WO1996021662A1 - Utilisation de composes heterocycliques comme antioxydants, piegeurs de radicaux, agents de complexation de fe2+, protecteurs tissulaires et/ou neuroprotecteurs - Google Patents

Utilisation de composes heterocycliques comme antioxydants, piegeurs de radicaux, agents de complexation de fe2+, protecteurs tissulaires et/ou neuroprotecteurs Download PDF

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WO1996021662A1
WO1996021662A1 PCT/SE1996/000007 SE9600007W WO9621662A1 WO 1996021662 A1 WO1996021662 A1 WO 1996021662A1 SE 9600007 W SE9600007 W SE 9600007W WO 9621662 A1 WO9621662 A1 WO 9621662A1
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Prior art keywords
ring
group
mmol
methyl
pharmaceutical composition
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PCT/SE1996/000007
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English (en)
Inventor
Frode Rise
Håkan WIKSTRÖM
Sigurd Ugland
Durk Dijkstra
Lise-Lotte Gundersen
Peter De Boer
Aalt Bast
Guido Haenen
Öyvind Gunnar ANTONSEN
Yi Liao
Achmad Izuddin Nasir
Original Assignee
Frode Rise
Wikstroem Haakan
Sigurd Ugland
Durk Dijkstra
Gundersen Lise Lotte
Peter De Boer
Aalt Bast
Guido Haenen
Antonsen Oeyvind Gunnar
Yi Liao
Achmad Izuddin Nasir
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Application filed by Frode Rise, Wikstroem Haakan, Sigurd Ugland, Durk Dijkstra, Gundersen Lise Lotte, Peter De Boer, Aalt Bast, Guido Haenen, Antonsen Oeyvind Gunnar, Yi Liao, Achmad Izuddin Nasir filed Critical Frode Rise
Priority to AU44614/96A priority Critical patent/AU4461496A/en
Publication of WO1996021662A1 publication Critical patent/WO1996021662A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the precent invention relates to the use of new and/or known compounds of a specific heterocyclic formula structure for the manufacture of a pharmaceutical composition having the effect of an antioxidant, radical scavenger, Fe 2+ complexing agent, tissue- and/or neuroprotectants, to new heterocyclic compounds having such effect and pharmaceutical compositions comprising such a compound, and to a method for the prevention or treatment of diseases in mammals, including man, caused by oxidative stress.
  • the present invention is based on the finding that certain compounds comprising a specific heterocyclic formula structure have the property, in some cases after bioactivation of their precursors (for instance compounds of Formula IV) , which are also included in this invention, (e.g. hydrolysis by esterases or other enzymes in the gut and/or intestinal wall, in the liver or in plasma, in the brain/central nervous system or any other target organ) , of being easily oxidized to a persistent free radical, while at the same time detoxifying endogenous radicals.
  • An alternative mode of action, among others, by which the compounds contemplated for use according to this invention may exert their action is by detoxifying non beneficial radicals prior to eventual hydrolysis. Still another mode of action may be as electron acceptors in electron transfer reactions involved in beneficial radical scavenging reactions. Fe 2+ complexation is another possible mode of action of the claimed compounds.
  • Topical ophthalmic compositions comprising a combination of calcium antagonists with known antiglauco a agents. Desantis, Louis, Jr. PCT Int. Appl., 20 PP. WO 9323082 Al 931125 .
  • Fantofarone (SR33557) : effects on myocardial oxygen consumption and coronary blood flow. Hodeige, D. ;
  • Hassle AB and others Other known compounds have been published in patents and publications from Hassle AB and others; Benzimidazoles for alleviating stomach ulcers in swine. Baile, C. A. ;
  • Timoprazole is a unique cytoprotective agent in the rat. Ruwart, M. J.; Nezamis, J . E. ; Rush, B. D. ; Lancaster, C. ; Davis, J. P.; Nichols, N. M.; Ochoa, R. Digestion 1984 30(1) 33-40. Effect of substituted benzimidazoles on acid secretion in isolated and enriched guinea pig parietal cells. Sewing, K. F. ; Harms, P.; Schulz, G. ; Hannemann, H. Gut 1983 24(6) 557- 60.
  • Benzimidazole derivatives for the treatment of intestinal disorders.
  • Aktiebolag Hassle, Swed. Jpn. Kokai Tokkyo Koho, 10 pp. JP 61205211 A2 860911 Showa. Substituted pyrido[l' ,2' :3 ,4] imidazo[1,2-a]benzimidazoles, their use and pharmaceutical preparations from these compounds.
  • Hitzel, V.; Rackur, G.; Bickel, M. Ger. Offen. 34 pp. DE 3333314 Al 850328 .
  • the molecules of the invention are cyclic ⁇ -systems which contain as a basic structural element the structure in Formula I.
  • X is a member selected from the 20 group consisting of O, S, Se, Te, SO, S0 2 , SeO, Se0 2 , TeO, Te0 2 ;
  • R represents a hydrogen atom, a deuterium atom or, when X is 0, S, Se or Te, a group C(0)R 8 , COOR 8 or CONR 9 R 10 ,
  • R 8 is selected from the group consisting of (C--Cg)alkyl, (C j -Cg)halogenalkyl, (C 2 -Cg)alkenyl, (C 2 -Cg)alkynyl, (C-J-CJ Q )cycloalkyl, (C4-C9)cycloalkylmethyl, alkylaryl, aralkyl, aryl, alkylheteroaryl and heteroarylalkyl; and
  • R" and R which are equal or different, each represents a hydrogen atom or R°, wherein R° is as defined above; or
  • X and R together form a group SR 8 , SOR 8 , S0 2 R 8 , OS0 2 R 8 ,
  • X is as defined above, X' is a member selected from the group consisting of O, S, Se and Te,
  • R' is Ac or R as defined above, which compound can carry a substituent at any or all posi ⁇ tions, said substituent being independently selected from (C,-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -
  • antioxidants include the known compound pyridofl' , 2 ' :3 ,4]- imidazo[l,2-a]benzimidazol-12-thiol, dimers of pyrido- [1' ,2' :3,4]imidazo[1,2-a]benzimidazol-12-thiol and analogs where sulfur is substituted with oxygen, selenium or tellurium, or more generally molecules of Formulas II and III and substituted derivatives thereof.
  • X is as defined above; Y and Z, which are equal or different, each represents N or
  • Ri and R 2 which are equal or different, are each selected from the group consisting of H, (C j -Cg)alkyl, (C 2 -
  • R 10 CONR 9 R 10 .
  • R3 is selected from the group consisting of hydrogen, deuterium, (C j -Cg)alkoxy, CN, CHO, C(0)R 8 , COOH and salts, esters and amides thereof or R3 represents an electron pair when Z is N;
  • R 4 is equal to R j , R 2 , R3, R5 or Rg, preferably H;
  • R5 and Rg which are equal or different, are each selected from unsubstituted or substituted aryl or heteroaryl groups, (C j -C j g)alkyl, (C--C j g)O-alkyl, O-aryl, (C j -C j g)S- alkyl and S-aryl;
  • R 7 represents a group COR , COOR 8 or CONR 9 R , when X is 0,
  • R , R , R 12 and R 13 are as defined above; or R j and R 2 together with the intervening atoms of the 6- membered ring form a 5- or 6-membered aromatic or heteroaromatic ring; or
  • R and R3 together with the intervening atoms of the 6- membered ring form a 5- or 6-membered aromatic or heteroaromatic ring;
  • R3 and R 4 together with the intervening atoms of the 6- membered ring form a 5- or 6-membered aromatic or heteromatic ring;
  • R4 and R5 together with the intervening 3 atoms of the fused ring system form a 5- or 6-membered aromatic or heteroaromatic ring;
  • R5 and Rg together with the intervening atoms of the 5-mem- bered ring form a 5- or 6-membered aromatic or heteromatic ring.
  • R is preferably an electronwithdrawing group (EWG) for the indolizinols ((Y) and (Z) equals C) , and may or may not preferably be an EWG or an electrondonating group (EDG) or a hydrogen atom for the various azaindolizinols.
  • EWG electronwithdrawing group
  • XR 7 is SRg, SORg, S0 2 8) , where Rg is defined as above;
  • XR 7 is Si(R JRJ 2 RJ ) , where RJJ, R 2 and R 1 are as defined above;
  • EWGs for substitution of either the protected alcohol/phenol or the deprotected molecule - nitrile, sulphonate, sulfoxide, sulfone, sulfonamide and salts thereof and, more preferably, carboxyl groups (and esters, amides and salts thereof) are especially preferred within any one aryl ring, however, generally only one, or at most two, such EWGs will be desired. At least one EWG substituent are preferred in the indolizine series.
  • EDGs electron donor groups
  • a preferred group of compounds to be used according to the invention comprises compounds of formulas IV and V wherein
  • X is 0; one or both of Y and Z is C;
  • R j and R3 when being bound to Y and Z, respectively, rep- resenting C, represent hydrogen
  • R 2 is hydrogen, CN, CHO, C(0)R 8 or COOR 8 , wherein R° is as defined above;
  • R4 is hydrogen
  • R5 and Rg are each phenyl and (in case of Formula IV) R ⁇ represents a group COR , wherein R 8 is as defined above.
  • X, Y, Z, R j , R 2 , R3 and R4 are as defined above and
  • R' 7 is H or R 7 as defined above, or
  • X and R' 7 together form a group SR 8 , SOR 8 , S0 2 R 8 , OSi(R n R 12 R 13 ) , OR 8 , SR 8 , SeR 8 or TeR 8 ,
  • Ph is phenyl
  • R j and R 2 together with the intervening atoms of the 6- membered ring form a 5- or 6-membered aromatic or hetero ⁇ aromatic ring;
  • R j and R 4 together with the intervening atoms of the 6- membered ring form a 5- or 6-membered aromatic or hetero ⁇ aromatic ring; or R 3 and R 4 together with the intervening atoms of the 6- membered ring form a 5- or 6-membered aromatic or heteromatic ring;
  • X and R' 7 together form a group SR 8 , SOR 8 , S0 2 R 8 , OSi(R U R 12 R 13 ) , OR 8 , SR 8 , SeR 8 or TeR 8 , wherein R 8 , R 11 , R 12 are as defined above, Ph is phenyl, or
  • R and R together with the intervening atoms of the 6- membered ring form a 5- or 6-membered aromatic or hetero- aromatic ring;
  • R j and R 4 together with the intervening atoms of the 6- membered ring form a 5- or 6-membered aromatic or hetero ⁇ aromatic ring;
  • R 2 and R 4 together with the intervening atoms of the 6- membered ring form a 5- or 6-membered aromatic or hetero ⁇ matic ring.
  • Preferred compounds may exhibit profound therapeutic antioxidant, tissue- and/or neuroprotective effects in any of the following non limiting organs and for instance against the following non limiting disease factors/diseases/disorders, which may be associated oxidative stress: Lung: bronchopulmonary dysplasia, asbestosis, silicosis, cigarette smoke, idiopathic pulmonary fibrosis, cystic fibrosis, ARDS, asthma, COPD, inhaled oxidants (N0 ⁇ , O3) .
  • Brain hyperbaric oxygen, Parkinson's disease, Alzheimer's disease, neurotoxins (for instance, aluminum, MPTP, 6-hydroxydopamine) , vitamine E deficiency, stroke, intracranial hemorrhage, subarachnoidal hemorrhage, braintrauma, cerebral malaria, cerebral trpanosomiasis, ALS, neuronal ceroid lipofuscinoses.
  • Kidney autoimmune nephrosis (inflammation) , chemicals (aminoglycosides, heavy metals, cis-Platin) , kidney transplantation (tissue protection) .
  • Cardiovascular system heart infarction, heart stop, reperfusion damage, heart transplantation (tissue protection) .
  • Gastrointenstinal system inflammatory bowel disease, reperfusion damage, chemicals (nonsteroidal antiinflammatory agents, ions) , emesis.
  • Liver liver cirrhosis, chemicals (halogenated hydrocarbons, iron, paracetamol, ethanol, quinones) , endotoxin, reperfusion damage, liver transplantation (tissue protection) .
  • Blood thalassemia, anemia (sickle cell, favism, Fanconi's) , chemicals (phenylhydrazine, sulfonamides, lead, primaquine) , malaria, protoporphyrine photooxidation.
  • Eye cataractogenesis, ocular hemorrhage, photochemical retiopathy, retrolental fibroplasia.
  • Muscle multiple sclerosis, muscular dystrophy, exercise.
  • Skin radiation (ionizing, solar), thermal injury, chemicals (i. e. tetracyclines) , contact dermatitis, porphyria, photodynamic therapy, psoriasis, skin rashes.
  • Miscellaneous ageing, radiation injury, inflammation in general, rheumatoid arthritis, chemicals (alloxan, radiosensitizers) , alcoholism, nutritional deficiencies (Kwashiorkor) .
  • steric hindrance of neighboring ring sites in order to enhance low reactivity of the byproducts (azaindoliziyls or indolizinyls) produced during the beneficial reactions, is preferably effected by substitution with bulky substituents such as for instance t-butylthio, t-butoxy or t-butyl substituents.
  • any alkyl or alkenyl moiety conveniently will contain up to 6, especially up to 4, carbon atoms and any aryl moiety will preferably contain 5 to 7 ring atoms in the ring or any aromatic ring and especially preferably will comprise an aromatic ring with 0, 1 or 2 further aromatic rings fused directly or indirectly thereto.
  • Preferred indolizine compounds include those wherein R is an EWG, especially a cyano, a formyl or keto functionality, an ester or amide or a carboxylic acid group or a salt thereof.
  • Preferred azaindolizine compounds do include those wherein R 2 is hydrogen.
  • R j hydrogen, alkoxy and carboxylic acid and salts, esters and amides thereof for R 2 : cyano, formyl, keto, carboxylic acid and salts, esters and amides thereof for R : hydrogen, alkoxy and carboxylic acid and salts, esters and amides thereof for R 4 : hydrogen and, in case of compounds of Formulas IV and V, for R j and R and intervening atoms in the 6-membered ring together: a 5- or 6-membered aromatic or hereoaromatic ring; for R and R3 and intervening atoms in the 6-membered ring together: a 5- or 6-membered aromatic or heteroaromatic ring; for R3 and R4 and intervening atoms in the 6-membered ring together: a 5- or 6-membered aromatic- or heteroaromatic ring; for R 4 and R5 and the intervening 3 atoms a 5- or 6- membered aromatic- or heteroaromatic ring which may or may not
  • Cyclic ⁇ t-system indolizines, indolizinols and the protected forms of the indolizinols are widely known from the literature and those suitable for use according to the invention may be prepared by the methods described in the literature. Substitution along the lines discussed above may be achieved using methods known from the literature or by using methods analogous to those discussed in
  • Photographic elements capable of providing oxoindolizine and oxoindolizinium dye compounds Eur . Pat . Appl . 1981 EP 68880 Al 830105. Inion, H. ; Rosseels, G. Indolizine derivatives, their salts, their pharmaceutical or veterinary compositions and method for treating pathological syndromes. Braz . Pedido 1979 PI 810609. Rosseels, G. ; Nokin, P. Indolizine derivatives and their therapeutic use. Eur . Pat . Appl . 1979 EP 22762 810121. Pohjala, E. K. Indolizine derivatives. Part XI.
  • Indolizines from the acylative cyclization of 3-(2-pyridyl)-2-propen-l-ones and related compounds Acta Chem . Scand. , B 30 (6) 1976 512-516. Pohjala, E. Indolizine derivatives.
  • III Cyclization of the aldol product of 2-pyridinecarbaldehyde and .beta.-dimethylamino (or .beta.-hydroxy) ketones.
  • the claimed compounds and the known compounds may themselves may be prepared by methods conventional in the art or analogous to those described in EPA 84402207.9, US 4,446,223, EPA 82303386.5, Tet . Lett . 1981 (22) 3569-3572, J. Org. Chem . 1986 (51) 4639-4644, J . Org . Chem . 1989 (54) 3652-3660, J . Org. Chem . 1989 (54) 3660-3664 and J. Org . Chem . 1991 (56) 5594-5598, WO 9302710, WO 92-EP1792, WO 9302711, WO 92-EP1793.
  • the indolizinols and the azaindolizinols may themselves be prepared by methods conventional in the art.
  • a suitable cyclopropenone is conveniently reacted with an appropriately substituted pyridine, pyrimidine or triazine, following for example the procedures described by Wadsworth et al. in ret. Lett . 1981 (22) 3569-3572 and J. Org. Chem . 1986 (51) 4639-4644, J. Org . Chem . 1989 (54), 3652-3660 J. Org. Chem . 1989 (54) 3660-3664, and J. Org . Chem . 1991 (56) 5594-5598.
  • the protected indolizinols and the protected azaindolizinols may themselves be prepared by methods conventional in the art.
  • a protected (aza)indolizinol a suitable cyclopropenone is conveniently reacted with an appropriately substituted pyridine, pyrimidine or triazine, and thereafter the OH functionality is protected as for instance an actetate, following for example the procedures described by Wadsworth et al. in Tet. Lett.
  • Hydrogenated indolizines for instance indolizinyl alkaloids like castanospermine or similar substances also represent useful reagents in the synthesis of the indolizinols. These hydrogenated substances can potentially be dehydrogenated and/or dehydrated to the indolizinols. See for instance: J.A.C.S. 1990, 8100; Tet. Lett. 1990 5689; Tet. Lett. 1990 7109; Tet. Lett. 1990 6949, Barton, D. H. R. et al. Tet. Lett. 1994 (35) 9157- 9158, Gurjar, M. K. et al. Tet. Lett. 1994 (35) 8871-8872. Martin-Lopez_ M. J. et al. Tet. Lett. 1994 (35) 8843-8846.
  • novel compounds of Formula IV wherein one of Y and Z is C and the other is N;
  • R is hydrogen, when Y is C, and an electron pair, when Y is N;
  • R 5 and Rg are each phenyl; and X and R together form a group OSi(R 11 R 12 R 13 ) , wherein R 11 ,
  • R ⁇ and R* 3 are as defined above in connection with Formula
  • compositions comprising said compounds together with a pharmaceutically acceptable carrier and the use of said compounds for the manufacture of a pharmaceutical composition having the effect of an antioxidant, radical scavenger, Fe 2 -complexing agent, tissue and/or neuroprotectant.
  • a method for the treatment of diseases in mammals comprising administering to said mammal of an effective dose of a compound of any of Formulas I to VII as defined above.
  • An example of application of the method according to the invention is the administration of the compound for the purpose of neuroprotection and for the prevention or treatment of stroke or a neurodegenerative disease.
  • Examples of neurodegenerative diseases to be prevented or treated are Alzheimer's disease and Parkinson's disease.
  • the compounds according to the invention can be formulated into pharmaceutical composition in any conventional way for the preparation of such compositions.
  • Formulation aids such as are conventional for therapeutic and diagnostic compositions in human or veterinary medicine.
  • the media may for example include solubilizing agents, emulsifiers, viscosity enhancers, buffers, etc.
  • the media may be in forms suitable for parenteral (e.g. intravenous) or enteral (e.g. oral) application. Solutions, suspensions and dispersions in physiologically tolerable media will generally be preferred.
  • Compounds of Formulas I-VII may be encapsulated, e.g. in gastric juice resistant capsules containing a medium in which they are stable, alternatively, the compounds may be presented as an encapsulated freeze dried powder in a soluble capsule. Such formulations might conveniently be dissolved shortly before in vivo use.
  • Diphenylcyclopropenone (Aldrich 17,737-7) (0.500 g, 2.42 x rt . . . . 10 "J mol) and isonicotinic acid (Aldrich 1-1,750-8) (0.2985 g 2.424 x 10 "J mol) were added in solid form to a carefully dried reaction flask.
  • the flask was equipped with a septum and the flask was evacuated three times with addition of nitrogen after each evacuation.
  • Chlorobenzene (Aldrich 27,064-4) (5 mL) was added with a gas tight syringe. The stirred mixture was cooled to 0 * C.
  • Triethylamine (Aldrich 23,962-3) (0.3379 mL, 2.42 x 10 "3 mol) was added dropwise with a gas tight syringe. The resulting mixture was stirred at ambient temperature for 2 days. The color of the mixture changed to yellow and then to green. The solvent was removed on a rotary evaporator, and the resulting semisolid was redissolved in hot ethanol and water. After cooling to ambient temperature, the product was filtered and washed with diethylether and dried in vacuum. All these operations were performed under an atmosphere of N 2 .
  • the reaction mixture was stirred at ambient temperature for 2.5 hours, while the title compound precipitated.
  • the mixture was cooled to about 0 'C and the product isolated by filtration under N 2 .
  • the product was washed with minute amounts of methanol and some diethyl ether and dried.
  • the product was identified by mass spectrometry; DCI probe and electron impact conditions identified the heterocyclic part and *H NMR identified the ammonium part.
  • the yellow/green (indolizinoleeee/indolizinyl) product was filtered under N2 and washed with small amounts of tetrahydrofuran and petrol ether. More solids formed in the filtration flask and were also collected. The products were identified as the title compound based on mass spectrometry.
  • 3,4-Pyridinedicarboxylic acid (0.4051 g, 2.424 10 "3 mol) , diphenylcyclopropenone (0.500 g, 2.424 x 10 "3 mol) and N- methylglucamine (0.9404 g, 4.848 x 10 " -* mol) were stirred in a mixture of tetrahydrofuran (10 mL, degassed with helium) and methanol (3 mL, degassed with helium) at ambient temperature for 24 hours. The solvent was removed and the product triturated with diethyl ether and methanol and dried.
  • Diphenylcyclopropenone (0.319 g, 1.55 mmol) and 3,4- dicyanopyridine (0.200 g, 1.55 mmol) were mixed in a dry, argon filled reaction flask. Chlorobenzene (2.5 mL) (oxygen free) was added, and the reaction was heated to 130 "C. After 2 h the heating was stopped and the reaction was allowed to reach room temperature.
  • Petroleum ether 40-60 * C (2.5 mL) was added in order to obtain a complete precipitate of the product. The solvent was filtered off and the precipitate was washed with petroleum ether. The crude product was stirred with chloroform (30 mL) for 1 h. The dark chloroform solution was filtered off leaving the title product as a yellow precipitate.
  • 1,1'-(2,2' ,3,3'-tetra-t-butylthio-6,6' ⁇ '-tetracyano- diindoli zine)-disulfide is treated with a reducing agent in an appropriate solvent until all disulfide is consumed.
  • the reaction is stopped and the product is isolated by chromatography or recrystallization, or by a combination thereof.
  • l,l'-(2,2',3,3-tetra-t-butylthio-7,7' ,8,8'-tetracyano- diindoliz ine)-disulfide is treated with a reducing agent in an appropriate solvent until all disulfide is consumed.
  • the reaction is stopped and the product is isolated by chromatography or recrystallization, or by a combination thereof.
  • Bis(t-butylthio)cyclopropenethione and pyridine-3,4- dicarboxylic acid are mixed in a dried, argon filled reaction flask. A dry degassed solvent is added. To the mixture is added triethylamine. The reaction is stirred until no more product is obtained. The product is isolated either by chromatography or by recrystallization, or by a combination thereof.
  • EXAMPLE 14 l-Mercapto-2 ,3-di-t-butylthio-6,7-di(trie hyla monium- carboxyla te) indolizine.
  • Bis(t-butylthio)cyclopropenethione and pyridine 3,4- dicarboxylic acid are mixed in a dried, argon filled reaction flask. A dry degassed solvent is added. To the mixture is added triethylamine. The reaction is stirred until no more product is obtained. The product is isolated either by chromatography or by recrystallization, or by a combination thereof.
  • 1,2-Di-tert-butoxycyclobutenedione is dissolved in diethyl ether and photolyzed under nitrogen by a mercury high pressure lamp through quartz glass for 2-8 h depending on the quality of the mercury lamp.
  • the title compound produced is purified by HPLC-RP, recrystallization or by distillation at low pressure, or by a combination of this techniques. (See E. V. Dehmlow Chem. Ber. 121, 569, 1988).
  • 2,3-Di-tert-butoxycyclopropenone and 3,4-dicyanopyridine are mixed in a dry, argon filled flask.
  • a solvent such as chlorobenzene (oxygen free) is used.
  • the product is purified by chromatography or recrystallization, or by a combination of these techniques.
  • 1,2-Di-tert-butoxycyclobutenedione is dissolved in diethyl ether and photolyzed under nitrogen by a mercury high pressure lamp through quartz glass for 2-8 h depending on the quality of the mercury lamp.
  • the title compound produced is purified by HPLC-RP, recrystallization or by distillation at low pressure, or by a combination of this techniques. (See E. V. Dehmlow Chem. Ber. 121, 569, 1988).
  • 2,3-Di-tert-butoxycyclopropenone and 3,4-dicyanopyridine are mixed in a dry, argon filled flask.
  • a solvent such as chlorobenzene (oxygen free) is used.
  • the product is purified by chromatography or recrystallization, or by a combination of these techniques.
  • the mixture was stirred for 1 h at 0 * C, then 15 min at ambient temperature.
  • the mixture was then diluted with chloroform until 100 mL total volume and washed with saturated aqueous copper sulfate (4 x 30 mL) and sat. aq.
  • Example 38 The compound obtained in Example 38 (80 mg, 0.34 mmol) was dissolved in CH 2 C1 (8 mL) and the solution was degassed with N 2 (g) and then cooled to 0°C. (CF3S0 2 ) 2 0 (0.2 mL) was added and then Et3N (0.1 mL) .
  • the solvents of reaction mixture were evaporated under reduced pressure and the residue was redissolved in CH 2 C1 2 and Si0 2 gel was added to the flask and the solvent was evaporated under reduced pressure to leave the raw product evenly distributed on the Si0 2 particles, which were applied at the top of a dry packed Si0 2 column. Elution with hexane:EtOAc (4:1) gave fractions with pure product. These fractions were collected, the solvent was evaporated under reduced pressure to leave a white solid (59 mg) , melting at 132- 133°C.
  • Example 38 To the compound obtained in Example 38 (50 mg, 0.21 mmol) was added CH 2 C1 2 (3 mL) and then Et N (2 drops) and the solution was degassed with N (g) and then cooled to 0°C. pH-N(CF3S0 2 ) 2 (100 mg, 0.31 mmol) was added. The reaction mixture was stirred at room temperature overnight.
  • Example 38 The compound obtained in Example 38 (23.7 mg, 0.100 mmol) was dissolved in THF (5 mL) and one drop of Et 3 N and methanesulfonyl chloride (7.7 ⁇ L, 0.1 mmol) were added. The reaction mixture was stirred for 2 h in room temperature and then quenched with the addition of 10% NaOH and extracting with EtOAc.
  • Example 38 The compound obtained in Example 38 (23.7 mg, 0.100 mmol) was dissolved in THF (5 mL) and one drop of Et 3 N and methanesulfonyl chloride (7.7 ⁇ L, 0.1 mmol) were added. The reaction mixture was stirred for 2 h at room temperature and then quenched with the addition of 10% NaOH and extracting with EtOAc.
  • Example 45 1-Methanesulfonyloxy-2,3-di-phenyl-7-cyanoindolizine was synthesized according to the synthesis of Example 45, using methanesulfonylchloride as the sulfonating agent. According to GC-MS all starting material was consumed and a new spot
  • the compounds according to in the present invention are stable structures which form cations, stable cation radicals or stable radicals upon oxidation. They constitute potent antioxidants as measured by inhibition of Fe 2+ - ascorbate induced lipid peroxidation in vitro. These properties suggest that the. compounds of the invention have a potential use in the protection or treatment of ischemic or reperfusion injury, particularly cerebral and cardiac ischemia/infarct, atherosclerosis, thrombosis, embolism,
  • Parkinson's disease ageing. Alzheiner's disease, neoplasms and toxicity of anti-neoplastic drugs, immunosuppresive agents and inflammation including allergic-inflammatory conditions like bronchial asthma and rheumatoid arthritis. Other potential applications are chemoprevention against chemical toxicity or radiation damage.
  • the compounds are not appreciably activated by UV light making them candidates for use in skin care products.
  • the most remarkable feature of the compounds of the invention is their efficacy as free-radical scavengers or antioxidants.
  • An assay system measuring the concentration of the compounds of formula I required to inhibit lipid peroxidation by 50% (IC 50 ) was used.

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Abstract

L'invention concerne la nouvelle utilisation de composés de formule (I), dans laquelle X représente un élément choisi dans le groupe constitué de O, S, Se, Te, SO, SO2, SeO, SeO2, TeO, TeO2; cette nouvelle utilisation est destinée à la fabrication d'une composition pharmaceutique ayant l'effet d'un antioxydant, d'un piégeur de radicaux, d'un agent de complexation de Fe2+, et de protecteur tissulaire et/ou de neuroprotecteur. L'invention porte également sur des nouveaux composés englobés par la formule (I) et des compositions pharmaceutiques les contenant, ainsi qu'une méthode de prévention ou de traitement de maladies induites par le stress oxydatif.
PCT/SE1996/000007 1995-01-09 1996-01-09 Utilisation de composes heterocycliques comme antioxydants, piegeurs de radicaux, agents de complexation de fe2+, protecteurs tissulaires et/ou neuroprotecteurs WO1996021662A1 (fr)

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AU44614/96A AU4461496A (en) 1995-01-09 1996-01-09 The use of heterocyclic compounds as antioxidants, radical scavengers, fe2+ complexing agents, tissue- and/or neuroprotectants

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SE9500051A SE9500051D0 (sv) 1995-01-09 1995-01-09 Antioxidants, tissue- and/or neuroprotectants
SE9500051-9 1995-01-09

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6525053B1 (en) 1997-08-22 2003-02-25 Abbott Laboratories Prostaglandin endoperoxide H synthase biosynthesis inhibitors
US7001895B2 (en) 1997-08-22 2006-02-21 Abbott Laboratories Prostaglandin endoperoxide H synthase biosynthesis inhibitors
WO2007113226A1 (fr) * 2006-03-31 2007-10-11 Novartis Ag Composés organiques
US8471005B2 (en) 2008-12-19 2013-06-25 Cephalon, Inc. Pyrrolotriazines as ALK and JAK2 inhibitors
US8835441B2 (en) 2005-05-20 2014-09-16 Amgen Inc. Heterobicyclic metalloprotease inhibitors
WO2024059220A3 (fr) * 2022-09-15 2024-05-02 Vanderbilt University Composés à noyau 6,5 southwestern utilisés en tant que modulateurs allostériques négatifs du mglu5 et leurs méthodes de production et d'utilisation

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0138034A1 (fr) * 1983-09-15 1985-04-24 Hoechst Aktiengesellschaft Pyrido[1,2-c]imidazo[1,2-a]benzimidazoles substitués, procédé pour leur préparation, leur application et compositions pharmaceutiques à base de ces composés

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0138034A1 (fr) * 1983-09-15 1985-04-24 Hoechst Aktiengesellschaft Pyrido[1,2-c]imidazo[1,2-a]benzimidazoles substitués, procédé pour leur préparation, leur application et compositions pharmaceutiques à base de ces composés

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6525053B1 (en) 1997-08-22 2003-02-25 Abbott Laboratories Prostaglandin endoperoxide H synthase biosynthesis inhibitors
US7001895B2 (en) 1997-08-22 2006-02-21 Abbott Laboratories Prostaglandin endoperoxide H synthase biosynthesis inhibitors
US7115591B2 (en) 1997-08-22 2006-10-03 Abbott Laboratories Prostaglandin endoperoxide H synthase biosynthesis inhibitors
US8835441B2 (en) 2005-05-20 2014-09-16 Amgen Inc. Heterobicyclic metalloprotease inhibitors
WO2007113226A1 (fr) * 2006-03-31 2007-10-11 Novartis Ag Composés organiques
JP2009531390A (ja) * 2006-03-31 2009-09-03 ノバルティス アクチエンゲゼルシャフト 有機化合物
US8097617B2 (en) 2006-03-31 2012-01-17 Novartis Ag Organic compounds
US8471005B2 (en) 2008-12-19 2013-06-25 Cephalon, Inc. Pyrrolotriazines as ALK and JAK2 inhibitors
WO2024059220A3 (fr) * 2022-09-15 2024-05-02 Vanderbilt University Composés à noyau 6,5 southwestern utilisés en tant que modulateurs allostériques négatifs du mglu5 et leurs méthodes de production et d'utilisation

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AU4461496A (en) 1996-07-31
SE9500051D0 (sv) 1995-01-09

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