopentylphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (cyclohexylacetyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (diphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (triphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [(1-phenylcyclopentyl) carbonyl] -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (3-methyl-1-oxo-2-phenylpentyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (1-oxo-2-phenylbutyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (cyclohexylphenyl-acetyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (1-oxo-2,2-diphenylpropyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [(9H-fluoren-9-yl) carbonyl] -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (1-oxo-3-phenylpropyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [1-oxo-3- [2,4,6-tris (1-methylethyl) phenyl] -2-propenyl] -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [(acetyloxy) [2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [hydroxy [2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (3-methyl-1-oxo-2-phenylpentyl) -2,6-bis (1-methylethyl) phenyl ester sodium salt;
Sulfamic acid [[2,4,6-tris (1-methylethyl) phenoxy] acetyl] -2,6-bis (1-methylethyl) phenyl ester; And
A compound of formula 1 selected from sulfamic acid [[2,6-bis (1-methylethyl) phenoxy] acetyl] -2,6-bis (1-methylethyl) phenyl ester or a pharmaceutically acceptable salt thereof.
[4" claim-type="Currently amended] 3. The sulfonylaminocarbonyl derivative according to claim 2, wherein the sulfonylaminocarbonyl derivative is sulfamic acid [[2,4,6-tris (1-methylethyl) phenyl] acetyl-2,6-bis (1-methylethyl) phenyl ester or its A composition that is a pharmaceutically acceptable salt.
[5" claim-type="Currently amended] The composition of claim 1, wherein the sulfonylaminocarbonyl derivative is a compound of Formula 2 or a pharmaceutically acceptable salt thereof.
<Formula 2>

Where
R ¹ is hydrogen, alkyl or alkoxy;
R ² to R ⁵ are alkyl, alkoxy, or unsubstituted or substituted phenyl;
R ⁶ is —CN, — (CH ₂ ) _0-1 —NR ⁷ R ⁸ , —O— (CH ₂ ) _1-10 —Z, wherein Z is —NR ⁹ R ¹⁰ , OR ¹ or CO ₂ R ¹ -OC (= O) R ¹¹ , -SR ¹¹ , -SCN, -S (CH ₂ ) _1-10 Z, -S (O) _1-2 R ¹² , wherein R ¹² is hydroxy, alkoxy , Alkyl, (CH ₂ ) _1-10 Z or NR ⁷ R ⁸ , -C (= 0) XR ¹¹ , or -CH ₂ -R ¹³ , wherein R ¹³ is (CH ₂ ) _0-5 -Y — (CH ₂ ) _0-5 Z or 1-20 carbons having 1 to 3 double bonds, wherein alkyl is selected from —CN, NO ₂ , halogen, OR ¹ , NR ⁹ R ¹⁰ and CO ₂ R ¹ Optionally substituted with one or more residues)
Wherein R ⁷ and R ⁸ are each independently hydrogen, wherein at least one of R ⁷ and R ⁸ is other than hydrogen, — (CH ₂ ) _1-10 Z {where Z is as defined above and R ⁹ and R ¹⁰ is each independently hydrogen, alkyl and unsubstituted or substituted phenyl, or R ⁹ and R ¹⁰ together with the nitrogen attached thereto

Form a ring selected from: wherein R ¹⁴ , R ¹⁵ and R ¹⁶ are each independently hydrogen, alkyl and unsubstituted or substituted phenyl; and, -C (= Q) XR ¹¹ , wherein X is a bond Or NH, Q is O or S and R ¹¹ is hydrogen, alkyl, unsubstituted or substituted phenyl,-(CH ₂ ) _0-5 -Y- (CH ₂ ) _0-5 Z, wherein Z is As defined above, Y is phenyl or a bond), -C (= 0) -CR ¹⁷ R ¹⁸ Z, -C (= 0) NHCR ¹⁷ R ¹⁸ Z, wherein R ¹⁷ and R ¹⁸ are each Independently hydrogen, alkyl, phenyl, substituted phenyl or side chains of naturally occurring amino acids, -S (O) _1-2 R ¹⁹ , wherein R ¹⁹ is alkyl, unsubstituted or substituted phenyl, naphthyl or heteroaromatic Ring or NR ⁹ R ¹⁰ ), or
R ⁷ and R ⁸ together with the attached nitrogen

To form a ring selected from wherein R ¹⁴ , R ¹⁵ and R ¹⁷ are as above;
Provided that [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-formyl-2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2-cyano-vinyl) -2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4- (4-methyl-piperazin-1-ylmethyl) -phenyl ester, dihydrochloride ;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [bis- (2-hydroxy-ethyl) -amino] -2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4- (3-phenyl-thioureido] -phenyl ester; and
Excludes compounds selected from [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4-sulfamoyl-phenyl ester.
[6" claim-type="Currently amended] The method of claim 5, wherein the sulfonylaminocarbonyl derivative is
6- (3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -phenyl) -hexanoic acid ethyl ester;
3- [3- (3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -phenyl) -ureido] -propionic acid ethyl ester;
{[4- (1-hydroxy-1-methyl-ethyl) -2,6-diisopropyl-phenyl] -acetyl} -sulfonic acid 2,6-diisopropyl-phenyl ester;
[2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-((S) -2-amino-4-methyl-pentanoylamino) -2,6-diisopropyl- Phenyl esters; Compound with trifluoroacetic acid;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (3-tert-butyl-ureido) -2,6-diisopropyl-phenyl ester;
[2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (3-amino-propionylamino) -2,6-diisopropyl-phenyl ester; Compounds with trifluoro acetic acid;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2-cyano-vinyl) -2,6-diisopropyl-phenyl ester;
[2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfonic acid 4-((S) -2-amino-3-hydroxy-propionylamino) -2,6-diisopropyl -Phenyl esters; Compounds with trifluoro acetic acid;
[2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-((S) -2-amino-4-carbamoyl-butyrylamino) -2,6-diiso Propyl-phenyl esters; Compounds with trifluoro acetic acid;
[2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-((S) -2-amino-3-methyl-butyrylamino) -2,6-diisopropyl- Phenyl esters; Compounds with trifluoro acetic acid;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [3- (3,5-dichloro-phenyl) -thioureido] -2,6-diisopropyl-phenyl ester;
(S)-[5-tert-butoxycarbonylamino-5- (3,5-diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -Phenylcarbamoyl) -pentyl] -carbamic acid tert-butyl ester;
(S)-[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2,6-diamino-hexanoylamino) -2,6-diisopropyl-phenyl ester di Hydrochloride;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2-t-butoxycarbonylamino-acetylamino) -2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-amino-acetylamino) -2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-t-butoxycarbonylamino-4-methylsulfanyl-butyrylamino) -2,6-diiso Propyl-phenyl esters;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-amino-4-methylsulfanyl-butyrylamino) -2,6-diisopropyl-phenyl ester trifluor Low acetate;
3- [3- (3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -phenyl) -ureido] -propionic acid ethyl ester;
3- [3- (3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -phenyl) -ureido] -propionic acid;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [2-amino-3- (1H-indol-3-yl) -propionylamino] -2,6-diiso Propyl-phenyl esters;
[(2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (5-amino-pentanoylamino) -2,6-diisopropyl-phenyl ester trifluoroacetate (1: 1 ) (Salts);
(D)-[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2-amino-propionylamino) -2,6-diisopropyl-phenyl ester trifluoroacetate (1; 1) (salt);
(L)-[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2-amino-propionylamino) -2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2-amino-2-methyl-propionylamino) -2,6-diisopropyl-phenyl ester;
[(2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (3-dimethylamino-propoxy) -2,6-diisopropyl-phenyl ester;
[(2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (3-dimethylamino-propoxy) -2,6-diisopropyl-phenyl ester hydrochloride salt;
[(2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (3-amino-propoxy) -2,6-diisopropyl-phenyl ester hydrochloride salt;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4-thiocyanato-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-cyano-2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4-[(2-amino-acetylamino) -methyl] -2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (benzylamino-methyl) -2,6-diisopropyl-phenyl ester mono hydrochloride;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfame acid 4-carbamoyl-2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-hydroxymethyl-2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-acetylamino-2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2-hydroxy-ethylamino) -2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [3- (2,6-diisopropyl-phenyl) -ureido] -2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4- (3-phenyl-ureido] -phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4- (thiophene-2-sulfonylamino) -phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (5-dimethylamino-naphthalene-1-sulfonylamino) -2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4-methanesulfonylamino-phenyl ester;
6- (3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl-acetyl] sulfamoyloxy} -phenyl) -hexanoic acid ethyl ester; and
(6- (3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl-acetyl] sulfamoyloxy} -phenyl) -hexanoic acid, or a compound of formula (2) A composition that is a pharmaceutically acceptable salt.
[7" claim-type="Currently amended] The method of claim 1, wherein the sulfonylaminocarbonyl derivative is
(9H-Xanthene-9-carbonyl) -sulfamic acid 2,6-diisopropyl-phenyl ester;
((E) -2-methyl-3-phenyl-acryloyl) -sulfamic acid 2,6-diisopropyl-phenyl ester, and
Or a pharmaceutically acceptable salt thereof, or a compound selected from (2-oxo-2H-chromen-3-carbonyl) -sulfamic acid 2,6-diisopropyl-phenyl ester, or
The sulfonylaminocarbonyl derivative
Carbamic acid, [(phenylamino) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [(phenylamino) sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-hydroxyphenyl ester;
Carbamic acid, [(phenylamino) sulfonyl]-, 2,6-bis (1,1-dimethylethyl) phenyl ester;
Carbamic acid, [(didecylamino) sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester;
Carbamic acid, [[bis (1-methylethyl) amino] sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [(dipentylamino) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[(diphenylmethyl) amino] sulfonyl] methyl-, 2,6-bis (1,1-dimethylethyl) phenyl ester;
DL-tryptophan, α-methyl-N-[[[((tricyclo [3.3.1.1 ^3,7 ] dec-2-yloxy) carbonyl] amino] sulfonyl]-, methyl ester;
Carbamic acid, sulfonylbis-, bis [2,6-bis (1-methylethyl) phenyl] ester;
Carbamic acid, [[[2- (phenylmethyl) phenyl] amino] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) phenyl ester;
Methyl [[2,6-bis (1-methylethyl) phenyl amino] sulfonyl] carbamate;
Dodecyl [[2,6-bis (1-methylethyl) phenyl] amino] sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methoxyphenyl [[(2,2-diphenylethyl) -amino] sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methoxy phenyl [[[2,6-bis (1-methylethyl) phenyl] amino] sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) phenyl-[[(diphenylmethyl) amino] -sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) phenyl [[[2,6-bis (1-methylethyl) phenyl] -amino] sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) phenyl [[(2,2-diphenylethyl) amino] -sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) phenyl [[bis (phenylmethyl) amino] -sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [(diphenyl-amino) sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [(dibutyl-amino) sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [[bis (phenyl-methyl) amino] sulfonyl] -carbamate;
2,6-bis (1-methylethyl) phenyl [(1H-benzimidazol-2-ylamino) -sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [[(2,2-diphenylethylamino] sulfonyl] -carbamate;
2,6-bis (1-methylethyl) phenyl [[[2,6-bis (1-methylethyl) phenyl] -amino] sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [[(diphenyl-methyl) amino] sulfonyl] -carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[(diphenylmethyl) -amino] sulfonyl]] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[[bis (2,6-bis (1-methylethyl) phenyl] amino] sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[(2,2-diphenylethyl) -amino] sulfonyl] -carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [(dibutylamino) -sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [(dipentylamino) -sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[bis (1-methylethyl) amino] sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [(dihexylamino) -sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [(hexylamino) -sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[methyl (2-phenylethyl) amino] sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[[bis-3- (dimethylamino) -propyl] amino] -sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [(methyl octyl amino) -sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-[[bis (tetrahydro-2-furanyl) methyl] amino] sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [(dioctylamino) -sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[[methyl 2- (2-pyridinyl) ethyl] amino] sulfonyl] carbamate, hydrochloride salt;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[[methyl 2- (2-pyridinyl) ethyl] amino] -sulfonyl] carbamate, sodium salt;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [(dodecylamino) -sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [[bis (1-methylethyl) amino] sulfonyl] -carbamate;
2,6-bis (1-methylethyl) phenyl [[(1-methylethyl) phenylmethyl-amino] sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [(hexyl-amino) sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [(dioctyl-amino) sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [[cyclo-hexyl (1-methylethyl) amino] -sulfonyl] -carbamate;
2,6-bis (1-methylethyl) phenyl [(methyl-octylamino) sulfonyl] -carbamate;
2,6-bis (1-methylethyl) phenyl [(dihexyl-amino) sulfonyl] carbamate;
Dodecyl [[((2,4,6-trimethoxyphenyl) amino] -sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl ester (4-morpholinylsulfonyl) -carbamic acid;
2,6-bis (1-methylethyl) phenyl ester (1-piperidinylsulfonyl) carbamic acid;
2,6-bis (1-methylethyl) phenyl ester (1-pyrrolidinylsulfonyl) -carbamic acid;
2,6-bis (1-methylethyl) phenyl ester [(2,3-dihydro-1H-indol-1-yl) sulfonyl] carbamic acid;
2,6-bis (1-methylethyl) phenyl [(dibutylamino) sulfonyl] carbamate monosodium salt; And
2,6-bis (1,1-dimethylethyl) phenyl [[(diphenylmethyl) amino] -sulfonyl] methyl carbamate or a pharmaceutically acceptable salt thereof
The sulfonylaminocarbonyl derivative
Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dipropylamino) -sulfonyl]-;
Urea, N- (2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl) -N '-[[(tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) Amino] sulfonyl]-, (4S-cis)-;
Urea, N- (2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl) -N '-[[(2,2-dimethyl-4-phenyl-1,3-dioxane- 5-yl) amino] sulfonyl-, stereoisomer;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[bis (1-methylethyl) amino] -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[(diphenylmethyl) amino] -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(diphenylamino) -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dibutylamino) sulfonyl] urea;
N-[[[2,6-bis (1-methylethyl) phenyl] amino] -sulfonyl] -N '-(diphenylmethyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[[2,6-bis (1-methylethyl) -phenyl] amino] sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[(2,2-diphenylethyl) -amino] sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(9H-fluorene-9-ylamino] -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[bis (phenylmethyl) amino] -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[(1-methylethyl)-(phenylmethyl) amino] sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dioctylamino) sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(4-phenyl-1-piperidinyl) -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dihexylamino) sulfonyl] -urea;
N-[[bis [3- (dimethylamino) propyl] amino] -sulfonyl] -N '-[2,6-bis (1-methylethyl) phenyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(hexylamino) sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[bis-[(tetrahydro-2-furanyl) methyl] amino] sulfonyl] -urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(diethylamino) sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(methyloctylamino) sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[cyclohexyl (1-methylethyl) amino] sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dipentylamino) sulfonyl] -urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[bis (2-methylpropyl) amino] -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[ethyl (2-propenyl) amino] -sulfonyl] urea;
N-[[bis (3-methylbutyl) amino] sulfonyl] -N '-[2,6-bis (1-methylethyl) -phenyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(didecylamino) sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(didodecylamino) -sulfamoyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(diisopropylamino) -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dicyclohexylamino) -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(methyloctadecylamino) -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(di-2-propenylamino) -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[(1,1-dimethylethyl) (1-methylethyl) amino] sulfonyl] -urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[bis (1-methylpropyl) amino] -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(methyltetradecylamino) -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-(1-pyrrolidinylsulfonyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-(1-piperidinylsulfonyl) urea;
N '-[[[2,6-bis (1-methylethyl) phenyl] amino] sulfonyl] -N, N-bis (phenylmethyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dibutylamino) sulfonyl] urea, monosodium salt; And
N '-[2,6-bis (1-methylethyl) phenyl] -N-methyl-[(dibutyl-amino) sulfonyl] urea or a pharmaceutically acceptable salt thereof; or
The sulfonylaminocarbonyl derivative
Sulfamic acid, [[[2,4,6-tris (1-methylethyl) phenyl] amino] -carbonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid, [[[[1- [4- (dimethylamino) phenyl] cyclopentyl] -methyl] amino] carbonyl], 2,6-bis (1-methylethyl) phenyl ester;
(2,3-dihydro-indole-1-carbonyl) -sulfamic acid 2,6-diisopropyl phenyl ester;
Sulfamic acid, [[(triphenylmethyl) amino] carbonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Octadecyl [[[2,6-bis (1-methylethyl) phenyl] -amino] carbonyl] -sulfate;
Dodecyl-N-[[[2,6-bis (1-methylethyl) phenyl] -amino] carbonyl] -sulfate;
Decyl [[[2,6-bis (1-methylethyl) phenyl] amino] carbonyl] sulfate;
(±) 1-methylheptyl [[[2; 6-bis (1-methylethyl) phenyl] amino] -carbonyl] sulfate;
2,6-bis (1-methylethyl) phenyl [[[2; 6-bis (1-methylethyl) -phenyl] amino] carbonyl] sulfate;
(±) 1-methylundecyl [[[2; 6-bis (1-methylethyl) phenyl] amino] -carbonyl] sulfate; And
Dodecyl [[[2; 6-bis (1-methylethyl) phenyl] amino] carbonyl] -sulfate; A compound selected from sodium salt or a pharmaceutically acceptable salt thereof, or
The sulfonylaminocarbonyl derivative
Carbamic acid, [(dodecyloxy) sulfonyl]-, dodecyl ester;
Carbamic acid, [(dodecyloxy) sulfonyl]-, [1,1 ': 3', 1 "-terphenyl] -2'-yl ester;
Carbamothioic acid, [(dodecyloxy) sulfonyl]-, S- [2,6-bis (1-methylethyl) -phenyl] ester;
Carbamic acid, (phenoxysulfonyl)-, 2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [(2,6-dimethylphenoxy) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1,1-dimethylethyl) phenoxy] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) phenyl ester,
Carbamic acid, [[2,6-bis (1,1-dimethylethyl) phenoxy] sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [(2,6-difluorophenoxy) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [(hexadecyloxy) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-dimethoxyphenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 1-methylheptyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl-, 2,6-bis (1-methylethyl) -4-nitrophenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 1,2-ethanediyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 1,2,3-propanetriyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-bromo-2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, [1,1 ': 3', 1 "-terphenyl] -2'-yl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methoxyphenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-fluoro-2,3,5,6-tetrakis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-chloro-2,6-bis- (1-methylethyl) phenyl ester;
Stigmaster-5,22-dien-3-ol, [[2,6-bis (1-methylethyl) phenoxy] -sulfonyl] -carbamate, (3α)-;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester;
Stigmastan-3-ol, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl] -carbamate, (3α)-;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-methoxy-2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,4,6-tris (1-methylethyl) phenyl ester;
Carbamic acid, [[2,4,6-tris (1-methylethyl) phenoxy] sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,4,6-tris (1-methylethyl) phenoxy] sulfonyl]-, 2,4,6-tris (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,4,6-tris (1,1, -dimethylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] dithio ] -2,6-bis (1,1-dimethylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,4-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-[(dimethylamino) methyl] -2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, tricyclo [3.3.1.1 ^3,7 ] dec-2-yl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-hydroxy-2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, cyclohexyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 3,3 ', 5,5'-tetrakis (1-methylethyl) [1,1'-biphenyl ] -4,4'-diyl ester;
Carbamic acid, [[4-hydroxy-2,6-bis (1-methylethyl) phenoxy] -sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, tricyclo [3.3.1.1 ^3,7 ] dec-1-yl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2- (1,1-dimethylethyl) -6-methylphenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl] -5-methyl-2- (1-methylethyl) cyclohexyl ester;
Carbamothioic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, S- [2,6-bis (1-methylethyl) phenyl] ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, (2,6-diethylphenyl) methyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, (2S, 6S) -2,6-bis (1-methylethyl) cyclohexyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4- (1,1-dimethylethyl) -2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-fluorophenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,4-difluorophenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, pentafluorophenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-difluorophenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, (2R, 6S) -2,6-bis (1-methylethyl) cyclohexyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,3,5,6-tetramethylphenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 3-pyridinyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-dimethylphenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-acetyl-2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-fluoro-2,6-bis (1-methylethyl) phenyl ester;
2,6-bis (1-methylethyl) phenyl [[2,6-bis (1-methylethyl) phenoxy] -sulfonyl] carbamate;
2,6-bis (1; 1-dimethylethyl) -4-methylphenyl (phenoxysulfonyl) -carbamate;
2,6-bis (1,1-dimethylethyl) -4-methylphenyl [(hexyloxy) -sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methylphenyl [(dodecyloxy) -sulfonyl] carbamate;
Dodecyl [[2,6-bis (1-methylethyl) phenoxy] -sulfonyl] carbamate;
Methyl [[2,6-bis (1-methylethyl) phenoxy] -sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [(hexyloxy) -sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl] (dodecyloxy) -sulfonyl] carbamate; And
2,6-bis (1,1-dimethylethyl) phenyl [[2,6-bis (1-methylethyl) -phenoxy] sulfonyl] carbamate or a pharmaceutically acceptable salt thereof or
The sulfonylaminocarbonyl derivative
N- [2,6-bis (1-methylethyl) phenyl] -N '-(6-ethoxy-2-benzothiazolyl) -sulfonyl] -urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-(2-octadecylsulfonyl) urea;
N- [2,4,6-trimethoxyphenyl] -N '-(2-octadecylsulfonyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-(tetradecylsulfonyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-(dodecylsulfonyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-(hexadecylsulfonyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N'-methyl-N '-(dodecylsulfonyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-(tridecylsulfonyl) urea;
N- [2,4,6-trimethoxyphenyl] -N '-(hexadecylsulfonyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-(2-methyl-2-pentadedecylsulfonyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-(1-phenyl-1-tetradecylsulfonyl) urea;
N-2,6-bis (1-methylethyl) phenyl-N '-(dodecylsulfonyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-(1-phenyl-1-nonylsulfonyl) urea; And
A composition selected from N- [2,6-bis (1-methylethyl) phenyl] -N '-(2-decylsulfonyl) urea or a pharmaceutically acceptable salt thereof.
[8" claim-type="Currently amended] Rheumatoid arthritis, osteoarthritis, autoimmune disease, psoriasis, asthma, cardiovascular disease, acute coronary syndrome, congestive heart failure, Alzheimer's disease, multiple sclerosis, cancer, including sulfonylaminocarbonyl derivatives or pharmaceutically acceptable salts thereof A composition for the treatment of a disease or disorder responsive to the inhibition of nuclear factor-κB transcription factor, type 2 diabetes mellitus, metabolic syndrome X or inflammatory bowel disease.
[9" claim-type="Currently amended] 9. The disease or disorder to be treated is selected from the group consisting of systemic lupus erythematosus, Graves' disease, myasthenia gravis, insulin resistance, autoimmune hemolytic anemia, scleroderma with anti-collagen antibodies, pernicious anemia and diabetes Phosphorus composition.
[10" claim-type="Currently amended] The method of claim 8,
The disease or disorder being treated is rheumatoid arthritis, or
The disease or disorder being treated is osteoarthritis, or
The disease or disorder being treated is insulin resistant, or
The disease or disorder being treated is asthma, or
The disease or disorder being treated is atherosclerosis, or
The disease or disorder being treated is myocardial infarction, or
The disease or disorder being treated is unstable angina, or
The disease or disorder being treated is congestive heart failure, or
The disease or disorder being treated is Alzheimer's disease, or
The disease or disorder being treated is cancer, or
The disease or disorder being treated is an inflammatory bowel disease, or
The disease or disorder being treated is multiple sclerosis, or
The disease or disorder being treated is psoriasis, or
The disease or disorder being treated is type 2 diabetes, or
The composition or disease to be treated is metabolic syndrome X.
[11" claim-type="Currently amended] A composition for inhibiting NF-κB transcription factor comprising an NF-κB inhibitory amount of sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof.
[12" claim-type="Currently amended] Of a disease or disorder responsive to the inhibition of nuclear factor κB (NF-κB) transcription factors, comprising administering a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof to a subject in need thereof (except humans) How to treat
[13" claim-type="Currently amended] The method of claim 12, wherein the sulfonylaminocarbonyl derivative is a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
<Formula 1>

Where
X and Y are oxygen, sulfur and (CR'R ") _n , where n is an integer from 1 to 4, R 'and R" are each independently hydrogen, alkyl, alkoxy, halogen, hydroxy, acyloxy, Cycloalkyl, optionally substituted phenyl, or R 'and R "together form spirocycloalkyl or carbonyl;
Provided that when at least one of X and Y is-(CR'R ") _n -and X and Y together are (CR'R") _n, then R 'and R "are hydrogen, n is 1, and R ₁ And R ₂ is aryl;
R is hydrogen, straight or branched chain alkyl of 1 to 8 carbon atoms, or benzyl;
R ₁ and R ₂ are each independently selected from the following (a) to (e):
(a) phenyl, an alkyl group having 1 to 6 carbon atoms and straight or branched chain, an alkoxy group having 1 to 6 carbon atoms and straight or branched chain, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, Trifluoromethyl, —COOH, —COOalkyl having 1 to 4 carbon atoms and straight or branched chain alkyl, and — (CH ₂ ) _p NR ₃ R ₄ where p is 0 or 1 and R ₃ And R _{4 is} each phenyl or phenoxy unsubstituted or substituted with 1 to 5 substituents selected from hydrogen or a straight or branched chain alkyl group having 1 to 4 carbon atoms;
(b) phenyl, an alkyl group having 1 to 6 carbon atoms and straight or branched chain, an alkoxy group having 1 to 6 carbon atoms and straight or branched chain, hydroxy, phenoxy, fluorine, chlorine, bromine, nitro, Trifluoromethyl, -COOH, -COOalkyl having 1 to 4 carbon atoms and straight or branched chain alkyl, and-(CH ₂ ) _p NR ₃ R ₄ , wherein p, R ₃ and R ₄ are 1- or 2-naphthyl unsubstituted or substituted with one to three substituents selected from: (as defined);
(c) arylalkyl;
(d) straight or branched chain alkyl having 1 to 20 carbon atoms and saturated or comprising 1 to 3 double bonds;
(e) an adamantyl or cycloalkyl group in which the cycloalkyl moiety has 3 to 6 carbon atoms;
only,
(i) if X is (CH ₂ ) n, Y is oxygen and R ₁ is substituted phenyl, then R ₂ is substituted phenyl,
(ii) when Y is oxygen, X is (CH ₂ ) _n and R ₂ is phenyl or naphthyl, then R ₁ is not straight or branched alkyl,
(iii) subject to the exclusion of:

Sulfamic acid [1-oxo-3- [2,4,6-tris (1-methylethyl) phenyl] propyl] -2,6-bis (1-methylethyl) phenyl ester,
Sulfamic acid [fluoro [2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester, and
Further condition is the exclusion of compounds selected from the group consisting of sulfamic acid [[2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (phenyl) phenyl ester.
[14" claim-type="Currently amended] The method of claim 13 wherein the sulfonylaminocarbonyl derivative is
(1,2,3,4-tetrahydro-naphthalene-2-carbonyl) -sulfamic acid 2,6-diisopropyl-phenyl ester;
[Bis- (4-chloro-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-phenyl ester;
(Bromo-phenyl-acetyl) -sulfamic acid 2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4-hydroxy-2,6-diisopropyl-phenyl ester;
Methyl-[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-4-nitro-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4-fluoro-2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-dimethoxy-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-amino-2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,4,6-trimethoxy-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-tert-butyl-2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-acetyl-2-isopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-4-methoxy-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-dichloro-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid dodecyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4-bromo-2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 2,6-diisopropyl-4-methyl-phenyl ester;
[1- (4-Dimethylamino-phenyl) -cyclopentanecarbonyl] -sulfamic acid 2,6-diisopropyl-phenyl ester;
[1- (4-Nitro-phenyl) -cyclopentanecarbonyl] -sulfamic acid 2,6-diisopropyl-phenyl ester;
3,5-diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -benzoic acid methyl ester;
Sulfamic acid (phenylacetyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [[2,4,6-tris (1-methylethyl) phenyl] acetyl-2,6-bis (1-methylethyl) phenyl ester,
Sulfamic acid [[2,6-bis (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [[2,4,6-tris (1-methylethyl) phenyl] acetyl-2,4,6-tris (1-methylethyl) phenyl ester;
Sulfamic acid [[2,6-bis (1-methylethyl) phenyl] acetyl] -2,4,6-tris (1-methylethyl) phenyl ester;
Sulfamic acid [adamantaneacetyl] -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [[2,6-bis (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester-sodium salt;
Sulfamic acid [[2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester-sodium salt;
Sulfamic acid (decanoyl) -2,6-bis- (1-methylethyl) phenyl ester;
Sulfamic acid (dodecanoyl) -2,6-bis- (1-methylethyl) phenyl ester;
2,6-bis (1-methylethyl) -N-[[[2,4,6-tris (1-methylethyl) phenyl] -methyl] sulfonyl] benzeneacetamide;
2,6-bis (1-methylethyl) -N-[[[2,4,6-tris (1-methylethyl) phenyl] -methyl] -sulfonyl] benzeneacetamide-sodium salt;
2,6-bis (1-methylethyl) phenyl [[[[2,4,6-tris (1-methylethyl) phenyl] -methyl] sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [[[2,4,6-tris (1-methylethyl) phenyl] -methyl] sulfonyl] carbamate-sodium salt;
Sulfamic acid (1-oxo-3,3-diphenylpropyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [2,6-dichlorophenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [2,6-dichlorophenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester sodium salt;
Sulfamic acid trans-[(2-phenylcyclopropyl) carbonyl] -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [2,5-dimethoxyphenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [2,4,6-trimethoxyphenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [2,4,6-trimethylphenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [2-thiophenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [3-thiophenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [2-methoxyphenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (oxophenylacetyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [2-trifluoromethylphenyl (acetyl)]-2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (1-oxo-2-phenylpropyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (cyclopentylphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (cyclohexylacetyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (diphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (triphenylacetyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [(1-phenylcyclopentyl) carbonyl] -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (3-methyl-1-oxo-2-phenylpentyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (1-oxo-2-phenylbutyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (cyclohexylphenyl-acetyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (1-oxo-2,2-diphenylpropyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [(9H-fluoren-9-yl) carbonyl] -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (1-oxo-3-phenylpropyl) -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [1-oxo-3- [2,4,6-tris (1-methylethyl) phenyl] -2-propenyl] -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [(acetyloxy) [2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid [hydroxy [2,4,6-tris (1-methylethyl) phenyl] acetyl] -2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid (3-methyl-1-oxo-2-phenylpentyl) -2,6-bis (1-methylethyl) phenyl ester sodium salt;
Sulfamic acid [[2,4,6-tris (1-methylethyl) phenoxy] acetyl] -2,6-bis (1-methylethyl) phenyl ester; And
A sulfamic acid [[2,6-bis (1-methylethyl) phenoxy] acetyl] -2,6-bis (1-methylethyl) phenyl ester; or a pharmaceutically acceptable salt thereof.
[15" claim-type="Currently amended] 14. The sulfonylaminocarbonyl derivative according to claim 13, wherein the sulfonylaminocarbonyl derivative is a sulfamic acid [[2,4,6-tris (1-methylethyl) phenyl] acetyl-2,6-bis (1-methylethyl) phenyl ester or its A pharmaceutically acceptable salt.
[16" claim-type="Currently amended] The method of claim 12, wherein the sulfonylaminocarbonyl derivative is a compound of Formula 2 or a pharmaceutically acceptable salt thereof.
<Formula 2>

Where
R ¹ is hydrogen, alkyl or alkoxy;
R ² to R ⁵ are alkyl, alkoxy, or unsubstituted or substituted phenyl;
R ⁶ is —CN, — (CH ₂ ) _0-1 —NR ⁷ R ⁸ , —O— (CH ₂ ) _1-10 —Z, wherein Z is —NR ⁹ R ¹⁰ , OR ¹ or CO ₂ R ¹ -OC (= O) R ¹¹ , -SR ¹¹ , -SCN, -S (CH ₂ ) _1-10 Z, -S (O) _1-2 R ¹² , wherein R ¹² is hydroxy, alkoxy , Alkyl, (CH ₂ ) _1-10 Z or NR ⁷ R ⁸ , -C (= 0) XR ¹¹ , or -CH ₂ -R ¹³ , wherein R ¹³ is (CH ₂ ) _0-5 -Y — (CH ₂ ) _0-5 Z or 1-20 carbons having 1 to 3 double bonds, wherein alkyl is selected from —CN, NO ₂ , halogen, OR ¹ , NR ⁹ R ¹⁰ and CO ₂ R ¹ Optionally substituted with one or more residues)
Wherein R ⁷ and R ⁸ are each independently hydrogen, wherein at least one of R ⁷ and R ⁸ is other than hydrogen, — (CH ₂ ) _1-10 Z {where Z is as defined above and R ⁹ and R ¹⁰ is each independently hydrogen, alkyl and unsubstituted or substituted phenyl, or R ⁹ and R ¹⁰ together with the nitrogen attached thereto

Form a ring selected from: wherein R ¹⁴ , R ¹⁵ and R ¹⁶ are each independently hydrogen, alkyl and unsubstituted or substituted phenyl; and, -C (= Q) XR ¹¹ , wherein X is a bond Or NH, Q is O or S and R ¹¹ is hydrogen, alkyl, unsubstituted or substituted phenyl,-(CH ₂ ) _0-5 -Y- (CH ₂ ) _0-5 Z, wherein Z is As defined above, Y is phenyl or a bond), -C (= 0) -CR ¹⁷ R ¹⁸ Z, -C (= 0) NHCR ¹⁷ R ¹⁸ Z, wherein R ¹⁷ and R ¹⁸ are each Independently hydrogen, alkyl, phenyl, substituted phenyl or the side chain of a naturally occurring amino acid), -S (O) _1-2 R ¹⁹ , wherein R ¹⁹ is alkyl, unsubstituted or substituted phenyl, naphthyl or heteroaromatic Ring or NR ⁹ R ¹⁰ ), or
R ⁷ and R ⁸ together with the attached nitrogen

To form a ring selected from wherein R ¹⁴ , R ¹⁵ and R ¹⁷ are as above;
Provided that [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-formyl-2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2-cyano-vinyl) -2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4- (4-methyl-piperazin-1-ylmethyl) -phenyl ester, dihydrochloride ;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [bis- (2-hydroxy-ethyl) -amino] -2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4- (3-phenyl-thioureido] -phenyl ester; and
Excludes compounds selected from [(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4-sulfamoyl-phenyl ester.
[17" claim-type="Currently amended] The method of claim 16 wherein the sulfonylaminocarbonyl derivative is
6- (3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -phenyl) -hexanoic acid ethyl ester;
3- [3- (3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -phenyl) -ureido] -propionic acid ethyl ester;
{[4- (1-hydroxy-1-methyl-ethyl) -2,6-diisopropyl-phenyl] -acetyl} -sulfonic acid 2,6-diisopropyl-phenyl ester;
[2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-((S) -2-amino-4-methyl-pentanoylamino) -2,6-diisopropyl- Phenyl esters; Compound with trifluoroacetic acid;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (3-tert-butyl-ureido) -2,6-diisopropyl-phenyl ester;
[2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (3-amino-propionylamino) -2,6-diisopropyl-phenyl ester; Compounds with trifluoro acetic acid;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2-cyano-vinyl) -2,6-diisopropyl-phenyl ester;
[2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfonic acid 4-((S) -2-amino-3-hydroxy-propionylamino) -2,6-diisopropyl -Phenyl esters; Compounds with trifluoro acetic acid;
[2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-((S) -2-amino-4-carbamoyl-butyrylamino) -2,6-diiso Propyl-phenyl esters; Compounds with trifluoro acetic acid;
[2- (2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4-((S) -2-amino-3-methyl-butyrylamino) -2,6-diisopropyl- Phenyl esters; Compounds with trifluoro acetic acid;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [3- (3,5-dichloro-phenyl) -thioureido] -2,6-diisopropyl-phenyl ester;
(S)-[5-tert-butoxycarbonylamino-5- (3,5-diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -Phenylcarbamoyl) -pentyl] -carbamic acid tert-butyl ester;
(S)-[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2,6-diamino-hexanoylamino) -2,6-diisopropyl-phenyl ester di Hydrochloride;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2-t-butoxycarbonylamino-acetylamino) -2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-amino-acetylamino) -2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-t-butoxycarbonylamino-4-methylsulfanyl-butyrylamino) -2,6-diiso Propyl-phenyl esters;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (2-amino-4-methylsulfanyl-butyrylamino) -2,6-diisopropyl-phenyl ester trifluor Low acetate;
3- [3- (3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -phenyl) -ureido] -propionic acid ethyl ester;
3- [3- (3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl) -acetyl] sulfamoyloxy} -phenyl) -ureido] -propionic acid;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [2-amino-3- (1H-indol-3-yl) -propionylamino] -2,6-diiso Propyl-phenyl esters;
[(2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (5-amino-pentanoylamino) -2,6-diisopropyl-phenyl ester trifluoroacetate (1: 1 ) (Salts);
(D)-[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2-amino-propionylamino) -2,6-diisopropyl-phenyl ester trifluoroacetate (1; 1) (salt);
(L)-[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2-amino-propionylamino) -2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2-amino-2-methyl-propionylamino) -2,6-diisopropyl-phenyl ester;
[(2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (3-dimethylamino-propoxy) -2,6-diisopropyl-phenyl ester;
[(2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (3-dimethylamino-propoxy) -2,6-diisopropyl-phenyl ester hydrochloride salt;
[(2,4,6-Triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (3-amino-propoxy) -2,6-diisopropyl-phenyl ester hydrochloride salt;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4-thiocyanato-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-cyano-2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4-[(2-amino-acetylamino) -methyl] -2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (benzylamino-methyl) -2,6-diisopropyl-phenyl ester mono hydrochloride;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfame acid 4-carbamoyl-2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-hydroxymethyl-2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4-acetylamino-2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfonic acid 4- (2-hydroxy-ethylamino) -2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- [3- (2,6-diisopropyl-phenyl) -ureido] -2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4- (3-phenyl-ureido] -phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4- (thiophene-2-sulfonylamino) -phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 4- (5-dimethylamino-naphthalene-1-sulfonylamino) -2,6-diisopropyl-phenyl ester;
[(2,4,6-triisopropyl-phenyl) -acetyl] -sulfamic acid 2,6-diisopropyl-4-methanesulfonylamino-phenyl ester;
6- (3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl-acetyl] sulfamoyloxy} -phenyl) -hexanoic acid ethyl ester; and
(6- (3,5-Diisopropyl-4-{[(2,4,6-triisopropyl-phenyl-acetyl] sulfamoyloxy} -phenyl) -hexanoic acid; or a compound thereof A pharmaceutically acceptable salt.
[18" claim-type="Currently amended] The method of claim 12, wherein the sulfonylaminocarbonyl derivative is
(9H-Xanthene-9-carbonyl) -sulfamic acid 2,6-diisopropyl-phenyl ester;
((E) -2-methyl-3-phenyl-acryloyl) -sulfamic acid 2,6-diisopropyl-phenyl ester, and
Or a pharmaceutically acceptable salt thereof, or a compound selected from (2-oxo-2H-chromen-3-carbonyl) -sulfamic acid 2,6-diisopropyl-phenyl ester, or
The sulfonylaminocarbonyl derivative
Carbamic acid, [(phenylamino) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [(phenylamino) sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-hydroxyphenyl ester;
Carbamic acid, [(phenylamino) sulfonyl]-, 2,6-bis (1,1-dimethylethyl) phenyl ester;
Carbamic acid, [(didecylamino) sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester;
Carbamic acid, [[bis (1-methylethyl) amino] sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [(dipentylamino) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[(diphenylmethyl) amino] sulfonyl] methyl-, 2,6-bis (1,1-dimethylethyl) phenyl ester;
DL-tryptophan, α-methyl-N-[[[((tricyclo [3.3.1.1 ^3,7 ] dec-2-yloxy) carbonyl] amino] sulfonyl]-, methyl ester;
Carbamic acid, sulfonylbis-, bis [2,6-bis (1-methylethyl) phenyl] ester;
Carbamic acid, [[[2- (phenylmethyl) phenyl] amino] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) phenyl ester;
Methyl [[2,6-bis (1-methylethyl) phenyl amino] sulfonyl] carbamate;
Dodecyl [[2,6-bis (1-methylethyl) phenyl] amino] sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methoxyphenyl [[(2,2-diphenylethyl) -amino] sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methoxy phenyl [[[2,6-bis (1-methylethyl) phenyl] amino] sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) phenyl-[[(diphenylmethyl) amino] -sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) phenyl [[[2,6-bis (1-methylethyl) phenyl] -amino] sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) phenyl [[(2,2-diphenylethyl) amino] -sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) phenyl [[bis (phenylmethyl) amino] -sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [(diphenyl-amino) sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [(dibutyl-amino) sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [[bis (phenyl-methyl) amino] sulfonyl] -carbamate;
2,6-bis (1-methylethyl) phenyl [(1H-benzimidazol-2-ylamino) -sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [[(2,2-diphenylethylamino] sulfonyl] -carbamate;
2,6-bis (1-methylethyl) phenyl [[[2,6-bis (1-methylethyl) phenyl] -amino] sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [[(diphenyl-methyl) amino] sulfonyl] -carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[(diphenylmethyl) -amino] sulfonyl]] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[[bis (2,6-bis (1-methylethyl) phenyl] amino] sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[(2,2-diphenylethyl) -amino] sulfonyl] -carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [(dibutylamino) -sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [(dipentylamino) -sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[bis (1-methylethyl) amino] sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [(dihexylamino) -sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [(hexylamino) -sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[methyl (2-phenylethyl) amino] sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[[bis-3- (dimethylamino) -propyl] amino] -sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [(methyl octyl amino) -sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-[[bis (tetrahydro-2-furanyl) methyl] amino] sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [(dioctylamino) -sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[[methyl 2- (2-pyridinyl) ethyl] amino] sulfonyl] carbamate, hydrochloride salt;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [[[methyl 2- (2-pyridinyl) ethyl] amino] -sulfonyl] carbamate, sodium salt;
2,6-bis (1,1-dimethylethyl) -4-methyl-phenyl [(dodecylamino) -sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [[bis (1-methylethyl) amino] sulfonyl] -carbamate;
2,6-bis (1-methylethyl) phenyl [[(1-methylethyl) phenylmethyl-amino] sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [(hexyl-amino) sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [(dioctyl-amino) sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [[cyclo-hexyl (1-methylethyl) amino] -sulfonyl] -carbamate;
2,6-bis (1-methylethyl) phenyl [(methyl-octylamino) sulfonyl] -carbamate;
2,6-bis (1-methylethyl) phenyl [(dihexyl-amino) sulfonyl] carbamate;
Dodecyl [[((2,4,6-trimethoxyphenyl) amino] -sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl ester (4-morpholinylsulfonyl) -carbamic acid;
2,6-bis (1-methylethyl) phenyl ester (1-piperidinylsulfonyl) carbamic acid;
2,6-bis (1-methylethyl) phenyl ester (1-pyrrolidinylsulfonyl) -carbamic acid;
2,6-bis (1-methylethyl) phenyl ester [(2,3-dihydro-1H-indol-1-yl) sulfonyl] carbamic acid;
2,6-bis (1-methylethyl) phenyl [(dibutylamino) sulfonyl] carbamate monosodium salt; And
2,6-bis (1,1-dimethylethyl) phenyl [[(diphenylmethyl) amino] -sulfonyl] methyl carbamate or a pharmaceutically acceptable salt thereof
The sulfonylaminocarbonyl derivative
Urea, N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dipropylamino) -sulfonyl]-;
Urea, N- (2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl) -N '-[[(tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl) Amino] sulfonyl]-, (4S-cis)-;
Urea, N- (2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl) -N '-[[(2,2-dimethyl-4-phenyl-1,3-dioxane- 5-yl) amino] sulfonyl-, stereoisomer;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[bis (1-methylethyl) amino] -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[(diphenylmethyl) amino] -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(diphenylamino) -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dibutylamino) sulfonyl] urea;
N-[[[2,6-bis (1-methylethyl) phenyl] amino] -sulfonyl] -N '-(diphenylmethyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[[2,6-bis (1-methylethyl) -phenyl] amino] sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[(2,2-diphenylethyl) -amino] sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(9H-fluorene-9-ylamino] -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[bis (phenylmethyl) amino] -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[(1-methylethyl)-(phenylmethyl) amino] sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dioctylamino) sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(4-phenyl-1-piperidinyl) -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dihexylamino) sulfonyl] -urea;
N-[[bis [3- (dimethylamino) propyl] amino] -sulfonyl] -N '-[2,6-bis (1-methylethyl) phenyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(hexylamino) sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[bis-[(tetrahydro-2-furanyl) methyl] amino] sulfonyl] -urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(diethylamino) sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(methyloctylamino) sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[cyclohexyl (1-methylethyl) amino] sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dipentylamino) sulfonyl] -urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[bis (2-methylpropyl) amino] -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[ethyl (2-propenyl) amino] -sulfonyl] urea;
N-[[bis (3-methylbutyl) amino] sulfonyl] -N '-[2,6-bis (1-methylethyl) -phenyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(didecylamino) sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(didodecylamino) -sulfamoyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(diisopropylamino) -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dicyclohexylamino) -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(methyloctadecylamino) -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(di-2-propenylamino) -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[(1,1-dimethylethyl) (1-methylethyl) amino] sulfonyl] -urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[[bis (1-methylpropyl) amino] -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(methyltetradecylamino) -sulfonyl] urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-(1-pyrrolidinylsulfonyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-(1-piperidinylsulfonyl) urea;
N '-[[[2,6-bis (1-methylethyl) phenyl] amino] sulfonyl] -N, N-bis (phenylmethyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-[(dibutylamino) sulfonyl] urea, monosodium salt; And
N '-[2,6-bis (1-methylethyl) phenyl] -N-methyl-[(dibutyl-amino) sulfonyl] urea or a pharmaceutically acceptable salt thereof; or
The sulfonylaminocarbonyl derivative
Sulfamic acid, [[[2,4,6-tris (1-methylethyl) phenyl] amino] -carbonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Sulfamic acid, [[[[1- [4- (dimethylamino) phenyl] cyclopentyl] -methyl] amino] carbonyl], 2,6-bis (1-methylethyl) phenyl ester;
(2,3-dihydro-indole-1-carbonyl) -sulfamic acid 2,6-diisopropyl phenyl ester;
Sulfamic acid, [[(triphenylmethyl) amino] carbonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Octadecyl [[[2,6-bis (1-methylethyl) phenyl] -amino] carbonyl] -sulfate;
Dodecyl-N-[[[2,6-bis (1-methylethyl) phenyl] -amino] carbonyl] -sulfate;
Decyl [[[2,6-bis (1-methylethyl) phenyl] amino] carbonyl] sulfate;
(±) 1-methylheptyl [[[2; 6-bis (1-methylethyl) phenyl] amino] -carbonyl] sulfate;
2,6-bis (1-methylethyl) phenyl [[[2; 6-bis (1-methylethyl) -phenyl] amino] carbonyl] sulfate;
(±) 1-methylundecyl [[[2; 6-bis (1-methylethyl) phenyl] amino] -carbonyl] sulfate; And
Dodecyl [[[2; 6-bis (1-methylethyl) phenyl] amino] carbonyl] -sulfate; A compound selected from sodium salt or a pharmaceutically acceptable salt thereof, or
The sulfonylaminocarbonyl derivative
Carbamic acid, [(dodecyloxy) sulfonyl]-, dodecyl ester;
Carbamic acid, [(dodecyloxy) sulfonyl]-, [1,1 ': 3', 1 "-terphenyl] -2'-yl ester;
Carbamothioic acid, [(dodecyloxy) sulfonyl]-, S- [2,6-bis (1-methylethyl) -phenyl] ester;
Carbamic acid, (phenoxysulfonyl)-, 2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [(2,6-dimethylphenoxy) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1,1-dimethylethyl) phenoxy] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) phenyl ester,
Carbamic acid, [[2,6-bis (1,1-dimethylethyl) phenoxy] sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [(2,6-difluorophenoxy) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [(hexadecyloxy) sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-dimethoxyphenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 1-methylheptyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl-, 2,6-bis (1-methylethyl) -4-nitrophenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 1,2-ethanediyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 1,2,3-propanetriyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-bromo-2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, [1,1 ': 3', 1 "-terphenyl] -2'-yl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methoxyphenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-fluoro-2,3,5,6-tetrakis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-chloro-2,6-bis- (1-methylethyl) phenyl ester;
Stigmaster-5,22-dien-3-ol, [[2,6-bis (1-methylethyl) phenoxy] -sulfonyl] -carbamate, (3α)-;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-bis (1,1-dimethylethyl) -4-methylphenyl ester;
Stigmastan-3-ol, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl] -carbamate, (3α)-;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-methoxy-2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,4,6-tris (1-methylethyl) phenyl ester;
Carbamic acid, [[2,4,6-tris (1-methylethyl) phenoxy] sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,4,6-tris (1-methylethyl) phenoxy] sulfonyl]-, 2,4,6-tris (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,4,6-tris (1,1, -dimethylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-[[3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl] dithio ] -2,6-bis (1,1-dimethylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,4-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-[(dimethylamino) methyl] -2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, tricyclo [3.3.1.1 ^3,7 ] dec-2-yl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-hydroxy-2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, cyclohexyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 3,3 ', 5,5'-tetrakis (1-methylethyl) [1,1'-biphenyl ] -4,4'-diyl ester;
Carbamic acid, [[4-hydroxy-2,6-bis (1-methylethyl) phenoxy] -sulfonyl]-, 2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, tricyclo [3.3.1.1 ^3,7 ] dec-1-yl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2- (1,1-dimethylethyl) -6-methylphenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl] -5-methyl-2- (1-methylethyl) cyclohexyl ester;
Carbamothioic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, S- [2,6-bis (1-methylethyl) phenyl] ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, (2,6-diethylphenyl) methyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, (2S, 6S) -2,6-bis (1-methylethyl) cyclohexyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4- (1,1-dimethylethyl) -2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-fluorophenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,4-difluorophenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, pentafluorophenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-difluorophenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, (2R, 6S) -2,6-bis (1-methylethyl) cyclohexyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,3,5,6-tetramethylphenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 3-pyridinyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 2,6-dimethylphenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-acetyl-2,6-bis (1-methylethyl) phenyl ester;
Carbamic acid, [[2,6-bis (1-methylethyl) phenoxy] sulfonyl]-, 4-fluoro-2,6-bis (1-methylethyl) phenyl ester;
2,6-bis (1-methylethyl) phenyl [[2,6-bis (1-methylethyl) phenoxy] -sulfonyl] carbamate;
2,6-bis (1; 1-dimethylethyl) -4-methylphenyl (phenoxysulfonyl) -carbamate;
2,6-bis (1,1-dimethylethyl) -4-methylphenyl [(hexyloxy) -sulfonyl] carbamate;
2,6-bis (1,1-dimethylethyl) -4-methylphenyl [(dodecyloxy) -sulfonyl] carbamate;
Dodecyl [[2,6-bis (1-methylethyl) phenoxy] -sulfonyl] carbamate;
Methyl [[2,6-bis (1-methylethyl) phenoxy] -sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl [(hexyloxy) -sulfonyl] carbamate;
2,6-bis (1-methylethyl) phenyl] (dodecyloxy) -sulfonyl] carbamate; And
2,6-bis (1,1-dimethylethyl) phenyl [[2,6-bis (1-methylethyl) -phenoxy] sulfonyl] carbamate or a pharmaceutically acceptable salt thereof or
The sulfonylaminocarbonyl derivative
N- [2,6-bis (1-methylethyl) phenyl] -N '-(6-ethoxy-2-benzothiazolyl) -sulfonyl] -urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-(2-octadecylsulfonyl) urea;
N- [2,4,6-trimethoxyphenyl] -N '-(2-octadecylsulfonyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-(tetradecylsulfonyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-(dodecylsulfonyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-(hexadecylsulfonyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N'-methyl-N '-(dodecylsulfonyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-(tridecylsulfonyl) urea;
N- [2,4,6-trimethoxyphenyl] -N '-(hexadecylsulfonyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-(2-methyl-2-pentadedecylsulfonyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-(1-phenyl-1-tetradecylsulfonyl) urea;
N-2,6-bis (1-methylethyl) phenyl-N '-(dodecylsulfonyl) urea;
N- [2,6-bis (1-methylethyl) phenyl] -N '-(1-phenyl-1-nonylsulfonyl) urea; And
N- [2,6-bis (1-methylethyl) phenyl] -N '-(2-decylsulfonyl) urea or a pharmaceutically acceptable salt thereof.
[19" claim-type="Currently amended] Rheumatoid arthritis comprising a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof, comprising administering a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof to a subject in need thereof (except human) Nuclear factor-κB transcription factor, osteoarthritis, autoimmune disease, psoriasis, asthma, cardiovascular disease, acute coronary syndrome, congestive heart failure, Alzheimer's disease, multiple sclerosis, cancer, type 2 diabetes, metabolic syndrome X or inflammatory bowel disease A method of treating a disease or disorder that is responsive to the inhibition of.
[20" claim-type="Currently amended] 20. The disease or disorder being treated is selected from the group consisting of systemic lupus erythematosus, Graves' disease, myasthenia gravis, insulin resistance, autoimmune hemolytic anemia, scleroderma with anti-collagen antibodies, pernicious anemia and diabetes How to be.
[21" claim-type="Currently amended] The method of claim 19,
The disease or disorder being treated is rheumatoid arthritis, or
The disease or disorder being treated is osteoarthritis, or
The disease or disorder being treated is insulin resistant, or
The disease or disorder being treated is asthma, or
The disease or disorder being treated is atherosclerosis, or
The disease or disorder being treated is myocardial infarction, or
The disease or disorder being treated is unstable angina, or
The disease or disorder being treated is congestive heart failure, or
The disease or disorder being treated is Alzheimer's disease, or
The disease or disorder being treated is cancer, or
The disease or disorder being treated is an inflammatory bowel disease, or
The disease or disorder being treated is multiple sclerosis, or
The disease or disorder being treated is psoriasis, or
The disease or disorder being treated is type 2 diabetes, or
The disease or disorder being treated is metabolic syndrome X.
[22" claim-type="Currently amended] A method of inhibiting NF-κB transcription inhibitory factor comprising administering to a mammal (excluding humans) an NF-κB inhibitory amount of a sulfonylaminocarbonyl derivative or a pharmaceutically acceptable salt thereof.

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同族专利:

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公开号 | 公开日

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IL148034D0|2002-09-12|

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ZA200201161B|2003-08-11|

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HU0200493A2|2002-10-28|

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JP2002275062A|2002-09-25|

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CA2369967A1|2002-08-12|

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US20020183384A1|2002-12-05|

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CN1370526A|2002-09-25|

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HU0200493A3|2003-04-28|

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HU0200493D0|2002-04-29|

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EP1236468A1|2002-09-04|

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AU1539402A|2002-08-15|

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NZ517021A|2003-09-26|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2001-02-12|Priority to US26820301P

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2001-02-12|Priority to US60/268,203

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2002-02-09|Application filed by 워너-램버트 캄파니

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2002-08-21|Publication of KR20020067011A

优先权:

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申请号 | 申请日 | 专利标题

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US26820301P| true| 2001-02-12|2001-02-12|

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US60/268,203|2001-02-12|