Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use

专利摘要:
The present invention relates to at least one of novel nitrified and / or nitrosylated cyclooxygenase-2 (COX-2) inhibitors and nitrosified and / or nitrosylated cyclooxygenase-2 (COX-2); And donating, transporting, releasing nitric oxide, stimulating endogenous synthesis of nitric oxide, increasing endogenous levels of endothelial-releasing factors, or substrates of nitric oxide synthesis At least one of the compounds; And / or steroids, non-steroidal anti-inflammatory compound (NSAID), 5- Lipoxygenase (5-lipoxygenase) (5- LO) inhibitors, leukotriene B 4 (leukotriene B 4; LTB 4) receptor antagonist (receptor antagonists), Leukotriene A 4 (LTA 4 ) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglucaryl coenzyme A (HMG-CoA) inhibitors, H 2 antagonists, antineoplastic agents ), Antihistamines used as antiplatelet agents, decongestants, diuretics, sedatives or anxiety agents, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors A novel composition optionally containing at least one or more therapeutic agents, including proton pump inhibitors, isoprostane inhibitors, mixtures thereof, and the like. The present invention also provides novel compositions containing at least one COX-2 inhibitor. In another aspect, the present invention is to treat inflammation (inflammation), pain (pain), fever; Gastrointestinal treatment and / or amelioration of COX-2 inhibitors; Promote healing; Treating and / or preventing kidney toxicity; And methods for treating and / or preventing other diseases resulting from high levels of cyclooxygenase-2.
公开号:KR20020067574A
申请号:KR1020027008246
申请日:2000-12-22
公开日:2002-08-22
发明作者:반다라게라미니알.；반다라게업플케이.；팡진킨；가베이데이비드；렛츠엘.고돈；쉐로우더요셉디.；탐생윌리엄
申请人:니트로메드 인코포레이티드；
IPC主号:

专利说明:

Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use
[5] Nonsteroidal anti-inflammatory compounds (NSAIDs) are widely used for analgesia, inflammation, and acute and chronic inflammatory diseases such as osteoarthritis and rheumatoid arthritis. These compounds are enzymes that convert arachidonic acid to prosteoids and inhibit the activity of cyclooxygenase (hereinafter referred to as "COX"), also known as prostaglandin G / H synthase. NSAIDs also inhibit the production of other prostaglandins, in particular prostaglandin G ₂ , prostaglandin H ₂ and prostaglandin E ₂ , thereby reducing boils associated with analgesic and inflammatory responses induced by prostaglandins. Frequent use of NSAIDs has caused side effects such as gastrointestinal ulceration and kidney toxicity. These unwanted side effects are also due to the inhibition of prostaglandins in the affected tissues.
[6] Recently, two isoforms of cyclooxygenase, encoded from two different genes (Kujubu et al., Biol. Chem ., 266 , 12866-12872 (1991)), are cyclooxygenase-1, a constituent enzyme. (Hereinafter referred to as "COX-1") and the inducible form of cyclooxygenase-2 (hereinafter referred to as "COX-2"). The anti-inflammatory effect of NSAIDs is due to the inhibitory effect of COX-2, while the side effects are known to occur due to the inhibitory action of COX-1. NSAIDs currently available on the market suppress both COX isozymes without selecting either isoenzyme or COX-1 alone. Recently, COX-2 inhibitor compounds that selectively inhibit only COX-2 have been developed and marketed. Such selective COX-2 inhibitors are required in the therapeutic aspect of anti-inflammatory drugs that have no side effects due to the inhibitory action of COX-1. However, these compounds cause dyspepsia and gastropathy (Mohammed et al., N. Engl. J. Med ., 340 (25) , 2005 (1999)).
[7] Selective COX-2 inhibitors are disclosed in the following documents: US Pat. Nos. 5,681,842, 5,750,558, 5,756,531, 5,776,984 and WO 97/41100, filed by Abbott Laboratories. WO 98/39330, WO 99/10331, WO 99/10332 and WO 00/24719; International Publication Nos. WO 98/50075, WO 00/29022 and WO 00/29023, filed by Algos Pharmaceutical Corporation; WO 99/15205, filed by Almirall Prodesfarma S.A .; US Patent No. 5,980,905, filed by AMBI Inc .; U.S. Patent Nos. 5,945,538, filed by American Cyanamid Company; U.S. Patents 5,776,967, 5,824,699, 5,830,911, and WO 98/04527 and WO 98/21195, filed by American Home Products Corporation; Angelini Richerche S.P.A. International Publication No. WO 98/22442, filed by Societa Consortile; US Patent Nos. 6,046,191 filed by Astra Pharmaceuticals Ltd. and WO 99/18960 and WO 00/00200; US Patent Nos. 5,905,089 filed by the Board of Supervisors of Louisiana State University; WO 97/13767, filed by Chemisch Pharmazeutische Forschungsgesellschaft MBH; WO 98/57924 and WO 99/61436, filed by Chugai Seiyaku Kabushiki Kaisha; WO 00/13685, filed by Cornell Research Foundation Inc .; WO 96/10021, filed by The Du Pont Merck Pharmaceutical Company; E.I. European Patent 0 087 629 filed by Du Pont de Nemours and Company; International Publication No. WO 99/13799, filed by Euro-Celtique; Fujisawa Pharmaceutical Co. United States Patent No. 5,134,142, WO 91/19708, WO 97/13755, WO 99/15505, and European Patent No. 0 418 845 and European Patent No. 0 554 829 number; G.D. Nos. 5,344,991, 5.393,790, 5,434,178, 5,466,823, 5,486,534, 5,504,215, 5,508,426, 5,510,496, 5,516,907, 5,521,207, filed by Searle & Co. 5,563,165 5,580,985, 5,596,008, 5,616,601, 5,620,999, 5,633,272, 5,643,933, 5,668,161, 5,686,470, 5,696,143, 5,700,816,5,5,719,588,753 5,756,530, 5,760,068, 5,859,257, 5,908,852, 5,935,990, 5,972,986, 5,985,902, 5,990,148, 6,025,353, 6,028,072, 6,136,839 and International WO 94/15932, WO 94/27980, WO 95/11883, WO 95/15315, WO 95/15316, WO 95/15317, WO 95/15318, WO 95/21817, WO 95/30652, WO 95/30656, WO 96/03392, WO 96/03385, WO 96/03387, WO 96/03388, WO 96 / 09293, WO 96/09304, WO 96/16934, WO 96/25405, WO 96/2458 4, WO 96/24585, WO 96/36617, WO 96/38418, WO 96/38442, WO 96/41626, WO 96/41645, WO 97/11704 WO 97/27181, WO 97/29776, WO 97/38986, WO 98/06708, WO 98/43649, WO 98/47509, WO 98/47890 WO 98/52937, WO 99/22720, WO 00/23433, WO 00/37107, WO 00/38730, WO 00/38786 and WO 00/53149; International Publication Nos. WO 96/31509, WO 99/12930, WO 00/26216 and WO 00/52008, filed by Glaxo Group Limited; EP 1 006 114 and WO 98/46594 filed by Grelan Pharmaceutical Co., Ltd .; WO 97/34882, filed by Grupo Farmaceutico Almirall; WO 97/03953, filed by Hafslund Nycomed Pharma AG; WO 98/32732 filed by Hoffmann-La Roche AG; United States Patent Nos. 5,945,539, 5,994,381, 6,002,014, WO 96/19462, WO 96/19463, and WO 0 745 596, filed by Japan Tobacco, Inc .; US Pat. Nos. 5,686,460, 5,807,873 and WO 97/37984, WO 98/05639, WO 98/11080 and WO 99/21585, filed by Laboratories USPA; Laboratores Del Dr. WO 99/62884, filed by Esteve, S.A .; WO 00/08024, filed by Laboratories S.A.L.V.A.T., S.A .; Merck & Co. Nos. 5,585,504, 5,840,924, 5,883,267, 5,925,631, 6,001,843, 6,080,876, and WO 97/44027, WO 97/44028, WO, filed by Inc. 97/45420, WO 98/00416, WO 98/47871, WO 99/15503, WO 99/15513, WO 99/20110, WO 99/45913, WO 99 / 55830, WO 00/25779, WO 00/27382; United States Patent Nos. 5,409,944, 5,436,265, 5,474,995, 5,536,752, 5,550,142, 5,510,638, 5,521,213, 5,552,422, 5,604,253, 5,604,260, and 5,604,260, filed by Merck Frosst Canada & Co. 5,639,780, 5,677,318, 5,691,374, 5,698,584, 5,710,140, 5,733,909, 5,789,413, 5,817,700, 5,840,746, 5,849,943, 5,861,419,598,598,5 5,994,379, 6,020,343, 6,071,936, 6,071,954 and European Patent 0 788 476, European Patent 0 863 134, European Patent 0 882 016 and WO 94/20480, WO 94/20480. WO 94/13635, WO 94/26731, WO 95/00501, WO 95/18799, WO 96/06840, WO 96/13483, WO 96/19469, WO 96/21667, WO 96/23786, WO 96/36623, WO 96/37467, WO 96/37468, WO 96/37469, WO 97/14691, WO 97 / 16435, WO 97/28120, WO 97/28121, WO 97/36863, WO 98/03484, WO 98/41511, WO 98/41516, WO 98/43966, WO 99/14194, WO 99/14195, WO 99/23087, WO 99/41224 and WO 00/68215; WO 99/59635, filed by Merck Sharp & Dohme Limited; 5,380,738, filed by Monsanto Company; International Publication No. WO 00/01380 filed by A. Nattermann & Co .; Nippon Shinyaku Co. International Publication No. WO 99/61016, filed by Ltd .; WO 99/33796, filed by Nissin Food Products Co., Ltd .; WO 99/11605, filed by Novartis AG; WO 98/33769, filed by Nycomed Austria GMBH; US Patent Nos. 6,077,869 and 6,083,969 and WO 00/51685, filed by Ortho-McNeil Pharmaceutical, Inc .; US Patent No. 5,783,597 filed by Ortho Pharmaceutical Corporation; WO 98/07714, filed by Oxis International Inc .; International Publication No. WO 00/10993 filed by Pacific Corporation; EP 0 937 722 and WO 98/50033, WO 99/05104, WO 99/35130 and WO 99/64415, filed by Pfizer Inc .; WO 00/48583, filed by Pozen Inc .; US Patent No. 5,908,858 to Sankyo Company Limited; WO 97/25045, filed by SmithKline Beecham Corporation; US Patent Nos. 5,399, 357, filed by Takeda Chemical Industries, Ltd .; WO 99/20589, filed by The University of Sydney; US Patent No. 5,475,021 and WO 00/40087, filed by Vanderbilt University; And WO 99/59634 filed by Wakamoto Pharmaceutical Co., Ltd. All of these documents are incorporated herein by reference.
[8] There is currently a need in the art for gastric defense mechanisms, promoting trauma therapy, reducing kidney toxicity and dyspepsia, and COX-2 inhibitor compounds that can be used at lower dosages. The present invention, like other documents, is directly linked to the effort to achieve the above object.
[9] The present invention relates to novel nitrosated and / or nitrosylated COX-2 inhibitors, wherein the COX-2 inhibitors bind at least one or more nitrogen monoxide groups (NO) and / or at least one or more nitrogen dioxide groups (NO ₂ ). (Ie nitrosylated and / or nitrosified groups, respectively). The resulting compounds have the efficacy of analgesics, are anti-inflammatory, and have the unexpected potential to promote healing of wounds. The novel compounds also have unexpected properties for treating and / or preventing kidney toxicity. COX-2 inhibitors may be nitrosated and / or nitrosylated at one or more sites, such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation) and / or nitrogen. COX-2 inhibitors include 1,5-diaryl such as CELEBREX (4- (5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl) benzenesulfonamide) And sulfonamides containing pyrazole (1,5-diarylpyrazole) derivatives. Further COX-2 also includes methylsulfonylphenyl-furanone derivatives such as Rofecoxib (VIOXX , 4- (4'-methylsulfonylphenyl) -3-phenyl-2- (5H) -furanone). The present invention also provides a composition that constitutes a compound to be a pharmaceutically acceptable carrier.
[10] The invention is also based on administering at least one nitric oxide donor that reduces gastrointestinal pain by nitrosation and / or at least one nitrosylated COX-2 inhibitor and COX-2 inhibitor. Nitric oxide donors contain a portion of nitric oxide and are compounds that release or chemically convert nitric oxide into other molecules. Nitric oxide donors include various isoenzymes of S-nitrosothiols, nitrites, nitrates, N-oxo-N-nitrosamines and nitric oxide synthase. And substrates. It is therefore an object of the present invention to provide at least one NO and / or NO ₂ group (nitrosominated and / or nitrosylated) and charged species, such as nitrosonium (NO ⁺ ) or nitro (NO ⁻ ), promotes, converts or releases nitrogen oxides and / or promotes endogenous supply of nitric oxide or EDRF in vivo, and / or nitric oxide synthase to charged species or neutral species such as nitric oxide (NO.) It is to provide a composition consisting of at least one COX-2 inhibitor substituted with at least one or more of the compounds to be a substrate for.
[11] Furthermore, it is an object of the present invention to provide at least one COX-2 inhibitor and at least one COX-2 inhibitor substituted with at least one NO and / or NO ₂ group (nitrosolation and / or nitrosylation) or nitrosonium (NO ⁺ ) or nitrooxy (NO). ^-) band charges, such as the species (charged species) or nitric oxide (NO ·) neutral group (neutral species), the increase of nitric oxide, transition or discharge, and / or nitric oxide or EDRF endogenously supplied in a living body, such as Optionally at least one of the compounds serving as a substrate for nitric oxide synthase, and / or not particularly limited to steroids, nonsteroidal anti-inflammatory compounds (NSAIDs), 5-lipoxygenase (5-lipoxygenase) ( 5-LO) inhibitors, leukotriene _{B 4 (leukotriene B 4; LTB} 4) receptor antagonist (receptor antagonists), leukotriene A ₄ (LTA ₄₎ hydrolase inhibitors, 5-HT agonists (agonists), 3- hydroxy-3 Methylglucaryl Coenzyme A (HMG-CoA) Inhibition Antihistamines, inducible nitric oxide synthase inhibitors, used as H ₂ antagonists, antineoplastic agents, antiplatelet agents, decongestants, diuretics, sedatives or anxiety agents, To provide a composition optionally containing at least one of therapeutic agents such as opioids, analgesics, Helicobacter pylori inhibitors, proton pump inhibitors, isoprostane inhibitors.
[12] In another aspect, the present invention at least one original (parent) COX-2 inhibitors and nitro sonyum (nitrosonium) (NO ⁺⁾ or knitted hydroxy (NO ^-) is a strip of charge, such as species (charged species) or nitric oxide (NO ·) Optionally at least one of compounds that promote, convert or release nitric oxide into neutral species such as and / or promote endogenous supply of nitric oxide or EDRF in vivo and / or are substrates for nitric oxide synthase , and in particular, but are not limited to steroids, non-steroidal anti-inflammatory compound (NSAID), 5- lipoxygenase (5-lipoxygenase) (5- LO) inhibitors, leukotriene _{B 4 (leukotriene B 4; LTB} 4) receptor antagonist, ( receptor antagonists), leukotriene A ₄ (LTA ₄ ) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglucaryl coenzyme A (HMG-CoA) inhibitors, H ₂ antagonists, antineoplastic Antineoplastic agents, antiplatelet agents, Blood emollient (decongestants), diuretics (diuretics), sedatives or antihistamines used anxiety agent, inducible nitric oxide synthase inhibitors, opioids (opioids), pain killers (analgesics), Helicobacter pylori inhibitors, proton pumps (proton pump) inhibitor, iso To provide a composition optionally containing at least one of therapeutic agents, such as isoprostane inhibitor.
[13] Furthermore, it is an object of the present invention to provide compounds and nitrosonium substituted with at least one or more nitrosified and nitrosylated COX-2 inhibitors and at least one NO and / or NO ₂ group (nitrosified and / or nitrosylated) ( NO ⁺⁾ or knitted hydroxy (NO ^-) band charges, such as the species (charged species) or nitric oxide (NO ·) a neutral group such as a (neutral species) by promoting nitric oxide, transition or discharge, and / or NO Or optionally at least one of the compounds that promote endogenous supply of EDRF in vivo, and / or which is a substrate for nitric oxide synthase (NO donors), and not particularly limited to steroids, nonsteroidal anti-inflammatory compounds (NSAIDs), 5-lipoxygenase (5-lipoxygenase) (5- LO) inhibitors, leukotriene _{B 4 (leukotriene B 4; LTB} 4) receptor antagonist (receptor antagonists), leukotriene A ₄ (LTA ₄₎ hydrolase inhibitors, 5-HT Agonists, 3-hydr -3-methylglucamine Khalil coenzyme A (HMG-CoA) inhibitors, H ₂ antagonists, anti-neoplastic agents (antineoplastic agents), antiplatelet agents (antiplatelet agents), decongestants (decongestants), diuretics (diuretics), sedative or Among therapeutic agents such as antihistamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, proton pump inhibitors, isoprostane inhibitors and mixtures thereof used as anxiety agents Administering a therapeutically effective amount of a composition optionally containing at least one to a patient to treat and / or prevent inflammation, analgesia, high fever; Treating and / or ameliorating gastrointestinal insufficiency of COX-2 inhibitors; Promote wound healing; Treating and / or preventing kidney toxicity; And a method for treating and / or preventing a disease associated with COX-2 (a disease due to high levels of COX-2). In the present invention, administration of nitrosified and / or nitrosylated COX-2 inhibitors, administration of nitrosified and / or nitrosylated COX-2 inhibitors and NO donors, administration of nitrosified and / or nitrosylated COX-2 inhibitors and therapeutic agents, Or to nitrosated and / or nitrosylated COX-2 inhibitors, NO donors and therapeutic agents. The nitrified and / or nitrosylated COX-2 inhibitors, nitric oxide donors, and / or therapeutic agents may be administered individually or as components of the same composition in one or more pharmaceutically acceptable carriers.
[14] The present invention relates to the treatment of inflammation, analgesia and high fever through the administration of at least one or more native COX-2 inhibitors and at least one nitric oxide donor and optionally at least one therapeutic agent; Treating and / or ameliorating gastrointestinal tract of COX-2 inhibitors; Promote wound healing; Treating and / or preventing kidney toxicity; And methods for preventing other diseases associated with COX-2.
[15] In another aspect, the present invention at least one COX-2 inhibitor and a nitro sonyum (nitrosonium) (NO ⁺⁾ or knitted ^{hydroxy-neutral} group, such as a charge strip, such as species (charged species) or nitric oxide (NO ·) (NO) (neutral species) promotes, converts or releases nitric oxide, and / or promotes endogenous supply of nitric oxide or EDRF in vivo, and / or optionally selects at least one of the compounds serving as substrates for nitric oxide synthase Relates to supply kits. The kit may further comprise at least one therapeutic agent. The nitrosized and / or nitrosylated COX-2 inhibitors, nitric oxide donors and / or therapeutic agents may be individually constituents of the kit, or may be used in the form of a composition in one or more pharmaceutically acceptable carriers. have.
[16] The invention is at least one original COX-2 inhibitor and a nitro sonyum (nitrosonium) (NO ⁺⁾ or knitted ^{hydroxy-neutral} such as a strip of charge, such as the species (charged species) or nitric oxide (NO ·) (NO) Promoting, converting or releasing nitric oxide as a neutral species and / or promoting endogenous supply of nitric oxide or EDRF in vivo, and / or optionally selecting at least one of the compounds serving as substrates for nitric oxide synthase It relates to supply kits (provide kits) comprising. The kit may further comprise at least one therapeutic agent. The nitrosized and / or nitrosylated COX-2 inhibitors, nitric oxide donors and / or therapeutic agents may be individually constituents of the kit, or may be used in the form of a composition in one or more pharmaceutically acceptable carriers. have.
[17] Hereinafter, the present invention will be described in more detail.
[1] Cross Reference to Related Applications
[2] This application claims the priority effect of US Provisional Application No. 60 / 171,623, filed December 23, 1999 and US Provisional Application No. 60 / 226,085, filed August 18, 2000.
[3] FIELD OF THE INVENTION
[4] The present invention provides novel nitrosated and / or nitrosylated cyclooxygenase-2 (COX-2) inhibitors; And at least one nitrosated and / or nitrosylated cyclooxygenase-2 (COX-2) inhibitor; And donating, transporting, releasing nitric oxide, stimulating endogenous synthesis of nitric oxide, increasing endogenous levels of endothelial-relaxing factors, or substrates of nitric oxide synthesis At least one compound being; And / or novel compositions optionally containing at least one or more therapeutic agents. The present invention also provides novel compositions containing at least one COX-2 inhibitor. In another aspect, the present invention is to treat inflammation (inflammation), pain (pain), high fever; Treating and / or ameliorating gastrointestinal tract of COX-2 inhibitors; Promote healing; Treating and / or preventing kidney toxicity; And methods for treating and / or preventing other diseases resulting from high levels of cyclooxygenase-2.
[1875] 1 shows: (a) isosorbide dinitrate (ISDN, unlocked triangle); (b) Example 1a (binitrosated compound, unlocked circle); And (c) relaxation of the aortic smooth muscle ring of the rat of Example 1b (nitrosulfated compound, unlocked square). The nonnitrosated compound of Example 1a did not relax the tissue. Relaxation of the nitrosized compound of Example 1b at high concentrations was similar to that seen in ISDN. The total number of samples varied from a minimum of five to a maximum of twelve. On the x-axis, logM corresponds to a 10-fold increase in test compounds from 100 nM (10 ^-7 ) to 100 μM (10 ^-4 ). The product is expressed as expected ± standard error of the expected value of the percent of total relaxation by 10 μM phenylephrine.
[1876] In Figure 2 (a) isosorbide dinitrate (ISDN, unlocked triangle); (b) Example 2a (binitrosated compound, unlocked square); And (c) relaxation of the aortic smooth muscle ring of the rat of Example 2b (nitrosated compound, unlocked circle). The nonnitrosated compound of Example 2a did not relax the tissue. At high concentrations, the relaxation of the nitrated compounds of Example 2b was similar to that seen in ISDN. The total number of samples varied from a minimum of six to a maximum of twelve. On the x-axis, logM corresponds to a 10-fold increase in test compounds from 100 nM (10 ^-7 ) to 100 μM (10 ^-4 ). The product is expressed as expected ± standard error of the expected value of the percent of total relaxation by 10 μM phenylephrine.
[1877] In Figure 3 (a) S-nitrosoglutathione (GSNO, unlocked triangle); (b) Example 3e (vinitrosylated compound, unlocked square); And (c) relaxation of the aortic smooth muscle ring of the rat of Example 3g (nitrosylated compound, unlocked circle). The nonnitrosylated compound of Example 3e did not relax the tissue. Relaxation of the nitrosized compound of Example 3g at high concentrations was similar to that seen in GSNO. The total number of samples varied from a minimum of four to a maximum of twelve. On the x-axis, logM corresponds to a 10-fold increase in test compounds from 100 nM (10 ^-7 ) to 100 μM (10 ^-4 ). The product is expressed as expected ± standard error of the expected value of the percent of total relaxation by 10 μM phenylephrine.
[1878] In Figure 4 (a) isosorbide dinitrate (ISDN, unlocked triangle); (b) Example 20c (binitrosated compound, unlocked circle); And (c) relaxation of the aortic smooth muscle ring of the rat of Example 20d (nitrosated compound, unlocked square). The nonnitrosated compound of Example 20c did not relax the tissue. Relaxation of the nitrosized compound of Example 20d at high concentrations was similar to that seen in ISDN. The total number of samples varied from a minimum of four to a maximum of sixteen. On the x-axis, logM corresponds to a 10-fold increase in test compounds from 100 nM (10 ^-7 ) to 100 μM (10 ^-4 ). The product is expressed as expected ± standard error of the expected value of the percent of total relaxation by 10 μM phenylephrine.
[1879] FIG. 5 shows: (a) Celecoxib (unblocked bar) using a carrageenan-induced paw edema test; (b) Example 2a (vinitrosated compound, horizontal bar); And (c) the anti-inflammatory effect of Example 2b (nitrosated compound, hatched rod). All samples had 5 concentrations of each of the test compounds. The x-axis represents the amount of test compound (μmol / kg) relative to the weight of the rat. The y-axis represents the increase in foot volume (ml). The product was expressed as expected ± standard error of foot volume change. The data were analyzed by AVONA analysis followed by Student Newmann-Keuls post-hoc test.
[18] All terms described in this specification are to be interpreted as meanings defined below unless otherwise specified.
[19] "NSAID" is considered a nonsteroidal anti-inflammatory compound or a nonsteroidal anti-inflammatory drug. NSAIDs are inhibitors that inhibit both cyclooxygenase and lipoxygenase and are a combination of prostaglandins and various isoenzymes of defined biosynthetic and cyclooxygenase (but not limited to cyclooxygenase-1 and -2). Inhibits cyclooxygenase, an enzyme responsible for the biosynthesis of certain autocoid inhibitors, including inhibitors.
[20] A "cyclooxygenase-2 inhibitor" is a compound that selectively inhibits a cyclooxygenase-2 enzyme in the presence of a cyclooxygenase-1 enzyme. Preferably the compound is cyclooxygenase-2 with an IC ₅₀ = 0.5 μM or more, furthermore, the selective inhibition of cyclooxygenase-2 in the presence of cyclooxygenase-1 is at least 50, more preferably Is preferably at least 100. Even more preferably, the compound is cyclooxygenase-2 having an IC ₅₀ = 1 μM or more, and even more preferably 20 μM or more. The compounds may also inhibit enzymes such as lipoxynases and / or phosphodiestases. Appropriate selectivity in common exhibits a function of reducing the incidence of side effects caused by NSAIDs.
[21] "Parent COX-2 inhibitors" are non-nitrosified and / or non-nitrosylated COX-2 inhibitors, as well as the novel compounds described herein, as well as those described in the patents and publications cited herein. It includes those already known in the prior art. "Original COX-2 inhibitors" include compounds of the general formulas (I) to (XVI) which are compounds prior to nitrosation and / or nitrosylation by the process according to the invention.
[22] "Therapeutic agent" includes any therapeutic agent that can be used to treat or prevent the diseases described herein. "Cure" roneun-based anti-inflammatory compounds, steroids, non-steroidal (NSAID), 5- Lipoxygenase (5-lipoxygenase) (5- LO) inhibitors, leukotriene _{B 4 (leukotriene B 4; LTB} 4) receptor antagonist (receptor antagonists) , Leukotriene A ₄ (LTA ₄ ) hydrolase inhibitor, 5-HT agonists, 3-hydroxy-3-methylglucaryl coenzyme A (HMG-CoA) inhibitor, H ₂ antagonist, antineoplastic antihistamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori used as agents, antiplatelet agents, decongestants, diuretics, sedatives or anxiety agents Inhibitors, proton pump inhibitors, isoprostane inhibitors and the like. Although the NO donor has therapeutic activity, the present invention is separately defined as a NO donor without including the NO donor in the term "therapeutic agent".
[23] "Patient" is an animal, preferably a mammal, most preferably a human, where man includes both sexes.
[24] "Therapeutically effective amount" refers to the amount of a compound and / or composition that has an effect that achieves the desired outcome.
[25] "Transdermal" refers to the transport of a compound through the skin into the bloodstream.
[26] "Transmucosal" refers to the transport of a compound through mucosal tissue into the bloodstream.
[27] "Penetration enhancement" or "permeation enhancement" refers to the increase in permeability of skin or mucosal tissue by pharmacologically selecting the active compound, such as the rate at which the penetration of the compound through skin or mucosal tissue is increased. Say that.
[28] "Carriers" or "vehicles" refer to suitable carriers for the administration of a compound, which are liquids, gels, solvents, diluents, solubilizers or non-toxic and And materials known in the art, such as those which do not adversely interact with any component.
[29] "The addition of nitric oxide product (adduct)" or "NO adduct" are three kinds of the oxidized form of nitrogen monoxide which acts at a site designated the biological activity of the nitrogen monoxide species in physiological conditions ^{(NO +, NO -, NO} ·) Refers to compounds and functional groups that can be converted, released, or donated directly or indirectly.
[30] "Nitrogen oxide emissions (Nitric oxide releasing)" or "nitric oxide donation (nitric oxide donating)" are three kinds of redox forms of nitrogen oxide ^{(NO +, NO -, NO} ·) nitrogen monoxide which is expressed in regions that the activity intended It refers to a method of delivering, releasing, direct or indirectly transporting a species' biological activity.
[31] "Alkyl" is a lower alkyl group, haloalkyl group, hydroxyalkyl group, alkenyl group, alkynyl group, bridged cycloalkyl group, cycloalkyl group or It is defined as a heterocyclic ring. Alkyl groups also consist of one or more radical species, such as cycloalkylalkyl groups or heterocyclicalkyl groups.
[32] "Lower alkyl" is an acyl alkyl group having a branched or straight chain composed of 1 to 10 carbon atoms (preferably composed of 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms) Say The lower alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neoopentyl, iso-amyl, hexyl ( hexyl), octyl, and the like.
[33] "Substituted lower alkyl" refers to a lower alkyl group in which one or more hydrogen atoms have been replaced by one or more R ¹⁰⁰ groups. R ¹⁰⁰ here independently means a hydroxy, oxo, carboxyl, carboxamido, halo, cyano or amino group as defined herein.
[34] "Haloakyl" refers to the addition of one or more halogens as defined in the present invention to a lower alkyl group, alkenyl group, alkynyl group, bridged cycloalkyl group, cycloalkyl group or heterocyclic ring as defined herein. Say what you did.
[35] "Alkenyl" refers to branched or straight chain C ₂ -C ₁₀ hydrocarbons (preferably C ₂ -C ₈ hydrocarbons, more preferably C ₂ -C ₆ hydrocarbons) having one or more inter-carbon double bonds; Say. Alkenyl groups include propylenyl, buten-1-yl, isobutenyl, penten-1-yl, 2,2-methylbuten-1-yl, 3-methylbuten-1-yl, hexane-1-yl, heptene -1-yl, octen-1-yl, and the like.
[36] "Low cost alkenyl" refers to a branched or straight chain C ₂ -C ₄ hydrocarbon having one or more intercarbon double bonds.
[37] "Substituted alkenyl" has one or more hydrogen atoms are replaced by one or more R ¹⁰⁰ groups one or more carbon-to-side chain having a double bond or straight-chain C ₂ -C ₁₀ hydrocarbon (preferably a C ₂ -C ₈ hydrocarbons, more preferably C ₂ -C ₆ hydrocarbons). R ¹⁰⁰ here independently means a hydroxy, oxo, carboxyl, carboxamido, halo, cyano or amino group as defined herein.
[38] "Alkynyl" is an unsaturated ancyclic C ₂ -C ₁₀ hydrocarbon (preferably C ₂ -C ₈ hydrocarbon, more preferably C ₂ -C ₆ ) having one or more triple carbon-to-carbon triple bonds. Hydrocarbons). Alkynyl groups include ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyl-1-yl, pentyl-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, Hexyl-2-yl, hexyl-3-yl, 3,3-dimethyl-butyn-1-yl and the like.
[39] "Bridged cycloalkyl" refers to a bond due to fusion between two or more cycloalkyl groups, heterocyclic groups, or adjacent or non-adjacent atoms. Crosslinked cycloalkyl groups include alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alkylcarboxylic ester, carboxamido, Alkylcarboxamidos include those substituted or unsubstituted with one, two or three substituents independently selected from oxo and nitro.
[40] "Cycloalkyl" refers to a hydrocarbon ring that is substituted or unsubstituted with 3 to 10 carbon atoms. Cycloalkyl groups include alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alkylcarboxylic ester, carboxamido, alkylcar And those substituted or unsubstituted with one, two or three substituents independently selected from voxamido, oxo and nitro. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohepta, 1,3-dienyl, and the like.
[41] A "heterocyclic ring or group" has 2 to 10 carbon atoms (preferably 4 to 6 carbon atoms), with 1 to 4 carbon atoms replaced by one or more nitrogen, oxygen and / or sulfur atoms And substituted or unsubstituted hydrocarbon ring group. Sulfur is in the form of oxidized to thio, sulfinyl or sulfonyl. Heterocyclic groups include alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, carboxyl, alkylcarboxylic acid, aryl, amidyl, esters, alkylcarboxylic esters, carboxamido, alkylcar The voxamido may or may not be substituted with one, two or three substituents independently selected from oxo and nitro. Heterocyclic groups include pyrrolyl, 3-pyrrolinyl, 4,5,6-trihydro-2H-pyranyl, pyridinyl, 1,4-dihydropyridinyl, pyrazolyl ( pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, pyridazinyl, oxazolyl, thiazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl (thiophenyl), furanyl, tetrahydrofuranyl, tetrazolyl, tetrazolyl, pyrrolinyl, pyrazolinyl, oxazolindinyl 1,3-dioxoanyl (dioxolanyl), imidazolinyl, imidazolindinyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1, 2,3-oxadiazolyl (1,2,3-oxadiazolyl), 1,2,3-triazolyl (1,2,3-triazolyl), 1,3,4-thiadiazolyl (1,3,4 -thiadiazolyl), 2H-pyranyl, 4H-pyranyl (4H -pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholi Thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-tritianyl (1,3, 5-trithianyl), benzo (b) thiophenyl, benzimidazolyl, benzothiazolinyl, quinolinyl, and the like.
[42] "Heterocyclic compound" refers to a monocyclic or heterocyclic compound containing at least one or more aryl or heterocyclic rings.
[43] "Aryl" refers to a monocyclic, bicyclic, carbocyclic or heterocyclic ring system comprising one or two aromatic rings. Aryl groups include phenyl, pyridyl, naphthyl, quinoyl, tetrahydronaphthyl, furanyl, indanyl, indanyl, indenyl and indoyl. Can be mentioned. Aryl groups (bicyclic aryl groups) are alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, carboxyl, alkylcarboxylic acids, aryl, amidyl, esters, alkylcarboxylic esters, carboxamido And alkylcarboxamido may be substituted or unsubstituted with one, two or three substituents independently selected from oxo and nitro. Substituted aryl groups include tetrafluorophenyl, pentafluorophenyl, sulfonamide, alkylsulfonyl, arylsulfonyl, and the like.
[44] "Cycloalkenyl" is a saturated cyclic C ₂ -C ₁₀ hydrocarbon (preferably a C ₂ -C ₈ hydrocarbon, more preferably a C ₂ -C ₆ hydrocarbon) containing one or more triple carbon-to-carbon triple bonds. Say).
[45] "Arylalkyl" refers to an aryl radical defined in the present invention to which an alkyl radical as defined in the present invention is attached. Examples of the arylalkyl group include benzyl, phenylethyl, 4-hydroxybenzyl, 3-fluorobenzyl and 2-fluorophenylethyl.
[46] "Arylalkenyl" refers to an aryl radical defined in the present invention to which an alkenyl radical as defined in the present invention is attached. Examples of the arylalkenyl group include styryl and propenylphenyl.
[47] "Cycloalkylalkyl refers to an alkyl radical defined in the present invention attached to a cycloalkyl radical defined in the present invention.
[48] "Cycloalkylalkoxy" refers to an alkoxy radical as defined herein attached to a cycloalkyl as defined herein.
[49] "Cycloalkylalkylthio" refers to an alkylthio radical as defined herein attached to a cycloalkyl radical as defined herein.
[50] "Heterocyclicalkyl" refers to an alkyl radical as defined herein attached to a heterocyclic ring as defined herein.
[51] "Arylheterocylic ring" refers to a bicyclic or tricyclic ring comprising an aryl ring as defined herein, added between two adjacent carbons of the aryl ring in the heterocyclic ring as defined herein. Aryl heterocyclic rings include dihydroindole, 1,2,3,4-tetra-hydroquinoline.
[52] "Alkoxy" refers to R ₅₀ O-, wherein R ₅₀ is an alkyl group as defined herein (preferably a lower alkyl group or haloalkyl group as defined herein). Examples of the alkoxy group include methoxy, ethoxy, t-butoxy, cyclopentyloxy, trifluoromethoxy, and the like.
[53] "Aryloxy" refers to R ₅₅ O-, wherein R ₅₅ is an aryl group as defined herein. Examples of the aryloxy group include napthyloxy, quinolyloxy, isoquinolizinyloxy, and the like.
[54] "Alkylthio" refers to R ₅₀ S-, wherein R ₅₀ is an alkyl group as defined herein.
[55] "Arylalkoxy or alkoxyaryl" is the addition of the aryl group defined in the present invention to the alkoxy group defined in the present invention. Examples of the arylalkoxy group include benzyloxy, phenylethoxy, chlorophenylethoxy and the like.
[56] "Alkoxyalkyl" is the addition of the alkyl group defined in the present invention to the alkoxy group defined in the present invention. Examples of the alkoxyaryl group include methoxymethyl, methoxyethyl, isopropoxymethyl and the like.
[57] "Alkoxyhaloalkyl" is the addition of the haloalkyl group defined in the present invention to the alkoxy group defined in the present invention. 4-methoxy-2-chlorobutyl is mentioned as an alkoxy haloalkyl group.
[58] "Cycloalkoxy" refers to R ₅₄ O-, wherein R ₅₄ is a bridged cycloalkyl group as defined herein. Cycloalkoxy groups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
[59] "Cycloalkylthio" refers to R ₅₄ S-, wherein R ₅₄ is a bridged cycloalkyl group as defined herein. Cycloalkylthio is cyclopropylthio, cyclopentylthio, cyclohexylthiio, etc. are mentioned.
[60] "Haloalkoxy" refers to an alkoxy group wherein one or more hydrogen atoms in the alkoxy group as defined herein are substituted with a halogen as defined herein. Examples of haloalkoxy groups include 1,1,1-trichloroethoxy and 2-bromobutoxy.
[61] "Hydroxy refers to -OH.
[62] "Oxo" refers to = O.
[63] "Oxy" refers to -O ^- R ₇₇ ⁺ , wherein R ₇₇ is an organic or inorganic cation.
[64] "Organic cation" refers to positively charged organic ions. Examples of the organic cation include an ammonium cation substituted with alkyl.
[65] "Inorganic cation" refers to a positively charged metal ion. Examples of the inorganic cations include group I metal cations such as sodium and potassium.
[66] "Hydroxyalkyl" is the addition of the alkyl group defined in the present invention to the hydroxy group defined in the present invention.
[67] "Nitrate" is -O-NO ₂ .
[68] "Nitrite" is -O-NO.
[69] "Thionitrate" is -S-NO ₂ .
[70] "Thionitrite" and "nitrosothiol" are -S-NO.
[71] "Nitro" refers to a -O-NO ₂ group and "nitrosated" refers to a compound substituted with a nitro group.
[72] "Nitroso" is an -O-NO group and "nitrosylated" refers to a compound substituted with nitroso.
[73] "Nitrile" and "cyano" are -CN.
[74] "Halogen" or "halo" refers to iodine (I), bromine (Br), chlorine (Cl) and / or fluorine (F).
[75] "Amino" includes -NH ₂ , alkylamino group, dialkylamino group, arylamino group, diarylamino group, alkylarylamino group or heterocyclic ring as defined in the present invention.
[76] "Alkylamino" refers to R ₅₀ NH-, wherein R ₅₀ is an alkyl group as defined herein. Examples of alkylamino include methylamino, ethylamino, butylamino, cyclohexylamino and the like.
[77] "Arylamino" refers to R ₅₅ NH-, wherein R ₅₅ is an aryl group as defined herein.
[78] "Dialkylamino" refers to R ₅₂ R ₅₃ N-, wherein R ₅₂ and R ₅₃ are each independently an alkyl group as defined herein. Dialkylamino groups include dimethylamino, diethylamino, methyl propargylamino and the like.
[79] "Diarylamino" refers to R ₅₅ R ₆₀ N-, wherein R ₅₅ and R ₆₀ are each independently an aryl group as defined herein.
[80] "Alkylarylamino or arylalkylamino" refers to R ₅₂ R ₅₅ N-, wherein R ₅₅ is an alkyl group as defined herein and R ₆₀ is an aryl group as defined herein.
[81] "Alkylarylalkylamino" refers to R ₅₂ R ₇₉ N-, wherein R ₅₂ is an alkyl group as defined herein and R ₇₉ is an arylalkyl group as defined herein.
[82] "Alkylcycloalkylamino" refers to R ₅₂ R ₈₀ N-, wherein R ₅₂ is an alkyl group as defined herein and R ₈₀ is a cycloalkyl group as defined herein.
[83] "Aminoalkyl" refers to an alkyl group as defined herein in the amino group, alkylamino group, dialkylamino group, arylamino group, diarylamino group, alkylarylamino group or heterocyclic ring as defined herein. It is added. Examples of aminoalkyl groups include dimethylaminopropyl, diphenylaminocyclopentyl, methylaminomethyl, and the like.
[84] "Aminoaryl" refers to an aryl group to which an alkylamino group, an arylamino group or an arylalkylamino group is added. Examples of the aminoaryl groups include anilino, N-methylanilino, and N-benzylanilino.
[85] "Thio is -S-.
[86] "Sulfinyl" is -S (O)-.
[87] "Methanthial" is -C (S)-.
[88] "Thial" is = S.
[89] "Sulfonyl" is -S (O ₂ ).
[90] "Sulfonic acid" refers to -S (O ₂ ) OR ₇₆ , wherein R ₇₆ is hydrogen, organic cation or inorganic cation as defined herein.
[91] "Akylsulfonic acid" is the addition of the alkyl group defined in the present invention to the sulfonic acid group defined in the present invention.
[92] "Arylsulfonic acid" is the addition of the aryl group defined in the present invention to the sulfonic acid group defined in the present invention.
[93] "Sulfonic ester" refers to -S (O) ₂ -NOR ₅₈ , wherein R ₅₈ is an alkyl group, aryl group or arylheterocyclic ring as defined herein.
[94] "Sulfonamido" refers to -S (O) ₂ -N (R ₅₁ ) (R ₅₇ ), wherein R ₅₁ and R ₅₇ are each independently a hydrogen atom, an alkyl group, The aryl group or arylheterocyclic ring or R ₅₁ and R ₅₇ are together with a heterocyclic ring, cycloalkyl group or bridged cycloalkyl group as defined herein.
[95] "Alkylsulfonamido" is the addition of the alkyl group defined in the present invention to the sulfonamido group defined in the present invention.
[96] "Arylsulfonamido" is the addition of the aryl group defined in the present invention to the sulfonamido group defined in the present invention.
[97] "Alkylthio" refers to R ₅₀ S-, wherein R ₅₀ is an alkyl group as defined herein.
[98] "Arylthio" refers to R ₅₅ S-, wherein R ₅₅ is an aryl group as defined herein.
[99] "Arylalkylthio" is the addition of the alkylthio group defined in the present invention to the aryl group defined in the present invention.
[100] "Alkylsulfinyl" refers to R ₅₀ -S (O)-, wherein R ₅₀ is an alkyl group as defined herein.
[101] "Alkylsulfonyl" refers to R ₅₀ -S (O) _2- , wherein R ₅₀ is an alkyl group as defined herein.
[102] "Alkylsulfonyloxy refers to R ₅₀ -S (O) ₂ -O-, wherein R ₅₀ is an alkyl group as defined herein.
[103] "Arylsulfinyl refers to R ₅₅ -S (O)-, wherein R ₅₅ is an aryl group as defined herein.
[104] "Arylsulfonyloxy" refers to R ₅₅ -S (O) ₂ -O-, wherein R ₅₅ is an aryl group as defined herein.
[105] "Amidyl" refers to R ₅₁ C (O) N (R ₅₇ )-, wherein R ₅₁ and R ₅₇ are each independently a hydrogen atom, an alkyl group, an aryl group or an aryl hetero as defined herein. Cyclic rings.
[106] "Ester" refers to R ₅₁ C (O) O-, wherein each R ₅₁ is independently a hydrogen atom, an alkyl group, an aryl group, or an arylheterocyclic ring as defined herein.
[107] "Carbamoyl" refers to -OC (O) N (R ₅₁ ) (R ₅₇ ), wherein R ₅₁ and R ₅₇ are each independently a hydrogen atom, an alkyl group, an aryl group or The arylheterocyclic ring or R ₅₁ and R ₅₇ are together with a heterocyclic ring, cycloalkyl group or bridged cycloalkyl group as defined herein.
[108] "Carboxyl" refers to -C (O) OR ₇₆ , wherein R ₇₆ is hydrogen, organic cation or inorganic cation as defined herein.
[109] "Carbonyl" is -C (O)-.
[110] "Alkylcarbonyl" refers to R ₅₂ -C (O)-, wherein R ₅₂ is an alkyl group as defined herein.
[111] "Arylcarbonyl" refers to R ₅₅ -C (O)-, wherein R ₅₅ is an aryl group as defined herein.
[112] "Arylalkylcarbonyl" refers to R ₅₅ -R ₅₂ -C (O)-, wherein R ₅₅ is an aryl group as defined herein and R ₅₂ is an alkyl group as defined herein in the group.
[113] "Alkylarylcarbonyl" refers to R ₅₂ -R ₅₅ -C (O)-, wherein R ₅₅ is an aryl group as defined herein, and R ₅₂ is an alkyl group as defined herein in the group. .
[114] "Heterocyclicalkylcarbonyl" refers to R ₇₈ C (O)-, wherein R ₇₈ is a heterocyclic alkyl group as defined herein.
[115] "Carboxylic ester" refers to -C (O) OR ₅₈ , wherein R _{58 is an} alkyl group, aryl group or arylheterocyclic ring as defined herein.
[116] "Alkylcarboxylic acid" and "alkylcarboxyl" are those in which the carboxyl group defined in the present invention is added to the alkyl group defined in the present invention.
[117] "Alkylcarboxylic ester" is the addition of the carboxy ester group defined in the present invention to the alkyl group defined in the present invention.
[118] "Arylcarboxylic acid" and "arylcarboxyl" are those in which the carboxyl group defined in the present invention is added to the aryl group defined in the present invention.
[119] "Arylcarboxylic ester" is a carboxyl group defined in the present invention to the aryl group defined in the present invention.
[120] “Carboxamido” refers to —C (O) N (R ₅₁ ) (R ₅₇ ), wherein R ₅₁ and R ₅₇ are each independently a hydrogen atom, an alkyl group, or an aryl as defined herein The group or arylheterocyclic ring or R ₅₁ and R ₅₇ are present together with a heterocyclic ring, cycloalkyl group or bridged cycloalkyl group as defined herein.
[121] "Alkylcarboxamido" is the addition of the carboxamido group defined in the present invention to the alkyl group defined in the present invention.
[122] "Arylcarboxamido" is the addition of the carboxamido group defined in the present invention to the aryl group defined in the present invention.
[123] "Urea" refers to -N (R ₅₉ ) -C (O) N (R ₅₁ ) (R ₅₇ ), wherein R ₅₁ , R ₅₇ and R ₅₉ are each independently hydrogen defined in the present invention. An atom, an alkyl group, an aryl group or an arylheterocyclic ring or R ₅₁ and R ₅₇ are present together with a heterocyclic ring, cycloalkyl group or bridged cycloalkyl group as defined herein.
[124] "Phosphoryl" refers to -P (R ₇₀ ) (R ₇₁ ) (R ₇₂ ), where R ₇₀ is an isolated pair of electrons, a tear or oxo, and R ₇₁ and R ₇₂ are each independently Covalent bonds, hydrogen atoms, lower alkyl, alkoxy, alkylamino, hydroxy, oxy or aryl as defined herein.
[125] "Silyl" refers to -Si (R ₇₃ ) (R ₇₄ ) (R ₇₅ ), wherein R ₇₃ , R ₇₄ and R ₇₅ are each independently a covalent bond, a lower alkyl, alkoxy as defined herein , Aryl or arylalkoxy.
[126] Compounds that confer, convert or release nitric oxide species in vivo are recognized to have a broad spectrum of advantages and applications. The present invention is based on the unexpected finding of the effect of the compound alone and one or more nitric oxide portions in combination with one or more COX-2 inhibitors, directly or indirectly bound. Treatment or prevention of inflammation, pain relief and high fever; Promotion of gastrointestinal properties of COX-2 inhibitors; Promoting wound healing; And the treatment and / or prophylaxis of diseases associated with renal toxicity and cyclooxygenase-2, according to the present invention include nitrosated and / or nitrosylated COX-2 inhibitors; Or optionally selecting one or more therapeutic agents and compounds that promote, release or convert nitric oxide and / or promote endogenous production of NO and / or EDRF in vivo and / or are substrates of nitric oxide synthase It has been found that it is possible to use nitrosated and / or nitrosylated COX-2 inhibitors in combination with or more compounds.
[127] Exemplary embodiments of the present invention include COX-2 inhibitors of the following formula (I): nitrosated and / or nitrosylated:
[128]
[129] In the above,
[130] When b is a double bond and a and c are single bonds, then -X ¹ -Y ¹ -Z ¹ -is:
[131] (a) -CR ⁴ (R ⁵ ) -CR ⁵ (R ⁵ ′) -CR ^4- (R ⁵ )-;
[132] (b) -C (O) -CR ⁴ (R ⁴ ′) -CR ^5- (R ⁵ ′)-;
[133] (b) -C (O) -CR ⁴ (R ⁴ ′) -CR ^5- (R ⁵ ′)-;
[134] (d)-(CR ⁵ (R ⁵ ′) _k -OC (O)-;
[135] (e) —C (O) —O (CR ⁵ (R ⁵ ′)) _k −;
[136] (f) -CR ⁴ (R ⁴ ′) -NR ³ -CR ⁵ (R ⁵ ′)-;
[137] (g) -CR ⁵ (R ⁵ ′) -NR ³ -C (O)-;
[138] (h) -CR ⁴ = CR ⁴ '-S-;
[139] (i) -S-CR ⁴ = CR ⁴ '-;
[140] (j) -SN = CR ^4- ;
[141] (k) -CR ⁴ = NS-;
[142] (l) -N = CR ⁴ -O-;
[143] (m) -O-CR ⁴ = N-;
[144] (n) -NR ³ -CR ⁴ = N-;
[145] (o) -N = CR ⁴ -S-;
[146] (p) -S-CR ⁴ = N-;
[147] (q) -C (O) -NR ³ -CR ⁵ '(R ⁵ ')-;
[148] (r) -R ³ N-CR ⁵ = CR ⁵ '-;
[149] (s) -CR ⁴ = CR ⁵ -NR ^3- ;
[150] (t) -ON = CR ^4- ;
[151] (u) -CR ⁴ = NO-;
[152] (v) -N = N-S-;
[153] (w) -S-N = N-;
[154] (x) -R ³ N-CR ⁴ = N-;
[155] (y) -N = CR ⁴ -NR ^3- ;
[156] (z) -R ³ NN = N-;
[157] (aa) -N = N-NR ^3- ;
[158] (bb) -CR ⁴ (R ⁴ ′) -O-CR ⁵ (R ⁵ ′)-;
[159] (cc) -CR ⁴ (R ⁴ ′) -S-CR ⁵ (R ⁵ ′)-;
[160] (dd) -CR ⁴ (R ⁴ ′) -C (O) —CR ⁵ (R ⁵ ′)-;
[161] (ee) -CR ⁴ (R ⁴ ′) -CR ⁵ (R ⁵ ′) -C (S) —;
[162] (ff)-(CR ⁵ (R ⁵ ′) _k -OC (S)-;
[163] (gg) -C (S) -O- (CR ⁵ (R ⁵ ′) _k- ;
[164] (hh)-(CR ⁵ (R ⁵ ′) _k -NR ³ -C (S)-;
[165] (ii) -C (S) -NR ^3- (CR ⁵ (R ⁵ ′)) _k- ;
[166] (jj)-(CR ⁵ (R ⁵ ′) _k -SC (O)-;
[167] (kk) -C (0) -S- (CR ⁵ (R ⁵ ')) _k- ;
[168] (ll) -O-CR ⁴ = CR ^5- ;
[169] (mm) -CR ⁴ = CR ⁵ -O-;
[170] (nn) -C (O) -NR ³ -S-;
[171] (oo) -S-NR ³ -C (0)-;
[172] (pp) -C (0) -NR ³ -0-;
[173] (qq) -O-NR ³ -C (O)-;
[174] (rr) -NR ³ -CR ⁴ = CR ^5- ;
[175] (ss) -CR ⁴ = N-NR ^3- ;
[176] (tt) -NR ³ -N = CR ^4- ;
[177] (uu) -C (0) -NR ³ -NR ^3- ;
[178] (vv) -NR ³ -NR ³ -C (O)-;
[179] (ww) -C (O) -O-NR ^3- ;
[180] (xx) -NR ³ -OC (O)-;
[181] ^{(yy) -CR 4 R 4 '} -CR 5 R 5'-;
[182] (zz) -C (O) -CR 4 'R 4' -
[183] (aaa) -CR ⁴ R ⁴ ′ -C (O) —;
[184] (bbb) -C (S) -CR ⁴ R ⁴ ′-;
[185] (ccc) -CR ⁴ R ⁴ '-C (S)-;
[186] (ddd) -C (= NR ³ ) -CR ⁴ R ⁴ '-; or
[187] (eee) -CR ⁴ R ⁴ '-C (= NR ³ )-;
[188] When a and c are double bonds and b is a single bond, then -X ¹ -Y ¹ -Z ^1- is:
[189] (a) = CR ⁴ -O-CR ⁵ =;
[190] (b) = CR ⁴ -NR ³ -CR ⁵ =;
[191] (c) = NS-CR ⁴ =;
[192] (d) = CR ⁴ -SN =;
[193] (e) = NO-CR ⁴ =;
[194] (f) = CR ⁴ -ON =;
[195] (g) = N-S-N =;
[196] (h) = N-O-N =;
[197] (i) = N-NR ³ -NR ⁴ =;
[198] (j) = CR ⁴ -NR ³ -N =;
[199] (k) = N-NR ³ -N =;
[200] (l) = CR ⁴ -S-CR ⁵ =; or
[201] (m) = CR ⁴ -CR ⁴ (R ⁴ ′) -CR ⁵ =;
[202] R ¹ is;
[203] (a) -S (0) ₂ -CH ₃ ;
[204] (b) -S (0) ₂ -NR ³ (D ¹ );
[205] (c) -S (0) ₂ -N (D ¹ ) -C (O) -CF ₃ ;
[206] (d) -S (0)-(NH) -NH (D ¹ );
[207] (e) -S (0)-(NH) -N (D ¹ ) -C (O) -CF ₃ ;
[208] (f) -P (O) (CH ₃ ) NH (D ² );
[209] (g) -P (O) (CH ₃ ) ₂ ;
[210] (h) -C (S) -NH (D ¹ );
[211] (i) -S (O) (NH) CH ₃ ;
[212] (j) -P (O) (CH ₃ ) OD ¹ ; or
[213] (k) -P (O) (CH ₃ ) NH (D ¹ );
[214] R ¹ ′;
[215] (a) hydrogen;
[216] (b) halogen;
[217] (c) methyl; or
[218] (d) CH ₂ OH;
[219] R ² is;
[220] (a) lower alkyl;
[221] (b) cycloalkyl;
[222] (c) mono-, di-, or tri-substituted phenyl or naphthyl, wherein the substituents are each independently:
[223] (1) hydrogen;
[224] (2) halo;
[225] (3) alkoxy;
[226] (4) alkylthio;
[227] (5) CN;
[228] (6) haloalkyl, preferably CF ₃ ;
[229] (7) lower alkyl;
[230] (8) N ₃ ;
[231] (9) -CO ₂ D ¹ ;
[232] (10) -CO ₂ -lower alkyl;
[233] (11)-(C (R ⁵ ) (R ⁶ )) _z -OD ¹ ;
[234] (12)-(C (R ⁵ ) (R ⁶ )) _z -O-lower alkyl;
[235] (13) lower alkyl-CO ₂ -R ⁵ ;
[236] (14) -OD ¹ ;
[237] (15) haloalkoxy;
[238] (16) amino;
[239] (17) nitro;
[240] (18) alkylsulfinyl; or
[241] (19) heteroaryl;
[242] (d) mono-, di- or tri-substituted heteroaryl, wherein the heteroaryl is a 5-membered monocyclic aromatic ring, the ring having a hetero atom which is S, O or N, optionally 1 , Has 2 or 3 added N atoms; Or said heteroaryl is a 6-membered monocyclic ring, said ring having N heteroatoms, optionally having 1, 2, 3 or 4 added N atoms; Wherein the substituents are each independently;
[243] (1) hydrogen;
[244] (2) halo;
[245] (3) lower alkyl;
[246] (4) alkoxy;
[247] (5) alkylthio;
[248] (6) CN;
[249] (7) haloalkyl, preferably CF ₃ ;
[250] (8) N ₃ ;
[251] (9) -C (R ⁵ ) (R ⁶ ) -OD ¹ ;
[252] (10) -C (R ⁵ ) (R ⁶ ) -O-lower alkyl; or
[253] (11) alkylsulfinyl;
[254] (e) benzoheteroaryl comprising an analog of (d) to which benzo is bonded;
[255] (f) -NR ¹⁰ R ¹¹ ;
[256] (g) -SR ¹¹ ;
[257] (h) -OR ¹¹ ;
[258] (i) -R ¹¹ ;
[259] (j) alkenyl;
[260] (k) alkynyl;
[261] (l) unsubstituted, mono-, di-, tri- or tetra-substituted cycloalkenyl, wherein the substituents are each independently:
[262] (1) halo;
[263] (2) alkoxy;
[264] (3) alkylthio;
[265] (4) CN;
[266] (5) haloalkyl, preferably CF ₃ ;
[267] (6) lower alkyl;
[268] (7) N ₃ ;
[269] (8) -CO ₂ D ¹ ;
[270] (9) -C0 ₂ -lower alkyl;
[271] (10) -C (R ¹² ) (R ¹³ ) -OD ¹ ;
[272] (11) -C (R ¹² ) (R ¹³ ) -O-lower alkyl;
[273] (12) lower alkyl-CO ₂ -R ¹² ;
[274] (13) benzyloxy;
[275] (14) -O- (lower alkyl) -CO ₂ R ¹² ;
[276] (15) -O- (lower alkyl) -NR ¹² R ¹³ ; or
[277] (16) alkylsulfinyl;
[278] (m) a 5, 6 or 7 membered mono-, di-tri- or tetra-substituted heterocycloalkyl group, or benzoheterocycle, wherein said heterocycloalkyl or benzoheterocycle is selected from O, S or N Or comprises two atoms, optionally, has a carbonyl group or a sulfonyl group, wherein the substituents are each independently:
[279] (1) halo;
[280] (2) lower alkyl;
[281] (3) alkoxy;
[282] (4) alkylthio;
[283] (5) CN;
[284] (6) haloalkyl, preferably CF ₃ ;
[285] (7) N ₃ ;
[286] (8) -C (R ¹² ) (R ¹³ ) -OD ¹ ;
[287] (9) -C (R ¹² ) (R ¹³ ) -O-lower alkyl; or
[288] (10) alkylsulfinyl;
[289] (n) styryl, mono or di-substituted styryl, wherein the substituents are each independently:
[290] (1) halo;
[291] (2) alkoxy;
[292] (3) alkylthio;
[293] (4) CN;
[294] (5) haloalkyl, preferably CF ₃ ;
[295] (6) lower alkyl;
[296] (7) N ₃ ;
[297] (8) -CO ₂ D ¹ ;
[298] (9) -CO ₂ -lower alkyl;
[299] (10) -C (R ¹² ) (R ¹³ ) -OD ¹ ;
[300] (11) -C (R ¹² ) (R ¹³ ) -O-lower alkyl;
[301] (12) lower alkyl-CO ₂ -R ¹² ;
[302] (13) benzyloxy;
[303] (14) -O- (lower alkyl) -CO ₂ R ¹² ; or
[304] (15) -O- (lower alkyl) -NR ¹² R ¹³ ;
[305] (o) phenylacetylene, mono- or di-substituted phenylacetylene, wherein the substituents are each independently:
[306] (1) halo;
[307] (2) alkoxy;
[308] (3) alkylthio;
[309] (4) CN;
[310] (5) haloalkyl, preferably CF ₃ ;
[311] (6) lower alkyl;
[312] (7) N ₃ ;
[313] (8) -CO ₂ D ¹ ;
[314] (9) -CO ₂ -lower alkyl;
[315] (10) -C (R ¹² ) (R ¹³ ) -OD ¹ ;
[316] (11) -C (R ¹² ) (R ¹³ ) -O-lower alkyl;
[317] (12) lower alkyl-CO ₂ -R ¹² ;
[318] (13) benzyloxy;
[319] (14) -O- (lower alkyl) -CO ₂ R ¹² ; or
[320] (15) -O- (lower alkyl) -NR ¹² R ¹³ ;
[321] (p) fluoroalkenyl;
[322] (q) 8, 9 or 10 membered mono-, di-substituted bicyclic heteroaryl, having 2, 3, 4 or 5 heteroatoms, wherein at least one heteroatom is said bicyclic hetero Located in each ring of aryl, the heteroatoms are each independently O, S, and N, and the substituents are each independently
[323] (1) hydrogen;
[324] (2) halo;
[325] (3) lower alkyl;
[326] (4) alkoxy;
[327] (5) alkylthio;
[328] (6) CN;
[329] (7) haloalkyl, preferably CF ₃ ;
[330] (8) N ₃ ;
[331] (9) -C (R ⁵ ) (R ⁶ ) -OD ¹ ; or
[332] (10) -C (R ⁵ ) (R ⁶ ) -O-lower alkyl;
[333] (r) potassium;
[334] (s) aryl;
[335] (t) arylalkyl;
[336] (u) cycloalkylalkyl;
[337] (v) -C (O) R ¹¹ ;
[338] (u) hydrogen;
[339] (v) arylalkenyl;
[340] (w) arylalkoxy;
[341] (x) alkoxy;
[342] (y) aryloxy;
[343] (z) cycloalkoxy;
[344] (aa) arylthio;
[345] (bb) alkylthio;
[346] (cc) arylalkylthio; or
[347] (dd) cycloalkylthio;
[348] R ³ is;
[349] (a) hydrogen;
[350] (b) haloalkyl, preferably CF ₃ ;
[351] (c) CN;
[352] (d) lower alkyl;
[353] (e)-(C (R _e ) (R _f )) _p -UV;
[354] (f) potassium;
[355] (g) substituted or unsubstituted:
[356] (1) lower alkyl-Q;
[357] (2) lower alkyl-O-lower alkyl-Q;
[358] (3) lower alkyl-S-lower alkyl-Q;
[359] (4) lower alkyl-0-Q;
[360] (5) lower alkyl-S-Q;
[361] (6) lower alkyl-0-V;
[362] (7) lower alkyl-S-V;
[363] (8) lower alkyl-0-K; or
[364] (9) lower alkyl-S-K;
[365] Wherein the substituent is on the lower alkyl group;
[366] (h) Q;
[367] (i) alkylcarbonyl;
[368] (j) arylcarbonyl;
[369] (k) alkylarylcarbonyl;
[370] (l) arylalkylcarbonyl;
[371] (m) carboxyl esters;
[372] (n) carboxamido;
[373] (o) cycloalkyl;
[374] (p) mono-, di- or tri-substituted phenyl or naphthyl, wherein the substituents are each independently:
[375] (1) hydrogen;
[376] (2) halo;
[377] (3) alkoxy;
[378] (4) alkylthio;
[379] (5) CN;
[380] (6) haloalkyl, preferably CF ₃ ;
[381] (7) lower alkyl;
[382] (8) N ₃ ;
[383] (9) -CO ₂ D ¹ ;
[384] (10) -CO ₂ -lower alkyl;
[385] (11)-(C (R ⁵ ) (R ⁶ )) _z -OD ¹ ;
[386] (12)-(C (R ⁵ ) (R ⁶ )) _z -O-lower alkyl;
[387] (13) lower alkyl-CO ₂ -R ⁵ ;
[388] (14) -OD ¹ ;
[389] (15) haloalkoxy;
[390] (16) amino;
[391] (17) nitro; or
[392] (18) alkylsulfinyl;
[393] (q) alkenyl;
[394] (r) alkynyl;
[395] (s) arylalkyl;
[396] (t) lower alkyl-OD ¹ ;
[397] (u) alkoxyalkyl;
[398] (v) aminoalkyl;
[399] (w) lower alkyl-CO ₂ R ¹⁰ ;
[400] (x) lower alkyl-C (O) NR ¹⁰ (R ¹⁰ );
[401] (y) heterocyclicalkyl; or
[402] (z) heterocyclic ring-C (O)-;
[403] R⁴, R⁴'_,R⁵And R⁵'Are each independently:
[404] (a) hydrogen;
[405] (b) amino;
[406] (c) CN;
[407] (d) lower alkyl;
[408] (e) haloalkyl;
[409] (f) alkoxy;
[410] (g) alkylthio;
[411] (h) Q;
[412] (i) -O-Q;
[413] (j) -S-Q;
[414] (k) K;
[415] (l) cycloalkoxy;
[416] (m) cycloalkylthio;
[417] (n) unsubstituted, mono-, or di-substituted phenyl or unsubstituted, mono-, di-substituted benzyl, wherein the substituents are each independently:
[418] (1) halo;
[419] (2) lower alkyl;
[420] (3) alkoxy;
[421] (4) alkylthio;
[422] (5) CN;
[423] (6) haloalkyl, preferably CF ₃ ;
[424] (7) N ₃ ;
[425] (8) Q;
[426] (9) nitro; or
[427] (10) amino;
[428] (o) unsubstituted, mono-, or di-substituted heteroaryl or unsubstituted, mono- or di-substituted heteroarylmethyl, wherein the heteroaryl is a 5-membered monocyclic aromatic ring, and The ring comprises one hetero atom selected from S, O or N, optionally having 1, 2 or 3 additional N atoms; Or said heteroaryl is a 6 membered monocyclic ring, said ring having N as one hetero atom, optionally having 1, 2, 3 or 4 additional N atoms; The substituents are each independently:
[429] (1) halo;
[430] (2) lower alkyl;
[431] (3) alkoxy;
[432] (4) alkylthio;
[433] (5) CN;
[434] (6) haloalkyl, preferably CF ₃ ;
[435] (7) N ₃ ;
[436] (8) -C (R ⁶ ) (R ⁷ ) -OD ¹ ;
[437] (9) -C (R ⁶ ) (R ⁷ ) -O-lower alkyl; or
[438] (10) alkylsulfinyl;
[439] (p) -CON (R ⁸ ) (R ⁸ );
[440] (q) -CH ₂ OR ⁸ ;
[441] (r) -CH ₂ OCN;
[442] (s) substituted or unsubstituted:
[443] (1) lower alkyl-Q;
[444] (2) -O-lower alkyl-Q;
[445] (3) -S-lower alkyl-Q;
[446] (4) lower alkyl-0-lower alkyl-Q;
[447] (5) lower alkyl-S-lower alkyl-Q;
[448] (6) lower alkyl-0-Q;
[449] (7) lower alkyl-S-Q;
[450] (8) lower alkyl-0-K;
[451] (9) lower alkyl-S-K;
[452] (10) lower alkyl-0-V; or
[453] (11) lower alkyl-S-V;
[454] Wherein the substituent is on the lower alkyl group;
[455] (t) cycloalkyl;
[456] (u) aryl;
[457] (v) arylalkyl;
[458] (w) cycloalkylalkyl;
[459] (x) aryloxy;
[460] (y) arylalkoxy;
[461] (z) arylalkylthio;
[462] (aa) cycloalkylalkoxy;
[463] (bb) heterocycloalkyl;
[464] (cc) alkylsulfonyloxy;
[465] (dd) alkylsulfonyl;
[466] (ee) arylsulfonyl;
[467] (ff) arylsulfonyloxy;
[468] (gg) -C (0) R ¹⁰ ;
[469] (hh) nitro;
[470] (ii) amino;
[471] (jj) aminoalkyl;
[472] (kk) -C (O) -alkyl-heterocyclic ring;
[473] (ll) halo;
[474] (mm) heterocyclic ring;
[475] (nn) -CO ₂ D ¹ ;
[476] (oo) carboxyl;
[477] (pp) amidyl; or
[478] (qq) alkoxyalkyl;
[479] Optionally, R ⁴ and R ⁵ together with the carbon to which they are attached are
[480] (a) cycloalkyl;
[481] (b) aryl; or
[482] (c) heterocyclic ring;
[483] Optionally, R ⁴ and R ⁴ ′ or R ⁵ and R ⁵ ′ taken with bonded carbon are:
[484] (a) cycloalkyl; or
[485] (b) heterocyclic ring;
[486] Optionally, when the substituent of the opposite carbon atom is taken together with the bonded carbon, R⁴And R⁵, R⁴'And R⁵', R⁴And R⁵', R⁴'And R⁵Is:
[487] (a) cycloalkyl;
[488] (b) heterocyclic ring; or
[489] (c) aryl;
[490] R ⁶ and R ⁷ are each independently:
[491] (a) hydrogen;
[492] (b) unsubstituted or mono- or di-substituted phenyl groups; Unsubstituted or mono- or di-substituted benzyl groups; Unsubstituted or mono- or di-substituted heteroaryl groups; Mono- or di-substituted heteroarylmethyl groups, wherein the substituents are each independently:
[493] (1) halo;
[494] (2) lower alkyl;
[495] (3) alkoxy:
[496] (4) alkylthio;
[497] (5) CN;
[498] (6) haloalkyl, preferably CF ₃ ;
[499] (7) N ₃ ;
[500] (8) -C (R ¹⁴ ) (R ¹⁵ ) -OD ¹ ; or
[501] (9) -C (R ¹⁴ ) (R ¹⁵ ) -O-lower alkyl;
[502] (c) lower alkyl;
[503] (d) -CH ₂ OR ⁸ ;
[504] (e) CN;
[505] (f) -CH ₂ CN;
[506] (g) haloalkyl, preferably fluoroalkyl;
[507] (h) -CON (R ⁸ ) (R ⁸ );
[508] (i) halo; or
[509] (j) -OR ⁸ ;
[510] R ⁸ is;
[511] (a) hydrogen;
[512] (b) K; or
[513] (c) R ⁹ _;
[514] Optionally, R with bonded carbon⁵And R⁵', R⁶And R⁷Or R⁷And R⁸Forms a saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms; Optionally oxygen, S (O)_oOr NR_OneIt contains two or more hetero atoms selected from;
[515] R ⁹ is;
[516] (a) lower alkyl;
[517] (b) lower alkyl-CO ₂ D ¹ ;
[518] (c) lower alkyl-NHD ¹ ;
[519] (d) phenyl or mono-, di- or tri-substituted phenyl, wherein the substituents are each independently:
[520] (1) halo;
[521] (2) lower alkyl;
[522] (3) alkoxy;
[523] (4) alkylthio;
[524] (5) lower alkyl-CO ₂ D ¹ ;
[525] (6) lower alkyl-NHD ¹ ;
[526] (7) CN;
[527] (8) CO ₂ D ¹ ; or
[528] (9) haloalkyl, preferably fluoroalkyl;
[529] (e) benzyl, mono-, di- or tri-substituted benzyl, wherein the substituents are each independently:
[530] (1) halo;
[531] (2) lower alkyl;
[532] (3) alkoxy:
[533] (4) alkylthio;
[534] (5) lower alkyl-CO ₂ D ¹ ;
[535] (6) lower alkyl-NHD ¹ ;
[536] (7) CN;
[537] (8) -CO ₂ D ¹ ; or
[538] (9) haloalkyl, preferably CF ₃ ;
[539] (f) cycloalkyl;
[540] (g) K; or
[541] (h) benzyl, mono-, di- or tri-substituted benzoyl, wherein the substituents are each independently:
[542] (1) halo;
[543] (2) lower alkyl;
[544] (3) alkoxy:
[545] (4) alkylthio;
[546] (5) lower alkyl-CO ₂ D ¹ ;
[547] (6) lower alkyl-NHD ¹ ;
[548] (7) CN;
[549] (8) -CO ₂ D ¹ ; or
[550] (9) haloalkyl, preferably CF ₃ ;
[551] R ¹⁰ and R ^{10 '} ' are each independently:
[552] (a) hydrogen; or
[553] (b) R ¹¹ ;
[554] R ¹¹ is;
[555] (a) lower alkyl;
[556] (b) cycloalkyl;
[557] (c) unsubstituted or mono-, di- or tri-substituted phenyl or naphthyl, wherein the substituents are each independently:
[558] (1) halo;
[559] (2) alkoxy:
[560] (3) alkylthio;
[561] (4) CN;
[562] (5) haloalkyl, preferably CF ₃ ;
[563] (6) lower alkyl;
[564] (7) N ₃ ;
[565] (8) -CO ₂ D ¹ ;
[566] (9) -CO ₂ -lower alkyl;
[567] (10) -C (R ¹² ) (R ¹³ ) -OD ¹ ;
[568] (11) -C (R ¹² ) (R ¹³ ) -O-lower alkyl;
[569] (12) lower alkyl-CO ₂ D ¹ ;
[570] (13) lower alkyl-CO ₂ R ¹² ;
[571] (14) benzyloxy;
[572] (15) -O- (lower alkyl) -CO ₂ D ¹ ;
[573] (16) -O- (lower alkyl) -CO ₂ R ¹² ; or
[574] (17) -O- (lower alkyl) -NR ¹² R ¹³ ;
[575] (d) unsubstituted or mono-, di- or tri-substituted heteroaryl groups, wherein the heteroaryl group is a 5-membered monocyclic aromatic ring, wherein the ring comprises a heteroatom of S, O or N And optionally have 1, 2, or 3 added N atoms; Or said heteroaryl group is a monocyclic ring of 6 atoms, said ring is N, and optionally a heteroatom added with 1, 2, or 3 N atoms, wherein said substituents are each independently:
[576] (1) halo;
[577] (2) lower alkyl;
[578] (3) alkoxy:
[579] (4) alkylthio;
[580] (5) CN;
[581] (6) haloalkyl, preferably CF ₃ ;
[582] (7) N ₃ ;
[583] (8) -C (R ¹² ) (R ¹³ ) -OD ¹ ; or
[584] (9) -C (R ¹² ) (R ¹³ ) -O-lower alkyl;
[585] (e) unsubstituted or mono- or di-substituted benzoheterocycles, wherein the benzoheterocycle contains one or two heteroatoms selected from O, S or N, optionally containing a carbonyl or sulfonyl group Is a ring of 5, 6 or 7 members, wherein the substituents are each independently:
[586] (1) halo;
[587] (2) lower alkyl;
[588] (3) alkoxy:
[589] (4) alkylthio;
[590] (5) CN;
[591] (6) haloalkyl, preferably CF ₃ ;
[592] (7) N ₃ ;
[593] (8) -C (R ¹² ) (R ¹³ ) -OD ¹ ; or
[594] (9) -C (R ¹² ) (R ¹³ ) -O-lower alkyl;
[595] (f) unsubstituted or mono- or di-substituted benzocarbocycles wherein the carbocycle is a ring of 5, 6, or 7-members, optionally containing a carboxyl group, each of which is independently:
[596] (1) halo;
[597] (2) lower alkyl;
[598] (3) alkoxy:
[599] (4) alkylthio;
[600] (5) CN;
[601] (6) haloalkyl, preferably CF ₃ ;
[602] (7) N ₃ ;
[603] (8) -C (R ¹² ) (R ¹³ ) -OD ¹ ; or
[604] (9) -C (R ¹² ) (R ¹³ ) -O-lower alkyl;
[605] (g) hydrogen; or
[606] (h) K
[607] R ¹² and R ¹³ are each independently:
[608] (a) hydrogen;
[609] (b) lower alkyl; or
[610] (c) aryl; or
[611] R ¹² and R ¹³ together with the bonded element form a saturated monocycle ring of 3, 4, 5, 6 or 7 elements.
[612] R ¹⁴ and R ¹⁵ are each independently:
[613] (a) hydrogen; or
[614] (b) lower alkyl; or
[615] R ¹⁴ and R ¹⁵ together with the bonded element form a carbonyl, thial or saturated monocycle ring of 3, 4, 5, 6 or 7 elements.
[616] D ¹ is:
[617] (a) hydrogen or
[618] (b) D;
[619] D Is:
[620] (a) V; or
[621] (b) K;
[622] U Is:
[623] (a) oxygen;
[624] (b) sulfur (sulfur); or
[625] (c) -N (R _a ) (R _I )-;
[626] V Is:
[627] (a) -NO;
[628] (b) -NO ₂ ; or
[629] (c) hydrogen
[630] K is -W _aa -E _b- (C (R _e ) (R _f )) _p -E _c- (C (R _e ) (R _f )) _x -W _d- (C (R _e ) (R _f )) _y -W _i -E _j -W _g- (C (R _e ) (R _f )) _z -UV;
[631] Aa, b, c, d, g, i and j are each independently an integer of 0 to 3; p, x, y and z are each independently integers of 0-10; In each case W is independently:
[632] (a) -C (O)-;
[633] (b) -C (S)-;
[634] (c) -T-;
[635] (d)-(C (R _e ) (R _f )) _h- ;
[636] (e) alkyl;
[637] (f) aryl;
[638] (g) heterocyclic rings;
[639] (h) arylheterocyclic ring, or
[640] (i)-(CH ₂ CH ₂ ) _q- ;
[641] In each case, E is independently:
[642] (a) -T-;
[643] (b) alkyl;
[644] (c) aryl;
[645] (d)-(C (R _e ) (R _f )) _h- ;
[646] (e) heterocyclic rings;
[647] (f) arylheterocyclic ring; or
[648] (g)-(CH ₂ CH ₂ ) _q- ;
[649] h is an integer from 1 to 10;
[650] q is an integer from 1 to 5;
[651] R _e and R _f are each independently:
[652] (a) hydrogen;
[653] (b) alkyl;
[654] (c) cycloalkoxy;
[655] (d) halogen;
[656] (e) hydroxy;
[657] (f) hydroxyalkyl;
[658] (g) alkoxyalkyl;
[659] (h) arylheterocyclic ring;
[660] (i) cycloalkylalkyl;
[661] (j) heterocyclic alkyl;
[662] (k) alkoxy;
[663] (l) haloalkoxy;
[664] (m) amino;
[665] (n) alkylamino;
[666] (o) dialkylamino;
[667] (p) arylamino;
[668] (q) diarylamino;
[669] (r) alkylarylamino;
[670] (s) alkoxyhaloalkyl;
[671] (t) haloalkoxy;
[672] (u) sulfoic acid;
[673] (v) alkylsulfoic acid;
[674] (w) arylsulfoic acid;
[675] (x) arylalkoxy;
[676] (y) alkylthio;
[677] (z) arylthio;
[678] (aa) cyano;
[679] (bb) aminoalkyl;
[680] (cc) aminoaryl;
[681] (dd) alkoxy;
[682] (ee) aryl;
[683] (ff) arylalkyl;
[684] (gg) carboxamido;
[685] (hh) alkylcarboxamido;
[686] (ii) arylcarboxamido;
[687] (jj) amidyl;
[688] (kk) carboxyl;
[689] (ll) carbamoyl;
[690] (mm) alkylcarboxylic acid;
[691] (nn) arylcarboxylic acid;
[692] (oo) alkylcarboxyl;
[693] (pp) arylcarboxyl;
[694] (qq) esters;
[695] (rr) carboxylic esters;
[696] (ss) alkylcarboxylic esters;
[697] (tt) arylcarboxylic esters;
[698] (uu) haloalkoxy;
[699] (vv) sulfonicamido;
[700] (ww) alkylsulfonamido;
[701] (xx) arylsulphonicamido;
[702] (yy) akylsulfonyl;
[703] (zz) alkylsulfonyloxy,
[704] (aaa) arylsulfonyl,
[705] (bbb) arylsulfonyloxy,
[706] (ccc) sulfonic esters;
[707] (ddd) carbamoyl;
[708] (eee) urea;
[709] (fff) nitoro; or
[710] (ggg) -U-V; or
[711] Taken together, R _e and R _f are:
[712] (a) oxo;
[713] (b) thial; or
[714] Taken with bound carbon, R _e and R _f are:
[715] (a) heterocyclic rings;
[716] (b) a cycloalkyl group; or
[717] (c) bridged bonded cycloalkyl groups;
[718] k is an integer of 1 to 2;
[719] In each case T is independently:
[720] (a) covalent bonds,
[721] (b) carbonyl,
[722] (c) oxygen,
[723] (d) -S (O) _o- ; or
[724] (e) -N (R _a ) (R _I )-;
[725] o is an integer from 0 to 2;
[726] Q is:
[727] (a) -C (O) -UD ¹ ;
[728] (b) -CO ₂ -loweralkyl;
[729] (c) tetrazolyl-5-yl;
[730] (d) -C (R ⁷ ) (R ⁸ ) (SD ¹ );
[731] (e) -C (R ⁷ ) (R ⁸ ) (OD ¹ ); or
[732] (f) -C (R ⁷ ) (R ⁸ ) (O-loweralkyl);
[733] R _a is:
[734] (a) a lone pair of electrons;
[735] (b) hydrogen; or
[736] (c) lower alkyl;
[737] R _i is:
[738] (a) hydrogen;
[739] (b) alkyl;
[740] (c) aryl:
[741] (d) alkylcarboxylic acids;
[742] (e) arylcarboxylic acids;
[743] (f) alkylcarboxylic esters;
[744] (g) arylcarboxylic esters;
[745] (h) alkylcarboxamido;
[746] (i) arylcarboxamido;
[747] (j) alkylsulfinyl;
[748] (k) alkylsulfonyl;
[749] (l) alkylsulfonyloxy;
[750] (m) arylsulfinyl;
[751] (n) arylsulfonyl;
[752] (o) arylsulfonyloxy;
[753] (p) sulfonamido;
[754] (q) carboxamido;
[755] (r) carboxyl esters;
[756] (s) aminoalkyl;
[757] (t) aminoaryl;
[758] (u) -CH ₂ -C (UV) (R _e ) (R _f );
[759] (v) an atom that combines with the opposite atom to form a double bond; or
[760] _{(w) - (N 2 O} 2 -) - and M ^+, wherein M ⁺ is an organic or inorganic cation; Conditionally, the compound of formula I should contain at least one member selected from nitrite, nitrate, thionitrite or thionitrate groups.
[761] R _e and R _f are heterocycling, or when R _e and R _f taken together with the bonded carbon are heterocycling, then R _i can be a substituent of a double substituted nitrogen containing ical, as defined above. have.
[762] When several names of consecutive variables are "covalent bonds" or the selected integer is zero, the object is to denote a single covalent bond which is radically bonded to another atom. For example, E ₀ represents a covalent bond, while E ₂ represents (EE) and (C (R _e ) R _f )) ₂ , -C (R _e ) (R _f ) -C- (R _e ) (R _f )-.
[763] Another embodiment of the invention provides a compound of formula 2 (II).
[764]
[765] Where A-B is:
[766] (a) N-C;
[767] (b) C-N; or
[768] (c) N-N;
[769] If the d and f sides are double bonds and the e and g sides are single bonds, then -X ² -Y ² -Z ² -is:
[770] (a) = CR ⁴ -CR ⁴ '= CR ^5- ;
[771] (b) = N-CR ⁴ = CR ⁴ '-;
[772] (c) = N-CR ⁴ = N-;
[773] (d) = CR ⁴ -N = CR ⁴ '-;
[774] (e) = CR ⁴ -N = N-;
[775] (f) = NN = CR ^4- ;
[776] (g) = N-N = N-;
[777] (h) = CR ⁴ -CR ⁵ = N-; or
[778] (i) = CR ² '-CR ⁵ = N-;
[779] Taken together, R ² and R ² ′ are:
[780] (a)
[781] or
[782] (b)
[783] ego,
[784] Or R ² ′ and R ⁵ taken with bonded carbon are:
[785] (a) cycloalkyl; or
[786] (b) heterocyclic ring;
[787] R ⁹⁷ is:
[788] (a) hydrogen;
[789] (b) arylthio;
[790] (c) alkylsulfinyl;
[791] (d) alkylsulfonyl;
[792] (e) cyano;
[793] (f) carboxyl;
[794] (g) amino;
[795] (h) lower alkyl;
[796] (i) haloalkyl;
[797] (j) hydroxy;
[798] (k) alkoxy;
[799] (l) haloalkoxy;
[800] (m) alkylarylalkylamino;
[801] (n) aminoalkyl;
[802] (o) aminoaryl;
[803] (p) sulfoamido;
[804] (q) alkylsulfoamido;
[805] (r) arylsulfoamido;
[806] (s) heterocyclic rings;
[807] (t) hydroxyalkyl; or
[808] (u) nitro;
[809] a is an integer of 1 to 3;
[810] If e and g are double bonds, and d and f are single bonds, then -X ² -Y ² -Z ² -is:
[811] (a) -CR ⁴ = NN =;
[812] (b) -N = N-CR ⁴ =;
[813] (c) -CR ⁴ = N-CR ⁴ '=;
[814] (d) -N = CR ⁴ -N =;
[815] (e) -CR ⁴ = CR ⁴ '-N =;
[816] (f) -N = CR ⁴ -CR ⁵ =;
[817] (g) -CR ⁴ = CR ⁵ -CR ⁵ '=; or
[818] (h) -N = N-N =;
[819] If g is a double bond and d, e and f are a single bond, then -X ² -Y ² -Z ² -is:
[820] (a) -C (O) -O-CR ⁴ =;
[821] (b) -C (0) -NR ³ -CR ⁴ =;
[822] (c) -C (O) -S-CR ⁴ =; or
[823] (d) -C (H) R ⁴ -C (OH) R ⁵ -N =;
[824] When d is a double bond and e, f and g are single bonds, then -X ² -Y ² -Z ² -is:
[825] (a) = CR ⁴ -OC (O)-;
[826] (b) = CR ⁴ -NR ³ -C (O)-;
[827] (c) = CR ⁴ -SC (O)-; or
[828] (d) = NC (OH) R ⁴ -C (H) R ^5- ;
[829] When f is a double bond and d, e and g are single bonds, -X ² -Y ² -Z ² -is:
[830] (a) -CH (R ⁴ ) -CR ⁵ = N-; or
[831] (b) -C (O) -CR ⁴ = CR ^5- ;
[832] When e is a double bond and d, f and g are single bonds, then -X ² -Y ² -Z ² -is:
[833] (a) -N = CR ⁴ -CH (R ⁵ )-; or
[834] (b) -CR ⁴ = CR ⁵ -C (O)-;
[835] When d, e, f and g are single bonds,
[836] -X ² -Y ² -Z ² -is:
[837] (a) -C (O) -CR ⁴ (R ^{4 '} ) -C (O)-;
[838] R ¹ , R ^{1 ′} , R ² , R ³ , R ⁴ , R ^{4 ′} , R ⁵ and R ^{5 ′} are as defined herein;
[839] Conditionally, the compound of formula II should comprise at least one member selected from the group of nitrites, nitrates, thionitrites or thionitrates.
[840] Another embodiment of the invention provides compounds of formula 3 (III):
[841]
[842] (Ⅲ)
[843] Where X ³ is:
[844] (a) C (O) -UD ¹ ;
[845] (b) -CH ₂ -UD ¹ ;
[846] (c) -CH ₂ -C (O) -CH ₃ ;
[847] (d) -CH ₂ -CH ₂ -C (O) -UD ¹ ;
[848] (e) -CH ₂ -OD ¹ ; or
[849] (f) -C (O) H and
[850] Y ³ is
[851] (a)-(CR ⁵ (R ^{5 '} )) _k -UD ¹ ;
[852] (b) -CH ₃ ;
[853] (c) -CH ₂ OC (O) R ⁶ ; or
[854] (d) -C (O) H;
[855] Optionally, both X ³ and Y ³ taken are —CR ⁸² (R ⁸³ ) —CR ^{82 ′} (R ^{83 ′} ) —;
[856] R ⁸² , R ^{82 '} , R ⁸³ and R ^83' are each independently;
[857] (a) hydrogen;
[858] (b) hydroxy;
[859] (c) alkyl;
[860] (d) alkoxy;
[861] (e) lower alkyl-OD ^{1 ′} ;
[862] (f) alkylthio;
[863] (g) CN;
[864] (h) -C (O) R ⁸⁴ ; or
[865] (i) -OC (O) R ⁸⁵ ;
[866] R ⁸⁴ is:
[867] (a) hydrogen;
[868] (b) lower alkyl; or
[869] (c) alkoxy;
[870] R ⁸⁵ is:
[871] (a) lower alkyl;
[872] (b) alkoxy
[873] (c) unsubstituted or mono-, di-, or tri-substituted phenyl or pyridyl, wherein the substituents are each independently:
[874] (1) halo;
[875] (2) alkoxy;
[876] (3) haloalkyl;
[877] (4) CN
[878] (5) -C (O) R ⁸⁴ ;
[879] (6) lower alkyl;
[880] (7) -S (O) ₀ -lower alkyl; or
[881] (8) OD ¹ ;
[882] Optionally, R ⁸² , R ^{82 '} , R ^82' and R ^{83 'taken} are all:
[883] (a) oxo;
[884] (b) thial;
[885] (c) = CR ⁸⁶ R ⁸⁷ ; or
[886] (d) = NR ⁸⁸ ;
[887] R ⁸⁶ and R ⁸⁷ are each independently:
[888] (a) hydrogen;
[889] (b) lower alkyl;
[890] (c) lower alkyl-OD ¹ ;
[891] (d) CN; or
[892] (e) -C (O) R ⁸⁴ ;
[893] R ⁸⁸ is
[894] (a) OD ¹ ;
[895] (b) alkoxy
[896] (c) lower alkyl; or
[897] (d) unsubstituted or mono-, di- or tri-substituted phenyl or pyridyl, wherein the substituents are each independently:
[898] (1) halo;
[899] (2) alkoxy;
[900] (3) haloalkyl;
[901] (4) CN;
[902] (5) -C (O) R ⁸⁴ ;
[903] (6) lower alkyl;
[904] (7) -S (O) ₀ -lower alkyl; or
[905] (8) -OD ¹ ;
[906] R ¹ , R ² , R ⁵ , R ^{5 '} , R ⁶ , U, D ¹ , o and k are as defined herein;
[907] Conditionally, the compound of formula III should comprise at least one member selected from the group of nitrites, nitrates, thionitrites or thionitrates.
[908] Another embodiment of the invention is provided as a compound of formula 4 (IV).
[909]
[910]
[911] (Ⅳ)
[912] Wherein X ⁴ and Z ⁴ are each independently:
[913] (a) N; or
[914] (b) CR ²¹ ;
[915] R ²⁰ is:
[916] (a) -S (O) ₂ -CH ₃ ;
[917] (b) -S (O) ₂ -NR ⁸ (D ¹ ); or
[918] (c) -S (O) ₂ -N (D ¹ ) -C (O) -CF ₃ ;
[919] R ²¹ and R ^{21 '} are each independently:
[920] (a) hydrogen;
[921] (b) lower alkyl;
[922] (c) alkoxy;
[923] (d) alkylthio;
[924] (e) haloalkyl, preferably fluoroalkyl;
[925] (f) haloalkoxy, preferably fluoroalkoxy;
[926] (g) CN;
[927] (h) -CO ₂ D ¹ ;
[928] (i) -CO ₂ R ¹⁴ ;
[929] (j) lower alkyl-OD ¹ ;
[930] (k) lower alkyl-CO ₂ D ¹ ;
[931] (l) lower alkyl-CO ₂ R ¹⁴ ;
[932] (m) halo;
[933] (n) -OD ¹ ;
[934] (o) -N ₃ ;
[935] (p) -NO ₂ ;
[936] (q) -NR ¹⁴ D ¹ ;
[937] (r) -N (D ¹ ) C (O) R ¹⁴ ;
[938] (s) -NHK;
[939] (t) aryl;
[940] (u) arylalkylthio;
[941] (v) arylalkoxy;
[942] (w) alkylamino;
[943] (x) aryloxy;
[944] (y) alkylarylalkylamino;
[945] (z) cycloalkylalkylamino; or
[946] (aa) cycloalkylalkoxy;
[947] R ²² is:
[948] (a) mono-, di- or tri-substituted phenyl or pyridinyl (or N-oxides thereof), wherein the substituents are each independently:
[949] (1) hydrogen;
[950] (2) halo;
[951] (3) alkoxy;
[952] (4) alkylthio;
[953] (5) CN;
[954] (6) lower alkyl;
[955] (7) haloalkyl, preferably fluoroalkyl;
[956] (8) N ₃ ;
[957] (9) -CO ₂ D ¹ ;
[958] (10) -CO ₂ -lower alkyl;
[959] (11) -C (R ¹⁴ ) (R ¹⁵ ) -OD ¹ ;
[960] (12) -OD ¹ ;
[961] (13) lower alkyl-CO ₂ -R ¹⁴ ; or
[962] (14) lower alkyl-CO ₂ -D ¹ ;
[963] (b) -TC (R ²³ ) (R ²⁴ )-(C (R ²⁵ ) (R ²⁶ )) ₀ -C (R ²⁷ ) (R ²⁸ ) -UD ¹ ;
[964] (c)
[965]
[966] (d) arylalkyl; or
[967] (e) cycloalkylalkyl;
[968] Wherein R ¹⁴ and R ¹⁵ are each independently:
[969] (a) hydrogen; or
[970] (b) lower alkyl;
[971] R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , and R ²⁸ are each independently:
[972] (a) hydrogen; or
[973] (b) lower alkyl; or
[974] R ²³ and R ²⁷ taken together with the bonded atom, or R ²⁷ and R ²⁸ , form a carbocyclic ring of 3, 4, 5, 6 or 7 atoms, or R ²³ and R ²⁵ form a covalent bond;
[975] Y ⁵ is:
[976] (a) CR ²⁹ R ³⁰ ;
[977] (b) oxygen; or
[978] (c) sulfur;
[979] R ²⁹ and R ³⁰ are each independently:
[980] (a) hydrogen;
[981] (b) lower alkyl;
[982] (c) (CH ₂ ) ₀ -OD ¹ ;
[983] (d) halo; or
[984] R ²⁹ and R ³⁰ taken together are an oxo group;
[985] s is an integer from 2 to 4.
[986] R ⁸ , D ¹ , T, U, K and o are as defined herein;
[987] Conditionally, the compound of formula IV should comprise at least one member selected from the group of at least one nitrite, nitrate, thionitrite or thionitrate.
[988] Another embodiment of the invention is provided as a compound of formula 5 (V):
[989]
[990] (Ⅴ)
[991] here,
[992] X ⁵ is:
[993] (a) oxygen; or
[994] (b) sulfur;
[995] R ³¹ is:
[996] (a) alkoxy;
[997] (b) haloalkoxy, preferably -OCH ₂ F, -OCHF ₂ or -OCHF _2;
[998] (c) alkylthio;
[999] (d) haloalkyl, preferably CF ₃ ;
[1000] (e) halo; or
[1001] (f) lower alkyl;
[1002] R ³² , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ and R ³⁷ are each independently:
[1003] (a) hydrogen;
[1004] (b) halo, preferably F or Cl;
[1005] (c) lower alkyl;
[1006] (d) cycloalkyl;
[1007] (e) haloalkyl, preferably CF ₃ , CF ₂ H or CFH ₂ ;
[1008] (f) -OD ¹ ;
[1009] (g) -OR ⁴³ ;
[1010] (h) -SD ¹ ;
[1011] (i) -SR ⁴³ ;
[1012] (j) -S (O) R ⁴³ ;
[1013] (k) -S (O) ₂ R ⁴³ ;
[1014] (l) unsubstituted or mono- or di-substituted benzyl, wherein the substituents are each independently:
[1015] (1) haloalkyl, preferably CF ₃ ;
[1016] (2) CN;
[1017] (3) halo;
[1018] (4) lower alkyl;
[1019] (5) -OR ⁴³ ;
[1020] (6) -SR ⁴³ ;
[1021] (7) -S (O) R ⁴³ ; or
[1022] (8) -S (O) ₂ R ⁴¹ ;
[1023] (m) phenyl or mono- or di-substituted phenyl, wherein the substituents are each independently:
[1024] (1) haloalkyl, preferably CF ₃ ;
[1025] (2) CN;
[1026] (3) halo;
[1027] (4) lower alkyl;
[1028] (5) -OR ⁴³ ;
[1029] (6) -SR ⁴³ ;
[1030] (7) -S (O) R ⁴³ ; or
[1031] (8) -S (O) ₂ R ⁴¹ ; or
[1032] R ³² together with R ³³ form an oxo group; or
[1033] R ³⁴ forms an oxo group with R ³⁵ ; or
[1034] R ³⁶ together with R ³⁷ form an oxo group; or
[1035] R ³² and R ³³ together with the carbon bonded to form a 3, 4, 5, 6, or 7 membered saturated monocycling and optionally contain heteroatoms which are preferred oxygen; or
[1036] R ³³ and R ³⁴ together with the carbon bonded to form a 3, 4, 5, 6, or 7 membered saturated or aromatic monocycling; or
[1037] R ³³ and R ³⁶ together with the carbon bonded to form a 3, 4, 5, 6, or 7 membered saturated or aromatic monocycling; or
[1038] R ³⁴ and R ³⁵ together with the carbon bonded to form a 3, 4, 5, 6, or 7 membered saturated monocycling and optionally contain heteroatoms which are preferred oxygen; or
[1039] R ³⁴ and R ³⁶ combine with the bonded carbon to form a 3, 4, 5, 6, or 7 membered saturated or aromatic monocycling; or
[1040] R ³⁶ and R ³⁷ together with the carbon bonded to form a 3, 4, 5, 6, or 7 membered saturated monocycling and optionally contain heteroatoms which are preferred oxygen;
[1041] R ³⁸ and R ³⁹ are hydrogen or R ³⁸ and R ³⁹ taken together are oxo;
[1042] R ⁴⁰ , R ⁴¹ and R ⁴² are each independently:
[1043] (a) hydrogen;
[1044] (b) halo;
[1045] (c) lower alkyl;
[1046] (d) alkoxy;
[1047] (e) alkylthio;
[1048] (f) -S (O) -loweralkyl;
[1049] (g) haloalkyl, preferably CF ₃ ;
[1050] (h) CN;
[1051] (i) -N ₃ ;
[1052] (j) -NO ₂ ;
[1053] (k) -SCF ₃ ; or
[1054] (l) -OCF ₃ ;
[1055] R ⁴³ is:
[1056] (a) lower alkyl; or
[1057] (b) optionally mono- or di-substituted benzyl, wherein the substituents are each independently:
[1058] (1) haloalkyl, preferably CF ₃ ;
[1059] (2) CN;
[1060] (3) halo; or
[1061] (4) lower alkyl;
[1062] Optionally, X ⁵ and U taken together with the bonded carbon form a heterocycle ring of 5-, 6-, or 7-members;
[1063] N is an integer of 0-1 in each case;
[1064] D ^1, U and K are as defined herein;
[1065] Conditionally, the compound of formula V should contain at least one member selected from the group of nitrites, nitrates, thionitrites or thionitrates.
[1066] Another embodiment of the invention provides a compound of formula 6 (VI).
[1067]
[1068] In the above formula,
[1069] X ⁶ is:
[1070] (a) oxygen;
[1071] (b) sulfur;
[1072] (c) CH ₂ ;
[1073] (d) -S (O) ₀ ;
[1074] (e) -NH; or
[1075] (f) -C (O);
[1076] Z ⁶ is:
[1077] (a) K;
[1078] (b) -C (O) CH ₃ ; or
[1079] (c) hydrogen;
[1080] R ⁴⁵ is:
[1081] (a) lower alkyl; or
[1082] (b) mono-, di-, tri-tetra- or per-substituted lower alkyl, wherein the substituents are halo, preferably fluorine;
[1083] R ⁴⁶ is:
[1084] (a) a 5 membered mono- or di-substituted aromatic ring containing one selected from O, S, or N, and optionally one, two, or three added N, wherein the substituents are each independently :
[1085] (1) hydrogen;
[1086] (2) lower alkyl;
[1087] (3) halo;
[1088] (4) -O-loweralkyl;
[1089] (5) -S-loweralkyl;
[1090] (6) haloalkyl, preferably CF ₃ ;
[1091] (7) -COCH ₃ ; or
[1092] (8) -S (O) ₂ -lower alkyl;
[1093] (b) a 6 membered mono- or di-substituted aromatic ring comprising 0, 1, 2, 3 or 4 nitrogen atoms, wherein the substituents are each independently:
[1094] (1) hydrogen;
[1095] (2) lower alkyl;
[1096] (3) halo;
[1097] (4) -O-loweralkyl;
[1098] (5) -S-loweralkyl;
[1099] (4) -O-haloalkyl;
[1100] (5) -S-haloalkyl;
[1101] (6) haloalkyl, preferably CF ₃ ;
[1102] (7) CN;
[1103] (8) -N ₃ ;
[1104] (9) -COCH ₃ ;
[1105] (10) -S (O) ₂ -lower alkyl;
[1106] (11) alkenyl; or
[1107] (12) alkynyl;
[1108] (c) cycloalkylalkyl;
[1109] (d) unsubstituted, mono-, di-, tri- or tetra-substituted phenyl or naphthyl, wherein the substituents are each independently:
[1110] (1) halo;
[1111] (2) CN;
[1112] (3) haloalkyl, preferably CF ₃ ;
[1113] (4) -N ₃ ;
[1114] (5) vinyl;
[1115] (6) acetylenyl;
[1116] (7) lower alkyl;
[1117] (8) alkoxy;
[1118] (9) haloalkoxy;
[1119] (10) alkylthio; or
[1120] (11) haloalkylthio;
[1121] (e) unsubstituted, mono-, di-, tri- or tetra-substituted benzoheteroaryl, wherein the substituents are each independently:
[1122] (1) halo;
[1123] (2) CN; or
[1124] (3) haloalkyl, preferably CF ₃ ;
[1125] (f) substituted lower alkyl;
[1126] (g) substituted alkenyl;
[1127] (h) cycloalkyl; or
[1128] (i) lower alkyl-O-lower alkyl;
[1129] R ⁴⁷ is:
[1130] (a) -C (O) -loweralkyl;
[1131] (b) -CN;
[1132] (c) -CO ₂ D ¹ ;
[1133] (d) -CO ₂ -lower alkyl esters;
[1134] (e) -C (O) -NHD ¹ ;
[1135] (f) -S (O) -loweralkyl;
[1136] (g) -S (O) ₂ -lower alkyl;
[1137] (h) -NO ₂ ;
[1138] (i) haloalkyl, preferably CF ₃ ;
[1139] (j) halo;
[1140] (k) K;
[1141] (l) -S (O) ₀ NR ¹⁰ R ¹¹ ; or
[1142] (m) -S (O) _o NR ¹² R ¹³ ;
[1143] R ⁴⁸ is:
[1144] (a) hydrogen; or
[1145] (b) lower alkyl; or
[1146] R ⁴⁷ and R ⁴⁸ are optionally substituted with a cyclic ring which optionally comprises -S (O) ₂ -of mono-, di- or tri-substituted saturated or unsaturated, unsubstituted 5, 6 or 7- Atoms in the bound form, each substituent being independent;
[1147] (a) oxo;
[1148] (b) lower alkyl
[1149] (c) OD ¹ ; or
[1150] (d) = N = OD ¹ ;
[1151] R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , K, D ¹ and o are defined herein;
[1152] It is conditional that the compound of formula VI necessarily comprises at least one nitrate, nitrite, thionitrate or thionitrate group.
[1153] Another embodiment of the present invention provides a compound of formula (VII).
[1154] ...
[1155] From here;
[1156] X ⁷ is:
[1157] (a) oxygen;
[1158] (b) sulfur;
[1159] (c) -NR ⁵¹ ;
[1160] (d) -NOR ⁵² ; or
[1161] (e) -N-NR ⁵² R ⁵³ ;
[1162] X ⁷ is:
[1163] (a) hydrogen;
[1164] (b) halo;
[1165] (c) lower alkyl;
[1166] (d) alkenyl; or
[1167] (e) alkynyl;
[1168] Z ⁷ is:
[1169] (a) -C (O)-;
[1170] (b) oxygen;
[1171] (c) -S (O) _o- ;
[1172] (d) -NR ⁹³ -; or
[1173] (e) covalent bonds;
[1174] R ⁴⁹ is:
[1175] (a) R ³ ; or
[1176] (b) R ⁴ ;
[1177] R ⁵⁰ and R ^{50 '} are independent of each other.
[1178] (a) hydrogen;
[1179] (b) halo;
[1180] (c) lower alkyl;
[1181] (d) aryl;
[1182] (e) arylalkyl
[1183] (f) cycloalkyl
[1184] (g) cycloalkylalkyl
[1185] (h) -OD ¹ ;
[1186] (i) lower alkyl-OD ¹ ;
[1187] (j) carboxamido;
[1188] (k) K;
[1189] R ⁵¹ is:
[1190] (a) lower alkyl;
[1191] (b) alkyl;
[1192] (c) cycloalkyl;
[1193] (d) cycloalkylalkyl;
[1194] (e) aryl;
[1195] (f) arylalkyl;
[1196] (g) heterocyclic rings; or
[1197] (h) lower alkyl-heterocyclic rings;
[1198] R ⁵² and R ⁵³ are independent of each other.
[1199] (a) lower alkyl;
[1200] (b) cycloalkyl;
[1201] (c) cycloalkylalkyl;
[1202] (d) aryl;
[1203] (e) arylalkyl;
[1204] (f) heterocyclic rings; or
[1205] (g) heterocyclic alkyls
[1206] R ⁹³ is:
[1207] (a) hydrogen;
[1208] (b) lower alkyl;
[1209] R ¹ , R ³ , R ⁴ , K and D ¹ and o are defined herein;
[1210] It is subject to the condition that the compound of formula VII must comprise at least one nitrate, nitrite, thionitrate or thionitrate group.
[1211] Yet another embodiment of the present invention provides a compound of formula 8 (iii).
[1212] ...
[1213] Where X ⁸ is:
[1214] (a) oxygen;
[1215] (b) sulfur;
[1216] (c) NR _i ; or
[1217] (d) -CR ⁵⁸ R ⁵⁹ ;
[1218] A ¹ , A ² , A ³ and A ⁴ are each independently carbon or nitrogen provided that at least two A ¹ , A ² , A ³ and A ⁴ are carbon atoms.
[1219] R ⁵⁴ is:
[1220] (a) haloalkylalkyl, preferably fluoroalkylalkyl;
[1221] (b) halo;
[1222] (c) alkylthio;
[1223] (d) alkoxy;
[1224] (e) -NO ₂ ;
[1225] (f) CN;
[1226] (g) lower alkyl-CN;
[1227] (h) heterocyclic rings;
[1228] (i) lower alkyl;
[1229] (j) arylalkyl;
[1230] (k) cycloalkyl; or
[1231] (l) phenyl or mono- or di-substituted phenyl, wherein the substituents are each independently.
[1232] (1) alkylthio
[1233] (2) nitro; or
[1234] (3) alkylsulfonyl;
[1235] R ⁵⁵ is:
[1236] (a) -CO ₂ D ₁ ;
[1237] (b) -C (O) -N (R ⁸ ) (R ⁸ );
[1238] (c) -CO ₂ -lower alkyl;
[1239] (d) -C (O) -N (D ¹ ) -S (O) _2- (C (R _e ) (R _f )) _P -UV; or
[1240] (e) -CO ₂ -lower alkyl -UV;
[1241] R ⁵⁶ is:
[1242] (a) hydrogen;
[1243] (b) phenyl;
[1244] (c) thienyl;
[1245] (d) alkynyl;
[1246] (e) alkenyl; or
[1247] (f) alkyl;
[1248] R _g is:
[1249] (a) hydrogen;
[1250] (b) lower alkyl;
[1251] (c) arylalkyl;
[1252] (d) alkoxy;
[1253] (e) aryloxy;
[1254] (f) arylalkoxy;
[1255] (g) haloalkyl
[1256] (h) haloalkoxy;
[1257] (i) alkylamino;
[1258] (j) arylamino;
[1259] (k) arylalkylamino;
[1260] (l) nitro;
[1261] (m) sulfonamido;
[1262] (n) carboxamido;
[1263] (o) aryl;
[1264] (p) -C (O) -aryl; or
[1265] (q) -C (O) -alkyl;
[1266] Optionally, the monocyclic ring radicals of A ¹ , A ² , A ³ and A ⁴ comprising R _g and 4 of 6 atoms;
[1267] (a) naphthyl;
[1268] (b) quinolyl;
[1269] (c) isoquinolyl;
[1270] (d) quinolizinyl;
[1271] (e) quinoxalinyl; or
[1272] (f) dibenzofuryl;
[1273] R ⁵⁸ and R ⁵⁹ are independent of each other.
[1274] (a) hydrogen;
[1275] (b) lower alkyl
[1276] (c) lower alkyl-phenyl;
[1277] (d) haloalkyl, preferably fluoroalkyl;
[1278] (e) halo;
[1279] (f) -NO ₂ ;
[1280] (g) CN
[1281] (h) lower alkyl-CN;
[1282] (i) alkoxy;
[1283] (j) alkylthio; or
[1284] (k) alkenyl;
[1285] Optionally, R ⁵⁸ and R ⁵⁹ are the cycloalkyls to which they are attached;
[1286] R ⁸ , R _i , R _e , R _f , D ¹ , U, V s and p are defined herein;
[1287] It is subject to the condition that the compound of formula VII must comprise at least one nitrate, nitrite, thionitrate or thionitrate group.
[1288] Another embodiment of the present invention provides a compound of formula 9 (iii).
[1289] ...
[1290] From here,
[1291] X ⁹ is —C (O) —UD ¹ and Y ⁹ is —CH ₂ —CR ⁵ (R ^{5 ′} ) —UD ¹ ; or
[1292] X ⁹ is —CH ₂ -CR ⁵ (R ^{5 ′} ) -UD ¹ and Y ⁹ s C (O) -UD ¹ ; or
[1293] X ⁹ and X ⁹ taken together
[1294] (a) -C (O) -O-CR ⁴ (R ^{4 '} ) -CR ⁵ (R ^5' )-;
[1295] (b)-(CR ⁴ (R ^{4 '} )) _K -CR ⁵ (R ^5' ) -CR ⁵ (R ^{5 '} )-;
[1296] (c) -C (O)-(CR⁴(R^4'))_K-CR⁵(R^{5 '})-;
[1297] (d)-(CR ⁴ (R ^{4 ′} )) _K -CR ⁵ (R ^{5 ′} ) -C (O) —; or
[1298] (e) -C (O)-(CR ⁴ (R ^{4 '} ))-CR ⁵ (R ^5' )-;
[1299] Where X ⁹ is the first carbon atom of a, b, c, d and e.
[1300] R ¹ , R ² , R ⁴ , R ^{4 ′} , R ⁵ , R ^{5 ′} , U, D ¹ and k are defined herein;
[1301] It is subject to the condition that the compound of formula VII must comprise at least one nitrate, nitrite, thionitrate or thionitrate group.
[1302] Another embodiment of the present invention provides a compound of formula 10 (iii)
[1303] ...
[1304] From here,
[1305] When sides h, k and j are single bonds and sides I and l are double bonds, then -X ¹⁰ -Y ¹⁰ -Z ¹⁰ is;
[1306] (a)
[1307] or
[1308] (b)
[1309]
[1310] When side i, k and l single bond and side h and j are double bond, -X ¹⁰ -Y ¹⁰ -Z ¹⁰ is;
[1311] ... (c)
[1312] When side i, k and l single bond and side h and j are double bonds, then -X ¹⁰ -Y ¹⁰ -Z ¹⁰ is
[1313] (a)
[1314] or
[1315] (b)
[1316]
[1317] P ¹⁰ is;
[1318] (a) -N =;
[1319] (b) -NR ^3- ;
[1320] (c) -O-; or
[1321] (d) -S-;
[1322] Q ¹⁰ and Q ¹⁰ are independent of each other:
[1323] (a) CR ⁶⁰ ; or
[1324] (b) nitrogen;
[1325] A ¹⁰ . B ¹⁰ -C... D ¹⁰ -is:
[1326] ^{(a) -CR 4 = CR 4} '-CR 5 = CR 5'-;
[1327] (b) -CR ⁴ (CR ^{4 '} ) -CR ⁵ (CR ^5' ) -CR ⁴ (CR ⁴ ) -C (O)-;
[1328] (c) -CR ⁴ (CR ^{4 '} ) -CR ⁵ (CR ^5' ) -C (O) -CR ⁴ (CR ^{4 '} )-;
[1329] (d) -CR ⁴ (CR ^{4 '} ) -C (O) -CR ⁴ (CR ⁴ ) -CR ⁵ (CR ^5' )-;
[1330] (e) -C (O) -CR ⁴ (CR ^{4 '} ) -CR ⁵ (CR ^5' ) -CR ⁴ (CR ⁴ )-;
[1331] (f) -CR ⁴ (CR ^{4 '} ) -CR ⁵ (CR ^5' ) -C (O)-;
[1332] (g) -CR ⁴ (CR ^{4 ′} ) -C (O) —CR ⁵ (CR ^{5 ′} ) —;
[1333] (h) -C (O) -CR ⁴ (CR ⁴ ) ^' -CR ⁵ (CR ^5' )-;
[1334] (i) -CR ⁴ (CR ^{4 '} ) -CR ⁵ (CR ^5' ) -OC (O)-;
[1335] (j) -CR ⁴ (CR ^{4 '} ) -OC (O) -CR ⁵ (CR ^5' )-;
[1336] (k) -OC (O) -CR ⁴ (CR ^{4 '} ) -CR ⁵ (CR ^5' )-;
[1337] (l) -CR ⁴ (CR ^{4 ′} ) -CR ⁵ (CR ^{5 ′} ) -C (O) —O;
[1338] (m) -CR ⁴ (CR ^{4 ′} ) -C (O) —O—CR ⁵ (CR ^{5 ′} ) —;
[1339] (n) —C (O) —O—CR ⁴ (CR ^{4 ′} ) —CR ⁵ (CR ^{5 ′} ) —;
[1340] (o) -CR ¹² (R ¹³ ) -OC (O) —;
[1341] (p) -C (O) -O-CR ¹² (R ¹³ )-;
[1342] (q) -OC (O) -CR ¹² (R ¹³ )-;
[1343] (r) -CR ¹² (R ¹³ ) -C (O) -O-;
[1344] (s) -N = CR ⁴ -CR ^{4 ′} = CR ⁵ −;
[1345] (t) -CR ⁴ = N-CR ^{4 ′} = CR ⁵ −;
[1346] (u) -CR ⁴ = CR ^{4 ′} -N = CR ^5- ;
[1347] (v) -CR ⁴ = CR ⁵ -CR ^{5 '} = N-;
[1348] (w) -N = CR ⁴ -CR ^{4 ′} = N-;
[1349] (x) -N = CR ⁴ -N = CR ^{4 ′} -;
[1350] (y) -CR ⁴ = N-CR ^{4 ′} = N-;
[1351] (z) -S-CR ⁴ = N-;
[1352] (aa) -SN = CR ^4- ;
[1353] (bb) -N = N-NR ^3- ;
[1354] (cc) -CR ⁴ = NS-;
[1355] (dd) -N = CR ⁴ -S-;
[1356] (ee) -O-CR ⁴ = N-;
[1357] (ff) -ON = CR ^4- ; or
[1358] (cc) -N = CR ⁴ -O-;
[1359] -A ^{10 '} ... B ^{10 '} ... D ^{10 '} ... Is:
[1360] (a) -CR ⁴ = CR ⁵ -CR ^{5 '} =
[1361] (b) -CR ⁴ (R ^{4 '} ) -CR ⁵ (R ^5' ) -CR ⁴ (R ^{4 '} )-;
[1362] (c) —C (O) ^{—CR 4} (R ^{4 ′ ′} ) ^{—CR 5} (R ^{5 ′} ) —;
[1363] (d) -CR ⁴ (R ^{4 '} ) -CR ⁵ (R ^5' ) -C (O)-;
[1364] (e) -N = CR ⁴ -CR ⁵ =;
[1365] (g) -N = N-CR ⁴ =;
[1366] (h) -N = N-NR ^3- ;
[1367] (i) -N = N-N =;
[1368] (j) -N = CR ⁴ -NR ^3- ;
[1369] (k) -N = CR ⁴ -N =;
[1370] (l) -CR ⁴ -N-NR ^3- ;
[1371] (m) -CR ⁴ = NN;
[1372] (n) -CR ⁴ = N-CR ⁵ =;
[1373] (o) -CR ⁴ = CR ⁵ -NR ^3- ;
[1374] (p) -CR ⁴ = CR ⁵ -N =;
[1375] (q) -S-CR ⁴ = CR ^5- ;
[1376] (r) -O-CR ⁴ = CR ⁵ ;
[1377] (s) -CR ⁴ = CR ⁵ -O-;
[1378] (t) -CR ⁴ = CR ⁵ -S-;
[1379] (u) -CR ⁴ = NS-;
[1380] (v) -CR ⁴ = NO-;
[1381] (w) -N = CR ⁴ -S-;
[1382] (x) -N = CR ⁴ -O-;
[1383] (y) -S-CR ⁴ = N-;
[1384] (z) -O-CR ⁴ = N-;
[1385] (aa) -N = N-S-;
[1386] (bb) -N = N-O-;
[1387] (cc) -S-N = N-;
[1388] (dd) -O-N = N-;
[1389] (ee) -CR ⁴ = CR ⁵ -S;
[1390] (ff) -CR ⁴ (R ^{4 '} ) -CR ⁵ (R ^5' ) -S-;
[1391] (gg) -CR ⁴ (R ^{4 '} ) -CR ⁵ (R ⁵ ) -O-;
[1392] (hh) -S-CR ⁴ (R ^{4 ′} ) -CR ⁵ (R ⁵ )-; or
[1393] (ii) -O-CR ⁴ (R ^{4 '} ) -CR ⁵ (R ^5' )-;
[1394] R ⁶⁰ and R ⁶¹ are independently;
[1395] (a) lower alkyl
[1396] (b) haloalkyl, preferably fluoroalkyl;
[1397] (c) alkoxy
[1398] (d) alkylthio
[1399] (e) lower alkyl-OD ¹ ;
[1400] (f) -C (O) H;
[1401] (h)-(CH ₂ ) _q -CO ₂ -lower alkyl
[1402] (i)-(CH ₂ ) _q -CO ₂ D ¹ ;
[1403] (j) -O- (CH ₂ ) _q -S-lower alkyl;
[1404] (k)-(CH ₂ ) _q -S-lower alkyl;
[1405] (l) -S (O) ₂ -lower alkyl;
[1406] (m)-(CH ₂ ) _q -NR ¹² R ¹³ ; or
[1407] (n) -C (O) N (R ⁸ ) (R ⁸ );
[1408] R ¹ , R ² , R ³ , R ⁴ , R ^{4 ′} , R ⁵ , R ^{5 ′} , R ⁸ , R ¹² , R ¹³ , T, D ¹ and q are compounds of formula 10 (VII) as defined herein Subject to at least one of nitrate, nitrite, thionitrate or thionitrate groups.
[1409] Another embodiment of the present invention provides a compound of formula 11 (XI).
[1410] ... (XI)
[1411] From here:
[1412] X ¹¹ is:
[1413] (a) oxygen; or
[1414] (b) CH ₂ ;
[1415] Y ¹¹ is:
[1416] (a) oxygen;
[1417] (b) -H ₂ ;
[1418] (c) -N-OD ¹ ;
[1419] (d) -N-O-lower alkyl;
[1420] (e) -N-O-aryl;
[1421] (f) -N-C (O) -O-lower alkyl;
[1422] (g) -NN (R ⁸ ) (R ⁸ ); or
[1423] (h) -NN (R ⁸ ) -S (O) ₂ -lower alkyl;
[1424] R ⁶² , R ⁶³ , R ⁶⁴ and R ⁶⁵ are independent of each other.
[1425] (a) hydrogen;
[1426] (b) lower alkyl;
[1427] (c) alkoxy;
[1428] (d) halo;
[1429] (e) CN;
[1430] (f) OD ¹ ;
[1431] (g) alkoxy;
[1432] (h) -NR ¹² R ¹³ ;
[1433] (i) -CF ₃ ;
[1434] (j) -NO ₂ ;
[1435] (k) alkylthio;
[1436] (l) -S (O) _O -lower alkyl;
[1437] (m) —C (O) N (R ⁸ ) (R ⁸ );
[1438] (n) -CO ₂ D ¹
[1439] (o) -CO ₂ -lower alkyl; or
[1440] (p) -NR ⁸ -C (O) -lower alkyl;
[1441] R ⁶⁶ i is:
[1442] (a) hydrogen;
[1443] (b) lower alkyl;
[1444] (c) alkenyl;
[1445] (d) alkoxyalkyl;
[1446] (e) cycloalkylalkyl;
[1447] R ⁸ , R ¹² , R ¹³ , o, K and D ¹ are defined herein;
[1448] It is conditional that the compound of formula 11 (XI) necessarily includes at least one nitrate, nitrite, thionitrate or thionitrate group.
[1449] Another embodiment of the present invention provides a compound of formula 12 (XII)
[1450]
[1451] ... (XII)
[1452] From here:
[1453] X ¹² is:
[1454] (a)
[1455]
[1456] (b)
[1457] or
[1458] (c) NR ⁷¹ ;
[1459] Y ¹² is:
[1460] (a)
[1461]
[1462] (b)
[1463]
[1464] (c)
[1465]
[1466] (d)
[1467]
[1468] (e) -NR ⁷³ (R ⁷⁴ );
[1469] (f) hydrogen; or
[1470] (g) K;
[1471] Z ¹² is:
[1472] (a)
[1473]
[1474] (b) R ⁶⁷ ;
[1475] R ⁶⁷ ;
[1476] (a) hydrogen;
[1477] (b) lower alkyl;
[1478] (c) lower alkyl-OD ¹ ;
[1479] (d) -OD ¹ ;
[1480] (e) haloalkyl; or
[1481] (f)
[1482]
[1483] R ⁶⁸ is:
[1484] (a) lower alkyl;
[1485] (b) halo;
[1486] (c) alkoxy
[1487] (d) haloalkyl;
[1488] (e) alkylthio;
[1489] (f) haloalkylthio;
[1490] (g) -OCH _2-
[1491] (h) unsubstituted, mono-, or di-substituted heteroaryl, wherein the heteroaryl is a 5-membered monocyclic aromatic ring, which ring is S, O, or N, and optically 1, 2 or One heteroatom such as 3 additional nitrogen atoms; Or said heteroaryl is a 6 membered monocyclic ring, said ring comprising N and one heteroatom such as optically 1, 2, or 3 additional nitrogens; The substituents are each independently.
[1492] (1) halo; or
[1493] (2) lower alkyl
[1494] (i) -S (O) ₀ -lower alkyl;
[1495] (j) -S (O) ₀ -lower haloalkyl;
[1496] (k) amino;
[1497] (l) alkylamino;
[1498] (m) dialkylamino;
[1499] (n) -N (H) SO ₂ -lower alkyl;
[1500] (o) -N (H) SO ₂ -lower haloalkyl;
[1501] (p) nitro;
[1502] (q) cyano;
[1503] (r) -CO ₂ D ¹ ;
[1504] (s) carboxylic esters;
[1505] (t) lower alkyl-OD ¹ ;
[1506] (u) carboxamides; or
[1507] (v) -C (O) N (R ¹² ) D ¹ ;
[1508] R ⁶⁹ is:
[1509] (a) lower alkyl;
[1510] (b) hydrogen;
[1511] (c) alkoxy;
[1512] (d) mono-di, tri, tetra- or penta-substituted phenyl, wherein the substituents are each independently.
[1513] (1) hydrogen;
[1514] (2) halo;
[1515] (3) alkoxy;
[1516] (4) alkylthio;
[1517] (5) -S (O) ₀ -lower alkyl;
[1518] (6) lower alkyl;
[1519] (7) halo alkyl;
[1520] (8) -CO ₂ D ¹ ;
[1521] (9) -lower alkyl-CO ₂ D ¹ ;
[1522] (10) OD ¹ ;
[1523] (11) -lower alkyl-OD ¹ ; or
[1524] (12) haloalkoxy;
[1525] (e) mono-, di-, tri-substituted heteroaryl, wherein heteroaryl is a 5-membered monocyclic aromatic ring, which ring is S, O, or N and optically 1, 2, or 3 Includes one heteroatom of an additional nitrogen atom; Heteroaryl is a 6 membered monocyclic ring, which ring optically contains one heteroatom of nitrogen and 1, 2, 3 or 4 additional nitrogen atoms; The substituents are each independently:
[1526] (1) hydrogen;
[1527] (2) halo;
[1528] (3) lower alkyl;
[1529] (4) alkoxy;
[1530] (5) alkylthio;
[1531] (6) aryloxy;
[1532] (7) arylthio;
[1533] (8) -CO ₂ D ¹ ;
[1534] (9) -C (O) NH (D ¹ );
[1535] (10) haloalkyl; or
[1536] (11) -OD ¹ ;
[1537] R ⁷⁰ is:
[1538] (a) lower alkyl;
[1539] (b) hydrogen; or
[1540] (c) mono- or di-substituted phenyl, wherein the substituents are each independently.
[1541] (1) hydrogen;
[1542] (2) halo;
[1543] (3) alkoxy;
[1544] (4) haloalkyl; or
[1545] (5) lower alkyl;
[1546] R ⁷¹ is:
[1547] (a) benzoyl, or mono- or di-substituted benzoyl, wherein the substituents are each independently:
[1548] (1) halo;
[1549] (2) lower alkyl;
[1550] (3) alkoxy;
[1551] (b) benzoyl, or mono- or di-substituted benzyl, wherein the substituents are each independently:
[1552] (1) halo;
[1553] (2) lower alkyl;
[1554] (3) alkoxy;
[1555] (c) lower alkyl-pyridinyl, or unsubstituted, mono-di-substituted pyridinyl, wherein the substituents are each independently:
[1556] (1) halo;
[1557] (2) lower alkyl;
[1558] (3) alkoxy;
[1559] (d) -C (O) -pyridinyl, or mono-, or di-substituted -C (O) -pyridinyl, wherein the substituents are each independently:
[1560] (1) halo;
[1561] (2) lower alkyl;
[1562] (3) alkoxy;
[1563] (e) hydrogen;
[1564] (f) aryl;
[1565] (g) cycloalkyl;
[1566] (h) cycloalkylalkyl
[1567] R ⁷² is:
[1568] (a) lower alkenyl-CO ₂ D ¹ ; or
[1569] (b) K;
[1570] R ⁷³ is unsubstituted or mono-substituted lower alkyl, wherein the substituents are each independently:
[1571] (a) hydroxy;
[1572] (b) alkoxy;
[1573] (c) nitro;
[1574] (d) -NH ₂ ;
[1575] (e) alkylamino;
[1576] (f) dialkylamino;
[1577] (g) carboxyl;
[1578] (h) carboxylic esters; or
[1579] (i) carboxamides;
[1580] R ⁷⁴ is:
[1581] (a) hydrogen;
[1582] (b) lower alkyl; or
[1583] (c) -C (O) R ⁷⁶ ;
[1584] R ⁷⁵ is:
[1585] (a) lower alkyl;
[1586] (b) haloalkyl;
[1587] (c) substituted lower alkyl;
[1588] (d) cycloalkyl; or
[1589] (e) unsubstituted, mono-, di- or tri-substituted phenyl or naphthyl, wherein the substituents are each independently:
[1590] (1) halo;
[1591] (2) alkoxy;
[1592] (3) -S (O) ₀ -lower alkyl;
[1593] (4) hydroxy;
[1594] (5) -S (O) ₀ -haloalkyl;
[1595] (6) lower alkyl;
[1596] (7) haloalkyl;
[1597] (8) -CO ₂ D ¹ ;
[1598] (9) -CO ₂ -lower alkyl;
[1599] (10) -S (O) ₂ NR ⁸ (D ¹ );
[1600] (11) -lower alkyl-O-lower alkyl;
[1601] (12) -CN;
[1602] (13) lower alkyl-OD ¹ ;
[1603] (14) aryl alkoxy;
[1604] (15) -C (O) NR ⁸ (D ¹ ); or
[1605] (16) aryl;
[1606] (f) mono-, di-tri-substituted heteroaryl, wherein heteroaryl is a 5-membered monocyclic aromatic ring, which ring is S, O, or N and optically 1, 2, or 3 additional One heteroatom of a nitrogen atom; Heteroaryl is a 6 membered monocyclic ring, which ring optically contains one heteroatom of nitrogen and 1, 2, 3 or 4 additional nitrogen atoms; The substituents are each independently:
[1607] (1) halo;
[1608] (2) alkoxy;
[1609] (3) -S (O) ₀ -lower alkyl;
[1610] (4) hydroxy;
[1611] (5) -S (O) ₀ -haloalkyl;
[1612] (6) lower alkyl;
[1613] (7) haloalkyl;
[1614] (8) -CO ₂ D ¹ ;
[1615] (9) -CO ₂ -lower alkyl;
[1616] (10) -S (O) ₂ NR ⁸ (D ¹ );
[1617] (11) -lower alkyl-O-lower alkyl;
[1618] (12) -N (D ¹ ) S (O) ₂ -lower alkyl;
[1619] (13) lower alkyl-OD ¹ ;
[1620] (14) -N (D ¹ ) S (O) ₂ -haloalkyl;
[1621] (15) -C (O) NR ⁸ (D ¹ ); or
[1622] (16) aryl;
[1623] R ⁷⁶ is:
[1624] (a) alkyl;
[1625] (b) substituted alkyl;
[1626] (c) alkyl-N (D ¹ ) S (O) ₂ -aryl;
[1627] (d) substituted alkyl-cycloalkyl;
[1628] (e) substituted alkyl-heterocyclic rings; or
[1629] (f) arylalkoxy;
[1630] R ⁷⁷ is:
[1631] (a) -OD ¹ ;
[1632] (b) alkoxy; or
[1633] (c) -NR ⁷⁸ R ⁷⁹ ;
[1634] R ⁷⁸ and R ⁷⁹ are independent of each other:
[1635] (a) hydrogen;
[1636] (b) hydroxy;
[1637] (c) alkoxy;
[1638] (d) lower alkyl;
[1639] (e) substituted lower alkyl; or
[1640] R ⁷⁸ and R ⁷⁹ , together with the nitrogen to which they are attached, are heterocyclic rings;
[1641] R ⁸⁰ and R ⁸¹ are independent of each other:
[1642] (a) hydrogen;
[1643] (b) lower alkyl; or
[1644] (c) halo;
[1645] R ⁸⁹ and R ⁸⁹ are independent of each other:
[1646] (a) hydrogen;
[1647] (b) lower alkyl; or
[1648] And R ⁸⁹ and R ^{89 ′} to which they are located together with the carbon to which they are attached are cycloalkyl rings;
[1649] m is an integer from 0 to 6.
[1650] D ¹ , R ¹ , R ⁸ , R ¹² , K, X ⁵ , a, p and o are defined herein; And
[1651] It is conditional that the compound of formula Must contain at least one nitrate, nitrite, thionitrate or thionitrate group.
[1652] Another embodiment of the present invention provides a compound of formula 13 (XIII)
[1653] ... (XIII)
[1654] X ¹³ and Y ¹³ are independent of each other:
[1655] (a) = C (H)-; or
[1656] (b) = N-;
[1657] R ⁹⁰ is:
[1658] (a) lower alkyl;
[1659] (b) lower alkyl-OD ¹ ;
[1660] (c) alkenyl;
[1661] (d) lower alkyl-CN;
[1662] (e) lower alkyl-CO ₂ D ¹ ;
[1663] (f) aryl;
[1664] (g) heterocyclic rings; or
[1665] (h) heterocyclic alkyl;
[1666] R ⁹¹ is:
[1667] (a) mono-, di- or tri-substituted phenyl, wherein the substituents are each independently:
[1668] (1) hydrogen;
[1669] (2) halo;
[1670] (3) alkoxy;
[1671] (4) alkylthio;
[1672] (5) CN;
[1673] (6) haloalkyl;
[1674] (7) lower alkyl;
[1675] (8) -CO ₂ D ¹ ;
[1676] (9) -CO ₂ -lower alkyl;
[1677] (10) lower alkyl-OD ¹ ;
[1678] (11) lower alkyl-NR ¹² R ¹³ ;
[1679] (12) lower alkyl-CO ₂ D ¹ ; or
[1680] (13) -OD ¹ ;
[1681] (b) mono-, di- or tri-substituted heteroaryl, wherein the heteroaryl is a 5-membered monocyclic aromatic ring, which ring is S, O, or N and optically 1, 2, or 3 Includes one heteroatom of an additional nitrogen atom; Heteroaryl is a 6 membered monocyclic ring, which ring optically contains one heteroatom of nitrogen and 1, 2, 3 or 4 additional nitrogen atoms; The substituents are each independently:
[1682] (1) hydrogen;
[1683] (2) halo;
[1684] (3) alkoxy;
[1685] (4) alkylthio;
[1686] (5) CN;
[1687] (6) haloalkyl;
[1688] (7) lower alkyl;
[1689] (8) -CO ₂ D ¹ ;
[1690] (9) -CO ₂ -lower alkyl;
[1691] (10) lower alkyl-OD ¹ ;
[1692] (11) lower alkyl-NR ¹² R ¹³ ;
[1693] (12) lower alkyl-CO ₂ D ¹ ; or
[1694] (13) -OD ¹ ;
[1695] D ¹ , R ¹ , R ¹² and R ¹³ are defined herein;
[1696] It is conditional that the compound of formula 13 (XIII) necessarily includes at least one nitrate, nitrite, thionitrate or thionitrate group.
[1697] Another embodiment of the present invention provides a compound of formula 14 (XIV)
[1698] ... ( Ⅴ)
[1699] X ¹⁴ is:
[1700] (a) -C (O)-; or
[1701] (b) -C (S)-;
[1702] Y ¹⁴ is:
[1703] (a) -O-; or
[1704] (b) -S-;
[1705] A ¹⁴ . B ¹⁴ ... D ¹⁴ is:
[1706] ^{(a) -CR 4 = CR 4} '-CR 5 = CR 5'-;
[1707] (b) -CR ⁴ (R ^{4 ′} ) -CR ⁵ (R ^{5 ′} ) -C (O) —;
[1708] (c) -CR ⁴ (R ^{4 ′} ) -C (O) —CR ⁵ (R ^{5 ′} ) —;
[1709] (d) -C (O) -CR ⁴ (R ^{4 '} ) -CR ⁵ (R ^5' )-;
[1710] (e) -CR ⁴ (R ⁵ ) -OC (O) —;
[1711] (f) -C (O) -O-CR ⁴ (R ⁵ )-;
[1712] (g) -OC (O) -CR ⁴ (R ⁵ )-;
[1713] (h) -SN = CR ^4- ;
[1714] (i) -ON = CR ^4- ;
[1715] (j) -CR ⁴ (R ⁵ ) -NR ³ -C (O) —;
[1716] (k) -C (O) -NR ³ -CR ⁴ (R ⁵ )-;
[1717] (l) -NR ³ -C (O) -CR ⁴ (R ⁵ )-;
[1718] (m) -CR ⁴ (R ⁵ ) -SC (O) —;
[1719] (n) -C (O) -S-CR ⁴ (R ⁵ )-;
[1720] (o) -SC (O) -CR ⁴ (R ⁵ )-;
[1721] (p) -CR ⁴ = CR ^{4 ′} -C (O) —;
[1722] (q) -C (O) -CR ⁴ = CR ^{4 '} -;
[1723] (r) -0-CR ⁴ = CR ^{4 '} -;
[1724] (s) -S-CR ⁴ = CR ^{4 '} -;
[1725] (t) -NR ³ -CR ⁴ = CR ^5- ;
[1726] (u) -S-NR ³ -C (O)-;
[1727] (v) -O-NR ³ -C (O)-; or
[1728] (w) -NR ³ = N = CR ^4- ;
[1729] R ¹ , R ² , R ³ , R ⁴ , R ^{4 ′} , R ⁵ and R ^{5 ′} are defined herein; And
[1730] It is conditional that the compound of formula XIV necessarily includes at least one nitrate, nitrite, thionitrate or thionitrate group.
[1731] Another embodiment of the present invention provides a compound of formula 15 (XV)
[1732]
[1733] ... (ⅩⅤ)
[1734] X ¹⁵ is:
[1735] (a) -C (O)-;
[1736] (b) -CH _2- ;
[1737] (c) -CH (OD ¹ );
[1738] (d) -C = N-O-lower alkyl-;
[1739] (e) -O-;
[1740] (f) -S (O) _0- ;
[1741] (g) -NR ⁹² ; or
[1742] (h) covalent bonds;
[1743] Y ¹⁵ is:
[1744] (a) aryl; or
[1745] (b) cycloalkyl;
[1746] Z ¹⁵ is:
[1747] (a) hydrogen;
[1748] (b) alkyl;
[1749] (c) haloalkyl;
[1750] (d) cycloalkyl-;
[1751] (e) alkoxy;
[1752] (f) alkylthio;
[1753] (g) cycloalkylalkylthio;
[1754] (h) cycloalkylalkoxy;
[1755] (i) -OD ^1- ;
[1756] (j) halo;
[1757] (k) cyano;
[1758] (l) -C (O) OD ¹ ;
[1759] (m) -C (O) -loweralkyl; or
[1760] R ⁹² is:
[1761] (a) hydrogen;
[1762] (b) lower alkyl;
[1763] (c) -C (O) -lower alkyl; or
[1764] (d) -K-;
[1765] R ¹ , D ¹ , K and o are defined herein; And
[1766] It is conditional that the compound of formula XV necessarily contains at least one nitrate, nitrite, thionitrate or thionitrate group.
[1767] Another embodiment of the present invention provides a compound of formula 16 (VI).
[1768] ... (ⅩⅥ)
[1769] From here:
[1770] X ¹⁶ is:
[1771] (a)
[1772]
[1773] (b)
[1774]
[1775] Y ¹⁶ is:
[1776] (a) hydrogen;
[1777] (b) halogen;
[1778] (c) methyl; or
[1779] (d) ethyl;
[1780] Z ¹⁶ is:
[1781] (a) hydrogen; or
[1782] (b) methyl;
[1783] R ⁹³ is:
[1784] (a) chloro; or
[1785] (b) floro;
[1786] R ⁹⁴ and R ^{94 "} are each independently.
[1787] (a) hydrogen; or
[1788] (b) floro;
[1789] R ⁹⁵ is:
[1790] (a) chloro;
[1791] (b) floro;
[1792] (c) hydrogen;
[1793] (d) methyl;
[1794] (e) ethyl;
[1795] (f) methoxy;
[1796] (g) ethoxy; or
[1797] (h) hydroxy;
[1798] R ⁹⁶ is
[1799] (a) chloro;
[1800] (b) floro;
[1801] (c) trifluoromethyl; or
[1802] (d) methyl;
[1803] R ^95: is
[1804] (a) lower alkyl;
[1805] (b) lower alkenyl;
[1806] (c) alkoxy; or
[1807] (d) alkylthio;
[1808] K and X ¹³ are as defined herein;
[1809] It is conditional that the compound of formula (VI) must include at least one nitrate, nitrite, thionitrate or thionitrate group.
[1810] Compounds according to the present invention having one or more asymmetric carbon atoms can be prepared by optically pure enantiomers, pure diastereomers, mixtures of enantiomers, mixtures of diastereomers, racemic mixtures of enantiomers ( racemic mixtures, diastereomeric racemates or mixtures of diastereomeric racemates. All isomers and mixtures of these compounds are included within the scope of the present invention.
[1811] In another aspect, the present invention relates to a novel compound according to the present invention and a method for preparing an intermediate used in the process of preparing the compound. The reaction was carried out with a suitable reaction reagent with a solvent, and the reactants were suitably used to effectively modify. It is a commonly known technique in the art related to organic synthesis that functional aspects in the molecule should be combined by chemical transformation proposed. This sometimes requires judgment by a routineer in the order of the synthesis step, the requirement of a protecting group, and deprotection conditions. Substituents in the starting material may not meet some of the reaction conditions required by some of the preparation methods described, but will readily prepare suitable techniques known in the art with reaction conditions such that these preparation methods and substituents are suitably compatible. The use of sulfur and oxygen protecting groups is well known to protect thiols and alcohol groups against undesired reactions in the synthesis, and many of these protecting groups are already well known and described in Greene and Wuts, Protective Group in Organic Synthesis , Third Edition, John Wiley & Sons, New York (1999).
[1812] The chemical reactions described in the present invention are generally represented in terms most widely used in the preparation of the compounds according to the invention. Occasionally, this reaction may not have been used in the description of each compound that falls within the indicated range. Such compounds should be recognized as techniques commonly used in the art. All these reactions can be carried out by conventional techniques known in the art, such as proper protection of the interfering group, optional alteration of conventional reagents, modification of the procedure of the reaction conditions, or other reactions disclosed in the present invention or compounds of the present invention. It could be done successfully by variations of other conventional methods that can be used in the preparation. In all production methods according to the invention all starting materials are prepared from known or already known starting materials.
[1813] General formulas (I), (II), (III), (IV), (V), (VI), (Ⅶ), (Ⅷ), (Ⅸ), (Ⅹ), (IX), (XII), Compounds of (XIII), (XIV), (XV) and (XVI) are prepared by conventional methods known in the art and examples thereof are described herein. The synthesis of native COX-2 inhibitors (vinitrosated and / or nonnitrosylated COX-2 inhibitors) is disclosed in the following documents: Patents relating to the original compounds of general formulas (I) and (II) U.S. Pat. 5,563,165, 5,616,601, 5,620,999, 5,677,318, 5,668,161, 5,691,374, 5,698,584, 5,710,140, 5,753,688, 5,859,257, 5,908,858,5,5,595,994,385,945 6,020,876, 6,083,969 and 6,071,954, and WO 91/19708, WO 94/15932, WO 94/26731, WO 94/27980, WO 95 / 00501, WO 95/11883, WO 95/15315, WO 95/15316, WO 95/15317, WO 95/15318, WO 95/18799, WO 95/21817 WO 95/30652, WO 96/30 656, WO 96/03387, WO 96/03392, WO 96/03385, WO 96/03387, WO 96/03388, WO 96/09293, WO 96/09304 WO 96/16934, WO 96/19462, WO 96/19463, WO 96/19469, WO 96/25405, WO 96/36617, WO 96/36623 , WO 97/11704, WO 97/13755, WO 97/27181, WO 97/14691, WO 97/16435, WO 97/34882, WO 97/36863, WO 97/40012, WO 97/45420, WO 98/00416, WO 98/11080, WO 98/22422, WO 98/41516, WO 98/46594, NO. WO 98/52937, WO 99/15531, WO 99/23087, WO 99/33796, WO 99/25695, WO 99/61016, WO 99/62884 and WO 99/64415 and European Patent No. 0 745 596, European Patent No. 0 087 629, European Patent No. 0 418 845, European Patent No. 0 554 829, European Patent No. 0 863 134, European Publication Patent 1 006114; Patents related to the original compounds of general formula (III) include US Pat. Nos. 5,733,909 5,789,413 and 5,849,943 and WO 96/13483, WO 97/28120 and WO 97/28121. ; Patents related to the original compounds of general formula (IV) include US Pat. Nos. 5,861,419 and 6,001,843, and WO 96/10012, WO 96/16934, WO 96/24585, and WO. 98/03484, WO 98/24584, WO 98/47871, WO 99/14194, WO 99/14195; Patents related to the original compound of general formula (V) include U.S. Patents 5,436,265, 5,510,368, 5,604,253 and 5,639,780, WO 96/37467, WO 96/37468, WO 96/37469, WO 98/39330 and WO 00/40087; Patents relating to the original compounds of general formula (VI) include US Pat. Nos. 5,409,944, 604,260, 5,968,859, 5,776,984, 5,968,958 and WO 94/13635 and WO 94/20480 WO 96/23786, WO 97/03953, WO 98/33769 and WO 99/15503; Patents related to the original compounds of general formula (iii) include WO 98/41511, WO 99/10331, WO 99/10332 and WO 00/24719; Patents related to the original compound of general formula (iii) include WO 98/47890 and WO 00/23443; Patents related to the original compound of general formula (iii) include US Pat. No. 5,807,873 and WO 98/43966; Patents related to the original compounds of general formula (i) include U.S. Pat.Nos. 5,521,213 and 5,552,422, and WO 96/06840, WO 96/21667, WO 96/31509, WO 99/12930, WO 00/08024 and WO 00/26216; Patents related to the original compound of Formula (XI) include US Pat. Nos. 5,776,967, 5,824,699 and 5,830,911, and International Publication No. 98/04527; Patents related to the original compounds of general formula (XII) include U.S. Patents 5,750,558 and 5,756,531, and WO 97/41100, WO 98/05639, WO 98/21195, WO 98/57924, WO 99/05104 and WO 99/35130; Patents related to the original compound of general formula (XIII) include WO 99/61436; Patents related to the original compound of general formula (XIV) include WO 00/10993; Patents related to the original compound of general formula (XV) include WO 98/32732; Patents related to the original compound of general formula (XVI) include WO 97/09977, WO 99/11605 and WO 99/41224; All of these disclosures are incorporated herein by reference. Originally, the COX-2 inhibitor compound may be nitrified and / or nitrosylated using the methods described in the Examples herein and conventional methods known in the art at one or more sites with oxygen, sulfur and / or nitrogen and the like. Can be. For example, conventional methods for nitrosating and nitrosylating compounds are described in US Pat. Nos. 5,380,758, and 5,703,073; International Publication Nos. WO 97/27749, WO 98/19672; And Oae et al., Org. Prep. Proc. Int., 15 (3) : 165-198 (1983) and the like, all of which are incorporated herein by reference. Methods of nitrosating and / or nitrosylating a compound are described in the Examples herein, and in the above references, in the art for preparing the nitrosated and / or nitrosylated COX-2 inhibitors described herein. Technology can be applied.
[1814] The compounds according to the invention, which inherently comprise a COX-2 inhibitor, are characterized in that they are nitrated and / or nitrosylated at one or more sites, such as oxygen (hydroxy condensation), sulfur (sulphhydryl condensation) and / or nitrogen. It is described. Nitrogenated and / or nitrosylated COX-2 inhibitors according to the present invention are bestowed, converted or released in the biologically active form of nitrogen monoxide (nitric oxide).
[1815] Nitrogen monoxide NO is ^- there are three types of (nitroxyl), NO · (uncharged nitric oxide) and NO ⁺ (nitro sonyum). NO. Is a highly reactive short-lived species that is potentially toxic to cells. There is a limit because the pharmacological efficacy of NO depends on the form being delivered. Nitric oxide radical (NO ·) In contrast to the nitro sonyum (NO ⁺⁾ is O ₂ or O ₂ ^- species and do not react, and NO ⁺ and NO ^- the transport and release functionality is decomposed in the presence of many redox metals Interfere with being. Thus, administration of charged NO equivalents (positive and / or negative) is a more effective vehicle for biologically activated NO at the desired site of activity.
[1816] Compounds intended to be used in the present invention (nitrogenated and / or nitrosylated COX-2 inhibitors) are intended to release nitric oxide and nitric oxide or others directly or indirectly, or to induce the activity of nitric oxide, such as cell membranes in vivo. And optionally used through compound binding to convert nitrogen monoxide to a biologically active form at the site.
[1817] The term “nitric oxide” includes non-charged nitric oxide (NO ·) and charged nitrogen monoxide species, and more preferably charged nitric oxide species, such as nitrosonium ions (NO ⁺ ) and Nitroxyl ions (NO ⁻ ) and the like. The reaction form of nitric oxide can be prepared in the form of nitric oxide gas. Compounds that release, transport, or convert nitrogen monoxide have an F-NO structure, where F is a portion that releases, transports, or converts nitrogen monoxide, and some and all of the above compounds are activated in a form for which nitrogen monoxide is intended. Nitrogen monoxide is supplied to the intended active site. The term "NO adduct" refers to mono-nitrosylated, poly-nitrosylated, mono-nitrosified and / or poly-nitrosified at various binding sites that naturally accept or artificially supply biologically activated forms of nitrogen monoxide. Can be.
[1818] A group of NO addition products is S-nitrosothiols, a compound containing at least one -S-NO group. The compounds include S-nitroso-polypeptides (the term "polypeptide" includes proteins and polyamino acids and derivatives thereof that do not have the identified biological function); S-nitrosylated amino acids (including natural and synthetic amino acids and their stereoisomers, racemic mixtures and derivatives thereof); S-nitrosylated sugars; S-nitrosylated, modified and unmodified oligonucleotides (preferably at least 5 and more preferably 5-200 nucleotides); Straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted S-nitrosylated hydrocarbons; And S-nitroso heterocyclic compounds. S-nitrosothiols and methods for their preparation are described in US Pat. Nos. 5,380,758 and 5,703073; International Publication Nos. WO97 / 27749, WO 98/19672; And Oae et al, Org. Prep. Proc. Int ., 15 (3) : 165-198 (1983), incorporated herein by reference in their entirety.
[1819] Another embodiment of the present invention includes S-nitroso amino acids which are nitroso groups bonded with sulfur groups consisting of sulfur-containing amino acids or derivatives thereof. Examples of such compounds include S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine, S-nitroso-cysteine, S-nitroso-glutathione, S-nitroso-cysteinyl-glycine have.
[1820] Suitable S-nitrosylated proteins include tissue-type plasminogen activator (TPA) and cathepsin B; Carrier proteins such as lipoproteins; Heme proteins, such as hemoglobin and serum albumin; And thiol-containing proteins (in the NO group in amino acids and their derivatives) in several functional classes, including enzymes such as biologically protective proteins such as immunoglobulins, antibodies and cytokines. Or more sulfur groups attached). Such nitrosylated proteins are described in WO 93/09806, which is incorporated herein by reference in its entirety. Embodiments also include polynitrosylated albumins in which one or more thiols or other nucleophilic centers of the protein have been modified.
[1821] Examples of suitable S-nitrosothiols are as follows:
[1822] (Iii) HS (C (R _e ) (R _f )) _mm SNO;
[1823] (Ii) ONS (C (R _e ) (R _f )) _mm R _e ; And
[1824] (Iii) H ₂ N—CH (CO ₂ H) — (CH ₂ ) _mm —C (O) NH—CH (CH ₂ SNO) —C (O) NH—CH ₂ —CO ₂ H;
[1825] Wherein mm is an integer from 2-40; R _e and R _f are each independently hydrogen, alkyl, cycloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, arylheterocyclic ring, cycloalkylalkyl, heterocyclicalkyl, alkoxy, haloalkoxy, amino, Alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, alkoxyhaloalkyl, haloalkoxy, sulfonic acid, sulfonic esters, alkylsulfonic acid, arylsulfonic acid, arylalkoxy, alkylthio, arylthio, Cyano, aminoalkyl, aminoaryl, alkoxy, aryl, arylalkyl, carboxamido, alkylcarboxamido, arylcarboxamido, amidyl, carboxyl, carbamoyl, alkylcarboxylic acid, arylcarboxyl Acids, alkylcarbonyls, arylcarbonyls, esters, carboxyl esters, alkylcarboxyl esters, arylcarboxyl esters, haloalkoxy, sulfonamido, alkylsulfonamido, arylsulfonamido, alkyl Sulfonyl, alkylsulfonyloxy, arylsulfonyl, aryl sulfonyloxy, carbamoyl, a urea, a nitro, -TQ-, or _{(C (R e) (R} f)) k -TQ-, or R _e and R _{f is} all oxo, methaneial, heterocyclic ring, cycloalkyl group or bridged cycloalkyl group; Q is -NO or -NO ₂ ; And T is independently a covalent bond, carbonyl, acid, -S (O) _o -or -N (R _a ) R _i- , where o is an integer from 0-2 and R _a is an isolated pair of electrons, Hydrogen or an alkyl group; R _i is hydrogen, alkyl, aryl, alkylcarboxylic acid, arylcarboxylic acid, alkylcarboxyl ester, arylcarboxyl ester, alkylcarboxamido, arylcarboxamido, arylsulfinyl, arylsulfonyloxy, Arylsulfonyl, sulfonamido, carboxamido, carboxyl ester, aminoalkyl, aminoaryl, -CH ₂ -C (TQ) (R _e ) (R _f )), or-(N ₂ O ₂ −) ^- · M ^+, where M ⁺ is an organic or inorganic proton; "-TQ" is hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group.
[1826] Wherein when R _e and R _f are heterocyclic rings or R _e and R _f are both heterocyclic rings, R _i as defined above may be a substituent in the disubstituted nitrogen contained in the radical.
[1827] Nitrosothiol can be prepared by various synthetic methods. In general, thiol precursors are first prepared and then reacted with NaNO ₂ under acidic conditions (about pH 2.5) to nitrosate the thiol groups to convert to S-nitrosothiol derivatives to produce S-nitroso derivatives. Acids usable above include water-soluble sulfuric acid, acetic acid and hydrochloric acid. Thiol precursors can also be nitrosylated by reaction with organic nitrites such as tert-butyl nitrite or nitrosonium salts such as nitrosonium tetraflurorborate in an inert solvent.
[1828] Another group of NO addition products used in the present invention include compounds consisting of at least one ON-O-, ON-N- or ON-C group, which compounds donate, transport and release nitric oxide. The compound consisting of at least one ON-O-, ON-N- or ON-C group preferably comprises ON-O-, ON-N- or ON-C-polypeptides (the term "polypeptide" Proteins and polyamino acids having no function, and derivatives thereof); ON-O-, ON-N- or ON-C-amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures); ON-O-, ON-N- or ON-C-sugars; ON-O-, ON-N- or ON-C- modified or unmodified oligonucleotides (comprising at least 5 or more nucleotides, preferably 5-200 nucleotides); ON-O-, ON-N- or ON-C- straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbons; And ON-O-, ON-N- or ON-C-heterocyclic compounds and the like can be used.
[1829] Another group of the NO addition product used in the present invention includes a compound consisting of at least one O ₂ NO—, O ₂ NN— or O ₂ NC group, and the compound may contain nitrates that donate, transport and release nitrogen oxides. Include. Preferred examples of such compounds include O ₂ NO—, O ₂ NN— or O ₂ NC-polypeptides (the term “polypeptide” includes proteins and polyamino acids, and derivatives thereof, having no identified biological function); O ₂ NO-, 0 ₂ NN- or 0 ₂ NC-amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures); O ₂ NO—, O ₂ NN— or O ₂ NC-sugars; O ₂ NO—, O ₂ NN— or O ₂ NC— modified or unmodified oligonucleotides (comprising at least 5 or more nucleotides, preferably 5-200 nucleotides); O ₂ NO—, O ₂ NN— or O ₂ NC— straight or branched chain, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon; And O ₂ NO—, O ₂ NN— or O ₂ NC— heterocyclic compounds. More preferred examples of compounds consisting of at least one O ₂ NO—, O ₂ NN— or O ₂ NC group include isosorbide dinitrate, clonitrate, erythrityltetranitrate Mannitol hexanitrate, nitroglycerin, pentaerythritoltetraitrate, and pentrinitrol. Suitable -S-NO ₂ compounds are polypeptides or hydrocarbons in which there is one or more pairs of thiols structurally close enough to allow the thiol pair to be reduced to disulfide. Compounds that form disulfide species release nitroxyl ions (NO ⁻ ) and uncharged nitric oxide (NO ·). Compounds in which the thiol groups are not close enough to form disulfide bonds generally produce NO ^- form nitrogen oxides rather than non-charged NO.
[1830] Another NO adduct group is N-oxo-N-nitrosoamine which donates, transports and releases nitric oxide, which may be represented by the general formula R ¹ R ² -N (OM ⁺ ) -NO. . Wherein R ¹ and R ² are each independently a polypeptide, amino acid, sugar, modified or unmodified oligonucleotide, straight or branched chain, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or heterocyclic M ⁺ is an organic or inorganic cation such as alkyl substituted with an ammonium cation or a Group I metal cation.
[1831] The present invention also relates to compounds which promote endogenous NO in vivo or increase the level of EDRF induced in the endothelial endothelium or become substrates of nitric oxide synthase. Such compounds include, for example, L-arginine, L-homoarginine and N-hydroxy-L-arginine, and their nitrified and nitrosylated analogs (e.g., nitrosified L). Arginine, nitrosylated L-arginine, nitrosified N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosified L-homoarginine, nitrosylated L-homoarginine), L-arginine Precursors and / or their physiologically acceptable salts, such as citrulline, ornithine or glutamine, enzyme arginase inhibitors (N-hydroxy-L-arginine and 2 (S)) Substrates of amino-6-boronohexanoic acid) and nitric oxide synthase, cytokines, adenosine, bradykinin, calreticulin, bisaccodyl and Phenolphthalein. EDRF is an endothelial vascular relaxor identified as nitric oxide (NO) or closely related to its derivatives (Palmer et al., Nature , 327: 524-526 (1987); Ignarro et al., Proc) Natl.Acd.Sci . USA , 84; 9265-9269 (1987)).
[1832] In another embodiment of the present invention, at least one compound that is presenting, transporting, releasing at least one COX-2 inhibitor and nitric oxide, EDRF EH increases the level of nitric oxide, or is a substrate of nitric oxide synthase The compound containing the above is provided. Originally, COX-2 inhibitors include not only the novel compounds according to the invention, but also those already known in the prior art, including those described in the patents and publications cited herein.
[1833] The invention also relates to compounds and compositions according to the invention, such as steroids, nonsteroidal anti-inflammatory compounds (NSAIDs), which are used in part or in whole together with other therapeutic agents in adjuvant therapy instead of other conventional anti-inflammatory compounds, 5-lipoxygenase (5-lipoxygenase) (5- LO) inhibitors, leukotriene _{B 4 (leukotriene B 4; LTB} 4) receptor antagonist (receptor antagonists), leukotriene A ₄ (LTA ₄₎ hydrolase inhibitors, 5-HT Agonists, 3-hydroxy-3-methylglucaryl coenzyme A (HMG-CoA) inhibitors, H ₂ antagonists, antineoplastic agents, antiplatelet agents, decongestants Antihistamine, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, proton pump inhibitors, isoprostanes, used as diuretics, sedatives or anxiety agents prostane) inhibitors and mixtures thereof.
[1834] The leukotriene A ₄ (LTA ₄ ) hydrolase inhibitor is a compound that selectively inhibits only leukotriene A ₄ hydrolase, and the IC ₅₀ is about 10 μM or less, and more preferably the IC ₅₀ is about 1 μM. Suitable LTA ₄ hydrolase inhibitors are not particularly limited and include, but are not limited to, RP-64966, (S, S) -3-amino-4- (4-benzyloxyphenyl) -2-hydroxybutylic acid benzyl ester (Scripps Res. Inst.), N- (2 (R)-(cyclohexylmethyl) -3- (hydroxycarbomoyl) propionyl) -L-alanine (Searle), 7- (4- (4-ureidobenzyl) phenyl ) Peptanenoic acid (Rhone-Poulenc Rorer), and 3- (3- (1E, 3E-tetradecadienyl) -2-oxyranyl) benzoic acid lithium salt (Searle) and mixtures thereof.
[1835] Suitable LTB ₄ receptor antagonists include, but are not particularly limited to, ebselen, linazolast, ontazolast; YAY121006 from American Home Products; Bay-x-1005 from Bayer; BI-RM-270 from Boehringer Ingleheim; CGS-25019 from Ciba Geigy; ETH-615 from Leo Denmark; MAFP (Merck); TMK-688 from Terumo; T-0757 from Tanabe; LY 213024, LY 210073, LY 223982, LY 233469, LY 255283, LY 264086, LY 292728 and LY 293111 from Eli Lilly; ONO-LB457, ONO-4057 and ONO-LB-488 (ONO), S-2474, calcirol (Shitonigi); PF 10042 from Perdu Frederick; Pfizer 105696 from Pfizer Inc .; RP 66153 (Rhone-Poulenc); SC-53228, SC-41930, SC-50605, SC-51146 and SC-53228 (Searle); SB-201146 and SB-209247 from SmithKline Beecham; SKF-104493 from SmithKline &French; SM 15178 from Sumitamo; TMK-688 from Terumo; Warner Lambert, BPC 15; And mixtures thereof. Of the LTB ₄ receptor antagonists, preference is given to using calcitrol, ebbselen, Bay-x-1005, CGS-25019C, ETH-615, LY-293111, ONO-4057 and TMK-688 and mixtures thereof.
[1836] Suitable 5-LO inhibitors are not particularly limited and include A-76745, 78773 and ABT761 (Abbott compounds); Bay-x-1005 from Bayer; CMI-392 from Cytomed; E-3040 from Eisai; EF-40 from Scotia Pharmaceutical; F-1322 from Fufirebio; ML-3000 from Merckle; PF-5901 from Purdue Frederick; R-840 from 3M Pharmaceuticals; Rilopirox, flobufen, linasolast, lonapolene, mesoprocol, ontasolast, tenidap, zileuton ), Franlukast, tepoxalin, rilopirox, flezelastine hydrochloride, enzadrem phosphate, and bunaprolast ( bunaprolast) and mixtures thereof. As to suitable 5-LO inhibitors, see G.D. It is described in more detail in WO 97/29776 filed by Searle & Co ..
[1837] Suitable 5-HT agonists include, but are not particularly limited to, rizatriptan, sumatriptan, naratriptan, zolmitroptan, eleptriptan, almotriptan ( almotriptan), ergot alkaloids, ALX 1323, Merck L 741604 SB 220453 and LAS 31416. Suitable 5-HT agonists are described in more detail in WO 0025779 filed by Merck & Co., Inc. and WO 00/48583 filed by Pozen Inc. 5-HT agonists refer to compounds that are agents for any 5-HT receptor, including, but not limited to, 5-HT ₁ agonists, 5-HT _1B agonists, and 5-HT _1D agonists.
[1838] Suitable steroids include but are not limited to budesonide, dexamethasone, corticosterone, prednisolone and the corresponding ones. More suitable steroids are listed in the literature such as Merck Index on CD-ROM, Twelfth Edition, Version 12: 1, 1966.
[1839] Suitable HMG CoA inhibitors include reductase or synthase inhibitors, including, for example, squalene synthetase inhibitors, benzodiazepine squalene synthetase inhibitors, Squalene epoxidase inhibitors, acylcoenzyme A, bile acid sequestrants, cholesterol absorption inhibitors, and the like, but are not limited thereto.
[1840] Suitable NSAIDs include, but are not limited to, acetaminophen, aspirin, diclofenac, ibuprofen, ketoprofen, naproxen, and the like.
[1841] Suitable NSAIDs are described in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 617-657; And more such varieties in literature such as Merck Index on CD-ROM, Twelfth Edition, Version 12: 1, 1996.
[1842] Roneun suitable hydrogen receptor antagonist (H ₂ receptor antagonists) cimetidine (cimetidine), rock Sati Dean (roxatidine), it is not intended to be tidin (rantidine) and one including those corresponding limited thereto. Suitable hydrogen receptor antagonists include Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 901 to 915; And more such varieties in literature such as Merck Index on CD-ROM, Twelfth Edition, Version 12: 1, 1996.
[1843] Suitable tumor growth inhibitors include 5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, altretamine and anaxirone. ), Aclarubicin and its equivalents. Suitable tumor growth inhibitors are also described in US Pat. 6,025,353 and G.D. More varieties are listed in literature such as WO 00/38730, assigned to Searle & Co.
[1844] Suitable antiplatelet agents include, but are not limited to, aspirin, ticlopidine, dipyridamole, clopidogrel, glycoprotein IIb / IIIa receptor antagonists and their equivalents. It doesn't happen.
[1845] Suitable decongestants include phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline ), Propylhexedrine, levo-desoxyephedrine and the corresponding ones, but are not limited thereto.
[1846] Suitable antitussives include, but are not limited to, codeine, hydrocodone, caramiphen, carbetapentane, dextramethorphan, and the like.
[1847] Suitable proton pump inhibitors include, but are not limited to, omeprazole, lansoprazole, rabeprazole, pantoprazole and the corresponding ones. Suitable proton pump inhibitors are described in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 901 to 915; And more such varieties in literature such as Merck Index on CD-ROM, Twelfth Edition, Version 12: 1, 1996.
[1848] The compounds and components of the present invention may be used in combination formulations with opioids and other analgesics. The opioids and other analgesics include nacotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic analgesics; For example, non-additive analgesics, monoamine uptake inhibitors, adenosine regulating agents, cannabinoid derivatives, neurokinin 1 receptor antagonists (neurokinin) 1 receptor antagonists, Substance P antagonists, neurokinin-1 receptor antagonists, sodium channel blockers, N-methyl-D-aspartate receptor antagonists ( N-methyl-D-aspartate receptor antagonists) and mixtures thereof, including but not limited to. The combination formulation is morphine, meperidine, codeine, pentazocine, buprenorphine, butorphanol, dezocine, meptazinol (meptazinol), hydrocodone, oxycodone, methadone, tramadol (+ enantiomer) (Tramadol (+ enantiomer)), DuP 747, Dynorphine A, Enadoline , RP-60180, HN-11608, E-2078, ICI-204448, acetominophene (paracetamol), propoxyphene, nalbuphine, E-4018, philenadol ( filenadol), mirtentanil, amitriptyline, DuP631, tramadol (-enantiomer), GP-531, acadeine, AKI-1, AKI- 2, GP-1683, GP-3269, 4030W92, tramadol racemate, Dynorphine A, E-2078, AXC3742, SNX-111, ADL2-1294, ICI-204448, CT-3 , CP-99,994, CP-99,994 and mixtures thereof.
[1849] The compounds and components of the present invention may also be used in combination with nitric oxide synthase inhibitors. Suitable nitric oxide synthase inhibitors are described in US Pat. 5,132,453 and 5,273,875 and WO 97/38977 and WO 99/18960, each of which is hereby incorporated by reference in its entirety.
[1850] The present invention is also based on the discovery that the administration of an amount that exhibits a therapeutic effect of the compounds and components described in this article is effective in treating inflammation, pain (both chronic and acute pain) and fever. Painkillers for treating pain, including, but not limited to, headaches, migraines, postoperative pain, tooth pain, muscle pain, pain caused by cancer, rheumatism fever, pandemic flu or other viral Symptoms associated with infection, fever, including but not limited to common cold, low back and throat pain, menstrual irregularities, headache, toothache, sprains, sprains, myositis, neuralgia, synovitis Arthritis, including but not limited to antipyretics, rheumatoid arthritis, degenerative joint disease (osteoarthritis), spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, and arthritis for children. For example, a patient may receive at least one nitrosedated and / or nitrosylated COX-2 inhibitor of the invention in an amount that will be therapeutically effective. In another embodiment, the patient can donate, transfer, or release at least one nitrosated and / or nitrosylated COX-2 inhibitor and nitric oxide, or endogenous EDRF. Or increase the level of nitric oxide or at least one compound that is the substrate of nitric oxide synthase may be administered in an amount that will be therapeutically effective. In another embodiment, the patient has at least one nitrosated and / or nitrosylated COX-2 inhibitor and steroid, nonsteroidal anti-inflammatory compound (NSAID), 5-lipoxygenase (5-LO) inhibitor (5-lipoxygenase inhibitors), Lu KOTRA two yen B ₄ (LTB ₄₎ receptor antagonist _{(leukotriene B 4 (LTB 4)} receptor antagonists), Lu KOTRA two yen A ₄ (LTA ₄₎ hydrolase inhibitors (leukotriene A ₄ (LTA ₄ ) hydrolase inhibitors, 5-HT antagonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H ₂ antagonists, antineoplastic agents, antiplatelet agents agents), decongestants, diuretics, calm or non-truly anti-histamine (sedating or non-sedating anti- histamines), inductive (inducible) nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori (Helicobacter pylori) inhibitor , Proton pump Second, isoprostane inhibitors and, optionally, donate, transfer or release nitric oxide, raise the degree of endogenous EDRF or nitric oxide, or At least one compound that is the substrate of the oxide synthase may be administered in an amount that will be therapeutically effective. The compound may also be administered in the form of a composition or alone.
[1851] Furthermore, in another embodiment of the present invention, the administration of a compound or composition described herein in a therapeutically effective amount to a patient according to their needs to reduce and / or prevent gastrointestinal disorders, or to parent Provided are methods for increasing the gastrointestinal properties of COX-2 inhibitors (eg, non-nitrosated and / or non-nitrosylated COX-2 inhibitors). These gastrointestinal disorders include inflammatory bowel disease, Crohn's disease, gastritis, excitable visceral syndrome, ulcerative colitis, peptic ulcer, stress ulcer, hyperacidity, indigestion, gasparparesis, Zollinger-Ellison syndrome, gastroesophageal liver reflux disease (gastroesophageal reflux disease), bacterial infections (for example, the condition and the high associated to Helicobacter pylori (with the Helicobacter pylori)), short-bowel (anastomosis) syndrome, a predecessor of master Toshio Sat system (mastocytosis) or Lancet Hypersecretory states associated with basophilic leukomia, hyperhistaminemia and hemorrhagic peptic ulcers including neurosurgery, brain damage, severe physical trauma or burns It refers to any disease or disorder of the gastrointestinal system (eg, esophagus, stomach, duodenum and jejunum). For example, a patient may receive at least one nitrosedated and / or nitrosylated COX-2 inhibitor of the invention in an amount that will be therapeutically effective. In another embodiment, the patient can donate, transfer, or release at least one nitrosated and / or nitrosylated COX-2 inhibitor and nitric oxide, or endogenous EDRF. Or increase the level of nitric oxide or at least one compound that is the substrate of nitric oxide synthase may be administered in an amount that will be therapeutically effective. In another embodiment, the patient has at least one nitrosated and / or nitrosylated COX-2 inhibitor and steroid, nonsteroidal anti-inflammatory compound (NSAID), 5-lipoxygenase (5-LO) inhibitor (5-lipoxygenase inhibitors), Lu KOTRA two yen B ₄ (LTB ₄₎ receptor antagonist _{(leukotriene B 4 (LTB 4)} receptor antagonists), Lu KOTRA two yen A ₄ (LTA ₄₎ hydrolase inhibitors (leukotriene A ₄ (LTA ₄ ) hydrolase inhibitors, 5-HT antagonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H ₂ antagonists, antineoplastic agents, antiplatelet agents agents), decongestants, diuretics, calm or non-truly anti-histamine (sedating or non-sedating anti- histamines), inductive (inducible) nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori (Helicobacter pylori) inhibitor , Proton pump Second, isoprostane inhibitors and, optionally, donate, transfer or release nitric oxide, raise the degree of endogenous EDRF or nitric oxide, or At least one compound that is the substrate of the oxide synthase may be administered in an amount that will be therapeutically effective. The compound may also be administered in the form of a composition or alone.
[1852] Moreover, another embodiment of the present invention promotes wound healing (eg, treating ulcers) by administering to a patient as needed their therapeutically effective amounts of the compounds and / or components described herein. Provide a way to. Wounds include and refer to any disorder characterized by damage to muscles or nerve tissue, including but not limited to ulcers, cuts, burns and similar wounds. Ulcers include, but are not limited to, gastrointestinal ulcers, duodenal ulcers, gastritis, and similar diseases, including, but not limited to, disorders of the inner gastrointestinal system characterized by damage to muscles or nervous tissues. For example, a patient may receive at least one nitrosedated and / or nitrosylated COX-2 inhibitor of the invention in an amount that will be therapeutically effective. In another embodiment, the patient can be administered at least one nitrosated and / or nitrosylated COX-2 inhibitor and at least one nitric oxide donor in an amount that will be therapeutically effective. Furthermore, in another embodiment of the present invention, the patient is treated with at least one nitrosedated and / or nitrosylated COX-2 inhibitor and at least one therapeutic agent, optionally at least one nitric oxide donor. Can be administered in an amount effective. The compound may also be administered in the form of a composition or alone.
[1853] Another embodiment of the present invention provides renal and other toxicity (such as, for example, renal toxicity) by administering to a patient the therapeutically effective amount of the compounds and / or components described herein to the patient as needed. It provides a method of reducing or conducting. For example, a patient may receive at least one nitrosedated and / or nitrosylated COX-2 inhibitor of the invention in an amount that will be therapeutically effective. In another embodiment, the patient can be administered at least one nitrosated and / or nitrosylated COX-2 inhibitor and at least one nitric oxide donor in an amount that will be therapeutically effective. Furthermore, in another embodiment of the present invention, the patient is treated with at least one nitrosedated and / or nitrosylated COX-2 inhibitor and at least one therapeutic agent, optionally at least one nitric oxide donor. Can be administered in an amount effective. The compound may also be administered in the form of a composition or alone.
[1854] Another embodiment of the present invention is directed to treating a disorder resulting from increased levels of COX-2 by administering to the patient as needed their therapeutically effective amounts of the compounds and / or components described herein. Provide a way to prevent it. For example, a patient may receive at least one nitrosedated and / or nitrosylated COX-2 inhibitor of the invention in an amount that will be therapeutically effective. In another embodiment, the patient can donate, transfer, or release at least one nitrosated and / or nitrosylated COX-2 inhibitor and nitric oxide, or endogenous EDRF. Alternatively, the level of nitric oxide may be increased or at least one compound that is a substrate of nitric oxide synthase may be administered in an amount that will be therapeutically effective. In another embodiment, the patient has at least one nitrosated and / or nitrosylated COX-2 inhibitor and steroid, nonsteroidal anti-inflammatory compound (NSAID), 5-lipoxygenase (5-LO) inhibitor (5-lipoxygenase inhibitors), Lu KOTRA two yen B ₄ (LTB ₄₎ receptor antagonist _{(leukotriene B 4 (LTB 4)} receptor antagonists), Lu KOTRA two yen A ₄ (LTA ₄₎ hydrolase inhibitors (leukotriene A ₄ (LTA ₄ ) hydrolase inhibitors, 5-HT antagonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H ₂ antagonists, antineoplastic agents, antiplatelet agents agents), decongestants, diuretics, calm or non-truly anti-histamine (sedating or non-sedating anti- histamines), inductive (inducible) nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori (Helicobacter pylori) inhibitor , Proton pump Second, isoprostane inhibitors and, optionally, donate, transfer or release nitric oxide, raise the degree of endogenous EDRF or nitric oxide, or At least one compound that is the substrate of the oxide synthase may be administered in an amount that will be therapeutically effective. The compound may also be administered in the form of a composition or alone.
[1855] Disorders resulting from elevated levels of COX-2 (eg, COX-2 mediated disorders) include, but are not limited to, the following examples. For example, angiogenesis, arthritis, asthma, bronchitis, menstrual abdominal pain, premature birth, tendon inflammation, bursitis; Skin-related conditions such as, for example, psoriasis, eczema, skin trauma, burns, dermatitis; Post-operative inflammation, including, for example, cataract surgery, refractive surgery, and similar ophthalmic surgery; For example, treatment of tumors such as brain cancer, bone cancer, e.g., epithelial cell-derived neoplasia derived from epithelial cells such as basal cell cancer, adenocarcinoma, For example, gastrointestinal cancer such as lip cancer, oral cancer, esophageal cancer, small intestine cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, squamous epithelial cells, and Squamous cell and basal cell cancer, prostate cancer, skin cancer such as renal cell cancer, and other known cancers that affect epithelial cells throughout the body, benign and malignant tumors, tumors, polyps, hereditary adenoma polyps adenomatous polyps, including, but not limited to, adenomatous polyposis, fibrusis manifested by radiation therapy, and similar symptoms, for example, vascular diseases, migraine headaches, and ferriteriosis (periarteritis nodosa), thyroid inflammation, aplastic anemia, Hodgkin's disease, sclerosis, rheumatic fever, form 1 diabetes, neuromuscular junction disease, including myasthenia gravis, multiple sclerosis White matter disease, including sarcoma, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, nephritis, irritability, boils caused by injury, myocarditis anemia and Inflammatory course of treatment of diseases of similar symptoms; For example, treatment of ophthalmic diseases or disorders of retinitis, retinal disease, uveitis, ocular photophobia, acute injury of eye tissues, glaucoma, inflammation of the eye, increased eye pressure and similar symptoms, e.g. viral infections, bladder Treatment of pulmonary inflammation associated with fibrosis and similar symptoms; For example, cerebral cortical dementia including Alzheimer's disease (aging dementia), vascular dementia, multi-infarct dementia, premature dementia, alcoholic dementia, old age dementia, seizures and shock Treatment of any central nervous system disorder with nervous system damage, anemia, traumatic injury and similar symptoms; Treatment of allergic rhinitis, diseases of the respiratory tract, endotoxin shock syndrome, atherosclerosis; Treatment of infection by inflammation and / or bacteria, including, for example, inflammation and / or infection of the eyes, ears, nose, throat, and / or skin; For example, coronary artery disease, aneurysms, atherosclerosis, for example, heart transplant atherosclerosis, myocardial infarction, anemia, embolism, seizures, thrombosis, hypertension, venous thrombosis, thromboembolism, thromboembolism Hearts including atherosclerosis, including but not limited to reclusion, restenosis, peritonitis, unstable peritonitis, shock, heart failure, coronary plaque inflammation Disorders of the vessels, and for example chlamydia induced inflammation, viral induced inflammation, such as vascular grafts, coronary artery bypass surgery, such as angioplasty, stent placement, endometrial resection Treatment and / or prophylaxis of inflammation and similar symptoms associated with surgical operations such as vascular regeneration surgery such as vascular surgery involving arteries, veins, capillaries; For example, treatment and / or prevention of incontinence and similar urinary and / or urogenital tracts; For example, diseases caused by endothelial cell dysfunction, damage to the endothelial cell layer due to hypercholesterolemia in the blood, damage to the endothelial cell layer due to hypoxia, damage to the endothelial cell layer by epidemiological and chemical pests (especially drug use). During or after, also, for example, epidemiologic resumption of stenosis vessels, followed by percutaneous transluminal angiography (PTA) and percutaneous transluminal coronary angiography (PTCA), in the post-infarction phase Treatment of endothelial cell layer dysfunction, including cardiovascular and similar diseases, as well as endothelial cell layer injury, endothelial layer-mediated reocclusion following bypass surgery, and impaired blood supply to peripheral arteries And / or prevention; For example, preservation of organs or positions in organ transplantation and the like; Inhibition and / or prevention of activation, adhesion and infiltration of neutrophils in the inflamed area; There is inhibition and / or prevention of platelet aggregation. The compounds and compositions of the present invention can also be used as pre-anesthetic medications in emergency surgery to reduce the risk of aspiration of acidic gastric juice contents.
[1856] When administered in vivo, the compounds and compositions of the present invention may be combined with acceptable carriers in taxation and may be administered in dosages described herein. The compounds and compositions of the present invention may be administered in a mixture with at least one nitrosated and / or nitrosilicated COX-2 inhibitor and at least one nitric oxide donor and / or therapeutic agent, which are also therapeutic It can be used in combination with one or more additional compounds known to be effective against the condition of a particular disease for the purpose of. Nitric oxide donors, therapeutic agents and / or other additional compounds may be administered immediately prior to or following or concurrently with the administration of nitrosated and / or nitrosilicated COX-2 inhibitors.
[1857] Another embodiment of the invention is a method of treating inflammation, local pain and fever; Treating and / or enhancing the gastrointestinal properties of the COX-2 inhibitor; How to promote wound healing; Treating and / or preventing kidney toxicity; To treat another cyclooxygenase-2 mediated disorders consisting of administration of at least one parent COX-2 inhibitor and at least one nitric oxide donor, optionally, at least one therapeutic agent And / or methods for preventing. For example, a patient may receive at least one parental COX-2 inhibitor of the invention and at least one nitric oxide donor in a therapeutically effective amount. In another embodiment, the patient can receive at least one parent COX-2 inhibitor and at least one nitric oxide donor and at least one therapeutic agent in a therapeutically effective amount. The compound may also be administered in the form of a composition or alone.
[1858] Compounds and compositions of the present invention may be formulated in dosage units comprising a vehicle, adjuvant, and excipient, which are usually nontoxic and therapeutically available, for oral, buccal, parenteral methods, inhalation spray, topical application. application), injections, methods via the skin, methods via the rectum (eg, by the use of suppositories), and may be administered by any useful and effective delivery system. Parenteral methods include subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection or infusion technique.
[1859] Administration of the transdermal compound involves the delivery of a compound of the medicament that is supplied through the skin of the compound to the circulation of the patient's whole body, known to the medical community. Local administration also includes the use of transdermal administration, such as transdermal patches or iontophoresis devices. Other components may also be used in conjunction with the transdermal patch. For example, the composition and / or transdermal patch may comprise one or more preservatives or methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chromide. (benzalkonium chloride) and the like, but may be configured with a disinfectant. Formulation forms for topical administration of the compounds and compositions include creams, sprays, lotions, gels, ointments, eye drops, and nose drops. Ear drops, and similar forms. In this dosage form, the compositions of the present invention are, for example, 1% or 2% (wt / wt) of benzyl alcohol as preservative, emulsified wax, glycerin, isopropyl palmitate, lactic acid, It can be mixed to form a white, smooth, homogeneous, opaque cream or lotion consisting of purified water and sorbitol solution. The composition may also contain polyethylene glycol 400. Compositions include, for example, benzyl alcohol 2% (wt / wt), white petrolatum, emulsified wax, and tenox II (butylated hydroxyanisole, propyl gallate, sheet, as a preservative Citric acid, propylene glycol, can be mixed to make an ointment. Woven pads or rolls of bandaging material (eg gauze) can be infused with a composition of solution, lotion, cream, ointment and can also be used for local application in other forms. have. The composition may also be applied locally using a transdermal system, such as one of an acrylic-based polymer adhesive, infused into the composition with a crosslinking agent or flakes an impermeable lining.
[1860] Solid dosage forms for oral administration include capsules, tablets, effervescent tablets, chewable tablets, pills, powders, sachets, Granules and gels state. In this solid preparation form, the potent compound may be mixed with at least one kind of inert diluent such as sucrose, lactose or starch. Such formulations may also be included in conventional practice with a separate substance, for example a lubricant such as magnesium stearate, in addition to the inert diluent. In the case of capsules, tablets, effervescent tablets, and pills, the dosage form may also include a buffering agent. Soft gelatin capsules may be prepared to include the active compound or a mixture of the composition of the present invention and vegetable oil. Hard gelatin capsules include lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives of gelatin and Granules of the active compound in combination with the same solid powdered carrier. Tablets or pills can be prepared by enteric coatings.
[1861] Liquid dosage forms for oral administration include medically acceptable emulsions, solutions, suspensions, syrups and elixirs, which are inert, commonly used in the art. Diluents, such as water, for example. Such compositions may also contain auxiliaries such as wetting agents, emulsifying and suspending agents and flavoring, sweetening, flavoring and perfuming agents.
[1862] Suppositories for rectal or vaginal of the compounds and compositions of the present invention for treating such as pediatric fever include suitable non-irritating additives such as cocoa butter and polyethylene glycol that are solid at room temperature but liquid at rectal temperature. It can be prepared by mixing with a compound or composition, which will melt in the intestine and release the drug.
[1863] Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, can be prepared according to the known art using suitable dispersing agents, wetting agents and / or suspending agents. Sterile injectable preparations can be sterile injectable solutions or solutions such as non-toxic and injectable diluents or solvents, for example 1,3-butanediol. Among the available vehicles and solvents are water, Ringer's solution, and isotonic sodium chloride solution. In addition, the oil-fixed fungicide is usefully used as a solvent or a suspension medium.
[1864] The composition of the present invention may further contain an organic or inorganic carrier substance which is suitable as an injectable agent and does not deleteriously react with useful additives such as the active compound. Suitable pharmaceutically acceptable carriers include, for example, water, salt solutions, alcohols, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, tarc, surfactants, silicic acid (silicic acid), viscous paraffins, flavor oils, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrolidone, etc. It may contain. Pharmaceutical preparations can be sterilized and, if desired, auxiliaries such as lubricants, preservatives, sterilizers, wetting agents, emulsifiers, salts which affect osmotic pressure, which do not adversely react with the active compound. , Buffers, colorants, aesthetics and / or flavors may be mixed. Particularly suitable carriers for injectables consist of solutions, in particular solutions such as oily or liquid suspensions, emulsions, or implants. Liquid suspensions may include substrates that increase the viscosity of the suspension, for example sodium carboxymethylcellulose, sorbitol and / or dextran and the like. Optionally, the suspension may contain a stabilizer.
[1865] The composition may contain minor amounts of wetting agents, emulsifiers and / or pH buffers as desired. The composition may be a liquid solution, suspension, emulsion, tablet, pill, capsule, powder, which continuously releases the medicament. The compositions can be prepared as suppositories with conventional binders and carriers such as triglycerides. Oral use may contain common carriers such as pharmaceutical levels of mannitol, lactose, starch, magnesium stearate, sodium saccharides, cellulose, magnesium carbonate, and the like. .
[1866] Various delivery systems are known and can be used for administration of the compounds and compositions of the invention, including encapsulation into liposomes, microbubbles, emulsions, microparticles, microcapsules and the like. The formulations required may be administered in a single unit or in the form of a sustained release of the medicament.
[1867] The bioavailability of the composition can be achieved using useful techniques such as grinding, milling, spray dryin, etc., in the presence of suitable additives or agents such as phospholipids or surfactants. Can be increased by micronization.
[1868] Preferred methods of administration of the nitrosed and / or nitrosylated COX-2 inhibitor compositions or the present COX-2 inhibitors for the treatment of gastrointestinal disorders are by oral or inhalation. Preferred methods of administration for the treatment of inflammatory or bacterial infections are oral, topical, transdermal or by inhalation.
[1869] The compositions or compounds of the present invention may be prepared in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, for example, alkali metal salts and addition salts of free acids and free bases. The original nature of the salt is not dangerous and is pharmaceutically acceptable. Suitable pharmaceutically-acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of such inorganic acids include hydrochloric, hydromic, hydrodic, nitric, carbonic, sulfuric and phosphoric acid. However, it is not limited thereto. Suitable organic acids include formic, acetic, propionic, succinic, glycolic, glyconic, lactic, malic, malic, Tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, Glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydrobenzoic, phenylacetic, mandelic (mandelic), embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulphonic, pantothenic, toluensulfonic, 2-hydroxy Ethanolsulphonic, sulfanilic, algenic, β-hydroxybutylic, cyclohexylaminosulfonic, galactaric and galac Aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic groups of organic acids such as galacturonic acid and the like. Suitable pharmaceutically-acceptable base addition salts include metallic salts derived from aluminum, calcium, lithium, magnesium potassium, sodium and zinc or primary, secondary and tertiary amines, cycloamines, N, N'-di Organic salts derived from benzylethylenediamine, chloroprocane, choline, didetanolamine, ethylenediamine; Meglumine (including but not limited to N-methylglucamine and procaine, etc.) All such salts can be prepared by useful methods from the corresponding compounds by reaction of the compound with the appropriate acid or salt.
[1870] As personal needs vary, determination of the optimal range for effective amounts of compounds and / or compositions is known in the art. In general, agents required to provide effective amounts of compounds and compositions that can be applied by those skilled in the art will include age, health condition, physical condition, sex, dietary condition, weight, degree of dysfunction of the patient, Pharmacological considerations such as frequency and status or extent of dysfunction or disease, medical condition of the patient, route of administration, activity, effect, pharmacokinetics and poisoning experience for the specific compound used, drug delivery system in use, and It can vary depending on the administration of the compound as a drug combination.
[1871] The amount of nitrosated and / or nitrosylated COX-2 inhibitors or parent COX-2 inhibitors effective for the treatment of a particular disorder or condition depends on the nature of the disorder or condition. And Goodman and Gilman's standard clinic techniques described above, The Physician's Desk Reference, Medical Economics Company, Inc., Oradell, NJ, (1995); Drug Facts and Comparisons, Inc., St. Luis, Mo, (1993)]. In addition, the precise amount used for manufacture depends on the route of administration and the severity of the disease or disorder, and is determined by the physical and patient conditions.
[1872] The content of the nitric oxide donor in the pharmaceutical composition may contain about 0.1 to 10 times the molar equivalent of the COX-2 inhibitor. A typical daily dose of nitrosated and / or nitrosylated COX-2 inhibitors is about 0.001 mg to 140 mg per kg of body weight, preferably 0.005 to 30 mg, or per day 0.5mg to 7g per patient is recommended. For example, inflammation can be effectively treated by administration of about 0.01 mg to 50 mg / kg body weight and about 0.5 mg to 3.5 h per day. In the administration thereof, the compound may be administered up to 6 times per day, preferably 1 to 4 times, and most preferably, once per day. Effective dosages can be estimated from drug-response curves derived from in-vitro or animal model test systems, and can be in the range of amounts as described below or lower for the commonly available compounds in Physician's Desk Reference. .
[1873] The present invention also provides a pharmaceutical kit comprising one or more containers filled with one or more components of the pharmaceutical compound and composition, which comprises one group of NO and / or NO 2 described herein and the At least one COX-2 inhibitor that can be optically substituted with one or more no donors.
[1874] Such kits include therapeutic agents or compositions such as steroids, NSAIDs, 5-lipoxygenase, (5-LO) inhibitors, leukotriene B4 (LTB4) receptor antagonists and leukotriene A4 ( LTA4) Hydrolase Inhibitor, 5-HT Agonist, HMG-CoA Inhibitor, H2 Antagonist, Antineoplastic, Antiplatlet, Dicongestant, Diuretic, Calm or Unstable Anti-Histamine, Inducible Nitrous oxide synthesis inhibitors, opioids, analgesics, helicobacter pylori inhibitors, proton pump inhibitors, isoprostane inhibitors, etc.], devices for administration of the composition, and governmental activities that control their manufacture. Sales of pharmaceutical or biological products may be added that reflect the form of caution, approval for use, sale or manufacture for human beings.
[1880] The following non-limiting examples are described to enable those skilled in the art to produce and use the present invention. In each example, flash chromatography was performed on 40 micron silica gel (Baker).
[1881] Example 1:
[1882] 4- {5- (4-chlorophenyl) -3-[(nitrooxy) methyl] -3-hydropyrazolyl] benzenesulfonamide.
[1883] 1a.4- {5- (4-chlorophenyl) -3- (hydroxymethyl] -3-hydropyrazolyl] benzenesulfonamide.
[1884] The compound is described in J. Med. Chem., 40: 1347-1365 (1997), the disclosure of which is incorporated by reference in its entirety. Synthesis was performed as described in Example 14a. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.87 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 6.54 (s, lH), 4.79 (s, 2H).
[1885] lb. 4- [5- (4-chlorophenyl) -3-[(nitrooxy) methyl] -3-hydropyrazolyl] benzenesulfonamide.
[1886] To a solution of the product of Example 1a (348 mg, 0.95 mmol) in EtOAc (10 mL) was added a mixture of acetic anhydride (400 μL) and HNO ₃ (85 μl, fuming fuming 90%) at room temperature for 5 minutes. It was added above. The reaction occurred at room temperature for 15 minutes. The mixture was poured into supersoluble Na ₂ CO ₃ . The aqueous layer was extracted with EtOAc. The combined organic layer was dried by Na ₂ SO ₄ and condensed. The residue was chromatographed on silica gel, extracted with 2: 1 Hex: EtOAc to give 210 mg (54%) of the title compound. ¹ H NMR (300 MHz, CDCl ₃ ) 7.90 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 6.61 (s, 1H), 5.55 (s, 2H), 4.97 (s. 2H); ^l ₃ C NMR (75 MHz, CDCl ₃ ) δ146.2, l43.8, 142.4, l4.2, 135.4, 130.0, 129.2, 128.2, 127.6, 127.5, 125.1, 109.2, 67.8.
[1887] Example 2:
[1888] 4- {5- [nitrooxy) methyl] -3-phenylisoxazol-4-yl} benzenesulfonamide.
[1889] 2a.4- [5- (hydroxymethyl) -3-phenylisoxazol-4-yl-] benzenesulfonamide.
[1890] The compound was synthesized according to patent application WO96 / 25405 (the disclosure of which is incorporated by reference in its entirety), as disclosed in Example 10. ^{l H NMR (300 MHz, DMSO} -d 6) δ 7.80 (d, J = 8.3 Hz, 2H), 7.32-7.45 (mult, 9H), 5.71 (t, J = 5.3 Hz, lH), 4.52 (d, J: 4.5 Hz, 2H); ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 69.5, 160.7, 143,5, 132.6, 130.1, 129.8, 128,8, 128.3, 128.2, 126.0, 115.2, 53.3; Scalpel spectrum (APl-TIS), m / z 331 (MH ⁺ ).
[1891] 2b.4- {5- [nitrooxy) methyl] -3-phenylisoxazol-4-yl} benzenesulfonamide.
[1892] Condensed HNO ₃ (40 μL, 0.90 mmol) was added to EtOAc (0.3 mL) at 0 ° C. and acetic anhydride (200 μL, 2.1 mmol) was added to the solution by syringe and at 0 ° C. Stir for 5 minutes. Next, the product of Example 2a (0.1 g, 0.3 mmol) in EtOAc (0.1 mL) was added and stirred at 0 ° C. for 5 minutes. The final mixture is then fractionated by preparative thin layer chromatography (PTLC) extraction with 1: 1 Hex: EtOAc to give the title compound (65 mg, 57%) as oil. The oil is dissolved in CH ₂ Cl ₂ (5 mL) and the solvent is slowly evaporated overnight at room temperature to afford the title compound as white crystals. mp 47-50 ° C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.96 (d, J = 8.4 Hz, 2H), 7.30-7.45 (mult, 7H), 5.49 (s, 2H), 4.89 (br s, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 161.4, 160.5, 142.3, 133.0, 130.4, l ₃ O. ₃ , l 28.9, 128.4, 127.2, l 27.l, 119.5, 62.7; Scalpel spectrum (APl-TIS), m / z 376 (MH ⁺ ).
[1893] Example 3:
[1894] 2- [l-methyl-4- (nitrosothio) -4-piperidyl] ethyl3- (N-{[4- (5-methyl-3-phenylisoxazol-4-yl) phenyl] sul Ponyyl} carbamoyl) propanoate citrate salt
[1895] 3a. Ethyl 2- {l-methyl-4-piperididane} acetate
[1896] n-BuLi (l.6M in Hex, 58.7 mL, 93.6 mmol) solution was added to THF (30 mL) at -78 ° C, N ₂ and triethyl phosphonoacetate (17.5 g, 78.0 mmol). Added. The resulting brown solution was stirred for 30 minutes and then a solution of 4-N-methylpiperidone (8.8 g, 78.0 mmol) in THF (20 mL) was added. The cold bath was removed and the mixture was stirred at room temperature for 2 hours. Water (250 mL) was added and the mixture was extracted with EtOAc (3xl00 mL). The combined organic extracts are dried by Na ₂ SO ₄ . The solvent is evaporated to afford the title compound (13.2 g, 92%). ^{l H NMR (300 MHz, CDCl} 3) δ5.64 (s, 1H), 4.14 (q, J = 7.1Hz, 2H), 3.00 (t, J = 5.1Hz, lOH), 2.32-2.53 (mult, 5H ), 2.29 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H); ^l ₃ C NMR (75 MHz, CDCl ₃ ) δ 1.664, 158.6, 114.2, 59.5, 56.7, 56.1, 45.7, 36.7, 29.3, 14.2.
[1897] Ethyl 2- {l-methyl-4- (phenylmethylthio) piperidyl} acetate
[1898] The product of Example 3a (13.2 g, 72.01 mmol) and benzylmercaptan (8.4 mL, 72.01 mmol) in piperidine (35 mL) were heated at 100 ° C. for 12 h and then cooled to room temperature. Water (50 mL) was added and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried by Na ₂ SO ₄ . The solvent was evaporated and the residue was purified by chromatography on silica gel extracting with 1: 9 MeOH: CH 2 Cl 2 to afford the title compound (11.7 g, 53%) as a viscous liquid. ¹ H NMR (300 MHz, CDCl ₃ ) δ7.18-7.34 (mult, 5H), 4.l7 (q, J = 7.1 Hz, 2H), 3.71 (s, 2H), 2.64 (s, 2H), 2.46- 2.54 (mult, 4H), 2.29 (s, 3H), 1.83-1.95 (mult, 4H), 1.29 (t, J = 7.1 Hz, 3H).
[1899] 3c. 2- [l-methyl-4- (phenylmethylthio) -4-piperidyl] ethan-l-ol
[1900] A solution of diisobutylaluminum hydride in hexane (83 mL, 83 mmol) was added to a solution in which the product of Example 3b (11.7 g, 38.74 mmol) was added to THF (40 mL) at -78 ° C and N ₂ . The cold bath was removed and the mixture was stirred for 1.5 hours. Solid Na ₂ SO ₄ .10H ₂ O (3 g) is added in proportion while stirring until a thick precipitate is formed. 10% MeOH of CH ₂ Cl ₂ (100 mL) was added and the mixture was filtered. The solid was washed with a solution of 10% MeOH added to CH ₂ Cl ₂ (100 mL) and the solvent was evaporated. The residue was chromatographed on silica gel extracted with 1: 9 MeOH: CH ₂ Cl ₂ to afford the title compound (5.2 g, 50.6%) as a solid. ^l N NMR (3OOMHz, CDCl ₃ ) δ 7.20-7.35 (mult, 5H), 3.86 (t, J = 6.4 Hz, 2H), 3.66 (s, 2H), 2.50-2.57 (mult, 4H), 2.29 ( s, 3H), 1.88 (t, J = 6.5 Hz, 2H), 1.65-1.84 (mult, 4H).
[1901] 3d.2- [l-methyl-4- (nitrosothio) -4-piperidyl] ethan-l-ol
[1902] The product of Example 3c (7.8 g, 29.38 mmol) was dissolved in THF (50 mL), cooled to -78 ° C and liquid NH ₃ (-100 mL) was added. Sodium metal (2 g) was added to keep the blue color for 10 minutes. Solid NH ₄ Cl (˜5 g) was added to decolorize, remove the cold bath and evaporate ammonia (12 h). Ether (100 mL) was added to a pale yellow solid and Et ₂ O (10 mL) HCl was added until the solution became acidic. The mixture was left in the cooler for 30 minutes. The solid formed was removed by filtration and washed with Et ₂ O (50 mL). The residue was triturated with MeOH (100 mL) and undissolved solids were removed by filtration. The solvent was condensed to 25 mL and concentrated HCl (2 mL) was added. 90% t-BuONO (3.1 mL, 23.7 mmol) was added by syringe. The resulting greenish yellow solution was stirred at room temperature for 20 minutes and then poured into ice flakes (5 g). 10% Na ₂ CO ₃ (10 mL) was added and the mixture was extracted with EtOAc (3 × 50 mL). The combined organics were dried and condensed with Na ₂ SO ₄ to afford the title compound (3.6 g, 60%) as a green oil. _{^{l H NMR (300MHz, CDCl 3}} ) δ3.88 (t, J = 6.9Hz, 2H), 2.25-2.95 (mult, l3H), 2.30 (s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 62.5, 58.5, 57.8, 51.5, 46-1, 36.4.
[1903] 3e.4- [5- (methyl) -3-phenylisoxan-4-yl] benzenesulfonamide.
[1904] The compound was synthesized according to the description of WO96 / 25405, Example 1. The disclosure of this document includes all references to that document. mp 170 ° C. ¹ H NMR (300 MHz, CD ₃ CN) δ7.90 (d, J = 8.4 Hz, 2H), 7.39-7.49 (mult, 7H), 5.48 (s, 2H), 2.50 (s, 2H); Scalpel spectrum (APl-TIS), m / z 315 (MH ⁺ ),
[1905] 3f.2- [l-methyl-4- (nitrosothio) -4-piperidyl] ethyl3- (N-{[4- (5-methyl-3-phenylisoxazol-4-yl) phenyl ] Sulfonyl) carbamoyl) propanoate.
[1906] The product of Example 3d (0.21 g, 1.03 mmol), the product of Example 3e (0,43 g, 1.03 mmol) and 4- (dimethylamino) pyridine (DMAP, 0.05 g) were mixed in CH ₂ Cl ₂ (10 mL). To the solution, solid DCC (0.34 g, 164 mmol) was added. The solution was stirred at room temperature for 24 hours. The precipitate formed was removed by filtration and the filtrate was condensed under reduced pressure. The crude product is classified by chromatography on silica gel which is extracted with 1: 1 EtOAc: Hex and then 1: 9 MeOH: CH ₂ Cl ₂ . This gives the title compound (178 mg, 29%) into a green foam. ¹ H-NMR (300 MHz, CDCl ₃ ) δ7.94 (d, J = 8.2 Hz, 2H), 7.22-7.39 (mult, 7H), 4.47-4.57 (mult, 2H), 3.56-3.60 (mult, 2H) 3.15-3.25 (mult, 2 H), 2.45-2.90 (mult, 10 H), 2,42 (s, 6H); ^{l 3} C-NMR (75 MHz, CDCl ₃ ) δ 178.5, 173.4, 167.1, 16l.0, 143.0, 133.5, 129.7, 129.5, 128.6, 128.5, 128.4, 126.7, 114.9, 60.0, 56.2, 51.7, 45.5, 41.0, 33.9, 31.8, 30-3, 11.6; Scalpel spectrum (AP1-TIS), m / z 601 (MH ⁺ ).
[1907] 3 g. 2- [l-methyl-4- (nitrosothio) -4-piperidyl] ethyl3- (N-{[4- (5-methyl-3-phenylisoxanol-4-yl) phenyl ] Sulfonyl} carbamoyl) propanoate citrate salt.
[1908] MeOH (0.2 mL) of citric acid (65 mg, 0.34 mmol) was added to the product of Example 3f (170 mg, 0.28 mmol) dissolved in EtOAc (0.8 mL) and MeOH (0.4 mL). 48 hours were left at -20 ° C to crystallize the green solution. The solvent was poured off and the solid was dried under reduced pressure for 16 hours to give the title compound (124 mg, 55%) as shiny green yellow crystals. mp 82-84 ° C. (decom). ¹ H-NMR (300 MHz, CDCl ₃ ) δ8.16 (d, J = 8.4 Hz, 2H), 7.52-7.60 (mult, 7H), 4.43 (t, J = 6.4 Hz, 2H), 3.15-3.25 (mult) , 2H), 2.50-2.99 (mult, 22H); Scalpel spectrum (API-TIS), m / z 601 (MH ⁺ ).
[1909] Example 4: (2- {l-[(4-chlorophenyl) methyl] -5-methoxy-2-methylindol-3-yl} ethyl) nitrooxy
[1910] 4a. 2- {l-[(4-chlorophenyl) methyl] -5-methoxy-2-methylindol-3-yl} ethane-l-ol
[1911] A solution of indometacin (10 g, 28 mmol) in THF (90 mL) was immersed in an ice bath and the internal temperature was maintained at 10-15 ° C. BF ₃ -Et ₂ O (30 mL, 230 mmol) was added to this solution for at least 5 minutes, resulting in a precipitate. Sodium borohydride (4,2g, 110mmol) was added in a portion of 10 minutes or more, resulting in vigorous effervescence. After the gas discharge had settled, the flask was capped and warmed to room temperature. After an hour the pressure leaked through the needle. The heterogeneous mixture was stirred for 6 hours. The mixture was cooled in an ice bath and quenched by addition of saturated NaHCO ₃ . To break the product emulsion, the mixture was acidified with 1N HCl and extracted with a 3: 1 mixture of Et ₂ O: Hexane (270 mL). The organic layer was washed with brine, dried over Na ₂ S0 ₄ and evaporated. The residue was taken up in a 3: 1 mixture of hot Hex: EtOAc (80 mL). Cooling to room temperature gave crystals. Crystallization was completed by cooling to -20 ° C. The solid was removed by filtration, washed with cold 3: 1 Hex: EtOAc (2 × 25), hexanes (1 × 25) and dried in vacuo. This gave the title compound (4.5 g, 49%) as a white solid. mp 113-115 ° C. ^{l H-NMR (300MHz, CDCl} 3) δ7.24 (d, J = 8.4Hz, 2H), 7.06 (d, J = 9.1 Hz, lH), 7.03 (d, J = 3.5 Hz, lH), 6.87 ( d, J = 8.3 Hz, 2H), 6.78 (dd, J = 2.4 and 8.7 Hz, 1H), 5.23 (s, 2H), 3.86 (s, 3H), 3.84 (t, J = 6.5 Hz, 2H), 2.99 (t, J = 6.5 Hz, 2H), 2.29 (s, 3H); Scalpel spectrum (APl-TIS) m / z 330 (MH ⁺ ). Anal calcd for C ₁₉ H ₂₀ ClNO ₂ : C, 69.19; H, 6. 11; N, 4.25; Cl, 10.75. Found: C, 68.98; H, 6. 30; N, 4.08; CI, 10.60.
[1912] 4b. 3- (2-bromoethyl) -l-[(4-chlorophenyl) methyl] -5-methoxy-2-methylindole
[1913] PBr ₃ (17 μL, 0.18 mmol) in the product of Example 4a (160 mg, 0.5 mmol) in toluene (1 mL). The reaction mixture was heated at 100 ° C. for 10 minutes and then cooled to room temperature. The mixture was partitioned between EtOAc and 1N HCl. The aqueous layer was extracted with EtOAc (1 × 10). The combined organic layer was washed with H ₂ O (1 × 10), brine (2 × 10), dried over Na ₂ SO ₄ and evaporated. This resulted in the title compound (170 mg, 87%) that was solidified at all times. This material was no longer purified and used for the next reaction. ¹ H-NMR (300 MHz, CDCl ₃ ) δ7.24 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 9.1 Hz, 1H), 6.99 (d, J = 2.4 Hz, lH), 6.86 (d, J = 8.4 Hz, 2H), 6.78 (dd, J = 2.4 and 8.8 Hz, 1H), 5.23 (s, 2H), 3.87 (s, 3H), 3.56 (t, J = 7.5 Hz, 2H) , 3.28 (t, J = 7.5 Hz, 2H), 2.29 (s, 3H).
[1914] 4c. (2- {l-[(4-chlorophenyl) methyl] -5-methoxy-2-methylindol-3-yl} ethyl) nitrooxy
[1915] The product of Example 4b (170 mg, 0.43 mmol) was dissolved in CH ₃ CN (6 mL). The addition of AgNO ₃ (85 mg, 0.5 mmol) allowed the precipitate to form immediately. After 20 minutes, the reaction was filtered through Celite to condense. The residue was purified by chromatography on silica gel extracted with 5: 1 Hex: EtOAc. This resulted in the title compound (90 mg, 56%) as a white crystalline solid. ^{l H-NMR (3OO MHz,} CDCl 3) δ7.23 (d, J = 8.5 Hz, 2H), 7.07 (d, J = 8.9 Hz, lH), 6.99 (d, J = 2.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.79 (dd, J = 2.4 and 8.4 Hz, 1H), 5.23 (s, 2H), 4,60 (t, J = 7.2 Hz, 2H), 3.87 (s, 3H), 3.14 (t, J = 7.3 Hz, 2H), 2.28 (s, 3H); Mass spectrum (APl-TIS): m / z 375 (MH ⁺ ). _{Anal calcd for C 19 H l9 ClN} 2 O 4: C, 60.88; H, 5.11; N, 7.47; Cl, 9.96. Found: C, 60.89; H, 5. 23; N, 7,36; Cl, 9.58.
[1916] Example 5:
[1917] l- [3- (4-fluorophenyl) -7- (nitrooxymethyl) (3a-hydroimidazolo [1,2-a] pyridin-2-yl] -4- (methylsulfonyl) benzene
[1918] 5a.l- [3- (4-fluorophenyl) -7- (hydroxymethyl) (3a-hydroimidazolo [l, 2-a] pyridin-2-yl)]-4- (methylsulfonyl )benzene
[1919] The compound was prepared according to the process described in patent application WO96 / 31509 (the disclosure of which is incorporated by reference in its entirety), Example 15. ^{l H-NMR (3OO MHZ,} CDCl 3) δ7.80-7.87 (m, 5H), 7.40-7.46 (m, 2H), 7.20-7.33 (m, 3H), 6.82-6.86 (t, 2H, J = 7.0 Hz), 5.11 (s, 2 H), 3.04 (s, 3 H); Scalpel spectrum (APl-TIS) m / z 397 (MH ⁺ ).
[1920] 5b.l- [3- (4-fluorophenyl) -7- (nitrooxymethyl) (3a-hydroimidazolo [l, 2-a] pyridin-2-yl)]-4- (methylsulfonyl )benzene
[1921] A suspension of the product of Example 5a (210 mg, 0.52 mmol) was added to an ice cold mixture of acetic anhydride (393 μL, 4.16 mmol) and nitric acid (110 μL, 2.61 mmol). The resulting mixture was warmed up to 10 ° C. and stirred for 1 hour. The mixture was then diluted with methylene chloride and washed with cold saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and condensed in vacuo. The residue was suspended in a hexane / ethyl acetate (2: 1) mixture and filtered to give 230 mg (99% yield) of an orange solid of the title mixture. mp 145-147 ° C. ^{l H-NMR (300MHZ, CDCl} 3) δ8.07-8.12 (d, 1H, J = 7.0Hz), 7.82-7.56 (m, 4H), 7.48-7.56 (m, 2H), 7.32-7.39 (m, 2H), 6.95-7.01 (t, 1H, J = 7.0 Hz), 5.96 (s, 2H), 3.12 (s, 3H).
[1922] Example 6: ethyl 6-chloro-8-[(nitrooxy) methyl] -2- (trifluoromethyl) -2H-chromen-3 carboxylate
[1923] 6a. Ethyl 6-chloro-8-formyl-2- (trifluoromethyl) -2H-chromen-3 carboxylate
[1924] The compound was synthesized as described in patent application W098 / 47890 (the disclosure of which is incorporated by reference in its entirety), Example 76. ^{l H-NMR (300MHz, CDCl} 3) δ10.39 (s, lH), 7.79 (s, lH), 7.69 (s, lH), 7.40 (s, lH), 5.86 (q, J = 6.6Hz, lH ), 4.31-4.44 (mult, 2H), 1.37 (t, J = 7.1 Hz, 3H); ^l3 C-NMR (75 MHz, CDCL ₃ ) δ 186.3, 163.0, 153.5, 134.4, 134.1, l3O.l, 128.4, 125.0, 124.8, l2l.8, 121.0, 119,2, 7l.1 (q, J _CF = 34 Hz), 62.0, 14.1.
[1925] 6b. Ethyl 6-chloro-8- (hydroxymethyl) -2- (trifluoromethyl) -2H-chromen-3 carboxylate
[1926] Na (OAc) ₃ BH (2.4 g, 11.2 mmol) was added to a solution containing the product of Example 6a (1.5 g, 4.5 mmol) in CH ₂ Cl ₂ (50 mL), and the resulting solution was stirred at room temperature. Stir for 3 days. The solution was poured into water (100 mL), the CH ₂ Cl ₂ layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ (2 × 25 mL). The combined organic layers were dried by Na ₂ SO ₄ . The solvent was evaporated under reduced pressure and the crude material was chromatographed on silica gel extracted with EtOAc: Hexne (1: 5) to afford the title compound (1.2 g, 79%) as a white solid. mp 98-100 ° C. ^{l H-NMR (300MHz, CDCl} 3) 7.66 (s, 1H), 7.41 (d, J = 2.3Hz, lH), 7.16 (d, J = 2.4 Hz, 1H), 5.76 (q, J = 6.7 Hz, lH), 4.71 (d, J: 5.5 Hz, 2H), 4.26-4.70 (mult, 2H), 2.06-2.10 (br mult, lH), 1.15-1.21 (mult, 3H); ^{l 3} C-NMR (75 MHz, CDCl ₃ ) δ 163.4, 146.7, 135.7, 131.2, 130.3, 127.7, 127.6, 121.3, 120.1. 118.0, 70.6 (q, J _CF = 133 Hz), 61.7, 59,6, 14.1; Mass spectrum (API-TIS) m / z 354 (M + NH ₄ ⁺ ). Anal. Calcd for C ₁₄ H ₁₂ ClF ₃ O ₄ : C, 49.94; H, 3.59; F, 16.93; Cl, 10.53. Found: C, 49.83; H, 3.52; F, 17.10; Cl, 10.77.
[1927] 6c. Ethyl 6-chloro-8-[(nitrooxy) methyl] -2- (trifluoromethyl) -2H-chromen-3 carboxylate
[1928] HNO ₃ (340 μL, 3.6 mmol) vapor was added to a solution of acetic anhydride (1.12 mL, 11.8 mmol) in EtOAc (10 mL) at 0 ° C. via an injector. The mixture was stirred at 0 ° C. for 5 minutes. Next, the product of Example 6b (0.5 g, 1.49 mmol) was added to EtOAc (10 mL) and stirred at 0 ° C. for 15 minutes. The reaction mixture was poured into ice cold saturated NaHCO ₃ (25 mL) and shaken well. The organic layer was separated and dried by Na ₂ SO ₄ . The solvent was evaporated under reduced pressure to give a viscous oil dissolved in hexane (15 mL). The resulting solution was allowed to stand for 12 hours at -20 ° C in a cooler to afford the title compound (0.44 g, 77%). mp 53 ° C. ^{l H-NMR (300MHz, CDCL} 3) δ7.65 (s, lH), 7.34 (d, J = 2.4 Hz, lH), 7.25 (d, J = 2.4 Hz, 1H), 5.78 (q, J = 6.6 Hz, 1H), 5,46 (s, 2H), 4.28-4.38 (mult, 3H), 1.35 (t, J = 7.1 Hz, 3H); ^{l 3} C-NMR (75 MHz, CDCl ₃ ) δ 163-0, 150.0, 135.0, l 33.O, 130.0, 127.6, 125,0, 121.8, 121.1, 120.8, 118.8, 71.3 (q, J _CF = 133 Hz), 68.0, 61.8, 14; Mass spectrum (API-TIS) m / z 399 (M + NH ₄ ⁺ ). Anal. Calcd for Cl ₄ H ₁₁ ClF ₃ O ₆ : C, 44.06; H, 2. 90; F, 14.93; Cl, 9.29; N, 3.67. Found: C, 44.00; H, 2.85; F, 14.83; Cl, 9, 14; N, 3.57.
[1929] Example 7: 2- {l-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindol-3-yl} -N- (2-methyl-2- (nitrosothio) propyl Acetamide
[1930] 7a. 2- {l-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindol-3-yl} -N- (2-methyl-2-sulfanylpropyl) acetamide
[1931] A solution of indomethacin (3.6 g, 10 mmol) and Et ₃ N (1.5 mL, ₁₁ mmol) in THF (50 mL) was cooled to 0 ° C. i-butyl chloroformate (1.5 mL, 11 mmol) was added in appropriate amounts and the reaction stirred for 20 minutes. To the resulting solution was added a slurry of 1-amino-2-methyl-2-propanethio.HCl (1.4 g, 10 mmol) and Et ₃ N (1.5 mL, ₁₁ mmol) in DMF (20 mL). The reaction mixture was kept cold for 2 hours, warmed to room temperature and stirred for 1 hour. The mixture was partitioned between Et ₂ O and dilute HCl. The organic layer was separated, washed with saturated NaHCO ₃ , brine, filtered and dried by Na ₂ SO ₄ . Evaporation of the solvent gave a residue that crystallized from EtOAc to give the title compound (1.1 g, 25%) as a white solid. mp 177-178 ° C. ^{l H-NMR (300MHz, CDCl} 3) δ7.67 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 2,3 Hz, lH), 6.91 (d, J = 9.0 Hz, lH), 6.71 (dd, J = 2.5 and 9.1 Hz, 1H), 6.10 (br t, J = 6,3 Hz, 1H), 3.83 (s, 3H), 3.69 (s , 2H), 3.27 (d, J = 6,3 Hz, 2H), 2.42 (s, 3H), 1.36 (s, 1H), 1.26 (s, 6H); Scalpel spectrum (API-TIS) m / z 445 (447) MH ⁺ (l-Cl).
[1932] 7b. 2- {l-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methylindol-3-yl} -N- (2-methyl-2- (nitrosothio) propyl) acetamide
[1933] The product of Example 7a (25 mg, 0.056 mmol) was dissolved in CH ₂ Cl ₂ (1 mL) and cooled to 0 ° C. A solution of t-BuONO (7.5 μL, 0.056 mmol) in CH ₂ Cl ₂ was added in appropriate amounts. The reaction mixture was warmed to room temperature with stirring for 30 minutes. Evaporation of the solvent gave the title compound (25 mg, 100%) as a green crystalline solid. mp 122-125 ° C. dec. ^{l H-NMR (300MHz, CDCl} 3) δ7.64 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 9.1 Hz, lH), 6.82 ( d, J = 2.5 Hz, lH), 6.78 (dd, J = 2.5 and 9,1 Hz, 1H), 5.96 (br t, J = 6.4 Hz, lH), 3.97 (d, J = 6.4 Hz, 2H) , 3.79 (s, 3H), 3,67 (s, 2H), 2.32 (s, 3H), 1.78 (s, 6H); Scalpel spectrum (API-TIS) m / z 491 (493) M + NH ⁺ (l-Cl).
[1934] Example 8: ethyl (2Z) -3- (4-chlorophenyl) -3- [4- (methylsulfonyl) phenyl] -2- [2- (nitrooxy) ethyl] prop-2-enoate
[1935] 8a. Ethyl (2Z) -3- (4-chlorophenyl) -2- (2-hydroxyethyl) -3- [4- (methylsulfonyl) phenyl] prop-2-enoate
[1936] The compound was synthesized as described in US Pat. No. 5,807,873 (the disclosure of which is incorporated by reference in its entirety), Example 64. mp 126 ° C. ^{l H-NMR (300 MHz,} CDCl 3) δ7.93 (dd, J = 1.75 and 8.3 Hz, 2H), 7.46 ( dd, J = 1.78 and 6.7 Hz, 2H), 7.25-7.30 ( mult, 2H), 7.04-7.09 (mult, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.76 (t, J = 6.2 Hz, 2H), 3.09 (s, 3H), 2.62 (t, J = 6.1 Hz, 2H ), 0.97 (t, J = 7.1 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 170.2, 145.6, 144.6, 140.0, 139.5, 134.2, 132.7, 130.3, 129.9, 128.5, 127.6, 61.3, 61.1, 44.4, 35.0, 13.6; Mess spectrum (API-TIS) m / z 409 (MH ⁺ ), 426 (MNH ₄ ⁺ ). Anal. Calcd for C ₂₀ H ₂₁ ClO ₅ S: C, 58.75; H, 5. 18; Cl, 8.67; S, 7.84. Found: C, 58.64; H, 5.02; Cl, 8.80; S, 7.79.
[1937] 8b. Ethyl (2Z) -3- (4-chlorophenyl) -3- [4- (methylsulfonyl) phenyl] -2- [2- (nitrooxy) ethyl] prop-2-enoate
[1938] An appropriate amount of the suspension of the product of Example 8a (2.02 g, 4.95 mmol) of CHCl ₃ (20 mL) in acetic anhydride (3.71 mL, 4.04 g, 39.6 mmol) and 90% nitric acid vapor at −12 ° C. (1.03 mL, 1.56 g, 24.8 mmol) was added to the mixture. The product solution was stirred at -12 ° C for 1 hour. CH ₂ Cl ₂ (30 mL) was added, washed with ice-cold saturated NaHCO ₃ , dried over Na ₂ SO ₄ , and filtered. Evaporation of the solvent gave a residue that crystallized from 1: 2 Hexane: CH ₂ Cl ₂ to give the title compound (1.82 g, 82%) as a white solid. mp 127-128 ° C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.97 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 7.8 Hz, 2H), 7.27-7.31 (mult, 2H), 7.03-7.08 (mult , 2H), 4.59 (t, J = 6.4 Hz, 2H), 4,02 (q, J = 7.1 Hz, 2H), 3.09 (s, 3H), 2.76 (t, J = 6.4 Hz, 2H), 0.98 (t, J: 7.1 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 168.8, 147.6, 145.3, 140.5, 139.2, 134.6, 129.9, 129.8, 129.4, 128.7, 128.0, 70.8, 61.4, 44.5, 29.9, 13.6; Scalpel spectrum (API-TIS) m / z 471 (MNH ₄ ⁺ ). Anal. Calcd for C ₂₀ H ₂₀ ClNO ₇ S: C, 52.92; H, 4. 44; N, 3.09; C1, 7.81; S, 7.06. Found: C, 52.91; H, 4. 35; N, 2.93; Cl, 7.89, S, 7.20.
[1939] Example 9: (2Z) -3- (4-chlorophenyl) -3- [4- (methylsulfonyl) phenyl] 2- [2- (nitrooxy) ethyl] prop-2-enoic acid
[1940] 9a. (2Z) -3- (4-chlorophenyl) -2- (2-hydroxyethyl) -3- [4- (methylsulfonyl) phenyl] prop-2-enoic acid
[1941] NaOH (6.4 mL of 1.5 N, 0.38 g, 9.6 mmol) was added in an appropriate amount to a solution of the product of Example 8a (3.62 g, 8.87 mmol) in EtOH (80 mL) at 0 ° C. The product yellow solution was stirred at room temperature for 2 hours. After evaporation of the solvent, the residue was dissolved in water and washed with EtOAc. Ice flakes were added to the aqueous layer and acidified with 10% HCl to ˜pH = 4 and extracted with EtOAc. The organic layer was dried over Na ₂ S0 ₄ and filtered. Evaporation of the solvent gave a residue that crystallized from EtOAc: Hex: CH ₂ Cl ₂ to give the title compound (2.79 g, 82%) as a white solid. mp 144-145 ° C. ¹ H-NMR (300 MHz, CDCl ₃ / MeOH-d ₄ ) δ 7.98 (d, J = 7.1 Hz, 2H), 7.53 (d, J = 7,0 Hz, 2H), 7.29-7.32 (mult, 2H ), 7.16-7.19 (mult, 2H), 3.71 (t, J = 6.9 Hz, 2H), 3.15 (s, 3H), 2.56 (t, J = 6.8 Hz, 2H); ^l ₃ C NMR (75 MHz, CDCl ₃ ) δ l73.l, 147.4, l45.l, l4l.4, 141.2, 134.9, 134.3, 131.4, 131.3, 129.4, 128.7, 61.3, 61.3, 44.3, 36.3; Mess spectrum (API-TIS) m / z 363 (MH ₂ O), 381 (MH ⁺ ), 398 (MNH ₄ ⁺ ). Anal. _{Calcd forC l8 H l7 ClO 5 S} : C, 56.77; H, 4.50; Cl, 9.31; S, 8.42. Found: C, 56.64; H, 4. 44; Cl, 9.40; S, 8.18.
[1942] 9b. (2Z) -3- (4-chlorophenyl) -3- [4- (methylsulfonyl) phenyl] 2- [2- (nitrooxy) ethyl] prop-2-enoic acid
[1943] An appropriate amount of the suspension of the product of Example 9a (1.37 g, 3.66 mmol) of CHCl ₃ (54 mL) in acetic anhydride (2.72 mL, 2.94 g, 28.8 mmol) and 90% nitric acid vapor at −12 ° C. (0.76 mL, 1.14 g, 18.0 mmol) was added to the mixture. The product solution was stirred at -12 ° C for 30 minutes. CH ₂ Cl ₂ (25 mL) was added, washed with water, dried over Na ₂ SO ₄ and filtered. Evaporation of the solvent gave a residue that crystallized from EtOAc: Hexane: CH ₂ Cl ₂ to give the title compound (0.9 g, 59%) as a white solid. mp 143-144 ° C. ¹ H-NMR (300 MHz / CDCl ₃ ) δ 7.98 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 7.27-7.32 (mult, 2H), 7.07-7.11 (mult , 2H), 4.61 (t, J = 6.3 Hz, 2H), 3.10 (s, 3H), 2.78 (t, J = 6.3 Hz, 2H); ^l ₃ C NMR (75 MHz, CDCl ₃ ) δ 172.8, 150.9, 145.4, l 40 .7, 138.7, l 35.1, 129.8, 129.7, 129.0, 128.1, 127.7, 70.8, 44.5, 30.0; Scalpel spectrum (API-TIS) m / z 443 (MNH ₄ ⁺ ). Anal. Calcd for C ₁₈ H ₁₆ ClNO ₇ S: C, 50.77; H, 3.79; N, 3.29; Cl, 8,33; S, 7.53. Found: C, 50.87; H, 3.67; N, 3.67; Cl, 8.26, S, 7.43,
[1944] Example 10: (2Z) -3- (4-chlorophenyl) -2- (2-hydroxyethyl) -N- [2-methyl-2 (nitrosothio) propyl] -3- [4- (methyl Sulfonyl) phenyl] prop-2-enamide
[1945] 10a. (2Z) -3- (4-chlorophenyl) -N- [2-methyl-2-sulfanylpropyl) -3- [4- (methylsulfonyl) phenyl] -2- [2- (1,1, 2,2-tetramethyl-1-silapropoxy) ethyl] prop-2-enamide
[1946] Dry THF (10 mL) t-butyldimethyl-chlorosilane (0.4 g, 2.63 mmol) in a solution of the product of Example 9a (0.5 g, 1.32 mmol) and imidazole (0.18 g, 2.63 mmol) in dry THF (10 mL). ) Was added in an appropriate amount at room temperature. The resulting white float was stirred at room temperature for 16 hours. The reaction mixture is partitioned between EtOAc and saturated NaHCO ₃ . The organic layer is separated, washed with 10% HCl, dried over Na ₂ SO ₄ , filtered, condensed in vacuo and no longer purified, but is used as a white foam, 1: 1 mono: disilylated product for the next process. To provide. Scalpel spectra (API-TIS) m / z 495 and 609 (MH ⁺ ). The entire white foam is dissolved in THF (10 mL). Bis (2-oxo-3-oxazolidinyl) phosphonic chloride (0.70 g, 1.58 mmol) and 4- (dimethylamino) pyridine (0.16 g, 1.32 mmol) were added at room temperature. After 5 minutes, 1-amino-2-methyl-2-propanethiol (0.15 g, 1.41 mmol) in THF (2 mL) was added in an appropriate amount. The resulting pale yellow solution was stirred at room temperature for 2.5 hours. Evaporation of the solvent extracted 1: 1 EtOAc: Hexane to give a residue that was chromatographed on silica gel to give a residue that gave the title compound (0.28 g, 37%) as a white foam. ^{l H-NMR (300MHz, CDCl} 3) δ7.90 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.15 ( d, J = 6.7 Hz, 2H), 5.91 (t, J = 6.2 Hz, lH), 3.77 (t, J = 5.9 Hz, 2H), 3.15 (d, J = 6.2 Hz, 2H), 3.09 (s, 3H), 2.64 (t, J = 5.9 Hz, 2H), 1.28 (s, 1H), 1.11 (s, 6H), 0.96 (s, 9H), 0.09 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 170.2, 145.9, 140.2, 139.8, 139.4, l37.9, 134.4, 130.9, 130.6, 129.1, 127,4, 60.6, 60.4, 53.5, 52.7, 44.6, 44.5, 35.0 , 29.9, 26,1, 21.1, l8.4, 14.3, -5.2; Scalpel spectrum (API-TIS) m / z 582 (MH ⁺ ). Anal. Calcd for C ₂₈ H ₄₀ ClNO ₄ S ₂ Si: C, 57.76; H, 6.92; N, 2.41. Found: Cl 57.79; H, 6.67; N, 2.30.
[1947] 10b. (2Z) -3- (4-chlorophenyl) -2- (2-hydroxyethyl) -N- [2-methyl-2-sulfanylpropyl) -3- [4- (methylsulfonyl) phenyl] prop 2-enamide
[1948] To a solution of the product of Example 10a (225 g, 0.39 mmol) in THF (10 mL) was added triroloacetic acid (129 μL, 1.67 mmol) in an appropriate amount at 0 ° C. Tetrabutylammonium fluoride (385 μL of THF 1M solution, 0.39 mmol) was added thereto in an appropriate amount. The resulting solution was gradually warmed to room temperature and stirred for 25 hours. The reaction mixture was partitioned between EtOAc (50 mL) and ice cold 1% HCl. The organic layer was separated, dried over Na ₂ S0 ₄ and filtered. The solvent was evaporated and the residue was chromatographed on silica gel extracted with 5% MeOH: CH ₂ Cl ₂ to afford the title compound (175 mg, 97%) as a white foam. mp 62-64 ° C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ7.93 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.28 (a, J: 8.5 Hz, 2H), 7.16 ( d, J = 8.4 Hz, 2H), 6.05 (t, J: 6.1 Hz, lH), 3.72 (t, J = 5.7 Hz, 2H), 3.14 (d, J = 6.1 Hz, 2H), 3.09 (s, 3H), 2.59 (t, J = 5.7 Hz, 2H), 1.36 (s, 1H), 1.16 (s, 6H); ^l ₃ C NMR (75 MHz, CDCl ₃ ) δ 171.1, 145.8, 141.1, 140.0, 138.8, 137.3, 134.7, 130.5, 130.4, 129.2, 127.8, 61.0, 52.9, 44.7, 44.6, 34.9, 30.0; Scalpel spectrum (API-TIS) m / z 468 (MH ⁺ ).
[1949] 10c. (2Z) -3- (4-chlorophenyl) -2- (2-hydroxyethyl) -N- [2-methyl-2 (nitrosothio) propyl) -3- [4- (methylsulfonyl) phenyl ] Prop-2-enamide
[1950] To a solution of 1: 1 MeOH: CH ₂ Cl ₂ (1.2 mL) in t-butyl nitrite (0.2 mL of 90% solution, 158 mg, 1.53 mmol) in 1: 1 MeOH: CH ₂ Cl ₂ (2 mL) at 0 ° C. The solution of the product of Example 10b (156 mg, 0.33 mmol) was added in an appropriate amount. The resulting solution was stirred in the dark for 30 minutes. In addition, t-butyl nitrite (0.15 mL of 90% solution, 188 mg, 1.15 mmol) was added, and the green solution as a product was further stirred for 30 minutes at 0 ° C., followed by 20 minutes at room temperature. The volatiles were removed in vacuo and the residue was chromatographed on silica gel extracted with 1: 1 EtOAc: CH ₂ Cl ₂ to afford the title compound (95 mg, 58%) as a green solid. mp 150-153 ° C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ7.90 (d, J = 8,3 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.24 (dd, J = 1.9 and 6.6 Hz, 2H ), 7.09-7.12 (mult, 2H), 6.40 (br t, J = 6.3 Hz, lH), 3.86 (d, J = 6.3 Hz, 2H), 3.66 (t, J = 5.9 Hz, 2H), 3.09 ( s, 3H), 2.54 (t, J = 5.8 Hz, 2H), 1.67 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 171.4, 145.8, 141.2, 139.8, 138.8, 136.9, 134.5, 130.5, 130.3, 129.0, 127.6, 60.5, 56.5, 44.5, 34.7, 26.8; Mess spectrum (API-TIS) m / z 467 (M-NO), 497 (MH ⁺ ).
[1951] Example 11: l- [5-methyl-l- (2-methyl-2- (nitrosothio) propyl) pyrrol-2-yl] -4- (methylsulfonyl) benzene
[1952] 11a. l- (4-methylthiophenyl) pentane-1,4-dione
[1953] 4- (methylthio) benzaldihydr (20 mL, 150 mmol)), 3-benzyl-5- (2-hydroxyethyl) -4-methylthiazolium chloride (7 g, 30 mmol), methyl vinyl ketone (15 mL, 180 mmol) , And Et ₃ N (21 mL, 150 mmol) were placed in a flask and soaked in an oil bath at 80 ° C. The initial purple solution turned orange after 30 minutes. The solution was cooled to room temperature and EtOAc (30 mL) was added to the precipitate thiazolium salt removed by filtration. The filter cake was washed with hot EtOAc (2 x 30 mL). The combined mother liquor and washes were condensed to give 43 g of residue. The residue was taken up in hot 1: 1 Hexane: EtOAc (100 mL) and cooled and precipitated into a solid. This solid was isolated on glass frit and washed with hot 4: 1 Hexane: EtOAc (50 mL). From this hot wash the title compound (16.4 g, 49%) precipitated out as a tan solid. mp 72-73 ° C. ^{l H, -NMR (300MHz, CDCl} 3) δ7.88 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 3.22 (t, J = 6.5 Hz, 2H), 2.87 (t, J = 6.2 Hz, 2H), 2.51 (s, 3H), 2.24 (s, 3H); Scalpel spectrum (API-TIS) m / z 223 (MH ⁺ ). Anal. Calcd. for C ₁₂ H ₄ O ₂ S: C, 64.84; H, 6. 35; S, 14.42. Found C, 64.68; H, 6. 19; S, 14.24 ..
[1954] 11b. l- [4- (methylsulfonyl) phenyl] pentane-l, 4-dione
[1955] The product of Example 11a (16.4 g, 74 mmol) was dissolved in CH ₂ Cl ₂ (300 mL) and cooled to 0 ° C. Solid 70% m-chloroperbenzoic acid (37 g, 150 mmol) was added after 5 minutes. After the addition was complete, the cooling bath was removed and the reaction mixture was warmed to room temperature with stirring for 3 hours. The formed precipitate was removed by filtration and washed with CH ₂ Cl ₂ (2 × 50 mL). The combined organic filtrate was washed with ₁ M Na ₂ CO ₃ , dried over Na ₂ SO ₄ and condensed. The residue was partitioned between EtOAc (200 mL) and 1 M Na ₂ CO ₃ (50 mL). The solid was kept in the aqueous layer and the mixture was extracted with EtOAc (50 mL). The aqueous layer was filtered and dried in vacuo to afford the title compound (8.9 g). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ and condensed to give additional title compound (6.5 g). The overall yield of the title compound was 15.4 g, 82%. mp 132-133 ° C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ8.15 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.3 Hz, 2H), 3.27 (t, 6.6 Hz, 2H), 3.07 (s, 3H), 2.93 (t, J = 6.4 Hz, 2H), 2.26 (s, 3H); Mass spectrum (API-TIS) m / z 255 (MH ⁺ ). Anal. Calcd. for C ₁₂ H ₄ O ₄ S: C, 56.68; H, 5.55; S, 12.61. Found: C, 56.39; 5.40; S, 13.36.
[1956] 11c. l- [5-methyl-l- (2-methyl-2-sulfanylpropyl) pyrrol-2-yl] -4- (methylsulfonyl) benzene
[1957] The product of Example 11b (2 g, 7.9 mmol), NaOAc (1.3 g, 16 mmol), and 1-amino-2-methyl-2-propanethiol. HCl (1.2 g, 8.7 mmol) were added to HOAc (15 mL). Heated to 80 ° C. for 3 hours. The reaction mixture was cooled to room temperature to remove HOAc under reduced pressure. The residue was partitioned between EtOAc (40 mL) and 1N Na ₂ CO ₃ (15 mL). The organic layer was separated, washed with 1N Na ₂ CO ₃ , brine, dried over Na ₂ SO ₄ and condensed. The residue was crystallized from hot MeOH (5 mL) to give the title compound (1.6 g, 63%) as an orange tan solid. mp 124-126 ° C. ^{l H-NMR (300MHz, CDCl} 3) δ7.93 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 6.22 (d, J = 3,6 Hz, 1H), 6.03 (d, J = 3.6 Hz, 1H), 4.24 (br, 2H), 3.08 (s, 3H), 2.41 (s, 3H), 1,55 (s, 1H), 1.04 (s, 6H); Scalpel spectrum (API-TIS) m / z 324 (MH ⁺ ).
[1958] 11d. l- [5-methyl-l- (2-methyl-2- (nitrosothio) propyl) pyrrol-2-yl] -4- (methylsulfonyl) benzene
[1959] The product of Example 11c (100 mg, 0.31 mmol) was dissolved in CH ₂ Cl ₂ and cooled to 0 ° C. A solution of t-BuONO (40 mL, 31 mmol) in CH ₂ Cl ₂ (1 mL) was added in an appropriate amount. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 1 hour. The solvent was evaporated and the residue was chromatographed on silica gel which was extracted with 2: 1 Hexane: EtOAc. This resulted in a 1: 3 mixture (67 mg, 61%) of the starting material and the desired product. Part of this mixture was reacted with t-BuONO to give the title compound as a black foam. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.89 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 6.22 (d, J = 3.6 Hz, 1H), 6.05 (d, J = 3.5 Hz, 1H), 4.60-5.00 (br, 2H), 3.15 (s, 3H), 2.39 (s, 3H), 1.6-2.0 (br s, 6H); Mass spectrum (API-TIS) m / z 353 (M−H ⁺ ).
[1960] Example 12 3- {4- [1-methyl-1- (nitrosodio) ethyl] -2-oxo-1,3-oxazolidine-3 yl} propyl (2Z) -4-acetyloxy-2 -(4-fluorophenyl) -3- [4 (methylsulfonyl) phenyl] -but-2-enoate
[1961] 12a. 3- (4-fluorophenyl) -4 [4- (methylsulfonyl) phenyl] -5-hydrofuran-2-one
[1962] The composite is synthesized according to the manner set forth in patent EP 0 788 476 B1, the disclosed part of which is incorporated by reference in its entirety. mp 163 ° C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ7.94 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.38-7.43 (mult, 2H), 7.06-7.27 ( mult, 2H), 5.18H (s, 2H), 3.08 (s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ172.5, 165.0, 161.7, 153.7, 142.2, 136.3, 131.4, 131.3, 128.6, 128.3, 128.0, 125.3, 125.2, 116.4, 116.1, 70.5, 44.4; Mass spectrum (API-TIS) m / z 333 (M−H ⁺ ), 350 (MNH ₄ ⁺ ). Anal. Calcd for C ₁₇ H ₁₃ FO ₄ S: C, 61.44; H, 3.94; F, 5.72; S, 9.65. Found: C, 61.24; H, 3.89; F, 5.70; S, 9.92.
[1963] 12b ,. 1-[(1Z) -2- (4-fluorophenyl) -3-hydroxy-1- (hydroxymethyl) prop-1-enyl] -4- (methylsulfonyl) benzene
[1964] Example 12a (4.68 g, 14.1 mmol) containing diisobutylaluminum hydride (70.2 mL, 1M solution in THF, 9.98 g, 70.2 mmol) in THF (190 mL) in THF (190 mL) at 0 ° C. Is added to the resulting solution. Stir at 0 ° C. for 30 minutes and leave for 1 hour at room temperature to cool the mixture to 0 ° C. Additional DIBAL (30 mL, 1M solution in THF, 4.27 g, 30 mmol) was added and stirred at room temperature for about 1 hour. The reaction mixture is poured into 1 M sodium potassium tartaric acid containing MeOH (50 mL). The hydrated mixture is extracted with EtOAc. The organic layer is dried over Na ₂ SO ₄ and filtered. The solvent is removed in vacuo and only the main component (4.7 g, 99%) is yielded as a colorless oil. ¹ H-NMR (300 MHz, MeOH-d ₄ ) δ7.73 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.07-7.12 (mult, 2H), 6.85-6.91 (mult, 2H), 4.64 (s, 2H), 4.62 (s, 2H), 3.06 (s, 3H); Mass spectrum (API-TIS) m / z 337 (M−H ⁺ ), 354 (MNH ₄ ⁺ ).
[1965] 12c. (2Z) -3- (4-fluorophenyl) -4-hydroxy-2- [4- (methylsulfonyl) phenyl] but-2-enyl acetate
[1966] Acetic anhydride (1.33 mL, 1.4 g, 14.0 mmol) was added to the result of Example 12b (4.7 g, 14.0 mmol), DMAP (56 mg, 0.46 mmol), and CH2Cl2 (600 ml) containing triethylamine (5.89 mL, 42.3 mmol). ) Is added to the solution at room temperature. The mixture is stirred for 1 hour at room temperature, washed with water and dried over Na ₂ SO ₄ . After evaporation of the solvent, the residue is produced as colorless oil as the main component (1.31 g, 25%) via silica gel chromatograph eluting with 1: 1 EtOAc: hexane, and its regio-isomer. ), (2Z) -2- (4-fluorophenyl) -4-hydroxy-3- [4- (methylsulfonyl) phenyl] but-2-enyl acetate (1.37 g, 26%) is also a colorless oil. It is calculated as a form. (2Z) -3- (4-fluorophenyl) -4-hydroxy-2- [4- (methylsulfonyl) phenyl] but-2-enyl acetate: ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7. 73 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 7.02-7.06 (mult, 2H), 6.80-6.86 (mult, 2H), 5.17 (s, 2H), 4.63 (s, 2H), 3.01 (s, 3H), 1.99 (s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 171.4, 163.6, 160.4, 145.9, 143.6, 139.0, 135.6 (J _19F-C = 3.4 Hz), 134.3, 131.0, 130.9, 130.5, 127.3, 115.5, 115.2, 64.4 , 63.4, 44.5, 21.0; Mass spectrum (API-TIS) m / z 396 (MNH ₄ ⁺ ). (2Z) -2- (4-fluorophenyl) -4-hydroxy-3- [4- (methylsulfonyl) phenyl] but-2-enyl acetate: ¹ H-NMR (300Mhz, CDCl ₃ ) δ7. 70 (d, J = 8.4Hz, 2H), 7.30 (d, J = 8.4Hz, 2H), 6.82-6.97 (mult, 4H), 5.16 (s, 2H), 4.61 (s, 2H), 2.99 (s , 3H), 1.99 (s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 171.4, 163.4, 160.1, 146.8, 141.0, 138.5, 136.7, 134.7 (J _19F-C = 3.5 Hz), 131.0, 130.9, 130.1, 126.9, 115.4, 115.1, 64.4 , 62.8, 44.3, 20.8; Mass spectrum (API-TIS) m / z 396 (MNH ₄ ⁺ ).
[1967] 12d. (2Z) -3- (4-fluorophenyl) -2- [4 [(methylsulfonyl) phenyl] -4-oxobut-2-enyl acetate
[1968] A mixture of 12c product (1.31 g, 3.47 mol) and Mn ₂ (6.96 g, 80 mmol) in CH ₂ Cl ₂ (175 mL) was stirred at room temperature for 16 hours and then filtered through a pad of Celite. The filtrate is dried over Na ₂ SO ₄ , filtered and condensed in vacuo to yield the main component (0.81 g, 62%) as a yellow solid. ¹ H-NMR (300Mhz, CDCl ₃ ) δ10.39 (s, 1H), 7.79 (d, J = 10.3Hz, 2H), 7.31 (d, J = 12.2Hz, 2H), 6.88-6.91 (mult, 4H ), 5.45 (s, 2H), 3.02 (s, 3H), 2.00 (s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ190.9, 170.4, 164.1, 160.8, 149.6, 143.9, 141.3, 140.3, 132.4, 132.3, 130.0, 129.9, 127.4,115.7, 115.5, 62.1, 44.4, 20.7; mass spectrum (API-TIS) m / z 394 (MNH ₄ ⁺ ).
[1969] 12e. (2Z) -4-acetyloxy-2- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] but-2-enoic acid
[1970] NaClO ₂ (4.87 g, 53.9 mmol) in a t-butanol (170 mL) solution containing the result of Example 12d (0.81 g, 2.15 nmol) and 2-methyl-2-butene (28.9 mL, 19.1 g, 273 mmol). And aqueous NaH ₂ PO ₄ (4.80 g, 40.1 mmol) solution (10 mL). The mixture is stirred for 2 hours at room temperature. After evaporation of the solvent, the residue is dissolved in pH 7 buffer solution (250 mL) and EtOAc is extracted. The aqueous layer is acidified with 10% HCL (pH 4-5) and extracted with EtOAc. The combined organic layers are dried over Na ₂ SO ₄ and filtered. The residue after evaporation of the solvent is recrystallized from EtOAc: Hex: CH _{2 Cl 2} to yield the main compound (0.31 g, 37%) as powder form. ¹ H-NMR (300 MHz, THF-d ₈ ) δ 7.87 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.21-7.25 (mult, 2H), 6.97-7.03 (mult, 2H), 5.35 (mult, 2H), 3.08 (s, 3H), 1.97 (s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 170.8, 169.7, 165.2, 162.0, 144.9, 142.2, 141.9, 137.7, 133.9 (J _CF = 3.5 Hz), 133.2, 133.1, 131.6, 128.4 116.3, 116.0, 65.9, 44.5 , 20.8, mass spectrum (API-TIS) m / z 333 (M-HOAc), 410 (M + NH ₄ ⁺ ). Anal. Calcd for C ₁₉ H ₁₇ FO ₆ S.½H 2 O: C, 56.85; H, 4.52; F, 4.73; S, 7.99.Found: C, 56.83; H, 4.45; F, 5.07; S, 7.94.
[1971] 12f. 2-amino-3-methyl-3-[(2,4,6-trimethoxyphenyl) methylthio] butanoic acid
[1972] Suspension of CH ₂ Cl ₂ of 2-amino-3-methyl-3-sulfurylbutanoic acid (D-penicillamine) (5.0 g, 34 mmol) is cooled to 0 ° C. Trifluoroacetic acid (54 mL, 703 mmol) is added dropwise over 5 minutes. Then, 2,4,6-trimethoxybenzyl alcohol (6.64 g, 34 mmol) contained in CH ₂ Cl ₂ (137 mL) was added dropwise while stirring at 0 ° C. The stirring is continued for 1 hour at 0 ° C. and then for 2 hours at room temperature. The solvent is removed in vacuo and the residue is dried for 3 hours at high vacuum. The crude red solid was recrystallized from 1: 1: 1 CH ₂ Cl ₂ / MeOH / EtOAc to yield the main compound (10.5 g, 95%) as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 6.10 (s, 2H), 3.84 (s, 6H), 3.76 (s, 3H), 3.40-4.10 (m, 3H), 1.69 (s, 3H), 1.23 (s, 3H); Mass spectrum (API-TIS) m / z 330 (M−H ⁺ ).
[1973] 12g. 2-amino-3-methyl-3-[(2,4,6-trimethoxyphenyl) methylthio] butan-1-ol
[1974] To a stirred solution of resultant (10.5 g, 32 mmol) in Example 12f in THF (80 mL) is added lithium aluminum hydride (1 M on TFT, 64 mL, 64 mmol) under a nitrogen atmosphere at 0 ° C. The resulting solution was stirred at 0 ° C. for 1 hour and then at room temperature for 2 hours. The excess reducing agent is removed by addition of Na ₂ S0 ₄ .10H ₂ 0 at 0 ° C. in a cautious proportion. The granular white precipitate is filtered and washed with 30% methanol in CH ₂ Cl ₂ . The combined filtrates are dried over Na ₂ S0 ₄ , filtered and evaporated to yield the main component (7.6 g, 76%) in the form of a yellow oil for the next step without further purification. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 6.10 (s, 2H), 3.85 (s, 6H), 3.81 (s, 3H), 3.74 (s, 2H), 3.60-3.80 (mult, 2H), 3.37 -3.43 (mult, 1H), 2.93-2.98 (mult, 1H), 1.45 (s, 3H), 1.30 (s, 3H); Mass spectrum (API-TIS) m / z 316 (MH ⁺ )
[1975] 12h. 4- {1-methyl-1-[(2,4,6-trimethoxyphenol) methylthio] ethyl} -1,3-oxazolidine-2-one
[1976] A mixture of K ₂ CO ₃ (0.33 g, 2.4 mmol), diethylcarbonate (50 mL) and the resulting 12 g of the result (7.6 g, 24 mmol) is heated at 100 ° C. for 24 h. After the excess diethylcarbonate is evaporated, the light brown slurry is cooled to room temperature, diluted with CH ₂ Cl ₂ and filtered to remove K ₂ CO ₃ . The filtrate was evaporated and the residue was purified via chromatograph of silica gel eluting with 1: 1 EtOAc: hexane to give 2.6 g (32%) of the main compound in the form of a viscous yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ) 66.13 (s, 2H), 6.07 (bs, 1H), 4.30-4.40 (mult, 1H), 4.25-4.28 (mult, 1H), 4.03-4.08 (mult, 1H), 3.86 (s, 6H), 3.83 (s, 2H), 3.81 (s, 3H), 1.32 (s, 3H), 1.27 (s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 160.7, 159.5, 158.7, 106.3, 90.9, 66.5, 59.5, 56.0, 55.5, 47.1, 23.8, 22.3, 20.3; Mass spectrum (API-TIS) m / z 342 (M−H ⁺ ), 359 (MNH ₄ ⁺ ).
[1977] 12i. 3-bromo-1- (1,1,2,2-tetramethyl-1-silapropoxy) propane
[1978] T-butyldimethylchlorosilane (17.4 g, 115 mmol) in dry THF (50 mL), 1,3-bromopropanol (16 g, 115 mmol) and imidazole (7.85 g, in dry THF (50 mL) 115 mmol) is added at room temperature. The resulting white suspension is stirred for 16 hours at room temperature. The reaction mixture is diluted with EtOAc (200 mL), washed with water, brine, dried over Na ₂ SO ₄ , filtered and condensed at room temperature in vacuo to yield 28.5 g (98%) of the main component as a colorless volatile liquid. ¹ H-NMR (300 MHz, CDCl ₃ ) δ3.74 (t, J = 5.7 Hz, 2H), 3.52 (t, J = 6.5 Hz, 2H), 2.02-2.06 (mult, 2H), 0.90 (s, 9H ), 0.07 (s, 6H); ¹³ C NMR (75 MHz, CDCl 3) δ 60.6, 35.7, 30.8, 26.1, -5.2.
[1979] 12j. 4- {1-methyl-1-[(2,4,6-trimethoxyphenyl) methylthio] ethyl} -3- [3- (1,1,2,2-tetramethyl-1-silapropoxy ) Propyl] -1,3-oxazolidine-2-one
[1980] To the resulting product (8.03 g, 35.3 mmol) in dry DMF (25 mL) was added NaH (0.84 g, 35.3 mmol) under nitrogen atmosphere at 0 ° C. The resulting suspension was stirred at 0 ° C. for 20 minutes to yield a reddish brown solution. The resulting product (7.14 g, 28.2 mmol) in DMF (7 mL) was stirred with dropwise addition at room temperature for 16 h, and the solvent evaporated. To the residue is added 1: 1 EtOAc: water and the organic layer is separated. EtOAc is extracted in the aqueous layer, the combined organic phases are washed with water, dried over Na ₂ SO ₄ and filtered. The remaining residue after evaporation of the solvent is yielded as 6.2 g (51%) of the main component in the form of a white foam via silica gel chromatography eluting with 5% to 25% EtOAc: hexanes. ¹ H-NMR (300 MHz, CDCl ₃ ) δ6.11 (s, 2H), 4.38-4.42 (mult, 1H), 4.05-4.11 (mult, 1H), 3.93-3.96 (mult, 1H), 3.83 (s, 6H), 3.80 (s, 3H), 3.77 (s, 2H), 3.65 (t, J = 6.1 Hz, 2H), 3.58-3.71 (mult, 1H), 3.34-3.44 (mult, 1H), 1.66-1.96 (mult, 2H), 1.56 (s, 3H), 1.24 (s, 3H), 0.89 (s, 9H), 0.04 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 160.7, 159.5, 158.7, 107.0, 90.8, 65.7, 61.7, 60.6, 55.9, 55.4, 48.3, 42.6, 30.3, 26.8, 26.0, 22.2, 20.4, 18.4, -5.3; Mass spectrum (API-TIS) m / z 514 (M−H ⁺ ).
[1981] 12k. 3- (3-hydroxypropyl) -4- (1-methyl-1-sulfurylethyl) -1,3-oxazolidine-2-one
[1982] The result of Example 12j (5.0 g, 9.75 mmol) is treated with water (4.0 mL), phenol (4.0 g), anisol (4.0 mL) and finally trifluoroacetic acid (49 mL). The solution is stirred for 1 hour at room temperature. The volatiles are evaporated and yellow oil is produced. The crude yellow oil was purified by silica gel chromatography to extract 5% MeOH: CH 2 Cl 2 with 1: 1 EtOAc: hexane to yield 1.4g (66%) of the main component as a pale yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 4.30-4.35 (mult, 2H), 3.50-3.82 (mult, 5H), 2.80-2.95 (bs, 1H), 1.83-1.89 (mult, 2H), 1.78 ( s, 1 H), 1.42 (s, 6 H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 160.5, 65.8, 65.4, 59.2, 47.2, 42.2, 30.1, 29.0, 28.0; Mass spectrum (API-TIS) m / z 220 (MH ⁺ ), 237 (MNH ₄ ⁺ ). Anal. Calcd for C ₉ H ₁₇ NO ₃ S: C, 49.29; H, 7.81; N, 6.31. Found: C, 48.99; H, 7.71; N, 6.04.
[1983] 12l.3- (3-hydroxypropyl) -4- [1-methyl-1- (nitrosodio) ethyl] -1,3-oxazolidine-2-one
[1984] The resulting solution of Example 12k (1.4 g, 6.4 mmol) in CH ₂ Cl ₂ was dissolved in t-BuONO (90% solution 1.67 mL, 1.32 g, 12.8 mmol) in CH ₂ Cl ₂ (10 mL). Drop by drop. The resulting green solution is stirred for 1 hour at 0 ° C. and then for 20 minutes in a dark room temperature. Evaporation of the solvent yielded 0.98 g (62%) of the main compound in the form of a green oil through silica gel chromatography, which left a residue and eluted up to 5% MeOH: CH2Cl2 with 1: 1 EtOAc: CH2Cl2. do. ¹ H-NMR (300 MHz, CDCl ₃ ) δ4.61-4.66 (mult, 1H), 4.36-4.46 (mult, 2H), 3.42-3.75 (mult, 4H), 2.30-2.45 (br s, 1H), 1.97 (s, 3H), 1.96 (s, 3H), 1.74-1.80 (mult, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 160.2, 65.3, 63.3, 59.3, 58.8, 42.3, 29.8, 25.4, 25.0; Mass spectrum (API-TIS) m / z 219 (M-NO), 249 (MH ⁺ ), 266 (MNH ₄ ⁺ ). Anal. Calcd for C ₉ H ₁₆ N ₂ O ₄ S: C, 43.54; H, 6.50; N, 11.28 Found: C, 43.61; H, 6.59; N, 10.99.
[1985] 12 m. 3- {4- [1-methyl-1- (nitrosodio) ethyl] -2-oxo-1,3-oxazolidine-3-yl} propyl (2Z) -4-acetyloxy-2- (4 -Fluorophenyl) -3- [4- (methylsulfonyl) phenyl] but-2-enoate
[1986] The result of Example 12l (100 mg, 0.40 mmol) in bis (2-oxo-3-oxozolidinyl) phosphonic chloride (0.14 g, 0.32 mmol) and 4- (dimethylamino) pyridine (19.0 mg, 0.16 mmol) and A solution of THF (2 mL) in which the product of Example 12e (61 mg, 0.16 mmol) is dissolved is added at 0 ° C. The solution is stirred at 0 ° C. for 1 hour and then at room temperature for 20 hours. Evaporation of the solvent leaves a residue, which is yielded as 68 mg (70%) of the main foam in the form of a green foam via silica gel chromatography using 1: 1 EtOAc: CH ₂ Cl ₂ . ¹ H-NMR (300 MHz, CDCl ₃ ) δ7.78 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 6.99-7.03 (mult, 2H), 6.82-6.88 (mult) , 2H), 5.17 (s, 2H), 4.53-4.57 (mult, 1H), 4.36-4.43 (m, 2H), 4.25 (t, J = 6.1 Hz, 2H), 3.64-3.74 (mult, 1H), 3.18-3.28 (mult, 1H), 3.02 (s, 3H), 1.95 (s, 3H), 1.91 (s, 3H), 1.87 (s, 3H), 1.85-2.06 (mult, 2H); mass spectrum (API -TIS) m / z 593 (M-NO), 623 (MH ⁺ ), 640 (MNH ₄ ⁺ ).
[1987] Example 13: (2Z) -3- (4-fluorophenyl) -3- {N-methyl-N- [2-methyl-2- (nitrosodio) propyl] carbamoyl} -2- [4 -(Methylsulfonyl) phenyl] prop-2-enyl acetate
[1988] 13a. (2Z) -3- (4-fluorophenyl) -3- [N-methyl-N- [2-methyl-2-sulfonylpropyl] capbamoyl] -2- [4- (methylsulfonyl) phenyl Prop-2-enyl Acetate
[1989] Bis (2-oxo-3-oxazolidinyl) phosphonic chloride (0.242 g, 0.55 mmol) was obtained as the result of Example 12e (0.18 g, 0.46 mmol), triethylamine (0.62 mL, 0.45 g, 4.4 mmol) and 4 To a THF (6 mL) solution containing-(dimethylamino) pyridine (56 mg, 0.46 mmol) at room temperature. After 5 minutes, 1-amino-2-methyl-2-thiopropane (85.6 mg, 0.55 mmol) is added. The final mixture is stirred for 16 hours at room temperature. The reaction mixture is diluted in EtOAc (50 mL), washed with water, brine, dried over Na ₂ SO ₄ and filtered. Evaporation of the solvent leaves a residue, which is yielded as a main compound (189 mg, 83%) in the form of a white powder on a silica gel chromatograph eluted with 2% MeOH: CH ₂ Cl ₂ . mp 45-47 ° C. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 7.44 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.08-7.11 (mult, 4H ), 4.95-5.05 (br s, 2H), 3.60 (s, 2H), 3.21 (s, 3H), 3.14 (s, 3H), 2.86 (s, 1H), 1.95 (s, 3H), 1.33 (s , 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ170.6, 170.2, 160.9, 143.9, 141.0, 139.8, 132.7, 131.3, 131.2, 130.6, 127.6, 116.1, 115.8, 65.5, 60.6, 46.5, 44.6, 39.4, 31.7, 21.0; Mass spectrum (API-TIS) m / z 494 (M−H ⁺ ).
[1990] 13b. (2Z) -3- (4-fluorophenyl) -3- {N-methyl-N- [2-methyl-2- (nitrosodio) propyl] carbamonyl} -2- [4- (methylsul Phenyl) phenyl] prop-2-enyl acetate
[1991] CH₂Cl₂CH in a solution of t-BuONO (14 μl in 90% solution, 111 mg, 1.08 mmol) dissolved in (1.4 mL)₂Cl₂The resulting solution of Example 13a (163 mg, 0.33 mmol) dissolved in (4.3 mL) was added dropwise at 0 ° C. The resulting green solution is stirred for 15 minutes at 0 ° C. and then for 15 minutes in the dark at room temperature. The residue left after evaporation of the solvent is EtOAc: CH from 1: 1 to 2: 1.₂Cl₂As a result, 60 mg (35%) of the main compound in the form of a green bubble was obtained by eluting silica gel chromatography. mp 37-38 ° C.^One H-NMR (300 MHz, CDCl₃δ 7.80 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.04-7.08 (mult, 2H), 6.85-6.90 (mult, 2H), 4.96 (s, 2H) ), 4.25 (s, 2H), 3.04 (s, 3H), 2.95 (s, 3H), 2.04 (s, 3H), 1.92 (s, 6H);¹³C NMR (75 MHz, CDCl₃δ 170.6, 170.5, 164.2, 160.9, 143.7, 140.6, 139.8, 133.0, 131.2, 131.1, 130.5, 130.2, 127.5, 116.1, 115.8, 65.4, 58.2, 57.8, 44.5, 39.3, 27.9, 20.9; Mass Spectrum (API-TIS) m / z 493 (M-NO), 523 (MH)⁺), 540 (MNH)₄ ⁺).
[1992] Example 14 2- [1-Methyl-4- (nitrosodio) -4-piperidyl] ethyl (2Z) -3- (4-acetyloxy-2- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] but-2-enoate
[1993] 14a. 2- [1-methyl-4- (nitrosodio) -4-piperidyl] ethyl (2Z) -3- (4-acetyloxy-2- (4-fluorophenyl) -3- [4- ( Methylsulfonyl) phenyl] but-2-enoate
[1994] To DCC (0.11 g, 0.53 mmol) in CH ₂ Cl ₂ (5 mL) the result of Example 12e (0.21 g, 0.53 mmol), 2- [1-methyl-4- (nitrosodio) -4-piperi Dill] ethan-1-ol (prepared by the invention disclosed in patent application WO / 025776, which is hereby incorporated by reference in its entirety), eg 13d, 0.123 g, 0.64 mmol) and 4- (dimethylamino) pyridine (33 mg, 0.27 mmol) of CH 2 Cl 2 (5 mL) solution is added dropwise at room temperature. The resulting suspension is stirred for 16 hours at room temperature, after which the precipitate is filtered off and washed with CH ₂ Cl ₂ (10 mL). The combined organic phases are dried over Na ₂ SO ₄ and filtered. The residue left after evaporation of the solvent was purified by silica gel chromatography eluting with 2% MeOH: CH ₂ Cl ₂ to yield 13 mg (4%) of the main compound as a green oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ7.76 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 9.1 Hz, 2H), 6.94-6.98 (mult, 2H), 6.81-6.86 (mult , 2H), 5.15 (s, 2H), 4.42 (t, J = 6.7 Hz, 2H), 3.00 (s, 3H), 2.68 (t, J = 6.8 Hz, 2H), 2.30 (s, 3H), 2.15 -2.43 (mult, 8H), 1.93 (s, 3H); Mass spectrum (API-TIS) m / z 549 (M-NO), 579 (M−H ⁺ ).
[1995] Example 15 (3Z) -4- (4-chlorophenyl) -3- (ethoxycarbonyl) -4- [4- (methylsulfonyl) phenyl] but-3-enoic acid
[1996] 15a. (3Z) -4- (4-chlorophenyl) -3- (ethoxycarbonyl) -4- [4- (methylsulfonyl) phenyl] but-3-enoic acid
[1997] The compound is synthesized by the method disclosed in US Pat. No. 5,807,873 (incorporated by reference in its entirety), Example 63. ¹ H-NMR (300 MHz, CDCl ₃ ) δ7.96 (d, J = 8.2 , 2H), 7.40 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 4.03 (q, J = 7.1 Hz, 2H ), 3.45 (s, 2H), 3.10 (s, 3H), 0.97 (t, J = 7.1 Hz, 3H); Mass spectrum (API-TIS) m / z 377 (M-CO 2), 423 (MH ⁺ ), 440 (MNH ₄ ⁺ ), 445 (MNa ⁺ ).
[1998] 15b. 2-bromo-1- (1,1,2,2-tetramethyl-1-silapropoxy) ethane
[1999] Dry THF (50 mL) dissolved in 1,2-bromoethanol (18 g, 144 mmol) and imidazole (9.81 g, 144 mmol) in t-butyldimethylchlorosilane (21.7 g, 144 mmol) in dry THF (50 mL) The solution is added dropwise at room temperature. The resulting white suspension is stirred for 16 hours at room temperature. The reaction mixture was diluted with EtOAc (200 mL), washed with water, brine, dried over Na ₂ SO ₄ , filtered and condensed at room temperature in vacuo to give 33.2 g (96%) of the main compound as a colorless liquid. Is calculated. ¹ H-NMR (300 MHz, CDCl ₃ ) δ3.89 (t, J = 6.5 Hz, 2H), 3.39 (t, J = 6.6 MHz, 2H), 0.90 (s, 9H), 0.10 (s, 6H) ; ¹³ C NMR (75 MHz, CDCl ₃ ) δ 63.7,60.5, 33.4, 26.0, 21.2, 14.3, -5.1.
[2000] 15c. 4- {1-methyl-1-[(2,4,6-trimethoxyphenyl) methylthio] ethyl} -3- [2- (1,1,2,2-tetramethyl-1-silapropoxy ) Ethyl] -1,3-oxazolidine-2-one
[2001] Example of dry DMF (50 mL) The resulting solution (15.3 g, 44.9 mmol) in 12 h was added to NaH (1.6 g, 66.7 mmol) at 0 ° C. under nitrogen atmosphere. The resulting suspension is stirred for 20 minutes at 0 ° C. to yield a reddish brown solution. Stir the resulting product of Example 15b (12.9 g, 53.8 mmol) in DMF (10 mL), dropwise, at room temperature for 16 h. The solvent evaporates. The residue is partitioned by 1: 1 EtOAc: water and the organic layer is split. The aqueous layer is extracted with EtOAc and the combined organic layers are washed with water, dried over Na ₂ SO ₄ and filtered. The residue remaining after evaporation of the solvent is yielded as white foam as main compound (18 g, 80%) via silica gel chromatography eluting with 1: 1 EtOAc: hexane. ¹ H-NMR (300 MHz, CDCl ₃ ) δ6.12 (s, 2H), 4.38-4.47 (mult, 1H), 4.09-4.21 (mult, 3H), 3.83 (s, 9H), 3.79 (s, 2H) 3.71-3.79 (mult, 2H), 3.42-3.53 (m, 1H), 1.50 (s, 3H), 1.29 (s, 3H), 0.95 (s, 9H), 0.08 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ160.8, 159.7,158.9, 106.5, 90.9, 65.9, 62.3, 60.5, 56.0, 55.5, 48.6, 47.5, 26.4, 26.0, 22.6, 21.2, 20.3, 18.3, 14.4,- 5.3; Mass spectrum (API-TIS) m / z 500 (M−H ⁺ ).
[2002] The result of Example 15c (14.9 g, 29.8 mol) is treated with water (11.8 mL), phenol (11.8 g), enazole (11.8 mL) and finally trifluoroacetic acid (147 mL). The resulting solution was stirred at room temperature for 1 hour, after which the solvent was evaporated to yield a yellow oil, which was 5% MeHO: CH with 1: 1 EtOAc: hexane.₂Cl₂Silica gel chromatograph eluting to yield 4.2 g (69%) of the main compound as a pale yellow oil.^One H-NMR (300 MHz, CDCl₃δ4.33-4.43 (mult, 2H), 3.72-3.92 (mult, 4H), 3.50-3.59 (mult, 1H), 2.55-2.80 (br s, 1H), 1.78 (s, 1H), 1.41 (s , 6H);¹³C NMR (75 MHz, CDCl₃) δ 160.6, 66.2, 66.0, 60.4, 48.3, 47.6, 29.0, 27.8; Mass spectrum (API-TIS) m / z 206 (MH⁺), 223 (MNH)₄ ⁺). Anal. Calcd for c₈H₁₅NO₃S: C, 46.82; H, 7.37; N, 6.82. Found: C, 46.81; H, 7.11; N, 6.61.
[2003] 15e. 3- (2-hydroxyethyl) -4- [1-methyl-1- (nitrosodio) ethyl] -1,3-oxazolidine-2-one
[2004] CH ₂ Cl ₂ (28mL) containing t- butyl nitrite product of example 15d contained in the (90% 4.45mL, 3.5g, 34.1mmol in solution) was added CH ₂ Cl ₂ (58mL) in a (3.88g, 18.9mmol ) Stir the solution at 0 ℃ and mix drop by drop. The resulting green solution is stirred for 1 hour at 0 ° C. and then stirred for 20 minutes at room temperature in the dark. The residue remaining after evaporation of the solvent was obtained as a green oil in 3.7 g (84%) of the main compound via a silica gel chromatograph eluting with 1: 1 EtOAc: CH ₂ Cl _{2 to} 5% MeOH: CH ₂ Cl ₂ . Is calculated. ¹ H-NMR (300 MHz, CDCl ₃ ) δ4.70-4.74 (mult, 1H), 4.41-4.52 (mult, 2H), 3.77-3.89 (mult, 3H), 3.44-3.50 (mult, 1H), 1.99 ( s, 3H), 1.96 (s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 160.4, 65.8, 63.9, 60.0, 59.3, 48.1, 25.7, 24.8; Mass spectrum (API-TIS) m / z 205 (M-NO), 235 (MH ⁺ ), 252 (MNH ₄ ⁺ ). Anal.Calcd for C ₈ H ₁₄ N ₂ O ₄ S: C, 41.02; H, 6.02; N, 11.96. Found: C, 41.30; H, 5.87; N, 11.68.
[2005] 15f. (3Z) -4- (4-chlorophenyl) -3- (ethoxycarbonyl) -4- [4- (methylsulfonyl) phenyl] but-3-enoic acid
[2006] DCC (32 mg, 0.155 mmol) in CH ₂ Cl ₂ (50 mL) to the result of Example 15a (66 mg, 0.155 mmol) in CH ₂ Cl ₂ (2 mL), the result of Example 15e (36 mg, 0.154 mmol) and 4- (dimethyl Agitated aqueous solution of amino) pyridine (19 mg, 0.155 mmol) is added dropwise at 0 ° C. The resulting suspension is stirred at 0 ° C. for 15 minutes and then at room temperature for 1.5 hours. The precipitate is filtered off and washed with CH ₂ Cl ₂ (5 mL). The combined organic phases are dried over Na ₂ SO ₄ and filtered. The residue left after evaporation of the solvent is yielded as a green solid as 69 mg (70%) of the main compound via silica gel chromatography eluting with 1: 3 EtOAc: CH ₂ Cl ₂ . ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.96 (d, J = 6.7 Hz, 2H), 7.39 (d, J = 6.6 Hz, 2H), 7.28-7.31 (mult, 2H), 7.04-7.07 (mult) , 2H), 4.69-4.73 (m, 1H), 4.01-4.47 (m, 2H + 2H + 1H), 3.98 (q, J = 7.1 Hz, 2H), 3.42-3.50 (mult, 1H), 3.37 (s , 2H), 3.09 (s, 3H), 1.96 (s, 3H), 1.93 (s, 3H), 0.93 (t, J = 7.1 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ170.7, 168.3, 159.1, 149.3, 145.6, 149.7, 139.4, 134.6, 130.0, 128.6, 128.0, 126.9, 65.4, 62.6, 61.3, 61.3, 59.1, 44.5, 44.3, 37.9 , 25.2, 25.1, 13.6; Mass spectrum (API-TIS) m / z 609 (M-NO), 639 (MH ⁺ ), 659 (MNH ₄ ⁺ ). Anal.Calcd for C ₂₈ H ₃₁ ClN ₂ O ₉ S ₂ : C, 52.62; H, 4.89; N, 4.38; Cl, 5.55; S, 10.03.Found: C, 52.40; H, 4.98; N, 4.17; Cl, 5.68; S, 9.80.
[2007] Example 16: 3-methyl-N-{[4- (5-methyl-3-phenyllysazole-4-yl) phenyl] sulfonyl} -3- (nitrosodio) butanamide
[2008] 16a. 3-methyl-N-{[4- (5-methyl-3-phenyllysazole-4-yl) phenyl] sulfonyl} -3-{(2,4,6-trimethoxyphenyl) methylthiobutanamide
[2009] 3-methyl-3-[(2,4,6-trimethoxyphenyl) methylthio] butanoic acid (patent application WO97 / 34871, the disclosure of which is hereby incorporated by reference in its entirety) Prepared according to the method, Example 1a, 1.05 g, 3.37 mmol) was added to 4- (5-methyl-3-phenylisosazole-4-yl) benzene sulfonamide in THF (30 mL) by Talley et. Prepared by the method described in Med. Chem. 43, 775 (2000), the disclosure of which is incorporated by reference in its entirety, 0.85 g, 2.70 mmol) and 4- (dimethylamino) pyridine (0.1 g). ) Is added to a well-stirred solution. The resulting aqueous solution is stirred well at room temperature for 15 minutes, then solid DCC (0.84 g, 4.04 mmol) is added. The reaction mixture is stirred for 3 hours at room temperature and the solids are removed by filtration. The filtrate is condensed and the residue is obtained as a white solid as main compound (0.92 g, 56%) via silica gel chromatography eluting with 1: 1 EtOAc: hexane. mp 138-140 ° C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.98 (s, 1 H), 7.93 (d, J = 8.4 Hz, 2 H), 7.25-7.42 (mult, 7H), 6.20 (s, 2H), 3.92 (s , 6H), 3.83 (s, 3H), 3.79 (s, 2H), 2.54 (s, 2H), 2.45 (s, 3H), 1.20 (s, 6H); ¹³ C-NMR (75 MHz, CDCl ₃ ) δ168.8, 167.3, 161.0, 158.5, 138.0, 136.1, 129.8, 129.7, 128.9, 128.7, 128.4, 114.5, 105.2, 91.1, 56.1, 55.4, 47.3, 43.8, 29.0, 21.2, 11.7; Mass spectrum (API-TIS) m / z 611 (M−H ⁺ ).
[2010] 16b. 3-methyl-N-{[4- (5-methyl-3-phenyllysazole-4-yl) phenyl] sulfonyl} -3-sulfonylbutanamide
[2011] The resulting product (0.6 g, 0.98 mmol) in CH ₂ Cl ₂ (5 mL) was added to a stirred solution of cysteine (1.1 g, 9.07 mol) in TFA (5 mL) and the resulting pale yellow solution at room temperature. Stir for 1 hour at. Add crushed ice (~ 3 g) and neutralize the mixture with concentrated NH ₄ OH (8 mL). The aqueous mixture is extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over Na ₂ SO ₄ and condensed to yield the main compound (0.4 g, 95%) in the form of a viscous oil. The material is used in the next reaction without further purification. mp 138-140 ° C. ¹ H-NMR (300 MHz, CDCl 3) δ8.05 (d, J = 8.3 Hz, 2H), 7.30-7.40 (mult, 7H), 2.57 (s, 2H), 2.49 (s, 3H), 2.09 (s, 1H), 1.37 (s, 6H); ¹³ C-NMR (75 MHz, CDCl ₃ ) δ 168.5, 167.5, 161.1, 137.6, 136.3, 130.0, 129.7, 128.8, 128.7, 128.4, 128.1, 114.4, 52.0, 42.0, 32.4, 11.7; Mass spectrum (API-TIS), m / z 431 (M−H ⁺ ).
[2012] 16c. 3-methyl-N-{[4- (5-methyl-3-phenyllysazole-4-yl) phenyl] sulfonyl} -3- (nitrosodio) butanamide
[2013] Add a few drops of HCl to a well stirred solution of Example 16b (0.4 g, 0.93 mmol) in CH ₂ Cl ₂ (5 mL) and MeOH (5 mL). Then t-BuONO (90%, 120 mL, 0.93 mmol) is added. Stir the resulting olive green solution at room temperature for 15 minutes under nitrogen atmosphere. After adding cold water (25 mL), the result is extracted with EtOAc (2 x 25 mL). The organic layer is dried over Na ₂ SO ₄ and condensed. The residue is produced as a green foam (0.32 g, 75%) via silica gel flash chromatography eluting with 1: 1 EtOAc: hexane. ¹ H-NMR (300 MHz, CDCl ₃ ) δ9.38 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.28-7.43 (mult, 7H), 3.22 (s, 2H), 2.52 (s , 3H), 1.98 (s, 6H); ¹³ C-NMR (75 MHz, CDCl ₃ ) δ167.8, 167.6, 161.1, 137.4, 136.2, 130.0, 129.8, 128.7, 128.5, 128.0, 114.4, 53.6, 48.3, 27.8, 11.6; Mass spectrum (API-TIS), m / z 460 (MH ⁺ )
[2014] Example 17 2-methyl-2- (nitrosodio) propyl-5- (4-chlorophenyl) -1- (4-sulfamoylphenyl) pyrazole-3-carboxylate
[2015] 17a. Methyl 5- (4-chlorophenyl) -1- (4-sulfamoylphenyl) pyrazole-3-carboxylate
[2016] The composite is described by Penning et. al. J. Med. Chem. 40, 1347-1365 (1997), the disclosure of which is hereby incorporated by reference in its entirety, prepared according to the method described in Compound 3a. mp 186 ° C. ¹ H-NMR (300 MHz, DMSO-d ₆ ) , 1H), 3.87 (s, 3H);
[2017] Example 17 2-methyl-2- (nitrosothio) propyl-5- (4-chlorophenyl) -1- (4-sulfamoylphenyl) pyrazole-3-carboxylate
[2018] 17a. Methyl 5- (4-chlorophenyl) -1- (4-sulfamoylphenyl) pyrazole-3-carboxylate
[2019] This compound is described by Penning et.al. J. Med. Chem. Compound 3a, melting point (mp) 186 ° C., ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ7.89 (d, J = 8.6 Hz, 2H) as described in 40, 1347-1365 (1997) 7.6-7.4 (m, 6H), 7.32 (d, J = 8.6 Hz, 2H), 7.21 (s, 1H), 3.87 (s, 3H); Mass spectra (API-TIS) m / z 392 (MH < + >).
[2020] 17b. 5- (4-Chlorophenyl) -1- (4-sulfamoylphenyl) pyrazole-3carboxylic acid
[2021] Example 17a (9.75 g, 24.9 mmol) of the stirred mixture of product, aqueous NaOH (1.5N, 60 mL), and THF (200 mL) were heated for 5 hours to reflux. This reaction mixture is condensed on a rotary evaporator. The remainder is partitioned between EtOAc (200 mL) and 2N aqueous HCl (100 mL). The organic layer is separated, washed with water, dried over Na ₂ SO ₄ , filtered and condensed to provide a solid phase. Crystals from EtOH / THF (1: 1) were off-white solids, melting point 203 ° C. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ8.02 (d, J = 8.4 Hz, 2H), 7.7-7.6 (m, 4H), 7.45 (d, J = 8.4 Hz, 2H), 7.28 ( s, 1 H); Mass spectrum (API-TIS) m / z 378 (MH < + >) provided to the compound (8.8 g, 90%).
[2022] 17c. 2-methyl-2-sulfonylpropan-1-ol
[2023] Sulfur monochloride (2 ml, 25 mmol) is added to 2-methylpropanal (3.53 g, 49 n mol) in carbon tetrachloride (30 ml) and the reaction mixture is stirred at 55 ° C. for 2 hours. After cooling to room temperature, the volatiles are evaporated in Vacuo to provide 2-[(1,1-dimethyl-2-oxoethyl) disulfanyl] -2-methylpropanal. Disulfide (17.5 g, 85.7 mmol) is dissolved in THF (100 ml) and slowly added to LiAlH ₄ (86 ml. 1 M / THF). After stirring for 1 hour at room temperature, the mixture is poured onto ice, treated with 3N HCl (150 ml) and extracted with EtOAc. The organic extract is dried over sodium sulphate and the volatile components are colorless oils. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 3.44 (s, 2H), 2.25 (brs, 1H), 1.63 (s, 1H), 1.36 (s, 6H); ¹³ C NMR (CDCl ₃ ) 73.3, 46.3, 28.3, yielding 12.8 g (71%) of the compound.
[2024] 17d. 2-methyl-2- (nitrosothio) propan-1-ol
[2025] To a solution of Example 17c (4.4 g, 41.5 mmol) in CH ₂ Cl ₂ (50 ml) is added t-BuONO (5.5 ml, 41.5 mmol). The reaction mixture was stirred at room temperature for 10 minutes, and the volatile component was dark green oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 3.44 (s, 2H), 2.25 (brs, 1H), 1.63 (s, 1H), 1.36 (s, 6H); ¹³ C NMR (CDCl ₃ ) evaporated in Bacuo at 40 ° C. to give 4.6 g (82%) of the compound at 70.5, 57.7, 25.1.
[2026] 17e. 2-methyl-2- (nitrosothio) propyl-5- (4-chlorophenyl) -1- (4-sulfamoylphenyl) pilazole-3-carboxylate
[2027] In a stirred solution of the product of Example 17b (3.78 g, 10.0 mmol), the product of Example 17d (1.35 g, 10.0 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide Hydrochloride (3.83 g, 20.0 mmol), 4- (dimethylamino) pyridine (10 mg) and triedilamine (2.79 mL, 20.0 mmol) are added. After stirring for 4 hours at room temperature, the mixture is diluted with EtOAc (200 mL), washed with 1N HCl, water, dried over Na 2 SO 4, filtered and concentrated. The remaining chromatography extracted with 1: 4 EtOAc: hexanes gave a green solid. Melting point 153 ℃. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 7.88 (d, J = 8.6 Hz, 2H), 7.55-7.49 (m, 4H), 7.32 (d, J = 8 Hz, 2H), 7.20 ( s, 1 H), 3.32 (s, 2 H), 1.82 (s, 6 H); Mass spectrum (API-TIS) m / z 495 (MH < + >). Anal. Calcd. for C ₂₀ H ₁₉ CIN ₄ O ₅ S ₂ : C, 48.53; H, 3.87; N, 11.32; Cl, 7.16; S, 12.96. Found: C, 48.79; H4. 12; N, 11.50; Cl, 6.81; As S12.76 is provided in the compound (0.20 g, 4%).
[2028] Example 18: 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -2-({4-[(nixy) methyl] phenyl} methyl] -2-hydroxyphylli Chopped-3-one
[2029] 18a. 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -2-benzyl-2-hydropyridazine-3-one
[2030] This compound is described in patent application WO99 / 10331 (the detailed description is omitted). ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.85 (d, J = 8.4 Hz, 2H), 7.83 (m, 1H), 7.53 (m, 2H), 7.31 (m, 5H), 7.15 (m, 2H), 6.93 (m, 2H), 5.93 (s, 2H), 3.02 (s, 3H); ¹³ C-NMR (75 MHz, CDCl ₃ ) δ 164.3, 161.0, 159.5, 140.5, 138.7, 13706, 135.8, 132.5, 132.4, 129.9, 129.1, 128.6, 128.1, 127.7, 115.2, 115.2, 56.1, 44.2; Synthesized in mass spectrum (API-TIS) m / z 435 (MH ⁺ ).
[2031] 18b. 4- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -2-hydropyridazine-3-one
[2032] AlBr 3 (140 mg, 0.52 mmol) is added to the product of Example 18a (74 mg, 0.17 mmol) in toluene (20 ml). The reaction mixture is heated at 90 ° C. for 15 minutes and cooled at 0 ° C. The reaction mixture is then poured into ice cold water, oxidized with 1N HCl, and extracted with ethyl acetate (2 x 50 mL). The combined extract is washed with water (2 × 25 mL) and brine (1 × 25 mL), dried over Na ₂ SO ₄ and filtered. Evaporation of the solvent is said compound (45 mg, 76%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ7.8-7.9 (m, 3H), 7.35 (d, J = 9 MHz, 2H), 7.2 (m, 2H), 7.0 (t, J = 9 MHz, 2H) , 3.05 (s, 3 H); The LRMS (APIMS) m / z 345 (M + H) is provided to the remainder filtered by column chromatography in silica galls extracted with 5% methanol in CH 2 Cl 2.
[2033] 18c. Methyl 4- (5-fluorophenyl) -4- [4- (methylsulfonyl) phenyl] -6-oxohydropyridazinyl} methyl) benzoate
[2034] The product of Example 18b (210 mg, 0.61 mmol) is dissolved in anhydrous DMF (3 mL) and K ₂ CO ₃ (336 mg, 2.44 mmol) is added. Methyl 4- (bromomethyl) benzoate (140 mg, 0.61 mmol) is added to the reaction mixture, which is stirred for 1 day at room temperature. The reaction mixture is diluted with water (25 mL) and extracted with ethyl acetate (2 x 50 mL). This combined extract is washed with water (4 × 50 mL), brine (1 × 25 mL) and dried sodium sulfite. Evaporation of the solvent is colorless foam. ¹ H-NMR (300 MHz, CDCl ₃ ) δ8.02 (d, J = 7.8 Hz, 2H), 7.86 (d, J = 8.5 MHz, 2H), 7.84 (s, 1H), 7.58 (d, J = 7.8 MHz, 2H), 7.32 (t, J = 7.9 MHz, 2H), 7.15 (t, J = 6.8 MHz, 2H), 6.94 (t, J = 8.2 MHz, 2H), 5.43 (s, 2H), 3.89 (s, 3H), 3.03 (s, 3H); ¹³ C-NMR (75 MHz, CDCl ₃ ) δ166.7, 164.5, 159.5, 140.8, 140.7, 140.4, 138.8, 137.4, 137.3, 132.5, 132.4, 130.0, 129.9, 129.0, 128.3, 127.8, 127.4,115.3, 55.8, 52.1, 44.3; To the compound (210 mg, 70%) to give the mass spectrum (API-TIS) m / z 493 (MH ⁺ ). To the remainder which was filtered by column chromatography on silica galls extracted with 1: 1 EtOAc: hexane. Is provided.
[2035] 18d. 4- (4-fluorophenyl) -2- {4- (hydroxymethyl) phenyl} -5- [4- (methylsulfonyl) phenyl] -2-hydroxypyrazine-3-one
[2036] The product of Example 18C (190 mg, 0.386 mmol) is dissolved in Anhayodor CH ₂ Cl ₂ (10 mL). This solution is cooled at 0 ° C. and 1M DIBAL-H (1.05 mL) is added dropwise under a nitrogen atmosphere. The reaction mixture is stirred at 0 ° C. for 30 minutes and then at room temperature for 15 minutes. It is then quenched in ice cold water, oxidized with 1N HCl and extracted with CH ₂ Cl ₂ (2 × 50 ml). The combined extract is washed with water (2 × 25 mL), brine (1 × 25 mL) and dried Na ₂ SO ₄ . Evaporation of the solvent is colorless foam. Melting point 155-164 ° C. ¹ H-NMR (CDCl ₃ ) δ 7.86 (d, J = 8.2 Hz, 2H), 7.82 (s, 1H), 7.52 (d, J = 7.8 MHz, 2H), 7.34 (d, J = 7.9 MHz, 2H), 7.29 (d, J = 8.1 MHz, 2H), 7.14 (t, J = 7.6 MHz, 2H), 6.93 (t, J = 8.5 MHz, 2H), 5.43 (s, 2H), 4.65 (s, 2H), 3.03 (s, 3H); ¹³ C-NMR (300 MHz, CDCl ₃ ) δ 164.4, 161.1, 159.5, 140.9, 140.7, 140.5, 138.8, 137.2, 135.1, 132.4, 129.9, 129.4, 127.7, 127.6, 115.6, 115.3, 64.8, 55.9, 44.3; Filtered by column chromatography on silica galls extracting 5% methanol in CH ₂ Cl ₂ to give the compound (210 mg, 70%) with a mass spectrum (API-TIS) m / z 465 (MH ⁺ ). Is provided for the rest.
[2037] 18e. 4- (4fluorophenyl) -5- [4- (methylsulfonyl) phenyl] -2-({4- (nitrooxy) -methyl] phenyl} methyl) -2-hydroxypyridazine-3-one
[2038] The product of Example 18d (30 mg, 0.065 mmol) is dissolved in anhydrous ethyl acetate (0.5 ml). In a separate flask, the nitrated mixture is prepared by continuously adding acetic anhydride (472 μL, 5.20 mmol) and flushing nitric acid (137 μL, 3.25 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C. for 5 minutes, quenched with water and extracted with ethyl acetate. The organic layer is prepared and washed with water, brine and dried Na ₂ SO ₄ . Evaporation of the solvent is a white solid. Melting point 78-87 ° C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.86 (d, J = 8.2 Hz, 2H), 7.84 (s, 1H), 7.58 (d, J = 8.0 MHz, 2H), 7.39 (d, J = 8.0 MHz, 2H), 7.31 (d, J = 8.2 MHz, 2H), 7.15 (t, J = 6.4 MHz, 2H), 6.95 (t, J = 8.6 MHz, 2H), 5.41 (s, 2H), 5.40 ( s, 2H), 3.04 (s, 3H); By thin layer chromatography (0.25 mm silica gel plate) using 6: 4 EtOAc: Hexane to give the compound (5.5 mg, 17%) in mass spectrum (API-TIS) m / z 510 (MH ⁺ ). To the purified residue.
[2039] Example 19: 4- (methylsulfonyl) -1- {1- [2- (nitoxy) ethyl] -4-benzylpilazol-5-yl} benzene
[2040] 19a. 1- (4-methylthiophenyl) -3-phenylpropane-1-one
[2041] To a stirred solution of 4- (methylthio) benzonitride (25.0 g, 0.17 mole) in THF (100 mL) in a nitrogen atmosphere is added phenethylmagnesium chloride (1.0 M in THF, 210 mL, 0.21 mole). The solution is heated to reflux for 4 hours, cooled at 0 ° C. and carefully quenched with water (10 mL). The remaining slurry is treated with 6N hydrochloric acid (200 mL) and stirred for 1 day at room temperature. THF is evaporated from the mixture and the remainder is extracted with EtOAc (2 × 300 mL). The combined organic extracts are washed with 2M Na ₂ CO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated to give a solid material. Green plate recrystallized from EtOAc-Hex (1: 4). Melting point 105 ℃. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.85 (d, J = 8.5 Hz, 2H), 7.32-7.19 (m, 7H), 3.24 (t, J = 6.8 MHz, 2H), 3.06 (t, J = 6.8 MHz, 2H), 2.50 (s, 3H); ¹³ C-NMR (75 MHz, CDCl ₃ ) δ 198.4, 145.8, 141.3, 133.2, 128.48, 128.42, 128.38, 126.1, 125.0, 40.2, 30.2, 14.7; Mass spectrum (API-TIS) m / z 257 (M + H). Provided for the compound (210 mg, 70%).
[2042] 19b. 2- [3- (4-methylthiophenyl) -4-benzylpilazolyl] ethan-1-ol and 2- [5- (4-methylthiophenyl) -4-benzylpilazolyl] ethan-1-ol
[2043] A stirred solution of the product of Example 19a (850 mg, 3.3 mmol) in THF (8 mL) at −78 ° C. in a nitrogen atmosphere was added to a drop of lithium diisopropylamide (1.5 M in cyclohexane, 2.66 mL, 4.0 mmol). Is added. After 30 minutes to THF (1 mL) a solution of HCO ₂ Et (0.32 mL, 4.0 mmol) is added, gradually heated at room temperature and stirred for one day. The mixture is poured into 1N HCl and extracted with EtOAc (2 × 20 mL). The combined organic extracts are washed with saturated NaHCO ₃ (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give an off-white solid (905 mg). A stirred solution of this solid and 2-hydroxyethylhydrazine (0.37 mL, 5.00 mmol) in EtOH (15 mL) were heated to reflux and concentrated for 3 h in a nitrogen atmosphere. The remainder is dissolved in EtOAc (50 mL), washed with 1N HCl, dried over Na ₂ SO ₄ , filtered and concentrated. The remainder is inseparable mixture (0.81 g, 75%). Quantum NMR ¹ H-NMR (300 MHz, CDCl ₃ ) δ7.53-7.09 (m, ArH), 4.17 (t, J = 4.5 Hz), 4.08 (t, J = 4.5 Hz), 3.98 (t, J = 5.0 Hz), 3.96 (s), 3.91 (t, 5.0 Hz), 3.71 (s), 2.51 (s), 2.49 (s); Chromatography is performed on silica gel extracted with EtOAc to give regioisomer pyrazole in a ratio of 3: 2 isomer to be determined by mass spectrum (API-TIS) m / z 325 (M + H).
[2044] 19c and 19d. 1- [1- (2-hydroxyethyl) -4-benzylpilazol-3-yl] -4- (methylsulfonyl) benzyl
[2045] The product of Example 19b (810 mg, 2.50 mmol) is dissolved in MeOH and treated with oxone (4.61 g, 7.50 mmol) and water (10 ml). The slurry is stirred for 30 minutes at room temperature. The reaction mixture is poured into water, neutralized with aqueous Na ₂ SO 4, and extracted with EtOAc (50 mL × 2). The combined organic extracts are dried over Na ₂ S0 ₄ , filtered and concentrated. Remainder Example 19d (260 mg, 29%). Physical data of Example 19c: R _f 0.47 (EtOAc, silica gel). Melting point 96 ℃. ¹ H-NMR (300 MHz, CDCl ₃ ) δ7.93 (d, J = 8.6 Hz, 2H), 7.81 (d, J = 8.6 Hz, 2H), 7.31-7.17 (m, 6H), 4.03 (t, J = 4.5 Mz, 2H), 4.00 (s, 2H), 3.05 (s, 3H); ¹³ C-NMR (75 MHz, CDCl ₃ ) δ147.7, 139.9, 139.1, 138.8, 131.8, 128.6, 128.3, 128.0, 127.4, 126.3, 118.6, 61.6, 54.0, 44.4, 30.7; Mass Spectrum (API-TIS) m / z 357 (M + H). Anal. calcd for C ₁₉ H ₂₀ N ₂ ) 3S: C, 64.02, H, 5.66; N, 8.10, S, 8.98. Physical data of Example 19d: R _f 0.38 (EtOAc, silica gel). Melting point 68 ℃. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.99 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.41 (s, 1H), 7.25-7.14 (m, 3H ), 7.06 (d, J = 7.2 Mz, 2H), 4.07 (t, J = 4.6 Hz, 2H), 3.93 (t, J = 4.6 Hz, 2H), 3.72 (s, 2H), 3.09 (s, 3H ); ¹³ C-NMR (75 MHz, CDCl ₃ ) δ140.5, 140.3, 139.6, 139.5, 135.5, 135.3, 130.9, 128.3, 128.1, 127.5, 126.0, 119.1, 61.3, 51.1, 44.2, 29.8; Mass Spectrum (API-TIS) m / z 357 (M + H). Anal. calcd for C ₁₉ H ₂₀ N ₂ O ₃ S: C, 64.02, H, 5.66; N, 7.86, S, 9.00. Found: C, 64.18; H, 5.87; N, 7.79; S, 8.94.
[2046] 19e. Fuming HNO ₃ (90%, 1 mL) is added to Ac ₂ O (5 mL) at 0 ° C. and the mixture is stirred for 10 minutes. The product of Example 19d (235 mg, 0.66 mmol) in EtOAc (6 ml) is added and the solution is stirred at 0 ° C. for 5 parts. The mixture is poured into ice cold saturated NaHCO 3 (10 mL) and extracted with EtOAc (2 × 20 mL). Combined organic extracts were oil (259 mg, 96%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ8.02 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.24-7.18 (m, 4H), 7.06 (m, 2H ), 4.77 (t, J = 5.0Mz, 2H), 4.31 (t, J = 5.0Mz, 2H), 3.72 (s, 2H), 3.10 (s, 3H); Washed again to make the product as mass spectrum (API-TIS) m / z 402 (M + H). Dried with Na 2 SO 4, filtered and concentrated.
[2047] Example 20: 4- {1-cyclohexyl-3-[(nitrooxy) methyl] pyrazol-5-yl} -1-methylsulfonyl) benzene
[2048] 20a. Methyl (2Z) -2-hydroxy-4- (4-methylthiophenyl) -4-oxobut-2-enoate
[2049] Dimethyloxalate (2 g, 180 mmol) is added to a stirred suspension of sodium methooxide (9.75 g, 180.7 mmol) in dry toluene (200 mL) at 0 ° C. The white suspension is pretreated for 15 minutes at 0 ° C. A 4 '-(methylthio) acetophenone (15 g, 90.4 mmol) solution in dry toluene (150 mL) is added to the droplets to give a stirred yellow suspension at room temperature for 2 hours. The thick yellow suspension is transferred to a 2 liter flask and vigorously stirred with 10% HCl (250 mL) and EtOAc (200 mL) to dissolve all solids. The organic layer is separated and the aqueous layer is extracted with EtOAc (100 mL). The combined organic extracts are washed with water and dried over Na ₂ SO ₄ , and the solvent is evaporated under reduced pressure to give a thick brown oil. Brown oil is dissolved in CH2Cl2 (25mL) and hexane (125mL) orange solid. Melting point 81 ℃. ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.83 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 6.97 (s, 1H), 3.89 (s, 3H), 2,47 (s, 3 H); ¹³ C-NMR (75 MHz, CDCl ₃ ); Mass spectra (API-TIS) m / z 253 (MH ⁺ ). Frozen to provide the compound (18 g, 79%) for 16 h at -20 ° C.
[2050] 20b. Methyl-1-cyclohexane-5- (4-methylthiophenyl) pilazole-3-carboxylate
[2051] The product of Example 20a (1.98 mg, 7.8 mmol) and cyclohexylazine hydrochlorite (1.54 g, 10.2 mmol) in methanol (40 mL) are heated at 70 ° C. for 3 hours and cooled at room temperature. The mixture is made on a 10% Na ₂ CO ₃ basis and extracted with EtOAc (3 × 25 mL). The organic extract is dried over Na 2 SO 4 and the solvent is evaporated under reduced pressure to give a thick oil. The oil was dissolved in CH 2 Cl 2 (4 mL) and hexane (20 mL) and cooled at −10 ° C. for 16 hours to give a white solid. Melting point 84 ℃. ¹ H-NMR (300 MHz, CDCl ₃ ) δ7.33 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 6.76 (s, 1H), 4.08-4.13 (mult, 3H ); ¹³ C-NMR (75 MHz, CDCl ₃ ) δ 163.1, 143.6, 142.3, 140.1, 129.4, 126.4, 126.2, 108.8, 58.7, 51.9, 33.1, 25.5, 24.8, 15.3; Mass Spectrum (API-TIS) m / z 331 (M−H ⁺ ). Anal. calcd for C ₁₉ H ₂₀ N ₂ O ₃ S: C, 65.43, H, 6.71; N, 8.48, S, 9.70. Found: C, 65.28; H, 6. 66; N, 8.47; S, 9.61.
[2052] 20c. 1-cyclohexyl-5- (4-axlfxldhvpslf) filazol-3-yl] methan-1-ol.
[2053] A solution of lithium aluminum hydride (2 mL at 1 M, 2 mmol) is added to the product of Example 20b (0.7 g, 2.1 mmol) in THF (15 mL). The resulting pure solution is stirred at room temperature for 1 hour. A small amount of solid Na ₂ SO ₄ 10H ₂ O (2 g) is added to stir until a thick precipitate is formed. Methanol in CH ₂ Cl 2 (10%, 50 mL) is added and the mixture is filtered. The solid was washed with added methanol in CH ₂ Cl 2 (10%, 50 mL) and the combined filtrate melted as a white solid at 97 ° C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ7.31 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.3 Hz, 2H), 6.20 (s, 1H), 4.71 (d, J = 4.8 Hz, 2H), 4.00-4.15 (mult, 1H), 2.53 (s, 3H), 1.65-2.10 (mult, 7H), 1.15-1.30 (mult, 3H); ¹³ C-NMR (75 MHz, CDCl ₃ ) δ151.0, 143.2, 139.3, 129.9, 127.5, 126.6, 104.1, 59.0, 57.7, 33.2, 25.6, 25.1, 15.4; Mass spectrum (API-TIS) m / z 303 (MH ⁺ ). Evaporated to give the compound (0.61 mg, 95%).
[2054] 20d. 4- [1-cyclohexyl-3- (hydroxymethyl) pyrazol-5-yl] -1- (methylsulfonyl) benzene
[2055] The product of Example 20c (0.6 g, 2.0 mmol) is dissolved in a mixture of MeOH (20 mL) and water (8 mL) and cooled at 0 ° C. Solid oxone (3 g) is added and the resulting suspension is stirred at 0 ° C. for 1 hour. Water (25 mL) and 15% NH ₄ OH (25 mL) are added. The mixture is extracted with EtOAc (3 × 25 mL) and the organic extract is dried over Na ₂ SO ₄ . The solvent is white solid. Melting point 148 ℃. ¹ H-NMR (300 MHz, CDCl ₃ ) δ8.03 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 6.31 (s, 1H), 4.73 (s, 2H), 3.90-4.10 (mult, 3 H); ¹³ C-NMR (75 MHz, CDCl ₃ ) δ151.4, 141.7, 140.4, 136.5, 129.7, 127.9, 105.5, 59.0, 58.2, 44.4, 33.3, 25.6, 25.0; The mass spectrum (API-TIS) m / z 335 (MH ⁺ ) was evaporated at low pressure to give a white solid recrystallized from CH 2 Cl 2 (5 mL) to give the compound (0.62 g, 94%).
[2056] 20e. 4- {1-cyclohexyl-3- (nitrooxy) methyl] pilazol-5-yl} -1- (methylsolfonyl) benzene
[2057] Fuming HNO ₃ (0.76 mL, 18 mmol) is added to Ac ₂ O (2.7 mL. 28.8 mmol) at 0 ° C. via a washer. The mixture is transferred to a Pasteur pipette in a stirred suspension of the product of Example 20d (1.2 g, 3.6 mmol) in EtOAc (40 mL) at room temperature and the mixture is stirred for 45 minutes at room temperature. Cold saturated NaHCO ₃ (40 mL) is added and mixed well in a separate funnel. The organic layer is separated and dried over Na ₂ SO ₄ . The solvent is evaporated under reduced pressure to give a viscous oil dissolved in CH ₂ Cl ₂ (5 mL) and hexane (25 mL). The resulting pure solvent is a yellow solid. Melting point 104 ℃. H-NMR (300MHz, CDCl ₃ ) δ8.05 (d, J = 8.4Hz, 2H), 7.55 (d, J = 8.4Hz, 2H), 6.39 (s, 1H), 5.50 (s, 2H), 3.95 -4.10 (mult, 1H), 3.13 (s, 3H), 1.60-2.10 (mult, 7H), 1.15-1.30 (mult, 3H); ¹³ C-NMR (75 MHz, CDCl ₃ ) δ143.1, 142.1, 140.7, 136.0, 129.8, 127.9, 107.3, 68.6, 58.6, 44.4, 33.3, 25.5, 25.0; Mass spectrum (API-TIS) m / z 380 (MH ⁺ ). Anal. calcd for C ₁₇ H ₂₁ N ₃ O ₅ S: C, 53.81, H, 5.58; N, 11.07, S, 8.45. Found: C, 53.55; H, 5.55; N, 10.83; Cool down at −10 ° C. for 4 h to afford S, 8.36. To the compound (1.05 g, 77%).
[2058] Example 21 Test for Obine COX-1 and COX-2 Activity
[2059] The measurement of the overine COX-1 and COX-2 activity and the synthesized prostaglandin product was performed using a COX immunosuppressant screening test (Casman, Chemcal, Ann, Arbor, MI, including Prostaglandin Determination EIA, Kit used for prostaglandin quantification). Is performed. The test compound dissolves the final concentration up to 50 times in DMSO or other suitable solvent as a stock solution.
[2060] This stock solution is whitened with the same solvent. Eight glass test tubes (13 × 100 mm) are placed in a water bath at 37 ° C. Each test tube contains 950 μL of reaction buffer (containing 0.1 M Tris-HCl, pH 8.0, 5.M EDTA, and 2 mM phenol), 10 μL (100 units) of 100 M gpa solution, and 10 μL of other Ovine COX-1 or COX-2 And the mixture is incubated with enzyme for 2 minutes. 20 μL of solvent is added to one tube (100% initial activity or solvent control) and 20 μL of each dilution of the test compound is added to one tube each. Each tube is vortexed upon addition. Enzymes are incubated with immunosuppressants at 37 ° C. for 3.5 minutes. The enzymatic reaction is started by adding 10 μL of freshly prepared 10 mM arachidonic acid (neutralized with KOH), vortex and incubated at 37 ° C. for 2 minutes. The reaction is inhibited by adding 50 μL of 1M HCl and is vortexed at room temperature. 100 μL of the evaporated Stanus chloride solution (0.1 M HCl 50 mg / mL) is added so that the reaction mixture is maintained at room temperature for at least 5 minutes.
[2061] Prostaglandins (PG) generated in the reaction are tested using the Prostaglandin Screening EIA Kit (Cayman, Chemcal, Ann, Arbor, MI) after 2000-hold dilution. Experiments included antibodies with broad specificity for all prostaglandin groups (PGF, PGE, PGD and thromboxane B-type) synthesized in the COZ-1 / COX-2 reaction. Computed prostaglandins counter PG tagged with acenycloline esterase to bind PG antibodies. The binding of the synthesized PGs lowers the colorimetric generation of Ellan's reagent (calculated as% B / B ₀ ). The actual amount of synthesized PG is included in the known standard curve (PGE2 concentration versus% B / B ₀ ) of the supplied prostaglandin E2 (PGE2). The data generated is the mean ± standard deviation of triplicate wells in EIA for a single response at a given immunosuppressant concentration. Plot% of control (i.e. solvent control without immunosuppressant) versus immunosuppressant concentration of test compound for two isozymes is used to determine IC ₅₀ for COX-1 and COX-2 for test compound. IC ₅₀ for compounds is provided in Table 1.
[2062] IC ₅₀ volume in COX-1 and COX-2 Test compoundCOX-1IC ₅₀ COX-2IC ₅₀Indomethacin0.180.35 Celecoxib340.34 Example 1a1003.3 Example 1b19010 Example 2aNo reaction inhibitor up to 30024 Example 2bNo reaction inhibitor up to 3001.2 Example 3e620.006 Example 3gNo reaction inhibitor up to 30070 Example 5aNo reaction inhibitor up to 30012 Example 5bNo reaction inhibitor up to 30033
[2063] NSAID, indomethacin is not optionally shown for COX-1 or COX-2. The celecoxib, selected COX-2 immunosuppressant used for control, is selected for COX-2. The results show that the nitrostated fluorides (ie, Examples 1b, 2b and 5b) have COX-2 selectivity as the compound that is not the parent nitrostedase. Thus, it can be seen that the nitrosation of sorbonamide in the parent COX-2 immunosuppressant influenced the COX-2 immunosuppressive properties of the nitrosified compound.
[2064] Example 22 Human COX-1 and COX-2 Activity Experiments
[2065] Measurement of human COX-1 and COX-2 activity and synthesized prostaglandin products was performed using a COX immunosuppressant screening test (Casman, Chemcal, Ann, Arbor, MI, including Prostaglandin Determination EIA, Kit used for prostaglandin quantification) do. The test compound dissolves the final concentration up to 50 times in DMSO or other suitable solvent as a stock solution. This stock solution is diluted with the same solvent. Eight glass test tubes (13 × 100 mm) were placed in a water bath at 25 ° C. Each test tube contains 950 μL of reaction buffer (containing 0.1 M Tris-HCl, pH 8.0, 5.M EDTA and 2 mM phenol), 10 μL (100 units) of 100 M gpa solution, and 10 μL of other human COX-1 or COX-2 The mixture is incubated with enzyme for 2 minutes. 20 μL of solvent is added to one tube (100% initial activity or solvent control) and 20 μL of each dilution of the test compound is added to one tube each. Each tube is vortexed upon addition. Enzymes are incubated with immunosuppressants at 20 ° C. for 25 minutes. The enzymatic reaction is started by adding 10 μL of freshly prepared 10 mM arachidonic acid (neutralized with KOH), vortexed and incubated at 37 ° C. for 2 minutes (30 seconds in EH in some cases as mentioned above). The reaction is inhibited by adding 50 μL of 1M HCl and is vortexed at room temperature. 100 μL of the evaporated Stanus chloride solution (0.1 M HCl 50 mg / mL) is added so that the reaction mixture is maintained at room temperature for at least 5 minutes.
[2066] Prostaglandins (PG) generated in the reaction are tested using the Prostaglandin Screening EIA Kit (Cayman, Chemcal, Ann, Arbor, MI) after 2000-hold dilution. Experiments included antibodies with broad specificity for all prostaglandin groups (PGF, PGE, PGD and thromboxane B-type) synthesized in the COZ-1 / COX-2 reaction. Computed prostaglandins counter PG tagged with acenycloline esterase to bind PG antibodies. The binding of the synthesized PGs lowers the colorimetric generation of Ellan's reagent (calculated as% B / B ₀ ). The actual amount of synthesized PG is included in the known standard curve (PGE2 concentration versus% B / B ₀ ) of the supplied prostaglandin E2 (PGE2). The data generated is the mean ± standard deviation of triplicate wells in EIA for a single response at a given immunosuppressant concentration. Plot% of control (ie, solvent control without immunosuppressive agents) versus immunosuppressant concentration of test compound for two isozymes is used to determine IC ₅₀ for COX-1 and COX-2 for test compound. % Immunosuppressants for selected concentrations of immunosuppressants tested are provided in Table 2.
[2067] % Inhibition in human COX-1 and COX-2 Test compoundCOX-1 inhibition (% at 100 μM)Inhibition at COX-2 (% at 10 μM) Example 2a0 ^a 65 Example 2b0 ^a 100 Example 4a89 ^b 69 ^bExample 4b49 ^b 91 ^bExample 19d95100 Example 19e0100 Example 20d1634 Example 20e037
[2068] In the table, a = Obine COX-1
[2069] b = incubate for 30 seconds with an arachidonic acid substrate
[2070] The results show the same or slightly improved COX- compared to the parent compound (ie, Examples 2a, 4a, 19d and 20d, respectively) where the nitrosated compounds (ie, Examples 2b, 5b, 19e and 20e) were not nitrosized. 2 shows selectivity. Thus, nitrosolation can improve COX-2 immunosuppressant properties without affecting the COX-2 immunosuppressant properties.
[2071] Example 23 Preparation of Striated Muscle Rings in Rat Aorta
[2072] Male Sprage-Dawley rats (Charles River Laboratories (Wilmington, Mass.)) Were euthanized by an intraperitoneal injection of a large amount of sodium pentobarbitone (80-100 mg). Buffer of Han (95% O ₂ and 5% CO ₂ ) Kreb (Milomolar Sugar Constitution: NaCl (119); KCl (4.69); CaCl ₂ H ₂ O (2.52); MgSO ₄ 7H ₂ O (0.57); NaHCO ₃ (25); located in Petri dish containing NaH ₂ PO ₄ H ₂ O (1.01) and glucose (11.1) In stereoscopic dissecting microscopy, the aorta was clean and free of attached fat and connected tissue. The tissue was cut into ring portions, each 2-3 mm long.
[2073] Stainless steel tissue supports and U-shaped stainless stell wires were inserted into the cells of the aortic rings as experiments to measure tissue relaxation under various conditions. The tissue support was connected to the FT-202 transducer by securing the ring at the bottom of the tracheal bath in such a way that the U-shaped steel wire was secured with fine silk thread. Tissue supports and steel wires along the aortic ring are then extended to a 5 mL double-filled temperature controlled glass tissue bath (Radnoti Glass Technology, Inc., Monrovia, Calif.) Filled with fresh Kreb's buffer. A mixture of 95% O 2 and 5% CO 2 is boiled through the pore sintered disc at the bottom of the bath. The ring is provided for 1.5 g of initial resting tension and the preparation is in equilibrium with the initial tension for about 90 minutes. During this equilibrium the bath fluid changes for every 15 minutes and is placed in a buffer of freshly preheated (37 ° C.) Kreb. The response to equidistant tension and other stimuli of the aortic muscle at rest is recorded on the Power Mackintosh 6100 computer via Maclab 8 / s computer interface (CB Science, Inc. Milford, MA) after initial amplification through low noise ETH-400. . The contractile response of the tissue strip is demonstrated with 10 μM of phenylephrine and the strip is incubated with the drug for 20 minutes to demonstrate a stable level of contraction. To test the relaxation effect, test compounds are added to phenylephrine strips pre-shrunk in tissue baths at cumulative concentrations of 0.1 μM to 0.1 mM. Shrinkage of the test compound increased only after relaxation had already reached a high level with preshrinkage.
[2074] Example 24 Relaxation of the Plain Pattern Muscle Ring of the Aorta According to Example 1
[2075] Tissue is prepared according to Example 23. The contraction ratio of contracted phenylephrine aortic smooth muscle ring reduced by isosorbide dinitride (ISDN), Examples 1a and 1b (nitrate) is measured. 1 shows that the non-nitrosified parent compound of Example 1a does not relax the aortic ring. The nitrified compound of Example 1b reduces the relaxation of the aortic ring. The relaxation observed is similar to the isosorbide dinitrate obtained by the nitrate compound.
[2076] Example 25 Relaxation of the Plain Pattern Muscle Ring of the Aorta according to Example 2
[2077] Tissue is prepared according to Example 23. The contraction rate of contracted phenylephrine aortic smooth muscle ring reduced by isosorbide dinitride (ISDN), Examples 2a and 2b (nitrate) is measured. 2 shows that the non-nitrosified parent compound of Example 2a does not relax the aortic ring. The nitrosized compounds of Example 2b reduce the relaxation of the aortic ring. The relaxation observed is similar to the isosorbide dinitrate obtained by the nitrate compound.
[2078] Example 26 Relaxation of the Aortic Plain Muscle Ring According to Example 3
[2079] Tissue is prepared according to Example 23. The contraction ratio of contracted phenylephrine aortic smooth muscle ring reduced by S-nitrosoludathione (GSNO), Example 3e and Example 3h (nitrosolthiol) is measured. 3 shows that the non-nitrosified parent compound of Example 3e does not relax the aortic ring. The nitrified compound of Example 3h reduces the relaxation of the aortic ring. The relaxation observed is similar to the isosorbide dinitrate obtained by the nitrate compound.
[2080] Example 27 Relaxation of the Aortic Plain Muscle Ring According to Example 20
[2081] Tissue is prepared according to Example 23. The contraction rate of contracted phenylephrine aortic smooth muscle ring reduced by isosorbide dinitride (ISDN), Example 20d and Example 20e (nitrate) is measured. 4 shows that the unnitrosed parent compound of Example 20d does not relax the aortic ring. The nitrified compound of Example 20e reduces the relaxation of the aortic ring. The relaxation observed is similar to the isosorbide dinitrate obtained by the nitrate compound.
[2082] Example 28 Anti-Inflammatory Poedama Test for Example 2
[2083] Carrageenan-induced rat poedema test is used to measure antiinflammatory activity. Four-edema testing is described in Winter et al, Proc. Soc. Exp. Biol. Med. 111: 544-547, 1962 measured according to the method. Male Sprague-Dawley rats (200-250 g) are fasted with water and libitium for 24 hours. Mice are dosed with the test compound in the stomach in an amount of 5 mL / kg. Bubble volume was measured 1 hour after dosing. Each rat was then injected with 50 μl subpalenta with a suspension of 1% carrageenan. The increase in vesicle volume was shown as mean ± SEM in 5 animals per group. Data was analyzed by performing an ANOVA test made by the Student-Keuls Post Hawk test.
[2084] FIG. 5 shows that Example 2, the nitrosified compound Sish Example 2b and celecoxib, both of the non-nitrosified parent compound, had reduced envelope volume and, therefore, these compounds had anti-inflammatory activity. Thus, nitrosoxin does not affect the COX-2 inhibitory properties of the compound.
[2085] The use of each patent, patent application and published material or a description of the invention's specification is incorporated by reference in its entirety.
[2086] Although the invention has been described in detail herein, the present technology is susceptible to various modifications and modifications within the scope of the invention and the scope of the invention is not limited to that described above.
[2087] The compounds according to the invention can be prepared in pharmaceutical compositions and kits and applied to the treatment, prevention and reduction of various diseases.

权利要求:
Claims (70)
[1" claim-type="Currently amended] Formula 1, Formula 2, Formula 3, Formula 4, Formula 5, Formula 6, Formula 7, Formula 8, Formula 9, Formula 10, Formula 11, Formula 12, Formula 13, Formula 14, Formula 15 or Formula 16 Compounds, or pharmaceutically acceptable salts thereof:
Wherein Formula 1 (I)
[Formula 1] Represented by
Here, when b side is a double bond and a side and c side are single bonds, -X ¹ -Y ¹ -Z ¹ -is:
(a) -CR ⁴ (R ⁵ ) -CR ⁵ (R ⁵ ′) -CR ^4- (R ⁵ )-;
(b) -C (O) -CR ⁴ (R ⁴ ′) -CR ^5- (R ⁵ ′)-;
(c) -CR ⁴ (R ⁴ ′) -CR ^5- (R ⁵ ′) -C (O) —;
(d)-(CR ⁵ (R ⁵ ′) _k -OC (O)-;
(e) —C (O) —O (CR ⁵ (R ⁵ ′)) _k −;
(f) -CR ⁴ (R ⁴ ′) -NR ³ -CR ⁵ (R ⁵ ′)-;
(g) -CR ⁵ (R ⁵ ′) -NR ³ -C (O)-;
(h) -CR ⁴ = CR ⁴ '-S-;
(i) -S-CR ⁴ = CR ⁴ '-;
(j) -SN = CR ^4- ;
(k) -CR ⁴ = NS-;
(l) -N = CR ⁴ -O-;
(m) -O-CR ⁴ = N-;
(n) -NR ³ -CR ⁴ = N-;
(o) -N = CR ⁴ -S-;
(p) -S-CR ⁴ = N-;
(q) -C (O) -NR ³ -CR ⁵ '(R ⁵ ')-;
(r) -R ³ N-CR ⁵ = CR ⁵ '-;
(s) -CR ⁴ = CR ⁵ -NR ^3- ;
(t) -ON = CR ^4- ;
(u) -CR ⁴ = NO-;
(v) -N = N-S-;
(w) -S-N = N-;
(x) -R ³ N-CR ⁴ = N-;
(y) -N = CR ⁴ -NR ^3- ;
(z) -R ³ NN = N-;
(aa) -N = N-NR ^3- ;
(bb) -CR ⁴ (R ⁴ ′) -O-CR ⁵ (R ⁵ ′)-;
(cc) -CR ⁴ (R ⁴ ′) -S-CR ⁵ (R ⁵ ′)-;
(dd) -CR ⁴ (R ⁴ ′) -C (O) —CR ⁵ (R ⁵ ′)-;
(ee) -CR ⁴ (R ⁴ ′) -CR ⁵ (R ⁵ ′) -C (S) —;
(ff)-(CR ⁵ (R ⁵ ′) _k -OC (S)-;
(gg) -C (S) -O- (CR ⁵ (R ⁵ ′) _k- ;
(hh)-(CR ⁵ (R ⁵ ′) _k -NR ³ -C (S)-;
(ii) -C (S) -NR ^3- (CR ⁵ (R ⁵ ′)) _k- ;
(jj)-(CR ⁵ (R ⁵ ′) _k -SC (O)-;
(kk) -C (0) -S- (CR ⁵ (R ⁵ ')) _k- ;
(ll) -O-CR ⁴ = CR ^5- ;
(mm) -CR ⁴ = CR ⁵ -O-;
(nn) -C (O) -NR ³ -S-;
(oo) -S-NR ³ -C (0)-;
(pp) -C (0) -NR ³ -0-;
(qq) -O-NR ³ -C (O)-;
(rr) -NR ³ -CR ⁴ = CR ^5- ;
(ss) -CR ⁴ = N-NR ^3- ;
(tt) -NR ³ -N = CR ^4- ;
(uu) -C (0) -NR ³ -NR ^3- ;
(vv) -NR ³ -NR ³ -C (O)-;
(ww) -C (O) -O-NR ^3- ;
(xx) -NR ³ -OC (O)-;
^{(yy) -CR 4 R 4 '} -CR 5 R 5'-;
(zz) -C (O) -CR 4 'R 4' -
(aaa) -CR ⁴ R ⁴ ′ -C (O) —;
(bbb) -C (S) -CR ⁴ R ⁴ ′-;
(ccc) -CR ⁴ R ⁴ '-C (S)-;
(ddd) -C (= NR ³ ) -CR ⁴ R ⁴ '-; or
(eee) -CR ⁴ R ⁴ '-C (= NR ³ )-; ego,
When the a side and c side are double bonds, and the b side is a single bond, -X ¹ -Y ¹ -Z ^1- is:
(a) = CR ⁴ -O-CR ⁵ =;
(b) = CR ⁴ -NR ³ -CR ⁵ =;
(c) = NS-CR ⁴ =;
(d) = CR ⁴ -SN =;
(e) = NO-CR ⁴ =;
(f) = CR ⁴ -ON =;
(g) = N-S-N =;
(h) = N-O-N =;
(i) = N-NR ³ -NR ⁴ =;
(j) = CR ⁴ -NR ³ -N =;
(k) = N-NR ³ -N =;
(l) = CR ⁴ -S-CR ⁵ =; or
(m) = CR ⁴ -CR ⁴ (R ⁴ ′) -CR ⁵ =; ego,
R ¹ is;
(a) -S (0) ₂ -CH ₃ ;
(b) -S (0) ₂ -NR ³ (D ¹ );
(c) -S (0) ₂ -N (D ¹ ) -C (O) -CF ₃ ;
(d) -S (0)-(NH) -NH (D ¹ );
(e) -S (0)-(NH) -N (D ¹ ) -C (O) -CF ₃ ;
(f) -P (O) (CH ₃ ) NH (D ² );
(g) -P (O) (CH ₃ ) ₂ ;
(h) -C (S) -NH (D ¹ );
(i) -S (O) (NH) CH ₃ ;
(j) -P (O) (CH ₃ ) OD ¹ ; or
(k) -P (O) (CH ₃ ) NH (D ¹ );
R ¹ ′;
(a) hydrogen (hydrogen)
(b) halogen
(c) methyl; or
(d) CH ₂ OH;
R ² is;
(a) lower alkyl;
(b) cycloalkyl;
(c) mono-, di-, or tri-substituted phenyl or naphthyl, wherein the substituents are each independently:
(1) hydrogen (hydrogen);
(2) halo;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) haloalkyl,
(7) lower alkyl;
(8) N ₃ ;
(9) -CO ₂ D ¹ ;
(10) -CO ₂ -lower alkyl;
(11)-(C (R ⁵ ) (R ⁶ )) _z -OD ¹ ;
(12)-(C (R ⁵ ) (R ⁶ )) _z -O-lower alkyl;
(13) lower alkyl-CO ₂ -R ⁵ ;
(14) -OD ¹ ;
(15) haloalkoxy;
(16) amino;
(17) nitro;
(18) alkylsulfinyl; or
(19) heteroaryl;
(d) mono-, di- or tri-substituted heteroaryl, wherein the heteroaryl is a 5-membered monocyclic aromatic ring, the ring having a hetero atom of S, O or N, optionally Has 1, 2 or 3 additional N atoms; Or said heteroaryl is a 6 membered monocyclic ring, said ring having a heteroatom of N, optionally having 1, 2, 3 or 4 additional N atoms; Wherein the substituents are each independently;
(1) hydrogen (hydrogen);
(2) halo;
(3) lower alkyl;
(4) alkoxy;
(5) alkylthio;
(6) CN;
(7) haloalkyl;
(8) N ₃ ;
(9) -C (R ⁵ ) (R ⁶ ) -OD ¹ ;
(10) -C (R ⁵ ) (R ⁶ ) -O-lower alkyl; or
(11) alkylsulfinyl;
(e) benzoheteroaryl comprising an analog of (d) to which benzo is bonded
(f) -NR ¹⁰ R ¹¹ ;
(g) -SR ¹¹ ;
(h) -OR ¹¹ ;
(i) -R ¹¹ ;
(j) alkenyl;
(k) alkynyl;
(i) unsubstituted, mono-, di-, tri- or tetra-substituted cycloalkenyl, wherein the substituents are each independently:
(1) halo;
(2) alkoxy;
(3) alkylthio;
(4) CN;
(5) haloalkyl;
(6) lower alkyl;
(7) N ₃ ;
(8) -CO ₂ D ¹ ;
(9) -C0 ₂ -lower alkyl;
(10) -C (R ¹² ) (R ¹³ ) -OD ¹ ;
(11) -C (R ¹² ) (R ¹³ ) -O-lower alkyl;
(12) lower alkyl-CO ₂ -R ¹² ;
(13) benzyloxy;
(14) -O- (lower alkyl) -CO ₂ R ¹² ;
(15) -O- (lower alkyl) -NR ¹² R ¹³ ; or
(16) alkylsulfinyl;
(m) a 5, 6 or 7 membered mono-, di-tri- or tetra-substituted heterocycloalkyl group, or benzoheterocycle, wherein said heterocycloalkyl or benzoheterocycle is selected from O, S or N Or comprises two atoms, optionally, has a carbonyl group or a sulfonyl group, wherein the substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) haloalkyl;
(7) N ₃ ;
(8) -C (R ¹² ) (R ¹³ ) -OD ¹ ;
(9) -C (R ¹² ) (R ¹³ ) -O-lower alkyl; or
(10) alkylsulfinyl;
(n) styryl, mono or di-substituted styryl, wherein the substituents are each independently:
(1) halo;
(2) alkoxy;
(3) alkylthio;
(4) CN;
(5) haloalkyl;
(6) lower alkyl;
(7) N ₃ ;
(8) -CO ₂ D ¹ ;
(9) -CO ₂ -lower alkyl;
(10) -C (R ¹² ) (R ¹³ ) -OD ¹ ;
(11) -C (R ¹² ) (R ¹³ ) -O-lower alkyl;
(12) lower alkyl-CO ₂ -R ¹² ;
(13) benzyloxy;
(14) -O- (lower alkyl) -CO ₂ R ¹² ; or
(15) -O- (lower alkyl) -NR ¹² R ¹³ ;
(o) phenylacetylene, mono- or di-substituted phenylacetylene, wherein the substituents are each independently:
(1) halo;
(2) alkoxy;
(3) alkylthio;
(4) CN;
(5) haloalkyl;
(6) lower alkyl;
(7) N ₃ ;
(8) -CO ₂ D ¹ ;
(9) -CO ₂ -lower alkyl;
(10) -C (R ¹² ) (R ¹³ ) -OD ¹ ;
(11) -C (R ¹² ) (R ¹³ ) -O-lower alkyl;
(12) lower alkyl-CO ₂ -R ¹² ;
(13) benzyloxy;
(14) -O- (lower alkyl) -CO ₂ R ¹² ; or
(15) -O- (lower alkyl) -NR ¹² R ¹³ ;
(p) fluoroalkenyl;
(q) 8, 9 or 10 membered mono-, di-substituted bicyclic heteroaryl having 2, 3, 4 or 5 heteroatoms, wherein at least one heteroatom is said bicyclic heteroaryl Each hetero atom is independently O, S, and N, and the substituents are each independently
(1) hydrogen (hydrogen);
(2) halo;
(3) lower alkyl;
(4) alkoxy;
(5) alkylthio;
(6) CN;
(7) haloalkyl CF ₃ ;
(8) N ₃ ;
(9) -C (R ⁵ ) (R ⁶ ) -OD ¹ ; or
(10) -C (R ⁵ ) (R ⁶ ) -O-lower alkyl;
(r) potassium;
(s) aryl;
(t) arylalkyl;
(u) cycloalkylalkyl;
(v) -C (O) R ¹¹ ;
(u) hydrogen (hydrogen);
(v) arylakenyl;
(w) arylalkoxy;
(x) alkoxy;
(y) aryloxy;
(z) cycloalkoxy;
(aa) arylthio;
(bb) alkylthio;
(cc) arylalkylthio; or
(dd) cycloalkylthio;
R ³ is;
(a) hydrogen (hydrogen);
(b) haloalkyl;
(c) -CN;
(d) lower alkyl;
(e)-(C (R _e ) (R _f )) _p -UV;
(f) potassium;
(g) substituted or unsubstituted:
(1) lower alkyl-Q;
(2) lower alkyl-O-lower alkyl-Q;
(3) lower alkyl-S-lower alkyl-Q;
(4) lower alkyl-0-Q;
(5) lower alkyl-S-Q;
(6) lower alkyl-0-V;
(7) lower alkyl-S-V;
(8) lower alkyl-0-K; or
(9) lower alkyl-S-K;
Wherein the substituent is on the lower alkyl group;
(h) Q;
(i) alkylcarbonyl;
(j) arylcarbonyl;
(k) alkylarylcarbonyl;
(l) arylalkylcarbonyl;
(m) carboxyl esters;
(n) carboxamido;
(o) cycloalkyl;
(p) mono-, di- or tri-substituted phenyl or naphthyl, wherein the substituents are each independently:
(1) hydrogen (hydrogen);
(2) halo;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) haloalkyl;
(7) lower alkyl;
(8) N ₃ ;
(9) -CO ₂ D ¹ ;
(10) -CO ₂ -lower alkyl;
(11)-(C (R ⁵ ) (R ⁶ )) _z -OD ¹ ;
(12)-(C (R ⁵ ) (R ⁶ )) _z -O-lower alkyl;
(13) lower alkyl-CO ₂ -R ⁵ ;
(14) -CD ¹ ;
(15) haloalkoxy;
(16) amino;
(17) nitro; or
(18) alkylsulfinyl;
(q) alkenyl;
(r) alkynyl;
(s) anilalkyl;
(t) lower alkyl-OD ¹ ;
(u) alkoxyalkyl;
(v) aminoalkyl;
(w) lower alkyl-CO ₂ R ¹⁰ ;
(x) lower alkyl-C (O) NR ¹⁰ (R ¹⁰ );
(y) heterocyclicalkyl; or
(z) heterocyclic ring-C (O)-;
R⁴, R⁴'_,R⁵And R⁵'Are each independently:
(a) hydrogen (hydrogen);
(b) amino;
(c) CN:
(d) lower alkyl;
(e) haloalkyl;
(f) alkoxy;
(g) alkylthio;
(h) Q;
(i) -O-Q;
(j) -S-Q;
(k) potassium (K);
(l) cycloalkoxy;
(m) cycloalkylthio;
(n) unsubstituted, mono-, or di-substituted phenyl or unsubstituted, mono-, di-substituted benzyl, wherein the substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) haloalkyl;
(7) N ₃ ;
(8) Q;
(9) nitro; or
(10) amino;
(o) unsubstituted, mono-, or di-substituted heteroaryl or unsubstituted, mono- or di-substituted heteroarylmethyl, wherein the heteroaryl is a 5-membered monocyclic aromatic ring, and The ring comprises one hetero atom selected from S, O or N, optionally, having 1, 2 or 3 additional N atoms; or wherein said heteroaryl is a 6 membered monocyclic ring and said ring is Having N as one hetero atom, optionally having 1, 2, 3 or 4 additional N atoms; The substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) haloalkyl, preferably CF ₃ ;
(7) N ₃ ;
(8) -C (R ⁶ ) (R ⁷ ) -OD ¹ ;
(9) -C (R ⁶ ) (R ⁷ ) -O-lower alkyl; or
(10) alkylsulfinyl;
(p) -CON (R ⁸ ) (R ⁸ );
(q) -CH ₂ OR ⁸ ;
(r) -CH ₂ OCN;
(s) substituted or unsubstituted:
(1) lower alkyl-Q;
(2) -O-lower alkyl-Q;
(3) -S-lower alkyl-Q;
(4) lower alkyl-0-lower alkyl-Q;
(5) lower alkyl-S-lower alkyl-Q;
(6) lower alkyl-0-Q;
(7) lower alkyl-S-Q;
(8) lower alkyl-0-K;
(9) lower alkyl-S-K;
(10) lower alkyl-0-V; or
(11) lower alkyl-S-V;
Wherein said substituent is on the lower alkyl group;
(t) cycloalkyl;
(u) aryl;
(v) arylalkyl;
(w) cycloalkylalkyl;
(x) aryloxy;
(y) arylalkoxy;
(z) arylalkylthio;
(aa) cycloalkylalkoxy;
(bb) heterocycloalkyl;
(cc) alkylsulfinyloxy;
(dd) alkylsulfinyl;
(ee) arylsulfinyl;
(ff) arylsulfonyloxy;
(gg) -C (0) R ¹⁰ ;
(hh) nitro;
(ii) amino;
(jj) aminoalkyl;
(kk) -C (O) -alkyl-heterocyclic ring;
(ll) halo;
(mm) heterocyclic ring;
(nn) -CO ₂ D ¹ ;
(oo) carboxyl;
(pp) amidyl; or
(qq) alkoxyalkyl;
Optionally, R ⁴ and R ⁵ together with the carbon to which they are attached are
(a) cycloalkyl;
(b) aryl; or
(c) heterocyclic ring;
Optionally, R ⁴ and R ⁴ ′ or R ⁵ and R ⁵ ′ taken with bonded carbon are:
(a) cycloalkyl; or
(b) heterocyclic ring;
Optionally, when the substituent of the opposite carbon atom is taken together with the bonded carbon, R⁴And R⁵, R⁴'And R⁵', R⁴And R⁵', R⁴'And R⁵Is:
(a) cycloalkyl;
(b) heterocyclic ring; or
(c) aryl;
R ⁶ and R ⁷ are each independently:
(a) hydrogen;
(b) unsubstituted or mono- or di-substituted phenyl groups; Unsubstituted or mono- or di-substituted benzyl groups; Unsubstituted or mono- or di-substituted heteroaryl groups; Mono- or di-substituted heteroarylmethyl groups, wherein the substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy:
(4) alkylthio;
(5) CN;
(6) haloalkyl;
(7) N ₃ ;
(8) -C (R ¹⁴ ) (R ¹⁵ ) -OD ¹ ; or
(9) -C (R ¹⁴ ) (R ¹⁵ ) -O-lower alkyl;
(c) lower alkyl;
(d) -CH ₂ OR ⁸ ;
(e) CN;
(f) -CH ₂ CN;
(g) haloalkyl;
(h) -CON (R ⁸ ) (R ⁸ );
(i) halo; or
(j) -OR ⁸ ;
R ⁸ is;
(a) hydrogen;
(b) K; or
(c) R ⁹ _;
Optionally, R with bonded carbon⁵And R⁵', R⁶And R⁷Or R⁷And R⁸Forms a saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms; Optionally oxygen, S (O)_oOr NR_OneIt contains two or more hetero atoms selected from;
R ⁹ is;
(a) lower alkyl;
(b) lower alkyl-CO ₂ D ¹ ;
(c) lower alkyl-NHD ¹ ;
(d) phenyl or mono-, di- or tri-substituted phenyl, wherein the substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy;
(4) alkylthio;
(5) lower alkyl-CO ₂ D ¹ ;
(6) lower alkyl-NHD ¹ ;
(7) CN;
(8) CO ₂ D ¹ ; or
(9) haloalkyl;
(e) benzyl, mono-, di- or tri-substituted benzyl, wherein the substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy:
(4) alkylthio;
(5) lower alkyl-CO ₂ D ¹ ;
(6) lower alkyl-NHD ¹ ;
(7) CN;
(8) -CO ₂ D ¹ ; or
(9) haloalkyl;
(f) cycloalkyl;
(g) K; or
(h) benzyl, mono-, di- or tri-substituted benzoyl, wherein the substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy:
(4) alkylthio;
(5) lower alkyl-CO ₂ D ¹ ;
(6) lower alkyl-NHD ¹ ;
(7) CN;
(8) -CO ₂ D ¹ ; or
(9) haloalkyl;
R ¹⁰ and R ^{10 '} ' are each independently:
(a) hydrogen; or
(b) R ¹¹ ;
R ¹¹ is;
(a) lower alkyl;
(b) cycloalkyl;
(c) unsubstituted or mono-, di- or tri-substituted phenyl or naphthyl, wherein the substituents are each independently:
(1) halo;
(2) alkoxy:
(3) alkylthio;
(4) CN;
(5) haloalkyl;
(6) lower alkyl;
(7) N ₃ ;
(8) -CO ₂ D ¹ ;
(9) -CO ₂ -lower alkyl;
(10) -C (R ¹² ) (R ¹³ ) -OD ¹ ;
(11) -C (R ¹² ) (R ¹³ ) -O-lower alkyl;
(12) lower alkyl-CO ₂ D ¹ ;
(13) lower alkyl-CO ₂ R ¹² ;
(14) benzyloxy;
(15) -O- (lower alkyl) -CO ₂ D ¹ ;
(16) -O- (lower alkyl) -CO ₂ R ¹² ; or
(17) -O- (lower alkyl) -NR ¹² R ¹³ ;
(d) unsubstituted or mono-, di- or tri-substituted heteroaryl groups, wherein the heteroaryl group is a 5-membered monocyclic aromatic ring, wherein the ring comprises a heteroatom of S, O or N And optionally have 1, 2, or 3 added N atoms; Or said heteroaryl group is a monocyclic ring of 6 atoms, said ring is N, and optionally a heteroatom added with 1, 2, or 3 N atoms, wherein said substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy:
(4) alkylthio;
(5) CN;
(6) haloalkyl;
(7) N ₃ ;
(8) -C (R ¹² ) (R ¹³ ) -OD ¹ ; or
(9) -C (R ¹² ) (R ¹³ ) -O-lower alkyl;
(e) unsubstituted or mono- or di-substituted benzoheterocycles, wherein the benzoheterocycle contains one or two heteroatoms selected from O, S or N, optionally containing a carbonyl or sulfonyl group Is a ring of 5, 6 or 7 members, wherein the substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy:
(4) alkylthio;
(5) CN;
(6) haloalkyl;
(7) N ₃ ;
(8) -C (R ¹² ) (R ¹³ ) -OD ¹ ; or
(9) -C (R ¹² ) (R ¹³ ) -O-lower alkyl;
(f) unsubstituted or mono- or di-substituted benzocarbocycles wherein the carbocycle is a ring of 5, 6, or 7-members, optionally containing a carboxyl group, each of which is independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy:
(4) alkylthio;
(5) CN;
(6) haloalkyl;
(7) N ₃ ;
(8) -C (R ¹² ) (R ¹³ ) -OD ¹ ; or
(9) -C (R ¹² ) (R ¹³ ) -O-lower alkyl;
(g) hydrogen; or
(h) K
R ¹² and R ¹³ are each independently:
(a) hydrogen;
(b) lower alkyl; or
(c) aryl; or
R ¹² and R ¹³ together with the bonded element form a saturated monocycle ring of 3, 4, 5, 6 or 7 elements.
R ¹⁴ and R ¹⁵ are each independently:
(a) hydrogen; or
(b) lower alkyl; or
R ¹⁴ and R ¹⁵ together with the bonded element form a carbonyl, thial or saturated monocycle ring of 3, 4, 5, 6 or 7 elements.
D ¹ is:
(a) hydrogen or
(b) D;
D Is:
(a) V; or
(b) K;
U Is:
(a) oxygen;
(b) sulfur (sulfur); or
(c) -N (R _a ) (R _I )-;
V Is:
(a) -NO;
(b) -NO ₂ ; or
(c) hydrogen
K is -W _aa -E _b- (C (R _e ) (R _f )) _p -E _c- (C (R _e ) (R _f )) _x -W _d- (C (R _e ) (R _f )) _y -W _i -E _j -W _g- (C (R _e ) (R _f )) _z -UV;
Aa, b, c, d, g, i and j are each independently an integer of 0 to 3; p, x, y and z are each independently integers of 0-10; In each case W is independently:
(a) -C (O)-;
(b) -C (S)-;
(c) -T-;
(d)-(C (R _e ) (R _f )) _h- ;
(e) alkyl;
(f) aryl;
(g) heterocyclic rings;
(h) arylheterocyclic ring, or
(i)-(CH ₂ CH ₂ ) _q- ;
In each case, E is independently:
(a) -T-;
(b) alkyl;
(c) aryl;
(d)-(C (R _e ) (R _f )) _h- ;
(e) heterocyclic rings;
(f) arylheterocyclic ring; or
(g)-(CH ₂ CH ₂ ) _q- ;
h is an integer from 1 to 10;
q is an integer from 1 to 5;
R _e and R _f are each independently:
(a) hydrogen;
(b) alkyl;
(c) cycloalkoxy;
(d) halogen;
(e) hydroxy;
(f) hydroxyalkyl;
(g) alkoxyalkyl;
(h) arylheterocyclic ring;
(i) cycloalkylalkyl;
(j) heterocyclic alkyl;
(k) alkoxy;
(l) haloalkoxy;
(m) amino;
(n) alkylamino;
(o) dialkylamino;
(p) arylamino;
(q) diarylamino;
(r) alkylarylamino;
(s) alkoxyhaloalkyl;
(t) haloalkoxy;
(u) sulfoic acid;
(v) alkylsulfoic acid;
(w) arylsulfoic acid;
(x) arylalkoxy;
(y) alkylthio;
(z) arylthio;
(aa) cyano;
(bb) aminoalkyl;
(cc) aminoaryl;
(dd) alkoxy;
(ee) aryl;
(ff) arylalkyl;
(gg) carboxamido;
(hh) alkylcarboxamido;
(ii) arylcarboxamido;
(jj) amidyl;
(kk) carboxyl;
(ll) carbamoyl;
(mm) alkylcarboxylic acid;
(nn) arylcarboxylic acid;
(oo) alkylcarboxyl;
(pp) arylcarboxyl;
(qq) esters;
(rr) carboxylic esters;
(ss) alkylcarboxylic esters;
(tt) arylcarboxylic esters;
(uu) haloalkoxy;
(vv) sulfonicamido;
(ww) alkylsulfonamido;
(xx) arylsulphonicamido;
(yy) akylsulfonyl;
(zz) alkylsulfonyloxy,
(aaa) arylsulfonyl,
(bbb) arylsulfonyloxy,
(ccc) sulfonic esters;
(ddd) carbamoyl;
(eee) urea;
(fff) nitoro; or
(ggg) -U-V; or
Taken together, R _e and R _f are:
(a) oxo;
(b) thial; or
Taken with bound carbon, R _e and R _f are:
(a) heterocyclic rings;
(b) a cycloalkyl group; or
(c) bridged bonded cycloalkyl groups;
k is an integer of 1 to 2;
In each case T is independently:
(a) covalent bonds,
(b) carbonyl,
(c) oxygen,
(d) -S (O) _o- ; or
(e) -N (R _a ) (R _I )-;
o is an integer from 0 to 2;
Q is:
(a) -C (O) -UD ¹ ;
(b) -CO ₂ -loweralkyl;
(c) tetrazolyl-5-yl;
(d) -C (R ⁷ ) (R ⁸ ) (SD ¹ );
(e) -C (R ⁷ ) (R ⁸ ) (OD ¹ ); or
(f) -C (R ⁷ ) (R ⁸ ) (O-loweralkyl);
R _a is:
(a) a lone pair of electrons;
(b) hydrogen; or
(c) lower alkyl;
R _i is:
(a) hydrogen;
(b) alkyl;
(c) aryl:
(d) alkylcarboxylic acids;
(e) arylcarboxylic acids;
(f) alkylcarboxylic esters;
(g) arylcarboxylic esters;
(h) alkylcarboxamido;
(i) arylcarboxamido;
(j) alkylsulfinyl;
(k) alkylsulfonyl;
(l) alkylsulfonyloxy;
(m) arylsulfinyl;
(n) arylsulfonyl;
(o) arylsulfonyloxy;
(p) sulfonamido;
(q) carboxamido;
(r) carboxyl esters;
(s) aminoalkyl;
(t) aminoaryl;
(u) -CH ₂ -C (UV) (R _e ) (R _f );
(v) an atom that combines with the opposite atom to form a double bond; or
_{(w) - (N 2 O} 2 -) - and M ^+, wherein M ⁺ is an organic or inorganic cation;
Conditionally, the compound of formula (I) must contain at least one member selected from nitrite, nitrate, thionitrite or thionitrate groups;
Where Formula 2 (II)
[Formula 2] Represented by
Where A-B is:
(a) N-C;
(b) C-N; or
(c) N-N;
If the d and f sides are double bonds and the e and g sides are single bonds, then -X ² -Y ² -Z ² -is:
(a) = CR ⁴ -CR ⁴ '= CR ^5- ;
(b) = N-CR ⁴ = CR ⁴ '-;
(c) = N-CR ⁴ = N-;
(d) = CR ⁴ -N = CR ⁴ '-;
(e) = CR ⁴ -N = N-;
(f) = NN = CR ^4- ;
(g) = N-N = N-;
(h) = CR ⁴ -CR ⁵ = N-; or
(i) = CR ² '-CR ⁵ = N-;
R ² and R ^{2 '} taken together are:
(a)
or
(b)
ego,
Or R ^{2 ′} and R ⁵ taken with bonded carbon are:
(a) cycloalkyl; or
(b) heterocyclic ring;
R ⁹⁷ is:
(a) hydrogen;
(b) arylthio;
(c) alkylsulfinyl;
(d) alkylsulfonyl;
(e) cyano;
(f) carboxyl;
(g) amino;
(h) lower alkyl;
(i) haloalkyl;
(j) hydroxy;
(k) alkoxy;
(l) haloalkoxy;
(m) alkylarylalkylamino;
(n) aminoalkyl;
(o) aminoaryl;
(p) sulfoamido;
(q) alkylsulfoamido;
(r) arylsulfoamido;
(s) heterocyclic rings;
(t) hydroxyalkyl; or
(u) nitro;
a is an integer of 1 to 3;
If e and g are double bonds, and d and f are single bonds, then -X ² -Y ² -Z ² -is:
(a) -CR ⁴ = NN =;
(b) -N = N-CR ⁴ =;
(c) -CR ⁴ = N-CR ⁴ '=;
(d) -N = CR ⁴ -N =;
(e) -CR ⁴ = CR ⁴ '-N =;
(f) -N = CR ⁴ -CR ⁵ =;
(g) -CR ⁴ = CR ⁵ -CR ⁵ '=; or
(h) -N = N-N =;
If g is a double bond and d, e and f are a single bond, then -X ² -Y ² -Z ² -is:
(a) -C (O) -O-CR ⁴ =;
(b) -C (0) -NR ³ -CR ⁴ =;
(c) -C (O) -S-CR ⁴ =; or
(d) -C (H) R ⁴ -C (OH) R ⁵ -N =;
When d is a double bond and e, f and g are single bonds, then -X ² -Y ² -Z ² -is:
(a) = CR ⁴ -OC (O)-;
(b) = CR ⁴ -NR ³ -C (O)-;
(c) = CR ⁴ -SC (O)-; or
(d) = NC (OH) R ⁴ -C (H) R ^5- ;
When f is a double bond and d, e and g are single bonds, -X ² -Y ² -Z ² -is:
(a) -CH (R ⁴ ) -CR ⁵ = N-; or
(b) -C (O) -CR ⁴ = CR ^5- ;
When e is a double bond and d, f and g are single bonds, then -X ² -Y ² -Z ² -is:
(a) -N = CR ⁴ -CH (R ⁵ )-; or
(b) -CR ⁴ = CR ⁵ -C (O)-;
When d, e, f and g are single bonds,
-X ² -Y ² -Z ² -is:
(a) -C (O) -CR ⁴ (R ^{4 '} ) -C (O)-;
R ¹ , R ^{1 ′} , R ² , R ³ , R ⁴ , R ^{4 ′} , R ⁵ and R ^{5 ′} are as defined herein;
Conditionally compound (II) of formula (2) must comprise at least one member selected from the group of nitrites, nitrates, thionitrites or thionitrates;
Where Formula 3 (III) is
[Formula 3] Represented by
(Ⅲ)
Where X ³ is:
(a) C (O) -UD ¹ ;
(b) -CH ₂ -UD ¹ ;
(c) -CH ₂ -C (O) -CH ₃ ;
(d) -CH ₂ -CH ₂ -C (O) -UD ¹ ;
(e) -CH ₂ -OD ¹ ; or
(f) -C (O) H and
Y ³ is
(a)-(CR ⁵ (R ^{5 '} )) _k -UD ¹ ;
(b) -CH ₃ ;
(c) -CH ₂ OC (O) R ⁶ ; or
(d) -C (O) H;
Optionally, both X ³ and Y ³ taken are —CR ⁸² (R ⁸³ ) —CR ^{82 ′} (R ^{83 ′} ) —;
R ⁸² , R ^{82 '} , R ⁸³ and R ^83' are each independently;
(a) hydrogen;
(b) hydroxy;
(c) alkyl;
(d) alkoxy;
(e) lower alkyl-OD ^{1 ′} ;
(f) alkylthio;
(g) CN;
(h) -C (O) R ⁸⁴ ; or
(i) -OC (O) R ⁸⁵ ;
R ⁸⁴ is:
(a) hydrogen;
(b) lower alkyl; or
(c) alkoxy;
R ⁸⁵ is:
(a) lower alkyl;
(b) alkoxy
(c) unsubstituted or mono-, di-, or tri-substituted phenyl or pyridyl, wherein the substituents are each independently:
(1) halo;
(2) alkoxy;
(3) haloalkyl;
(4) CN
(5) -C (O) R ⁸⁴ ;
(6) lower alkyl;
(7) -S (O) ₀ -lower alkyl; or
(8) OD ¹ ;
Optionally, R ⁸² , R ^{82 '} , R ^82' and R ^{83 'taken} are all:
(a) oxo;
(b) thial;
(c) = CR ⁸⁶ R ⁸⁷ ; or
(d) = NR ⁸⁸ ;
R ⁸⁶ and R ⁸⁷ are each independently:
(a) hydrogen;
(b) lower alkyl;
(c) lower alkyl-OD ¹ ;
(d) CN; or
(e) -C (O) R ⁸⁴ ;
R ⁸⁸ is
(a) OD ¹ ;
(b) alkoxy
(c) lower alkyl; or
(d) unsubstituted or mono-, di- or tri-substituted phenyl or pyridyl, wherein the substituents are each independently:
(1) halo;
(2) alkoxy;
(3) haloalkyl;
(4) CN;
(5) -C (O) R ⁸⁴ ;
(6) lower alkyl;
(7) -S (O) ₀ -lower alkyl; or
(8) -OD ¹ ;
R ¹ , R ² , R ⁵ , R ^{5 '} , R ⁶ , U, D ¹ , o and k are as defined herein;
Conditionally the compound of formula 3 (III) must comprise at least one member selected from the group of at least one nitrite, nitrate, thionitrite or thionitrate;
Wherein the compound of formula 4 (IV)
[Formula 4] Represented by (IV),
Wherein X ⁴ and Z ⁴ are each independently:
(a) N; or
(b) CR ²¹ ;
R ²⁰ is:
(a) -S (O) ₂ -CH ₃ ;
(b) -S (O) ₂ -NR ⁸ (D ¹ ); or
(c) -S (O) ₂ -N (D ¹ ) -C (O) -CF ₃ ;
R ²¹ and R ^{21 '} are each independently:
(a) hydrogen;
(b) lower alkyl;
(c) alkoxy;
(d) alkylthio;
(e) haloalkyl;
(f) haloalkoxy;
(g) CN;
(h) -CO ₂ D ¹ ;
(i) -CO ₂ R ¹⁴ ;
(j) lower alkyl-OD ¹ ;
(k) lower alkyl-CO ₂ D ¹ ;
(l) lower alkyl-CO ₂ R ¹⁴ ;
(m) halo;
(n) -OD ¹ ;
(o) -N ₃ ;
(p) -NO ₂ ;
(q) -NR ¹⁴ D ¹ ;
(r) -N (D ¹ ) C (O) R ¹⁴ ;
(s) -NHK;
(t) aryl;
(u) arylalkylthio;
(v) arylalkoxy;
(w) alkylamino;
(x) aryloxy;
(y) alkylarylalkylamino;
(z) cycloalkylalkylamino; or
(aa) cycloalkylalkoxy;
R ²² is:
(a) mono-, di- or tri-substituted phenyl or pyridinyl (or N-oxides thereof), wherein the substituents are each independently:
(1) hydrogen;
(2) halo;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) lower alkyl;
(7) haloalkyl;
(8) N ₃ ;
(9) -CO ₂ D ¹ ;
(10) -CO ₂ -lower alkyl;
(11) -C (R ¹⁴ ) (R ¹⁵ ) -OD ¹ ;
(12) -OD ¹ ;
(13) lower alkyl-CO ₂ -R ¹⁴ ; or
(14) lower alkyl-CO ₂ -D ¹ ; and
(b) -TC (R ²³ ) (R ²⁴ )-(C (R ²⁵ ) (R ²⁶ )) ₀ -C (R ²⁷ ) (R ²⁸ ) -UD ¹ ;
(c)

(d) arylalkyl; or
(e) cycloalkylalkyl;
Wherein R ¹⁴ and R ¹⁵ are each independently:
(a) hydrogen; or
(b) lower alkyl;
R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , and R ²⁸ are each independently:
(a) hydrogen; or
(b) lower alkyl; or
R ²³ and R ²⁷ taken with a bonded atom, or R ²⁷ and R ²⁸ , form a carbocyclic ring of 3, 4, 5, 6 or 7 atoms, or R ²³ and R ²⁵ form a covalent bond;
Y ⁵ is:
(a) CR ²⁹ R ³⁰ ;
(b) oxygen; or
(c) sulfur;
R ²⁹ and R ³⁰ are each independently:
(a) hydrogen;
(b) lower alkyl;
(c) (CH ₂ ) ₀ -OD ¹ ;
(d) halo; or
R ²⁹ and R ³⁰ taken together are an oxo group;
s is an integer from 2 to 4;
R ⁸ , D ¹ , T, U, K and o are as defined herein;
Conditionally, the compound of formula 4 (IV) must comprise at least one member selected from the group of nitrites, nitrates, thionitrites or thionitrates;
Wherein the compound of formula 5 (V) is:
[Formula 5] Represented by
(Ⅴ)
here,
X ⁵ is:
(a) oxygen; or
(b) sulfur;
R ³¹ is:
(a) alkoxy;
(b) haloalkoxy;
(c) alkylthio;
(d) haloalkyl;
(e) halo; or
(f) lower alkyl;
R ³² , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ and R ³⁷ are each independently:
(a) hydrogen;
(b) halo;
(c) lower alkyl;
(d) cycloalkyl;
(e) haloalkyl;
(f) -OD ¹ ;
(g) -OR ⁴³ ;
(h) -SD ¹ ;
(i) -SR ⁴³ ;
(j) -S (O) R ⁴³ ;
(k) -S (O) ₂ R ⁴³ ;
(l) unsubstituted or mono- or di-substituted benzyl, wherein the substituents are each independently:
(1) haloalkyl;
(2) CN;
(3) halo;
(4) lower alkyl;
(5) -OR ⁴³ ;
(6) -SR ⁴³ ;
(7) -S (O) R ⁴³ ; or
(8) -S (O) ₂ R ⁴¹ ;
(m) phenyl or mono- or di-substituted phenyl, wherein the substituents are each independently:
(1) haloalkyl;
(2) CN;
(3) halo;
(4) lower alkyl;
(5) -OR ⁴³ ;
(6) -SR ⁴³ ;
(7) -S (O) R ⁴³ ; or
(8) -S (O) ₂ R ⁴¹ ; or
R ³² together with R ³³ form an oxo group; or
R ³⁴ forms an oxo group with R ³⁵ ; or
R ³⁶ together with R ³⁷ form an oxo group; or
R ³² and R ³³ together with the carbon bonded to form a 3, 4, 5, 6, or 7 membered saturated monocycling and optionally contain heteroatoms which are preferred oxygen; or
R ³³ and R ³⁴ together with the carbon bonded to form a 3, 4, 5, 6, or 7 membered saturated or aromatic monocycling; or
R ³³ and R ³⁶ together with the carbon bonded to form a 3, 4, 5, 6, or 7 membered saturated or aromatic monocycling; or
R ³⁴ and R ³⁵ together with the carbon bonded to form a 3, 4, 5, 6, or 7 membered saturated monocycling and optionally contain heteroatoms which are preferred oxygen; or
R ³⁴ and R ³⁶ together with the carbon bonded to form a 3, 4, 5, 6, or 7 membered saturated or aromatic monocycling; or
R ³⁶ and R ³⁷ together with the carbon bonded to form a 3, 4, 5, 6, or 7 membered saturated monocycling and optionally contain heteroatoms which are preferred oxygen;
R ³⁸ and R ³⁹ are hydrogen or R ³⁸ and R ³⁹ taken together are oxo;
R ⁴⁰ , R ⁴¹ and R ⁴² are each independently:
(a) hydrogen;
(b) halo;
(c) lower alkyl;
(d) alkoxy;
(e) alkylthio;
(f) -S (O) -loweralkyl;
(g) haloalkyl, preferably CF ₃ ;
(h) CN;
(i) -N ₃ ;
(j) -NO ₂ ;
(k) -SCF ₃ ; or
(l) -OCF ₃ ;
R ⁴³ is:
(a) lower alkyl; or
(b) optionally mono- or di-substituted benzyl, wherein the substituents are each independently:
(1) haloalkyl;
(2) CN;
(3) halo; or
(4) lower alkyl;
Optionally, X ⁵ and U taken together with the bonded carbon form a heterocycle ring of 5-, 6-, or 7-members;
N is an integer of 0-1 in each case;
D ^1, U and K are as defined herein;
Conditionally, the compound of formula 5 (V) must contain at least one member selected from the group of nitrites, nitrates, thionitrites or thionitrates;
The compound of formula 6 (VI) is:
[Formula 6] Expressed as
In the above formula,
X ⁶ is:
(a) oxygen;
(b) sulfur;
(c) CH ₂ ;
(d) -S (O) ₀ ;
(e) -NH; or
(f) -C (O);
Z ⁶ is:
(a) K;
(b) -C (O) CH ₃ ; or
(c) hydrogen;
R ⁴⁵ is:
(a) lower alkyl; or
(b) mono-, di-, tri-tetra- or per-substituted lower alkyl, wherein the substituents are halo, preferably fluorine;
R ⁴⁶ is:
(a) a 5 membered mono- or di-substituted aromatic ring containing one selected from O, S, or N, and optionally one, two, or three added N, wherein the substituents are each independently :
(1) hydrogen;
(2) lower alkyl;
(3) halo;
(4) -O-loweralkyl;
(5) -S-loweralkyl;
(6) haloalkyl, preferably CF ₃ ;
(7) -COCH ₃ ; or
(8) -S (O) ₂ -lower alkyl;
(b) a 6 membered mono- or di-substituted aromatic ring comprising 0, 1, 2, 3 or 4 nitrogen atoms, wherein the substituents are each independently:
(1) hydrogen;
(2) lower alkyl;
(3) halo;
(4) -O-loweralkyl;
(5) -S-loweralkyl;
(4) -O-haloalkyl;
(5) -S-haloalkyl;
(6) haloalkyl;
(7) CN;
(8) -N ₃ ;
(9) -COCH ₃ ;
(10) -S (O) ₂ -lower alkyl;
(11) alkenyl; or
(12) alkynyl;
(c) cycloalkylalkyl;
(d) unsubstituted, mono-, di-, tri- or tetra-substituted phenyl or naphthyl, wherein the substituents are each independently:
(1) halo;
(2) CN;
(3) haloalkyl, preferably CF ₃ ;
(4) -N ₃ ;
(5) vinyl;
(6) acetylenyl;
(7) lower alkyl;
(8) alkoxy;
(9) haloalkoxy;
(10) alkylthio; or
(11) haloalkylthio;
(e) unsubstituted, mono-, di-, tri- or tetra-substituted benzoheteroaryl, wherein the substituents are each independently:
(1) halo;
(2) CN; or
(3) haloalkyl, preferably CF ₃ ;
(f) substituted lower alkyl;
(g) substituted alkenyl;
(h) cycloalkyl; or
(i) lower alkyl-O-lower alkyl;
R ⁴⁷ is:
(a) -C (O) -loweralkyl;
(b) -CN;
(c) -CO ₂ D ¹ ;
(d) -CO ₂ -lower alkyl esters;
(e) -C (O) -NHD ¹ ;
(f) -S (O) -loweralkyl;
(g) -S (O) ₂ -lower alkyl;
(h) -NO ₂ ;
(i) haloalkyl, preferably CF ₃ ;
(j) halo;
(k) K;
(l) -S (O) ₀ NR ¹⁰ R ¹¹ ; or
(m) -S (O) _o NR ¹² R ¹³ ;
R ⁴⁸ is:
(a) hydrogen; or
(b) lower alkyl; or
R ⁴⁷ and R ⁴⁸ are selected from the cyclic rings optionally containing mono-, di- or tri-substituted saturated or unsaturated -S (O) ₂ -unsubstituted 5, 6 or 7- Atoms in the bonded form, wherein the substituents are each independently;
(a) oxo;
(b) lower alkyl
(c) OD ¹ ; or
(d) = N = OD ¹ ;
R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , K, D ¹ and o are as defined herein;
Subject to compound of formula 6 (VI) necessarily comprising at least one nitrate, nitrite, thionitrate or thionitrate group;
Compound of formula (VII):
[Formula 7] Represented by (Ⅶ);
From here;
X ⁷ is:
(a) oxygen;
(b) sulfur;
(c) -NR ⁵¹ ;
(d) -NOR ⁵² ; or
(e) -N-NR ⁵² R ⁵³ ;
X ⁷ is:
(a) hydrogen;
(b) halo;
(c) lower alkyl;
(d) alkenyl; or
(e) alkynyl;
Z ⁷ is:
(a) -C (O)-;
(b) oxygen;
(c) -S (O) _o- ;
(d) -NR ⁹³ -; or
(e) covalent bonds;
R ⁴⁹ is:
(a) R ³ ; or
(b) R ⁴ ;
R ⁵⁰ and R ^{50 '} are independent of each other.
(a) hydrogen;
(b) halo;
(c) lower alkyl;
(d) aryl;
(e) arylalkyl
(f) cycloalkyl
(g) cycloalkylalkyl
(h) -OD ¹ ;
(i) lower alkyl-OD ¹ ;
(j) carboxamido;
(k) K;
R ⁵¹ is:
(a) lower alkyl;
(b) alkyl;
(c) cycloalkyl;
(d) cycloalkylalkyl;
(e) aryl;
(f) arylalkyl;
(g) heterocyclic rings; or
(h) lower alkyl-heterocyclic rings;
R ⁵² and R ⁵³ are independent of each other.
(a) lower alkyl;
(b) cycloalkyl;
(c) cycloalkylalkyl;
(d) aryl;
(e) arylalkyl;
(f) heterocyclic rings; or
(g) heterocyclic alkyls
R ⁹³ is:
(a) hydrogen;
(b) lower alkyl;
R ¹ , R ³ , R ⁴ , K and D ¹ and o are as defined herein;
Provided that the compound of formula (VII) comprises at least one nitrate, nitrite, thionitrate or thionitrate group;
The compound of formula (VII)
[Formula 8] ...
Where X ⁸ is:
(a) oxygen;
(b) sulfur;
(c) NR _i ; or
(d) -CR ⁵⁸ R ⁵⁹ ;
A ¹ , A ² , A ³ and A ⁴ are each independently carbon or nitrogen provided that at least two A ¹ , A ² , A ³ and A ⁴ are carbon atoms;
R ⁵⁴ is:
(a) haloalkylalkyl;
(b) halo;
(c) alkylthio;
(d) alkoxy;
(e) -NO ₂ ;
(f) CN;
(g) lower alkyl-CN;
(h) heterocyclic rings;
(i) lower alkyl;
(j) arylalkyl;
(k) cycloalkyl; or
(l) phenyl or mono- or di-substituted phenyl, wherein the substituents are each independently;
(1) alkylthio
(2) nitro; or
(3) alkylsulfonyl;
R ⁵⁵ is:
(a) -CO ₂ D ₁ ;
(b) -C (O) -N (R ⁸ ) (R ⁸ );
(c) -CO ₂ -lower alkyl;
(d) -C (O) -N (D ¹ ) -S (O) _2- (C (R _e ) (R _f )) _P -UV; or
(e) -CO ₂ -lower alkyl -UV;
R ⁵⁶ is:
(a) hydrogen;
(b) phenyl;
(c) thienyl;
(d) alkynyl;
(e) alkenyl; or
(f) alkyl;
R _g is:
(a) hydrogen;
(b) lower alkyl;
(c) arylalkyl;
(d) alkoxy;
(e) aryloxy;
(f) arylalkoxy;
(g) haloalkyl
(h) haloalkoxy;
(i) alkylamino;
(j) arylamino;
(k) arylalkylamino;
(l) nitro;
(m) sulfonamido;
(n) carboxamido;
(o) aryl;
(p) -C (O) -aryl; or
(q) -C (O) -alkyl;
Optionally, the monocyclic ring radicals of A ¹ , A ² , A ³ and A ⁴ comprising R _g and 4 of 6 atoms;
(a) naphthyl;
(b) quinolyl;
(c) isoquinolyl;
(d) quinolizinyl;
(e) quinoxalinyl; or
(f) dibenzofuryl;
R ⁵⁸ and R ⁵⁹ are independently of each other;
(a) hydrogen;
(b) lower alkyl
(c) lower alkyl-phenyl;
(d) haloalkyl, preferably fluoroalkyl;
(e) halo;
(f) -NO ₂ ;
(g) CN
(h) lower alkyl-CN;
(i) alkoxy;
(j) alkylthio; or
(k) alkenyl;
Optionally, R ⁵⁸ and R ⁵⁹ are the cycloalkyls to which they are attached;
R ⁸ , R _i , R _e , R _f , D ¹ , U, V s and p are as defined herein;
Provided that the compound of formula (VII) comprises at least one nitrate, nitrite, thionitrate or thionitrate group;
The compound of formula 9 (iii) is:
[Formula 9] Represented by (Ⅸ);
From here,
X ⁹ is —C (O) —UD ¹ and Y ⁹ is —CH ₂ —CR ⁵ (R ^{5 ′} ) —UD ¹ ; or
X ⁹ is —CH ₂ -CR ⁵ (R ^{5 ′} ) -UD ¹ and Y ⁹ s C (O) -UD ¹ ; or
X ⁹ and X ⁹ taken together
(a) -C (O) -O-CR ⁴ (R ^{4 '} ) -CR ⁵ (R ^5' )-;
(b)-(CR ⁴ (R ^{4 '} )) _K -CR ⁵ (R ^5' ) -CR ⁵ (R ^{5 '} )-;
(c) -C (O)-(CR⁴(R^4'))_K-CR⁵(R^{5 '})-;
(d)-(CR ⁴ (R ^{4 ′} )) _K -CR ⁵ (R ^{5 ′} ) -C (O) —; or
(e) -C (O)-(CR ⁴ (R ^{4 '} ))-CR ⁵ (R ^5' )-;
Wherein X ⁹ is the first carbon atom of a, b, c, d and e;
R ¹ , R ² , R ⁴ , R ^{4 ′} , R ⁵ , R ^{5 ′} , U, D ¹ and k are as defined herein;
Provided that the compound of formula (9) comprises at least one nitrate, nitrite, thionitrate or thionitrate group;
The compound of formula 10 (i) is:
[Formula 10] Represented by ...
From here,
When sides h, k and j are single bonds and sides I and l are double bonds, then -X ¹⁰ -Y ¹⁰ -Z ¹⁰ is;
(a)
or
(b)

When side i, k and l single bond and side h and j are double bond, -X ¹⁰ -Y ¹⁰ -Z ¹⁰ is;
... (c)
When side i, k and l single bond and side h and j are double bonds, then -X ¹⁰ -Y ¹⁰ -Z ¹⁰ is
(a)
or
(b)

P ¹⁰ is;
(a) -N =;
(b) -NR ^3- ;
(c) -O-; or
(d) -S-;
Q ¹⁰ and Q ¹⁰ are independent of each other:
(a) CR ⁶⁰ ; or
(b) nitrogen;
A ¹⁰ . B ¹⁰ -C... D ¹⁰ -is:
^{(a) -CR 4 = CR 4} '-CR 5 = CR 5'-;
(b) -CR ⁴ (CR ^{4 '} ) -CR ⁵ (CR ^5' ) -CR ⁴ (CR ⁴ ) -C (O)-;
(c) -CR ⁴ (CR ^{4 '} ) -CR ⁵ (CR ^5' ) -C (O) -CR ⁴ (CR ^{4 '} )-;
(d) -CR ⁴ (CR ^{4 '} ) -C (O) -CR ⁴ (CR ⁴ ) -CR ⁵ (CR ^5' )-;
(e) -C (O) -CR ⁴ (CR ^{4 '} ) -CR ⁵ (CR ^5' ) -CR ⁴ (CR ⁴ )-;
(f) -CR ⁴ (CR ^{4 '} ) -CR ⁵ (CR ^5' ) -C (O)-;
(g) -CR ⁴ (CR ^{4 ′} ) -C (O) —CR ⁵ (CR ^{5 ′} ) —;
(h) -C (O) -CR ⁴ (CR ⁴ ) ^' -CR ⁵ (CR ^5' )-;
(i) -CR ⁴ (CR ^{4 '} ) -CR ⁵ (CR ^5' ) -OC (O)-;
(j) -CR ⁴ (CR ^{4 '} ) -OC (O) -CR ⁵ (CR ^5' )-;
(k) -OC (O) -CR ⁴ (CR ^{4 '} ) -CR ⁵ (CR ^5' )-;
(l) -CR ⁴ (CR ^{4 ′} ) -CR ⁵ (CR ^{5 ′} ) -C (O) —O;
(m) -CR ⁴ (CR ^{4 ′} ) -C (O) —O—CR ⁵ (CR ^{5 ′} ) —;
(n) —C (O) —O—CR ⁴ (CR ^{4 ′} ) —CR ⁵ (CR ^{5 ′} ) —;
(o) -CR ¹² (R ¹³ ) -OC (O) —;
(p) -C (O) -O-CR ¹² (R ¹³ )-;
(q) -OC (O) -CR ¹² (R ¹³ )-;
(r) -CR ¹² (R ¹³ ) -C (O) -O-;
(s) -N = CR ⁴ -CR ^{4 ′} = CR ⁵ −;
(t) -CR ⁴ = N-CR ^{4 ′} = CR ⁵ −;
(u) -CR ⁴ = CR ^{4 ′} -N = CR ^5- ;
(v) -CR ⁴ = CR ⁵ -CR ^{5 '} = N-;
(w) -N = CR ⁴ -CR ^{4 ′} = N-;
(x) -N = CR ⁴ -N = CR ^{4 ′} -;
(y) -CR ⁴ = N-CR ^{4 ′} = N-;
(z) -S-CR ⁴ = N-;
(aa) -SN = CR ^4- ;
(bb) -N = N-NR ^3- ;
(cc) -CR ⁴ = NS-;
(dd) -N = CR ⁴ -S-;
(ee) -O-CR ⁴ = N-;
(ff) -ON = CR ^4- ; or
(cc) -N = CR ⁴ -O-;
-A ^{10 '} ... B ^{10 '} ... D ^{10 '} ... Is:
(a) -CR ⁴ = CR ⁵ -CR ^{5 '} =
(b) -CR ⁴ (R ^{4 '} ) -CR ⁵ (R ^5' ) -CR ⁴ (R ^{4 '} )-;
(c) —C (O) ^{—CR 4} (R ^{4 ′ ′} ) ^{—CR 5} (R ^{5 ′} ) —;
(d) -CR ⁴ (R ^{4 '} ) -CR ⁵ (R ^5' ) -C (O)-;
(e) -N = CR ⁴ -CR ⁵ =;
(g) -N = N-CR ⁴ =;
(h) -N = N-NR ^3- ;
(i) -N = N-N =;
(j) -N = CR ⁴ -NR ^3- ;
(k) -N = CR ⁴ -N =;
(l) -CR ⁴ -N-NR ^3- ;
(m) -CR ⁴ = NN;
(n) -CR ⁴ = N-CR ⁵ =;
(o) -CR ⁴ = CR ⁵ -NR ^3- ;
(p) -CR ⁴ = CR ⁵ -N =;
(q) -S-CR ⁴ = CR ^5- ;
(r) -O-CR ⁴ = CR ⁵ ;
(s) -CR ⁴ = CR ⁵ -O-;
(t) -CR ⁴ = CR ⁵ -S-;
(u) -CR ⁴ = NS-;
(v) -CR ⁴ = NO-;
(w) -N = CR ⁴ -S-;
(x) -N = CR ⁴ -O-;
(y) -S-CR ⁴ = N-;
(z) -O-CR ⁴ = N-;
(aa) -N = N-S-;
(bb) -N = N-O-;
(cc) -S-N = N-;
(dd) -O-N = N-;
(ee) -CR ⁴ = CR ⁵ -S;
(ff) -CR ⁴ (R ^{4 '} ) -CR ⁵ (R ^5' ) -S-;
(gg) -CR ⁴ (R ^{4 '} ) -CR ⁵ (R ⁵ ) -O-;
(hh) -S-CR ⁴ (R ^{4 ′} ) -CR ⁵ (R ⁵ )-; or
(ii) -O-CR ⁴ (R ^{4 '} ) -CR ⁵ (R ^5' )-;
R ⁶⁰ and R ⁶¹ are independently;
(a) lower alkyl
(b) haloalkyl;
(c) alkoxy
(d) alkylthio
(e) lower alkyl-OD ¹ ;
(f) -C (O) H;
(h)-(CH ₂ ) _q -CO ₂ -lower alkyl
(i)-(CH ₂ ) _q -CO ₂ D ¹ ;
(j) -O- (CH ₂ ) _q -S-lower alkyl;
(k)-(CH ₂ ) _q -S-lower alkyl;
(l) -S (O) ₂ -lower alkyl;
(m)-(CH ₂ ) _q -NR ¹² R ¹³ ; or
(n) -C (O) N (R ⁸ ) (R ⁸ );
R ¹ , R ² , R ³ , R ⁴ , R ^{4 ′} , R ⁵ , R ^{5 ′} , R ⁸ , R ¹² , R ¹³ , T, D ¹ and q are as defined herein;
Provided that the compound of formula 10 (iii) must include at least one nitrate, nitrite, thionitrate or thionitrate group;
Compound of formula 11 (XI)
[Formula 11] Expressed as ... (XI)
From here:
X ¹¹ is:
(a) oxygen; or
(b) CH ₂ ;
Y ¹¹ is:
(a) oxygen;
(b) -H ₂ ;
(c) -N-OD ¹ ;
(d) -N-O-lower alkyl;
(e) -N-O-aryl;
(f) -N-C (O) -O-lower alkyl;
(g) -NN (R ⁸ ) (R ⁸ ); or
(h) -NN (R ⁸ ) -S (O) ₂ -lower alkyl;
R ⁶² , R ⁶³ , R ⁶⁴ and R ⁶⁵ are independent of each other;
(a) hydrogen;
(b) lower alkyl;
(c) alkoxy;
(d) halo;
(e) CN;
(f) OD ¹ ;
(g) alkoxy;
(h) -NR ¹² R ¹³ ;
(i) -CF ₃ ;
(j) -NO ₂ ;
(k) alkylthio;
(l) -S (O) _O -lower alkyl;
(m) —C (O) N (R ⁸ ) (R ⁸ );
(n) -CO ₂ D ¹
(o) -CO ₂ -lower alkyl; or
(p) -NR ⁸ -C (O) -lower alkyl;
R ⁶⁶ i is:
(a) hydrogen;
(b) lower alkyl;
(c) alkenyl;
(d) alkoxyalkyl;
(e) cycloalkylalkyl;
R ⁸ , R ¹² , R ¹³ , o, K and D ¹ are as defined herein;
Wherein the compound of formula 11 (XI) necessarily comprises at least one nitrate, nitrite, thionitrate or thionitrate group;
Compound of formula 12 (XII)
[Formula 12] Expressed as ... (XII)
From here:
X ¹² is:
(a)

(b)
or
(c) NR ⁷¹ ;
Y ¹² is:
(a)

(b)

(c)

(d)

(e) -NR ⁷³ (R ⁷⁴ );
(f) hydrogen; or
(g) K;
Z ¹² is:
(a)

(b) R ⁶⁷ ;
R ⁶⁷ ;
(a) hydrogen;
(b) lower alkyl;
(c) lower alkyl-OD ¹ ;
(d) -OD ¹ ;
(e) haloalkyl; or
(f)

R ⁶⁸ is:
(a) lower alkyl;
(b) halo;
(c) alkoxy
(d) haloalkyl;
(e) alkylthio;
(f) haloalkylthio;
(g) -OCH _2-
(h) unsubstituted, mono-, or di-substituted heteroaryl, wherein the heteroaryl is a 5-membered monocyclic aromatic ring, which ring is S, O, or N, and optically 1, 2 or One heteroatom such as 3 additional nitrogen atoms; Or said heteroaryl is a 6 membered monocyclic ring, said ring comprising N and one heteroatom such as optically 1, 2, or 3 additional nitrogens; The substituents are each independently;
(1) halo; or
(2) lower alkyl
(i) -S (O) ₀ -lower alkyl;
(j) -S (O) ₀ -lower haloalkyl;
(k) amino;
(l) alkylamino;
(m) dialkylamino;
(n) -N (H) SO ₂ -lower alkyl;
(o) -N (H) SO ₂ -lower haloalkyl;
(p) nitro;
(q) cyano;
(r) -CO ₂ D ¹ ;
(s) carboxylic esters;
(t) lower alkyl-OD ¹ ;
(u) carboxamides; or
(v) -C (O) N (R ¹² ) D ¹ ;
R ⁶⁹ is:
(a) lower alkyl;
(b) hydrogen;
(c) alkoxy;
(d) mono-di, tri, tetra- or penta-substituted phenyl, wherein the substituents are each independently;
(1) hydrogen;
(2) halo;
(3) alkoxy;
(4) alkylthio;
(5) -S (O) ₀ -lower alkyl;
(6) lower alkyl;
(7) halo alkyl;
(8) -CO ₂ D ¹ ;
(9) -lower alkyl-CO ₂ D ¹ ;
(10) OD ¹ ;
(11) -lower alkyl-OD ¹ ; or
(12) haloalkoxy;
(e) mono-, di-, tri-substituted heteroaryl, wherein heteroaryl is a 5-membered monocyclic aromatic ring, which ring is S, O, or N and optically 1, 2, or 3 Includes one heteroatom of an additional nitrogen atom; Heteroaryl is a 6 membered monocyclic ring, which ring optically contains one heteroatom of nitrogen and 1, 2, 3 or 4 additional nitrogen atoms; The substituents are each independently:
(1) hydrogen;
(2) halo;
(3) lower alkyl;
(4) alkoxy;
(5) alkylthio;
(6) aryloxy;
(7) arylthio;
(8) -CO ₂ D ¹ ;
(9) -C (O) NH (D ¹ );
(10) haloalkyl; or
(11) -OD ¹ ;
R ⁷⁰ is:
(a) lower alkyl;
(b) hydrogen; or
(c) mono- or di-substituted phenyl, wherein the substituents are each independently.
(1) hydrogen;
(2) halo;
(3) alkoxy;
(4) haloalkyl; or
(5) lower alkyl;
R ⁷¹ is:
(a) benzoyl, or mono- or di-substituted benzoyl, wherein the substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy;
(b) benzoyl, or mono- or di-substituted benzyl, wherein the substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy;
(c) lower alkyl-pyridinyl, or unsubstituted, mono-di-substituted pyridinyl, wherein the substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy;
(d) -C (O) -pyridinyl, or mono-, or di-substituted -C (O) -pyridinyl, wherein the substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy;
(e) hydrogen;
(f) aryl;
(g) cycloalkyl;
(h) cycloalkylalkyl
R ⁷² is:
(a) lower alkenyl-CO ₂ D ¹ ; or
(b) K;
R ⁷³ is unsubstituted or mono-substituted lower alkyl, wherein the substituents are each independently:
(a) hydroxy;
(b) alkoxy;
(c) nitro;
(d) -NH ₂ ;
(e) alkylamino;
(f) dialkylamino;
(g) carboxyl;
(h) carboxylic esters; or
(i) carboxamides;
R ⁷⁴ is:
(a) hydrogen;
(b) lower alkyl; or
(c) -C (O) R ⁷⁶ ;
R ⁷⁵ is:
(a) lower alkyl;
(b) haloalkyl;
(c) substituted lower alkyl;
(d) cycloalkyl; or
(e) unsubstituted, mono-, di- or tri-substituted phenyl or naphthyl, wherein the substituents are each independently:
(1) halo;
(2) alkoxy;
(3) -S (O) ₀ -lower alkyl;
(4) hydroxy;
(5) -S (O) ₀ -haloalkyl;
(6) lower alkyl;
(7) haloalkyl;
(8) -CO ₂ D ¹ ;
(9) -CO ₂ -lower alkyl;
(10) -S (O) ₂ NR ⁸ (D ¹ );
(11) -lower alkyl-O-lower alkyl;
(12) -CN;
(13) lower alkyl-OD ¹ ;
(14) aryl alkoxy;
(15) -C (O) NR ⁸ (D ¹ ); or
(16) aryl;
(f) mono-, di-tri-substituted heteroaryl, wherein heteroaryl is a 5-membered monocyclic aromatic ring, which ring is S, O, or N and optically 1, 2, or 3 additional One heteroatom of a nitrogen atom; Heteroaryl is a 6 membered monocyclic ring, which ring optically contains one heteroatom of nitrogen and 1, 2, 3 or 4 additional nitrogen atoms; The substituents are each independently:
(1) halo;
(2) alkoxy;
(3) -S (O) ₀ -lower alkyl;
(4) hydroxy;
(5) -S (O) ₀ -haloalkyl;
(6) lower alkyl;
(7) haloalkyl;
(8) -CO ₂ D ¹ ;
(9) -CO ₂ -lower alkyl;
(10) -S (O) ₂ NR ⁸ (D ¹ );
(11) -lower alkyl-O-lower alkyl;
(12) -N (D ¹ ) S (O) ₂ -lower alkyl;
(13) lower alkyl-OD ¹ ;
(14) -N (D ¹ ) S (O) ₂ -haloalkyl;
(15) -C (O) NR ⁸ (D ¹ ); or
(16) aryl;
R ⁷⁶ is:
(a) alkyl;
(b) substituted alkyl;
(c) alkyl-N (D ¹ ) S (O) ₂ -aryl;
(d) substituted alkyl-cycloalkyl;
(e) substituted alkyl-heterocyclic rings; or
(f) arylalkoxy;
R ⁷⁷ is:
(a) -OD ¹ ;
(b) alkoxy; or
(c) -NR ⁷⁸ R ⁷⁹ ;
R ⁷⁸ and R ⁷⁹ are independent of each other:
(a) hydrogen;
(b) hydroxy;
(c) alkoxy;
(d) lower alkyl;
(e) substituted lower alkyl; or
R ⁷⁸ and R ⁷⁹ , together with the nitrogen to which they are attached, are heterocyclic rings;
R ⁸⁰ and R ⁸¹ are independent of each other:
(a) hydrogen;
(b) lower alkyl; or
(c) halo;
R ⁸⁹ and R ⁸⁹ are independent of each other:
(a) hydrogen;
(b) lower alkyl; or
And R ⁸⁹ and R ^{89 ′} to which they are located together with the carbon to which they are attached are cycloalkyl rings;
m is an integer from 0 to 6.
D ¹ , R ¹ , R ⁸ , R ¹² , K, X ⁵ , a, p and o are defined herein; And
Provided that the compound of formula 12 must include at least one nitrate, nitrite, thionitrate or thionitrate group;
Compound of formula 13 (XIII)
[Formula 13] Expressed as ... (ⅩⅢ)
X ¹³ and Y ¹³ are independent of each other:
(a) = C (H)-; or
(b) = N-;
R ⁹⁰ is:
(a) lower alkyl;
(b) lower alkyl-OD ¹ ;
(c) alkenyl;
(d) lower alkyl-CN;
(e) lower alkyl-CO ₂ D ¹ ;
(f) aryl;
(g) heterocyclic rings; or
(h) heterocyclic alkyl;
R ⁹¹ is:
(a) mono-, di- or tri-substituted phenyl, wherein the substituents are each independently:
(1) hydrogen;
(2) halo;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) haloalkyl;
(7) lower alkyl;
(8) -CO ₂ D ¹ ;
(9) -CO ₂ -lower alkyl;
(10) lower alkyl-OD ¹ ;
(11) lower alkyl-NR ¹² R ¹³ ;
(12) lower alkyl-CO ₂ D ¹ ; or
(13) -OD ¹ ;
(b) mono-, di- or tri-substituted heteroaryl, wherein the heteroaryl is a 5-membered monocyclic aromatic ring, which ring is S, O, or N and optically 1, 2, or 3 Includes one heteroatom of an additional nitrogen atom; Heteroaryl is a 6 membered monocyclic ring, which ring optically contains one heteroatom of nitrogen and 1, 2, 3 or 4 additional nitrogen atoms; The substituents are each independently:
(1) hydrogen;
(2) halo;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) haloalkyl;
(7) lower alkyl;
(8) -CO ₂ D ¹ ;
(9) -CO ₂ -lower alkyl;
(10) lower alkyl-OD ¹ ;
(11) lower alkyl-NR ¹² R ¹³ ;
(12) lower alkyl-CO ₂ D ¹ ; or
(13) -OD ¹ ;
D ¹ , R ¹ , R ¹² and R ¹³ are defined herein;
Subject to compound of formula 13 (XIII) necessarily comprising at least one nitrate, nitrite, thionitrate or thionitrate group;
Compound of formula 14 (XIV)
[Formula 14] ... (XIV)
X ¹⁴ is:
(a) -C (O)-; or
(b) -C (S)-;
Y ¹⁴ is:
(a) -O-; or
(b) -S-;
A ¹⁴ . B ¹⁴ ... D ¹⁴ is:
^{(a) -CR 4 = CR 4} '-CR 5 = CR 5'-;
(b) -CR ⁴ (R ^{4 ′} ) -CR ⁵ (R ^{5 ′} ) -C (O) —;
(c) -CR ⁴ (R ^{4 ′} ) -C (O) —CR ⁵ (R ^{5 ′} ) —;
(d) -C (O) -CR ⁴ (R ^{4 '} ) -CR ⁵ (R ^5' )-;
(e) -CR ⁴ (R ⁵ ) -OC (O) —;
(f) -C (O) -O-CR ⁴ (R ⁵ )-;
(g) -OC (O) -CR ⁴ (R ⁵ )-;
(h) -SN = CR ^4- ;
(i) -ON = CR ^4- ;
(j) -CR ⁴ (R ⁵ ) -NR ³ -C (O) —;
(k) -C (O) -NR ³ -CR ⁴ (R ⁵ )-;
(l) -NR ³ -C (O) -CR ⁴ (R ⁵ )-;
(m) -CR ⁴ (R ⁵ ) -SC (O) —;
(n) -C (O) -S-CR ⁴ (R ⁵ )-;
(o) -SC (O) -CR ⁴ (R ⁵ )-;
(p) -CR ⁴ = CR ^{4 ′} -C (O) —;
(q) -C (O) -CR ⁴ = CR ^{4 '} -;
(r) -0-CR ⁴ = CR ^{4 '} -;
(s) -S-CR ⁴ = CR ^{4 '} -;
(t) -NR ³ -CR ⁴ = CR ^5- ;
(u) -S-NR ³ -C (O)-;
(v) -O-NR ³ -C (O)-; or
(w) -NR ³ = N = CR ^4- ;
R ¹ , R ² , R ³ , R ⁴ , R ^{4 ′} , R ⁵ and R ^{5 ′} are as defined herein; And
Provided that the compound of formula IV has at least one group of nitrates, nitrites, thionitrates or thionitrates;
Compound of Formula 15 (XV)
[Formula 15] Represented by ... (XV);
X ¹⁵ is:
(a) -C (O)-;
(b) -CH _2- ;
(c) -CH (OD ¹ );
(d) -C = N-O-lower alkyl-;
(e) -O-;
(f) -S (O) _0- ;
(g) -NR ⁹² ; or
(h) covalent bonds;
Y ¹⁵ is:
(a) aryl; or
(b) cycloalkyl;
Z ¹⁵ is:
(a) hydrogen;
(b) alkyl;
(c) haloalkyl;
(d) cycloalkyl-;
(e) alkoxy;
(f) alkylthio;
(g) cycloalkylalkylthio;
(h) cycloalkylalkoxy;
(i) -OD ^1- ;
(j) halo;
(k) cyano;
(l) -C (O) OD ¹ ;
(m) -C (O) -loweralkyl; or
R ⁹² is:
(a) hydrogen;
(b) lower alkyl;
(c) -C (O) -lower alkyl; or
(d) -K-;
R ¹ , D ¹ , K and o are as defined herein; And
Provided that the compound of formula XV necessarily includes at least one nitrate, nitrite, thionitrate or thionitrate group;
The compound of formula 16 (VI) is
[Formula 16] ... (ⅩⅥ)
From here:
X ¹⁶ is:
(a)

(b)

Y ¹⁶ is:
(a) hydrogen;
(b) halogen;
(c) methyl; or
(d) ethyl;
Z ¹⁶ is:
(a) hydrogen; or
(b) methyl;
R ⁹³ is:
(a) chloro; or
(b) floro;
R ⁹⁴ and R ^{94 "} are each independently.
(a) hydrogen; or
(b) floro;
R ⁹⁵ is:
(a) chloro;
(b) floro;
(c) hydrogen;
(d) methyl;
(e) ethyl;
(f) methoxy;
(g) ethoxy; or
(h) hydroxy;
R ⁹⁶ is
(a) chloro;
(b) floro;
(c) trifluoromethyl; or
(d) methyl;
R ^95: is
(a) lower alkyl;
(b) lower alkenyl;
(c) alkoxy; or
(d) alkylthio;
K and X ¹³ are as defined herein;
It is conditional that the compound of formula (VI) must include at least one nitrate, nitrite, thionitrate or thionitrate group.
[2" claim-type="Currently amended] A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
[3" claim-type="Currently amended] A method of treating, preventing or reducing inflammation, pain or fever in a patient with inflammation, pain or fever, comprising administering to the patient a therapeutically effective amount of the composition of claim 2.
[4" claim-type="Currently amended] A method of treating or preventing a gastrointestinal disorder in a patient or improving the gastrointestinal properties of a COX-2 inhibitor in a patient, comprising administering to the patient a therapeutically effective amount of the composition of claim 2.
[5" claim-type="Currently amended] 5. The gastrointestinal disorder is inflammatory bowel disease, Crohn's diseas, gastritis, irritable bowel syndrom, ulcerative colitis, peptic ulcer, stress Ulcers, bleeding ulcers, gastric hyperacidity, indigestion, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, bacteri infection , Short-bowel (anastomosis), or hypersecretory state associated with mastocytosis or basophilic rheumatoid and hyperhistaminemia Way.
[6" claim-type="Currently amended] A method for facilitating wound healing comprising administering to the patient a therapeutically effective amount of the composition of claim 2.
[7" claim-type="Currently amended] 7. The method of claim 6, wherein the wound is an ulcer.
[8" claim-type="Currently amended] A method of treating or reversing a patient's renal or other toxicity, comprising administering to the patient a therapeutically effective amount of the composition of claim 2.
[9" claim-type="Currently amended] A method of treating or preventing a disease resulting from an increase in the level of COX-2 in a patient, comprising administering to the patient a therapeutically effective amount of the composition of claim 2.
[10" claim-type="Currently amended] 10. The method of claim 9, wherein the disease caused by an increase in the level of COX-2 is angiogenesis, arthritis, asthma, bronchitis, menstrual cramps, premature labor, tendinitis, bursitis (10). bursitis, skin-related conditions, neoplasia, inflammation in diseases, ophthalmic disorders, pulmonary inflammation, central nervous system disorders, allergic rhinitis , Respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis, inflammation and / or bacterial infection, cardiovascular disorders, urinary and / or urinary diseases and / or urological disorders, endothelial dysfucntion, preservation of organs and tissues, inhibition and / or prevention of activity, attachment and invasion of neutrophils at the site of inflammation, or platelet agg regulating) and / or preventing.
[11" claim-type="Currently amended] The composition of claim 2 further comprising at least one therapeutic agent.
[12" claim-type="Currently amended] The method of claim 11, wherein the therapeutic agent is a steroid, a nonsteroidal anti-inflammatory compound, a 5-lipooxyginase inhibitor, a leukotriene B ₄ receptor antagonist, a leukotriene A ₄ hydrolase inhibitor, a 5-HT antagonist, 3 Hydroxy-3methylglutaryl coenzyme A inhibitor, H ₂ receptor antagonist, antineoplastic agent, antiplatelet agent, decongestant, diuretic, sedative and / or unstable ( sedating and / or non-sedating) antihistamines, inducible nitric oxide synthesis inhibitors (inducible nitric oxide synthase inhibitor), opioids (opioid), pain relievers (analgesic), Helicobacter pylori inhibitors (Helicobacter pylori inhibitor), a proton pump inhibitor, a device profile stain (isoprostane) inhibitors, or mixtures thereof
[13" claim-type="Currently amended] A method of treating, preventing or reducing inflammation, pain or fever in a patient with inflammation, pain or fever, comprising administering to the patient a therapeutically effective amount of the composition of claim 11.
[14" claim-type="Currently amended] A method of treating or preventing a gastrointestinal disorder in a patient or enhancing the gastrointestinal properties of a COX-2 inhibitor in a patient, comprising administering to the patient a therapeutically effective amount of the composition of claim 11.
[15" claim-type="Currently amended] 15. The method of claim 14, wherein the gastrointestinal disease is inflammatory bowel disease, Crohn's diseas, gastritis, irritable bowel syndrom, ulcerative colitis, peptic ulcer. Stress ulcers, bleeding ulcers, gastric hyperacidity, indigestion, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, Bacterial infection, short-bowel (anastomosis) symptoms, or hypersecretory states associated with mastocytosis or basophilic rheumatoid and hyperhistaminemia How to feature.
[16" claim-type="Currently amended] A method for facilitating wound healing comprising administering to the patient a therapeutically effective amount of the composition of claim 11.
[17" claim-type="Currently amended] The method of claim 16, wherein the wound is an ulcer.
[18" claim-type="Currently amended] A method of treating or reversing a patient's renal or other toxicity comprising administering to the patient a therapeutically effective amount of the composition of claim 11.
[19" claim-type="Currently amended] A method of treating or preventing a disease resulting from increased levels of COX-2 in a patient, comprising administering to the patient a therapeutically effective amount of the composition of claim 11.
[20" claim-type="Currently amended] 20. The method of claim 19, wherein the disease caused by increased levels of COX-2 includes angiogenesis, arthritis, asthma, bronchitis, menstrual cramps, premature labor, and tendinitis. ), Bursitis, skin-related conditions, neoplasia, inflammation in diseases, ophthalmic disorders, pulmonary inflammation, central nervous system disorders, allergic rhinitis (allergic rhinitis), respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis, inflammation and / or bacterial infection, cardiovascular disorders, urinary system and / or Urinary and / or urological disorders, endothelial dysfucntion, preservation of organs and tissues, inhibition and / or prevention of activity, adhesion and invasion of neutrophils at inflammatory sites, or plateletsInhibiting and / or preventing platelet aggregation.
[21" claim-type="Currently amended] Donate, transfer or release at least one compound according to claim 1 or a pharmaceutically acceptable salt thereof, and nitric oxide, or an endogenous nitric oxide or endothelial inducer at least one compound that induces the production of a -derived relaxing factor or is a substrate of nitric oxide synthase.
[22" claim-type="Currently amended] The composition of claim 21 further comprising a pharmaceutically acceptable carrier.
[23" claim-type="Currently amended] 22. The compound of claim 21, wherein the compound is a donor, transfer or release of nitric oxide, or induces the production of intrinsic nitric oxide or endothelial-derived relaxing factor, or is a substrate of nitric oxide synthase. S-nitrosothiol (S-nitrosothiol), characterized in that the composition.
[24" claim-type="Currently amended] The method of claim 23, wherein the S-nitrosothiol is selected from the group consisting of S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylphenicylamine, S-nitroso-homocysteine, S-nitroso-cittain, S-nitroso-glutathione, or S-nitroso-cysteinyl-glycine.
[25" claim-type="Currently amended] The method of claim 23, wherein the S-nitrosothiol,
(Iii) HS (C (R _e ) (R _f )) _mm SNO;
(Ii) ONS (C (R _e ) (R _f )) _mm R _e ; And
(Iii) H ₂ N—CH (CO ₂ H) — (CH ₂ ) _mm —C (O) NH—CH (CH ₂ SNO) —C (O) NH—CH ₂ —CO ₂ H;
Wherein mm is an integer from 2-40; R _e and R _f are each independently hydrogen, alkyl, cycloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, arylheterocyclic ring, cycloalkylalkyl, heterocyclicalkyl, alkoxy, haloalkoxy, amino, Alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, alkoxyhaloalkyl, haloalkoxy, sulfonic acid, sulfonic esters, alkylsulfonic acid, arylsulfonic acid, arylalkoxy, alkylthio, arylthio, Cyano, aminoalkyl, aminoaryl, alkoxy, aryl, arylalkyl, carboxamido, alkylcarboxamido, arylcarboxamido, amidyl, carboxyl, carbamoyl, alkylcarboxylic acid, arylcarboxyl Acids, alkylcarbonyls, arylcarbonyls, esters, carboxyl esters, alkylcarboxyl esters, arylcarboxyl esters, haloalkoxy, sulfonamido, alkylsulfonamido, arylsulfonamido, alkyl Sulfonyl, alkylsulfonyloxy, arylsulfonyl, aryl sulfonyloxy, carbamoyl, a urea, a nitro, -TQ-, or _{(C (R e) (R} f)) k -TQ-, or R _e and R _{f is} all oxo, methaneial, heterocyclic ring, cycloalkyl group or bridged cycloalkyl group; Q is -NO or -NO ₂ ; And T is independently a covalent bond, carbonyl, acid, -S (O) _o -or -N (R _a ) R _i- , where o is an integer from 0-2 and R _a is an isolated pair of electrons, Hydrogen or an alkyl group; R _i is hydrogen, alkyl, aryl, alkylcarboxylic acid, arylcarboxylic acid, alkylcarboxyl ester, arylcarboxyl ester, alkylcarboxamido, arylcarboxamido, arylsulfinyl, arylsulfonyloxy, Arylsulfonyl, sulfonamido, carboxamido, carboxyl ester, aminoalkyl, aminoaryl, -CH ₂ -C (TQ) (R _e ) (R _f )), or-(N ₂ O ₂ −) ^- · M ^+, where M ⁺ is an organic or inorganic proton; "-TQ" is hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group.
[26" claim-type="Currently amended] 22. The method of claim 21, wherein at least one of donating, delivering or releasing said nitrogen monoxide, or inducing the production of intrinsic nitric oxide or endothelial-derived relaxing factor, or at least one substrate of a nitric oxide synthase Compounds of L-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy -L-arginine, nitrosilicated N-hydroxy-L-arginine, citrulline, ornithine, glutamine or arginase inhibitor.
[27" claim-type="Currently amended] 22. The method of claim 21, wherein at least one of donating, delivering or releasing said nitrogen monoxide, or inducing the production of intrinsic nitric oxide or endothelial-derived relaxing factor, or at least one substrate of a nitric oxide synthase The compound of:
(Iii) a compound comprising at least one ON-O-, ON-N- or 0N-C- group;
(Ii) compounds comprising at least one O ₂ NO—, O ₂ NN—, O ₂ NS—, or O ₂ NC— group;
(Iii) N-oxo-N-nitrosoamine represented by the formula R ¹ R ² -N (OM ⁺ ) -NO, wherein R ¹ and R ² are each independently a polypeptide, an amino acid, or a sugar (sugar) sugar), oligonucleotide, straight or branched chain, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or heterocyclic group, wherein M ⁺ is an organic or inorganic keion Composition.
[28" claim-type="Currently amended] 28. The compound of claim 27, wherein the compound comprising at least one ON-O-, ON-N- or 0N-C- group is ON-O-polypeptide, ON-N-polypeptide, 0N-C-polypeptide, ON-O- Amino acid, ON-N-amino acid, 0N-C-amino acid, ON-O-sugar, ON-N-sugar, 0N-C-sugar, ON-O-oligonucleotide, ON-N-oligonucleotide, 0N -C-oligonucleotides, straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON-O-hydrocarbons, straight or branched chain, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON-N-hydrocarbons, straight or branched chains, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic 0N-C-hydrocarbons, ON-O-heterocyclic compounds, ON-N-heterocyclic compounds or 0N -C-heterocyclic compound.
[29" claim-type="Currently amended] The compound of claim 27, wherein the compound comprising at least one O ₂ NO—, O ₂ NN—, O ₂ NS— or O ₂ NC— group is O ₂ NO-polypeptide, O ₂ NN-polypeptide, O ₂ NS-polypeptide. , O ₂ NC-polypeptide, O ₂ NO-amino acid, O ₂ NN-amino acid, O ₂ NS-amino acid, O ₂ NC-amino acid, O ₂ NO-sugar, O ₂ NN-sugar, O ₂ NS-sugar, O ₂ NC-sugar, O ₂ NO-oligonucleotide, O ₂ NN-oligonucleotide, O ₂ NS-oligonucleotide, O ₂ NC-oligonucleotide, straight or branched chain, Saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O ₂ NO-hydrocarbons, straight or branched chain, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O ₂ NN-hydrocarbons, straight or branched chain, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O ₂ NS- hydrocarbon, linear or branched, saturated or unsaturated, aliphatic or aromatic, Hwandoen or wherein the unsubstituted hydrocarbon group O ₂ NC-, O ₂ NO- heterocyclic compounds, O ₂ NN- heterocyclic compounds, O ₂ NS- heterocyclic compound, a heterocyclic compound O ₂ NC- Composition.
[30" claim-type="Currently amended] The composition of claim 21 further comprising at least one therapeutic agent.
[31" claim-type="Currently amended] The method of claim 30, wherein the therapeutic agent is a steroid, a nonsteroidal anti-inflammatory compound, a 5-lipooxyginase inhibitor, a leukotriene B ₄ receptor antagonist, a leukotriene A ₄ hydrolase inhibitor, a 5-HT antagonist, 3 Hydroxy-3methylglutaryl coenzyme A inhibitor, H ₂ receptor antagonist, antineoplastic agent, antiplatelet agent, decongestant, diuretic, sedative and / or unstable ( sedating and / or non-sedating) antihistamines, inducible nitric oxide synthesis inhibitors (inducible nitric oxide synthase inhibitor), opioids (opioid), pain relievers (analgesic), Helicobacter pylori inhibitors (Helicobacter pylori inhibitor), a proton pump inhibitor, a device profile stain (isoprostane) inhibitors, or mixtures thereof
[32" claim-type="Currently amended] A method of treating, preventing or reducing inflammation, pain or fever in a patient with inflammation, pain or fever, comprising administering to the patient a therapeutically effective amount of the composition according to claim 21.
[33" claim-type="Currently amended] A method of treating or preventing a gastrointestinal disorder in a patient or improving the gastrointestinal properties of a COX-2 inhibitor in a patient, comprising administering to the patient a therapeutically effective amount of the composition according to claim 21.
[34" claim-type="Currently amended] The method of claim 33, wherein the gastrointestinal disease is inflammatory bowel disease (Crohn's diseas), gastritis (gastritis), irritable bowel syndrom, ulcerative colitis, peptic ulcer Stress ulcers, bleeding ulcers, gastric hyperacidity, indigestion, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, Bacterial infection, short-bowel (anastomosis) symptoms, or hypersecretory states associated with mastocytosis or basophilic rheumatoid and hyperhistaminemia How to feature.
[35" claim-type="Currently amended] A method for facilitating wound healing comprising administering to the patient a therapeutically effective amount of a composition according to claim 21.
[36" claim-type="Currently amended] 36. The method of claim 35, wherein said wound is an ulcer.
[37" claim-type="Currently amended] A method for treating or reversing a patient's renal or other toxicity comprising administering to the patient a therapeutically effective amount of the composition according to claim 21.
[38" claim-type="Currently amended] A method of treating or preventing a disease resulting from an increased level of COX-2 in a patient, comprising administering to the patient a therapeutically effective amount of the composition of claim 21 or 30.
[39" claim-type="Currently amended] 40. The method of claim 38, wherein the disease caused by an increased level of COX-2 comprises angiogenesis, arthritis, asthma, bronchitis, menstrual cramps, premature labor, tendinitis. ), Bursitis, skin-related conditions, neoplasia, inflammation in diseases, ophthalmic disorders, pulmonary inflammation, central nervous system disorders, allergic rhinitis (allergic rhinitis), respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis, inflammation and / or bacterial infection, cardiovascular disorders, urinary system and / or Urinary and / or urological disorders, endothelial dysfucntion, preservation of organs and tissues, inhibition and / or prevention of activity, adhesion and invasion of nucleotiles in the inflammatory site, or platelets Inhibiting and / or preventing platelet aggregation.
[40" claim-type="Currently amended] A kit comprising at least one compound according to claim 1 or a pharmaceutically acceptable salt thereof.
[41" claim-type="Currently amended] Donate, transfer or release at least one compound according to claim 1 or a pharmaceutically acceptable salt thereof, and nitric oxide, or an endogenous nitric oxide or endothelial inducer A kit comprising at least one compound that induces the production of a -derived relaxing factor or is a substrate of nitric oxide synthase.
[42" claim-type="Currently amended] 42. The method of claim 41, wherein the compound according to claim 1 or a pharmaceutically acceptable salt thereof and the nitrogen monoxide are donated, transferred or released, or endogenous nitrogen monoxide or endothelial. At least one compound that induces the production of an endothelium-derived relaxing factor or that is a substrate of nitric oxide synthase is a separate component in the kit or is in the form of a composition in the kit.
[43" claim-type="Currently amended] A kit comprising at least one compound according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one therapeutic agent.
[44" claim-type="Currently amended] 44. The kit of claim 43, wherein the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and the at least one therapeutic agent are separate components in the kit or in the form of a composition in the kit.
[45" claim-type="Currently amended] 4- {5- (4-chlorophenyl) -3-[(nitrooxy) methyl] -3-hydropyrazolyl] benzenesulfonamide, 4- {5- [nitrooxy) methyl] -3-phenylisoxazole -4-yl} benzenesulfonamide, 2- [l-methyl-4- (nitrosothio) -4-piperidyl] ethyl3- (N-{[4- (5-methyl-3-phenylisoxo Sazol-4-yl) phenyl] sulfonyl} carbamoyl) propanoate, (2- {l-[(4-chlorophenyl) methyl] -5-methoxy-2-methylindol-3-yl} ethyl) Nitrooxy, l- [3- (4-fluorophenyl) -7- (nitrooxymethyl) (3a-hydroimidazolo [1,2-a] pyridin-2-yl] -4- (methylsulfonyl ) Benzene, ethyl 6-chloro-8-[(nitrooxy) methyl] -2- (trifluoromethyl) -2H-chromen-3 carboxylate, 2- {l-[(4-chlorophenyl) carbonyl ] -5-methoxy-2-methylindol-3-yl} -N- (2-methyl-2- (nitrosothio) propyl) acetamide, ethyl (2Z) -3- (4-chlorophenyl) -3- [4- (methylsulfonyl) phenyl] -2- [2- (nitrooxy) ethyl] prop-2-enoate, (2Z) -3- (4-chlorophenyl) -3- [4- (Methylsulfonyl) phenyl] 2- [2- (nitrooxy) Tyl] prop-2-enoic acid, (2Z) -3- (4-chlorophenyl) -2- (2-hydroxyethyl) -N- [2-methyl-2 (nitrosothio) propyl] -3 -[4- (methylsulfonyl) phenyl] prop-2-enamide, l- [5-methyl-l- (2-methyl-2- (nitrosothio) propyl) pyrrol-2-yl] -4- (Methylsulfonyl) benzene, 3- {4- [1-methyl-1- (nitrosodio) ethyl] -2-oxo-1,3-oxazolidine-3yl} propyl (2Z) -4-acetyloxy -2- (4-fluorophenyl) -3- [4 (methylsulfonyl) phenyl] -but-2-enoate, (2Z) -3- (4-fluorophenyl) -3- {N-methyl -N- [2-methyl-2- (nitrosodio) propyl] carbamoyl} -2- [4- (methylsulfonyl) phenyl] prop-2-enyl acetate, 2- [1-methyl-4 -(Nitrosodio) -4-piperidyl] ethyl (2Z) -3- (4-acetyloxy-2- (4-fluorophenyl) -3- [4- (methylsulfonyl) phenyl] but- 2-enoate, (3Z) -4- (4-chlorophenyl) -3- (ethoxycarbonyl) -4- [4- (methylsulfonyl) phenyl] but-3-enoic acid, 3-methyl- N-{[4- (5-methyl-3-phenyllysazole-4-yl) phenyl] sulfonyl} -3- (nitrosodi O) butanamide, 2-methyl-2- (nitrosodio) propyl-5- (4-chlorophenyl) -1- (4-sulfamoylphenyl) pyrazole-3-carboxylate, 2-methyl-2 -(Nitrosothio) propyl-5- (4-chlorophenyl) -1- (4-sulfamoylphenyl) pyrazole-3-carboxylate, 4- (4-fluorophenyl) -5- [4- ( Methylsulfonyl) phenyl] -2-({4-[(nidoxy) methyl] phenyl} methyl] -2-hydroxypyridazin-3-one, 1-1 (2-hydroxyethyl) -4-benzyl Pyrazol-3-yl) -4- (methylsulfonyl) benzene, 4- (methylsulfonyl) -1- {1- [2- (nitoxy) ethyl] -4-benzylpilazol-5-yl} Benzene, 4- (1-cyclohexyl-3- (hydroxymethyl) pyrazol-5-yl} -1- (methylsulfonyl) benzene and 4- {1-cyclohexyl-3-[(nitrooxy) methyl ] Pyrazol-5-yl} -1-methylsulfonyl) benzene.
[46" claim-type="Currently amended] A composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[47" claim-type="Currently amended] A kit comprising at least one compound according to claim 45.
[48" claim-type="Currently amended] At least one, formula 1, formula 2, formula 3, formula 4, formula 5, formula 6, formula 7, formula 8, formula 9, formula 10, formula 11, formula 12, formula 13, formula 14, formula 15 or formula Donate, transfer or release a parent COX-2 inhibitor and at least one nitric oxide of a compound represented by 16, or a pharmaceutically acceptable salt thereof, or A composition comprising a compound that induces the production of endogenous nitric oxide or endothelial-derived relaxing factor or is a substrate of nitric oxide synthase.
[49" claim-type="Currently amended] 49. The composition of claim 48, further comprising a pharmaceutically acceptable carrier.
[50" claim-type="Currently amended] 49. The compound of claim 48, wherein the compound is a donor, transfer or release of nitric oxide, induces the production of intrinsic nitric oxide or endothelial relaxing factor, or is a substrate of nitric oxide synthase. S-nitrosothiol (S-nitrosothiol), characterized in that the composition.
[51" claim-type="Currently amended] 51. The method of claim 50, wherein the S-nitrosothiol is selected from the group consisting of S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylphenicylamine, S-nitroso-homocysteine, S-nitroso-cittain, S-nitroso-glutathione, or S-nitroso-cysteinyl-glycine.
[52" claim-type="Currently amended] The method of claim 50, wherein the S-nitrosothiol,
(Iii) HS (C (R _e ) (R _f )) _mm SNO;
(Ii) ONS (C (R _e ) (R _f )) _mm R _e ; And
(Iii) H ₂ N—CH (CO ₂ H) — (CH ₂ ) _mm —C (O) NH—CH (CH ₂ SNO) —C (O) NH—CH ₂ —CO ₂ H;
Wherein mm is an integer from 2-40; R _e and R _f are each independently hydrogen, alkyl, cycloalkoxy, halogen, hydroxy, hydroxyalkyl, alkoxyalkyl, arylheterocyclic ring, cycloalkylalkyl, heterocyclicalkyl, alkoxy, haloalkoxy, amino, Alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, alkoxyhaloalkyl, haloalkoxy, sulfonic acid, sulfonic esters, alkylsulfonic acid, arylsulfonic acid, arylalkoxy, alkylthio, arylthio, Cyano, aminoalkyl, aminoaryl, alkoxy, aryl, arylalkyl, carboxamido, alkylcarboxamido, arylcarboxamido, amidyl, carboxyl, carbamoyl, alkylcarboxylic acid, arylcarboxyl Acids, alkylcarbonyls, arylcarbonyls, esters, carboxyl esters, alkylcarboxyl esters, arylcarboxyl esters, haloalkoxy, sulfonamido, alkylsulfonamido, arylsulfonamido, alkyl Sulfonyl, alkylsulfonyloxy, arylsulfonyl, aryl sulfonyloxy, carbamoyl, a urea, a nitro, -TQ-, or _{(C (R e) (R} f)) k -TQ-, or R _e and R _{f is} all oxo, methaneial, heterocyclic ring, cycloalkyl group or bridged cycloalkyl group; Q is -NO or -NO ₂ ; And T is independently a covalent bond, carbonyl, acid, -S (O) _o -or -N (R _a ) R _i- , where o is an integer from 0-2 and R _a is an isolated pair of electrons, Hydrogen or an alkyl group; R _i is hydrogen, alkyl, aryl, alkylcarboxylic acid, arylcarboxylic acid, alkylcarboxyl ester, arylcarboxyl ester, alkylcarboxamido, arylcarboxamido, arylsulfinyl, arylsulfonyloxy, Arylsulfonyl, sulfonamido, carboxamido, carboxyl ester, aminoalkyl, aminoaryl, -CH ₂ -C (TQ) (R _e ) (R _f )), or-(N ₂ O ₂ −) ^- · M ^+, where M ⁺ is an organic or inorganic proton; "-TQ" is hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group.
[53" claim-type="Currently amended] 49. The method of claim 48, wherein at least one of donating, delivering or releasing nitric oxide, inducing the production of intrinsic nitric oxide or endothelium-derived relaxing factor, or is a substrate of nitric oxide synthase Compounds of L-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy -L-arginine, nitrosilicated N-hydroxy-L-arginine, citrulline, ornithine, glutamine or arginase inhibitor.
[54" claim-type="Currently amended] 49. The method of claim 48, wherein at least one of donating, delivering or releasing nitric oxide, inducing the production of intrinsic nitric oxide or endothelium-derived relaxing factor, or is a substrate of nitric oxide synthase The compound of:
(Iii) a compound comprising at least one ON-O-, ON-N- or 0N-C- group;
(Ii) compounds comprising at least one O ₂ NO—, O ₂ NN—, O ₂ NS—, or O ₂ NC— group;
(Iii) N-oxo-N-nitrosoamine represented by the formula R ¹ R ² -N (OM ⁺ ) -NO, wherein R ¹ and R ² are each independently a polypeptide, an amino acid, or a sugar (sugar) sugar), oligonucleotide, straight or branched chain, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or heterocyclic group, wherein M ⁺ is an organic or inorganic keion Composition.
[55" claim-type="Currently amended] 55. The compound of claim 54, wherein the compound comprising at least one ON-O-, ON-N- or 0N-C- group is ON-O-polypeptide, ON-N-polypeptide, 0N-C-polypeptide, ON-O- Amino acid, ON-N-amino acid, 0N-C-amino acid, ON-O-sugar, ON-N-sugar, 0N-C-sugar, ON-O-oligonucleotide, ON-N-oligonucleotide, 0N -C-oligonucleotides, straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON-O-hydrocarbons, straight or branched chain, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON-N-hydrocarbons, straight or branched chains, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic 0N-C-hydrocarbons, ON-O-heterocyclic compounds, ON-N-heterocyclic compounds or 0N -C-heterocyclic compound.
[56" claim-type="Currently amended] The compound of claim 54, wherein the compound comprising at least one O ₂ NO—, O ₂ NN—, O ₂ NS— or O ₂ NC— group is O ₂ NO-polypeptide, O ₂ NN-polypeptide, O ₂ NS-polypeptide , O ₂ NC-polypeptide, O ₂ NO-amino acid, O ₂ NN-amino acid, O ₂ NS-amino acid, O ₂ NC-amino acid, O ₂ NO-sugar, O ₂ NN-sugar, O ₂ NS-sugar, O ₂ NC-sugar, O ₂ NO-oligonucleotide, O ₂ NN-oligonucleotide, O ₂ NS-oligonucleotide, O ₂ NC-oligonucleotide, straight or branched chain, Saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O ₂ NO-hydrocarbons, straight or branched chain, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O ₂ NN-hydrocarbons, straight or branched chain, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O ₂ NS- hydrocarbon, linear or branched, saturated or unsaturated, aliphatic or aromatic, Hwandoen or wherein the unsubstituted hydrocarbon group O ₂ NC-, O ₂ NO- heterocyclic compounds, O ₂ NN- heterocyclic compounds, O ₂ NS- heterocyclic compound, a heterocyclic compound O ₂ NC- Composition.
[57" claim-type="Currently amended] 49. The composition of claim 48, further comprising at least one therapeutic agent.
[58" claim-type="Currently amended] 58. The method of claim 57, wherein the therapeutic agent is a steroid, a nonsteroidal anti-inflammatory compound, a 5-lipooxyginase inhibitor, a leukotriene B ₄ receptor antagonist, a leukotriene A ₄ hydrolase inhibitor, a 5-HT antagonist, 3 Hydroxy-3methylglutaryl coenzyme A inhibitor, H ₂ receptor antagonist, antineoplastic agent, antiplatelet agent, decongestant, diuretic, sedative and / or unstable ( sedating and / or non-sedating) antihistamines, inducible nitric oxide synthesis inhibitors (inducible nitric oxide synthase inhibitor), opioids (opioid), pain relievers (analgesic), Helicobacter pylori inhibitors (Helicobacter pylori inhibitor), a proton pump inhibitor, a device profile stain (isoprostane) inhibitors, or mixtures thereof
[59" claim-type="Currently amended] 58. A method of treating, preventing or reducing inflammation, pain or fever in a patient with inflammation, pain or fever, comprising administering to the patient a therapeutically effective amount of the composition of claim 48 or 57.
[60" claim-type="Currently amended] 58. A method of treating or preventing a gastrointestinal disorder in a patient or enhancing the gastrointestinal properties of a COX-2 inhibitor in a patient comprising administering to the patient a therapeutically effective amount of the composition of claim 48 or 57.
[61" claim-type="Currently amended] 61. The method of claim 60, wherein the gastrointestinal disease is inflammatory bowel disease, Crohn's diseas, gastritis, irritable bowel syndrom, ulcerative colitis, peptic ulcer. Stress ulcers, bleeding ulcers, gastric hyperacidity, indigestion, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, Bacterial infection, short-bowel (anastomosis) symptoms, or hypersecretory states associated with mastocytosis or basophilic rheumatoid and hyperhistaminemia How to feature.
[62" claim-type="Currently amended] 58. A method for facilitating wound healing comprising administering to the patient a therapeutically effective amount of the composition of claim 48 or 57.
[63" claim-type="Currently amended] 63. The method of claim 62, wherein the wound is an ulcer.
[64" claim-type="Currently amended] 58. A method of treating or reversing a patient's renal or other toxicity comprising administering to the patient a therapeutically effective amount of the composition of claim 48 or 57.
[65" claim-type="Currently amended] 58. A method of treating or preventing a disease resulting from increased levels of COX-2 in a patient, comprising administering to the patient a therapeutically effective amount of the composition of claims 48-57.
[66" claim-type="Currently amended] 66. The method of claim 65, wherein the disease resulting from increased levels of COX-2 comprises angiogenesis, arthritis, asthma, bronchitis, menstrual cramps, premature labor, tendinitis. ), Bursitis, skin-related conditions, neoplasia, inflammation in diseases, ophthalmic disorders, pulmonary inflammation, central nervous system disorders, allergic rhinitis (allergic rhinitis), respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis, inflammation and / or bacterial infection, cardiovascular disorders, urinary system and / or Urinary and / or urological disorders, endothelial dysfucntion, preservation of organs and tissues, inhibition and / or prevention of activity, adhesion and invasion of nucleotiles in the inflammatory site, or platelets Inhibiting and / or preventing platelet aggregation.
[67" claim-type="Currently amended] Donate, transfer, or release at least one parent COX-2 inhibitor and at least one nitric oxide, or an endogenous nitric oxide or endothelial inducer A kit comprising a compound or a pharmaceutically acceptable salt thereof which induces the production of a -derived relaxing factor or which is a substrate of nitric oxide synthase.
[68" claim-type="Currently amended] 68. The kit of claim 67, further comprising at least one therapeutic agent.
[69" claim-type="Currently amended] 67. The method of claim 67, wherein said parent COX-2 inhibitor and said nitrogen monoxide are donated, transferred or released, or an intrinsic nitric oxide or endothelial inducer alleviator. at least one compound that induces production of endothelium-derived relaxing factor, or is a substrate of nitric oxide synthase, is an isolated component in the kit.
[70" claim-type="Currently amended] 67. The method of claim 67, wherein said parent COX-2 inhibitor and said nitrogen monoxide are donated, transferred or released, or an intrinsic nitric oxide or endothelial inducer alleviator. at least one compound that induces the production of endothelium-derived relaxing factor or is a substrate of nitric oxide synthase in the form of a composition in a kit.

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US7166618B2|2007-01-23|

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EP1246621A4|2004-11-24|

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RU2002119574A|2004-01-10|

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:
1999-12-23|Priority to US17162399P

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1999-12-23|Priority to US60/171,623

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2000-08-18|Priority to US22608500P

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2000-08-18|Priority to US60/226,085

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2000-12-22|Application filed by 니트로메드 인코포레이티드

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2000-12-22|Priority to PCT/US2000/035014

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2002-08-22|Publication of KR20020067574A

优先权:

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申请号 | 申请日 | 专利标题

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US17162399P| true| 1999-12-23|1999-12-23|

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US60/171,623|1999-12-23|

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US22608500P| true| 2000-08-18|2000-08-18|

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US60/226,085|2000-08-18|

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PCT/US2000/035014|WO2001045703A1|1999-12-23|2000-12-22|Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use|