Reference

Preparation of N-aminoalkyl amides as agonists of the k opioid receptor useful against gastrointestinal disorders, pain, and pruritus

Dolle, Roland E.; Chu, Guo-Hua; Gu, Minghua (USA ). U.S. Pat. Appl. Publ. US 2005107355 A1 19 May 2005,46 pp. (English). (United States of America). CODEN: USXXCO. CLASS: ICM: A61K031-397. ICS: A61K031-445; A61K031-40; A61K031-165. APPLICATION: US 2003-713746 14 Nov 2003. DOCUMENT TYPE: Patent CA Section: 27 (Heterocyclic Compounds (One Hetero Atom)) Section cross-reference(s): 1, 63 Amide derivs. (shown as I and II; variables defined below; e.g. N-[2-((S)-3-hydroxypyrrolidin-1-yl)-(S)-1-phenylethyl]-N-methyl-2-phenyla minoacetamide (shown as III)) are disclosed. Pharmaceutical compns. contg. these compds., and methods for their use, inter alia, for treating and/or preventing gastrointestinal disorders, pain, and pruritus (no data) are also disclosed. Although the methods of prepn. are not claimed, 36 example prepns. are included. For example, III was prepd. (45 %) by coupling of N-phenylglycine with N-[2-((S)-3-hydroxypyrrolidin-1-yl)-(S)-1-phenylethyl]-N-methylamine dihydrochloride. For I and II: R1 is H or OH; Ra is alkyl; R2 is alkyl, aryl, or aralkyl; R3 is alkyl, or R2 and R3 taken together with the atoms through which they are connected form a 4- to 8-membered heterocyclic ring; R4 is H, alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl; Z is -(CH2)oNR5R6 or -(CH2)oC(:O)NR7R8; R5 is H, alkyl, or aryl; R6 is aryl, alkaryl, -CO(NH)pR9, or -SO2R9, provided that at least one of R5 and R6 is other than aryl; R7 is H or alkyl; R8 is alkyl, aryl, aralkyl, alkaryl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl; R9 is alkyl, cycloalkyl, alkylcycloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl; m is the integer 1, 2, or 3; n is the integer 1, 2, or 3; o is the integer 0, 1, 2, or 3; p is the integer 0 or 1; and the quantity (m+n) is an integer 2-5. Compds. in all the examples showed k receptor affinity (K1) <10 mM. For example, III had a Ki = 0.17 nM against the human k receptor with >100′ selectivity vs. the human m and d receptors and was an agonist with an EC50 = 0.05 nM. It exhibited a % A = 96.2% at a dose of 300 mg, i.paw in the in vivo formalin-induced nociception assay. This compd. also blocked the action of HOAc-induced writhing when administered s.c. with an ED50 = 0.017 mg/kg. Keywords aminoalkyl carboxamide prepn kappa opioid receptor agonist therapeutic use nitrogen heterocycle aminoalkyl carboxamide prepn kappa opioid receptor agonist Index Entries Amides, preparation N-aminoalkyl, drug candidate; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Allergy allergic dermatitis; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Dermatitis allergic; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Allergy atopy; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Edema cerebral; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Dermatitis contact; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Anesthetics Anti-inflammatory agents Antibacterial agents Antiviral agents Fungicides Opioids drug candidates and codrugs; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Brain, disease edema; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Intestine, disease ileus; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Skin, disease insect bite; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Blood-brain barrier not crossed by drug candidates; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Allergy inhibitors Analgesics Antitussives Combination chemotherapy Cough Digestive tract, disease Diuretics Drug delivery systems Eczema Human Pain Pruritus Psoriasis prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus Opioid receptors k-opioid, in central nervous system, agonists; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus 57-27-2, biological studies 57-42-1 76-41-5 76-42-6 76-57-3 76-99-3 77-07-6 125-28-0 125-29-1 359-83-1 437-38-7 466-99-9 469-62-5 15686-91-6 20594-83-6 27203-92-5 42408-82-2 52485-79-7 53648-55-8 56030-54-7 71195-58-9 codrug; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus 851679-94-2 851679-95-3 851679-96-4 851679-98-6 851679-99-7 851680-00-7 851680-01-8 851680-03-0 851680-08-5 851680-15-4 851680-16-5 851680-17-6 851680-19-8 851680-20-1 851680-21-2 851680-22-3 851680-26-7 851680-28-9 851680-29-0 851680-30-3 851680-31-4 851680-34-7 851680-38-1 851680-40-5 851680-43-8 851680-46-1 851680-47-2 851680-48-3 851680-51-8 851680-52-9 851680-53-0 851680-54-1 851680-55-2 851680-57-4 851680-58-5 851680-59-6 851680-60-9 drug candidate; prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus 62-53-3, reactions 96-50-4 100-01-6, reactions 100-46-9, reactions 103-01-5 103-71-9, reactions 108-30-5, reactions 109-83-1 123-75-1, reactions 462-08-8 873-74-5 1694-92-4 1885-29-6 2237-30-1 2445-85-4 3153-37-5 5680-79-5 10147-36-1 14108-81-7 32807-28-6 37517-81-0 40204-26-0 53990-33-3 64377-71-5 91192-27-7 136780-20-6 142773-73-7 171056-73-8 207847-96-9 672951-66-5 102-14-7 103-40-2 579-98-6 619-91-0 2327-84-6 3016-39-5 5430-83-1 15580-32-2 19692-00-3 20059-60-3 21911-75-1 23284-84-6 25604-13-1 42288-26-6 58199-15-8 66825-16-9 67045-01-6 69479-87-4 76311-94-9 77311-21-8 78096-15-8 90544-88-0 104892-36-6 152085-47-7 163460-75-1 325168-04-5 327069-81-8 328011-26-3 329205-47-2 591234-88-7 773844-67-0 851679-97-5 851680-04-1 851680-10-9 851680-12-1 851680-13-2 851680-14-3 851680-18-7 851680-23-4 851680-24-5 851680-25-6 851680-27-8 851680-32-5 851680-33-6 851680-35-8 851680-36-9 851680-37-0 851680-39-2 851680-41-6 851680-42-7 851680-44-9 851680-45-0 851680-49-4 851680-50-7 851680-56-3 prepn. of N-aminoalkyl amides as agonists of k opioid receptor useful against gastrointestinal disorders, pain, and pruritus

Comparison of the metabolism of 5,6-dihydro-2-methyl-N-phenyl-1,4-oxathiin-3-carboxamide (carboxin) in peanut plants and peanut cell suspension cultures

Comparison of the metabolism of 5,6-dihydro-2-methyl-N-phenyl-1,4-oxathiin-3-carboxamide (carboxin) in peanut plants and peanut cell suspension cultures. Larson, John D.; Lamoureux, Gerald L. (Metab. Radiat. Res. Lab., Agric. Res. Serv., Fargo, ND 58105, USA). J. Agric. Food Chem., 32(3), 177-82 (English) 1984. CODEN: JAFCAU. ISSN: 0021-8561. DOCUMENT TYPE: Journal CA Section: 5 (Agrochemical Bioregulators) The metab. of carboxin (I) [5234-68-4] in seeds from peanut (Arachis hypogaea) was studied and compared to I metab. in peanut suspension cultures. The following metabolites were identified from both sources by chromatog. and mass spectral properties: carboxin sulfoxide [17757-70-9], carboxin sulfone [5259-88-1], malonanilic acid, p-hydroxymalonanilic acid b-D-O-glucoside [88412-31-1], and 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid glucose ester [88412-32-2]. Oxidn. of S and hydrolysis of the carboxamide bond appeared to be the initial metabolic reactions in peanut seeds and cultures. The major difference in metab. between the 2 systems appeared to be incorporation of 14C into the bound residue. Whereas 2.7% of the applied radioactivity was recovered in the bound residue from cultures, 20.7% of the recovered 14C was found in this fraction in seeds. 88412-31-1 and 17757-70-9 are just another two chemicals used in this study. A malonyl transferase [37257-17-3] that catalyzed the formation of malonanilic acid [15580-32-2] from aniline [62-53-3] and malonyl-CoA [524-14-1] was detected in cell-free exts. from cultures. .