EP0613463A1 - Derives de thioethers phenoliques cycliques utilises comme inhibiteurs ou stimulateurs de production de superoxyde - Google Patents

Derives de thioethers phenoliques cycliques utilises comme inhibiteurs ou stimulateurs de production de superoxyde

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Publication number
EP0613463A1
EP0613463A1 EP92924323A EP92924323A EP0613463A1 EP 0613463 A1 EP0613463 A1 EP 0613463A1 EP 92924323 A EP92924323 A EP 92924323A EP 92924323 A EP92924323 A EP 92924323A EP 0613463 A1 EP0613463 A1 EP 0613463A1
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Prior art keywords
alkyl
thio
phenyl
hydrogen
carbon atoms
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EP92924323A
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German (de)
English (en)
Inventor
Richard August Mueller
Richard Allen Partis
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GD Searle LLC
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GD Searle LLC
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/17—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/20—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered

Definitions

  • the present invention relates to cyclic phenolic thioethers and more particularly relates to the novel compounds of Formula I which are inhibitors or
  • stimulators of superoxide generation may also inhibit cyclooxygenase and/or 5-lipoxygenase.
  • the compounds of the present invention which stimulate superoxide generation may be useful as adjunctive therapeutic agents in the treatment of infections.
  • cyclooxygenase or 5-lipoxygenase are useful, for example, as anti-inflammatory and/or anti-allergy agents and in the treatment of hypersensitivity
  • RADICAL BIOLOGY & MEDICINE 5:403-408 (1988).
  • oxygen radicals are thought to be involved are, for example, inflammatory- immune injury, autoimmune diseases, ischemia-reflow states, aging disorders, cancer, cigarette-smoke effects, emphysema, acute respiratory distress syndrome (ARDS), atherosclerosis, rheumatoid arthritis, senile dementia, cataractogenesis, retinopathy of prematurity, radiation injury and contact dermatitis.
  • Oxygen radicals are capable of reversibly or irreversibly damaging compounds of all biochemical classes, including nucleic acids, protein and free amino acids, lipids and lipoproteins, carbohydrates, and connective tissue macromolecules. These species may have an impact on such cell activities as membrane function, metabolism, and gene expression. Oxygen radicals are formed in tissues by many processes (see Cross, et al., p. 528, Table 2). These are believed to be both endogenous, such as mitochondrial, microsomal and chloroplast electron transport chains; oxidant enzymes such as xanthine oxidase, indoleamine
  • phagocytic cells such as neutrophils, monocytes and macrophages, eosinophils, and endothelial cells; and antioxidation reactions; and exogenous, such as redoxcycling substances, drug oxidations, cigarette smoke, ionizing radiation, sunlight, heat shock and substances that oxidize glutathione. They may be involved in the action of toxins such as paraquat, cigarette smoke, and quinone antitumor drugs.
  • Those compounds of the present invention which inhibit superoxide generation may be useful in the treatment of diseases mediated by superoxide
  • arachidonic acid an essential unsaturated fatty acid
  • various products including,
  • prostaglandins thromboxanes, the 5-, 11-, 12- and15-hydroxyeicosatetraenoic acids (HETEs, DIHETEs) and hydroperoxyeicosatetraenoic acids (HPETEs) and the leukotrienes, all of which have potent physiological effects.
  • HETEs 5-, 11-, 12- and15-hydroxyeicosatetraenoic acids
  • HPETEs hydroperoxyeicosatetraenoic acids
  • leukotrienes all of which have potent physiological effects.
  • Those compounds of the present invention which inhibit cyclooxygenase inhibit the synthesis of prostaglandins via the cyclooxygenase pathway of arachidonic acid metabolism.
  • These prostaglandin synthetase inhibitors may exhibit anti-inflammatory, anti-pyretic and analgesic activity, and are useful in the treatment of inflammatory conditions such as arthritis.
  • the leukotrienes which are produced via the 5-lipoxygenase pathway, are the major contributors to the onset of the symptoms of asthma, and mediators for immediate hypersensitivity reactions, inflammation and other allergic responses.
  • Leukotrienes are found in inflammatory exudates and are involved in the process of cellular invasion during inflammation.
  • the term "leukotrienes” is used as a generic term to describe a class of substances, such as slow-reacting substance (SRS) which is an important mediator in asthma and other hypersensitivity reactions.
  • Immunologically generated SRS is usually referred to as slow-reacting substance of anaphylaxis (SRS-A).
  • SRS-A consists of leukotrienes (LT) known as A 4 , B 4r C 4 , D 4 , and E 4 .
  • LTC 4 is at least 100 times more potent than histamine in causing long lasting
  • LTB 4 may be an important mediator of inflammation in, for example, inflammatory bowel disease.
  • Chemotaxis is a reaction by which the direction of migration of cells is determined by substances in their environment. It is one of the major processes bringing leukocytes from the blood to an inflammatory site, whether the inflammation is caused by an infectious agent, allergic challenge, or other pro-inflammatory stimuli.
  • LTB 4 is not only chemotactic for neutrophils and monocytes, but is also highly active in stimulating eosinophil locomotion. LTB 4 also stimulates calcium influx and aggregation of polymorphonuclear leukocytes and LTB 4 may, thus, play an important role in mediating both acute and chronic inflammation.
  • LTB 4 is also present in gouty effusions; and exposure to urate crystals is known to stimulate LTB 4 production by neutrophils. Accordingly, those compounds of the present invention which inhibit 5-lipoxygenase through inhibition of neutrophil attraction and activation in arthritic joints should reduce the protease and
  • R 1 and R 2 are the same or different and independently represent tert-alkyl or phenyl;
  • A represents methylene or methylene substituted by alkyl, dialkyl or hydroxy, provided that when A includes hydroxymethylene, the hydroxymethylene group is not adjacent to a heteroatom; B represents sulfur,
  • the compounds are specific inhibitors of 5-lipoxygenase and are useful in the treatment of local and systematic inflammation, allergy and
  • Ar is phenyl or phenyl substituted by one to three of varied substituents, for example, alkyl, alkoxy, hydroxy, etc.
  • Q is oxygen, sulfur or an NH group
  • A is straight or branched chain, optionally substituted, alkylene, and R is hydrogen or straight or branched alkyl, optionally substituted by alkoxy, hydroxyl, carboxyl, alkoxycarbonyl, etc.
  • n is 0, 1 or 2.
  • the disclosed compounds are indicated to have anti-inflammatory and anti-allergic properties through inhibition of undefined anaphylactic and anaphylactoid reactions, although no test data are provided.
  • the preferred compounds are stated to be those in which Q represents oxygen and n is 0 without mention of any preference among the numerous possible substituents for R or substituted phenyl as Ar.
  • the compounds of the present invention all have cycloalkyl at the position corresponding to A as well as having di(tertiary)-alkyl or diphenyl groups as substituents on the phenol moiety corresponding to the substituted Ar group in the above publication which, as described therein, may or may not comprise a phenol.
  • a series of thioethers useful as, for example, polyfunctional antioxidants for polymers, and
  • the compounds resulting from the foregoing process have the general formulas RS(CH 2 ) n X and S(CH 2 CH 2 X) 2 in which R is 3,5-di-tert-butyl-4-hydroxyphenyl and X represents, for example, -C ⁇ N, NH 2 , CH(OH)CH 2 Cl, OH, COCl and various carboxy, carboxylate and amide functions.
  • R 3,5-di-tert-butyl-4-hydroxyphenyl
  • X represents, for example, -C ⁇ N, NH 2 , CH(OH)CH 2 Cl, OH, COCl and various carboxy, carboxylate and amide functions.
  • Compounds of formula I according to the present invention or 5-lipoxygenase activity for structurally related compounds are not disclosed.
  • Y is sulfur
  • X is hydrogen, benzyl, benzyloxy or benzylthio or substituted derivatives thereof
  • R is hydrogen, halogen, hydroxy, alkyl or alkoxy
  • a 1 and A 2 are hydrogen or alkyl
  • Z is amine or azacyclohydrocarbonyloxy.
  • JP 49116035 discloses a process for making compounds of the formula
  • R 1 , R 2 , R 3 and R 4 are hydrogen, alkyl or aryl groups, and R 1 and R 2 can be combined to form a
  • the compounds are said to be useful as drug intermediates, agricultural chemicals,
  • CA 107:197783q discloses dialkylphenol derivatives of the formula
  • the compounds are said to be useful as
  • EP0293900 discloses 5-lipoxygenase inhibiting compounds of the formula
  • This compound differs structurally from the claimed compounds. It has a butyrolactone (i.e., a dihydro-2(3H)-furanone) attached to the thio and lacks a carboxylic acid or ester moiety attatched to the heterocyclic ring through A-(CH 2 ) P or through A-(CH 2 ) p - C(O)-(CH 2 ) t .
  • a butyrolactone i.e., a dihydro-2(3H)-furanone
  • R 1 and R 2 are tert-alkyl and R 3 can be
  • R 6 and R 7 are C 1-4 alkyl.
  • Compound (c) has a dialkyl-1,3-dioxanyl group attached to the phenylthio through an alkylene bridge whereas compound (d) has a 4-hydroxy-2-pyranone attached to the phenylthio through an alkylene bridge.
  • Neither compound has a carboxylic acid or ester moiety attatched to the cycloalkyl ring through A-(CH 2 ) p or through A-(CH 2 ) p -C(O)-(CH 2 ) t as do the compounds of the present invention, and both compound have an alkylene bridge inserted between the phenylthio and the heterocyclic ring.
  • novel cyclic phenolic thioethers pharmaceutical compositions containing them and methods of using them, as well as intermediates for producing them.
  • novel cyclic phenolic thioethers of the present invention are compounds of the formula
  • R 1 , R 2 and R 10 are the same or different and independently represent alkyl, alkoxy, hydroxy, phenyl, halogen, trifluoromethyl, cyano, nitro, alkylthio or hydrogen with the proviso that when R 1 and R 2 are 3,5-di-tert-butyl, R 10 is not 4-hydroxy; q is 0 or 1; R 3 represents hydrogen, alkyl, alkoxy, or hydroxy; X represents O, S or (CH 2 ) m wherein m is an integer from 0 to 4; A represents O or S(O) n wherein n is 0, 1, or 2; Alk 1 is straight or branched chain alkyl having 1 to 6 carbon atoms; p is 0 or 1; y is 0, 1 or 2; and R represents :
  • heterocyclealkyl substituted heterocyclealkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, or Alk- NR 8 R 9 wherein Alk is alkyl of 1 to 10 carbon atoms and R 8 and R 9 each independently are hydrogen or alkyl; or NR 5 R 6 together form a heterocyclic ring which may optionally be substituted; or
  • arachidonic acid metabolic pathway for promoting anti-inflammatory and/or anti-allergic effects in mammals in need thereof by the administration of preselected dosages of compounds of the present
  • Some compounds of the present invention may inhibit 5-lipoxygenase and/or cyclooxygenase.
  • cyclooxygenase inhibitors since the 5-lipoxygenase inhibiting activity may have a mitigating effect on the patient's sensitivity to cyclooxygenase inhibitors.
  • This mitigating effect may also make compounds which inhibit both 5-lipoxygenase and cyclooxygenase useful for co-administration with cyclooxygenase inhibitors.
  • Another object of the present invention is to provide dosage unit forms adapted for, e.g., oral, topical, and/or parenteral administration and useful in the stimulation or inhibition of superoxide generation and in the treatment, management and mitigation of inflammation, allergies, psoriasis and hypersensitivity reactions and related disorders and conditions in which physiologically active agents formed in the arachidonic acid metabolic pathway are involved.
  • Those compounds of the present invention which inhibit superoxide generation may be useful in the therapeutic or prophylactic treatment of disease conditions which are mediated wholly or partly by superoxide generation such as adult respiratory
  • Those compounds of Formula I which are stimulators of superoxide generation in neutrophils may be useful in the therapeutic or prophylactic treatment of disease conditions in which superoxide generation is an
  • compositions of Formula I may also act as prodrugs which would be converted to superoxide inhibitors by stomach acid, blood, liver, or other organs.
  • some compounds of Formula I may inhibit 5-lipoxygenase and/or cyclooxygenase.
  • the present invention provides a method by which neutrophil activation and the generation of superoxide anions are accomplished utilizing compounds of Formula I having the ability to stimulate superoxide
  • compounds of Formula I which stimulate superoxide generation may be useful in the adjunctive therapy of microbial infections.
  • the compounds may also be useful in treating conditions such as Chediak-Higashi Syndrome in which the patient's macrophages and polymorphs are only weakly active causing the patients to suffer from recurring infections involving organisms with normally low pathogenicity.
  • Compounds of Formula I which stimulate superoxide generation may also be useful in the adjunctive therapy of patients whose immune systems have been weakened or impaired by disease or by chemotherapy or radiation therapy and who are more subject to microbial infections.
  • R 1 , R 2 and R 10 are the same or different and independently represent alkyl, alkoxy, hydroxy, phenyl, halogen, trifluoromethyl, cyano or hydrogen; q is 0 or 1; R 3 represents hydrogen, alkyl, alkoxy, or hydroxy; X represents O, S or (CH 2 ) m wherein m is 1 to 4;
  • n 0, 1, or 2
  • p is an integer from 0 to 4
  • R represents:
  • heterocyclealkyl cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, or Alk- NR 8 R 9 wherein Alk is alkyl of 1 to 10 carbon atoms and R 8 and R 9 each independently are hydrogen or alkyl; or NR 5 R 6 together form a heterocyclic ring which may optionally be substituted; or (e) (CH 2 ) t COOR 7 wherein t is an integer from 1 to 4 and R 7 is hydrogen or alkyl of 1 to 4 carbon atoms.
  • R 1 , R 2 and R 10 are the same or different and independently represent tert-alkyl of 4 to 10 carbon atoms, phenyl, halogen or hydrogen;
  • R 3 represents hydrogen or alkyl of 1 to 4 carbon atoms;
  • X represents O, S or (CH 2 ) m wherein m is 1 or 2;
  • A represents 0 or
  • heterocyclealkyl cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, or
  • Alk-NR 8 R 9 wherein Alk is straight or branched chain alkyl of 1 to 6 carbon atoms and R 8 and R 9 each independently are hydrogen or alkyl of
  • R 1 and R 2 are the same or different and
  • R 3 represents hydrogen or alkyl of 1 to 4 carbon atoms
  • X represents O or (CH 2 ) m wherein m is 1 or 2
  • A represents O or S
  • p is O or 1
  • R represents:
  • NR 5 R 6 wherein R 5 is hydrogen or alkyl of 1 to 4 carbon atoms and R 6 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxyalkyl wherein the alkyl moieties each have 1 to 6 carbon atoms, heterocyclealkyl wherein the alkyl moiety has 1 to 4 carbon atoms, or Alk-NR 8 R 9 wherein Alk is straight or branched chain alkyl of 1 to 6 carbon atoms and R 8 and R 9 are each
  • R 1 and R 2 are the same or different and
  • R 3 represents hydrogen or alkyl of 1 to 4 carbon atoms
  • X represents O or (CH 2 ) m wherein m is 1 or 2
  • A represents O or S
  • p is O or 1
  • R represents:
  • NR 5 R 6 wherein R 5 is hydrogen or alkyl of 1 to 4 carbon atoms and R 6 is hydrogen, alkyl of 1 to 4 carbon atoms, alkoxyalkyl wherein the alkyl moieties each have 1 to 6 carbon atoms, heterocyclealkyl wherein the alkyl moiety has 1 to 4 carbon atoms, or Alk-NR 8 R 9 wherein Alk is straight or branched chain alkyl of 1 to 6 carbon atoms and R 8 and R 9 are each
  • R 1 , R 2 , R 3 , R 10 , q, y and X are defined as in Formula I, and Z represents hydroxy, halogen, sulfonate ester, or perfluoroacyl ester.
  • the present invention includes
  • R 1 , R 2 , R 3 , R 10 , q, y and X are defined as above. These compounds are useful as intermediates for making compounds of Formula I.
  • the present invention includes compounds of the formula IV:
  • R 1 and R 2 are the same or different and
  • X is (CH 2 ) m wherein m is 2, A is S or O; and R is:
  • R 5 is hydrogen or alkyl of 1 to 4 carbon atoms and R 6 is alkyl of 1 to 4 carbon atoms; alkoxyalkyl; heterocyclealkyl wherein the alkyl moiety has 1 to 4 carbon atoms;
  • phenyl substituted phenyl having one or more substituents selected from the group consisting of alkyl, hydroxy, alkoxy,
  • Alk-NR 8 R 9 wherein Alk is straight or branched chain alkyl of 1 to 4 carbon atoms and R 8 and R 9 are each
  • R 1 and R 2 are both tert-butyl;
  • X is (CH 2 ) m wherein m is 2;
  • A is S or 0; and
  • R is:
  • Alk-NR 8 R 9 wherein Alk is alkyl of 1 to 4 carbon atoms and R 8 and R 9 are alkyl of 1 to 4 carbon atoms;
  • Compounds of the present invention can possess one or more asymmetric atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or nonracemic mixtures thereof.
  • the optical isomers can be obtained by resolution of the racemic mixtures by conventional processes.
  • tert-alkyl refers to branched chain alkyl moieties of from about 4 to about 10 carbon atoms having a tertiary carbon atom attached to the phenyl ring substituted by R 1 and R 2 .
  • examples of such groups are tert-butyl, i.e., 1,1-dimethylethyl, 1,1-dimethylpropyl,
  • alkyl defines straight or branched chain monovalent hydrocarbon radicals having between about 1 to 10 carbon atoms including, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, isobutyl, pentyl, l-methylbutyl, isopentyl, neopentyl, hexyl, octyl, nonyl, decyl, etc.
  • alkoxyalkyl refers to alkoxyalkyl moieties in which the alkyl moieties are straight or branched chain alkyl of 1 to 6 carbon atoms.
  • heterocycle and “heterocyclic ring” as used herein refer to aromatic or nonaromatic
  • heterocyclic rings which contain one or more
  • heteroatoms include but are not limited to
  • azabicycloalkyl e.g., 3-azabicyclo[3,2,2]nonane, azatricycloalkyl, 1,2,3,4- tetrahydroisoquinoline, 5,6,11,12- tetrahydrodibenz[b,f]azocine, iminostilbene, and the like which may optionally be substituted with one or more substituents selected from alkyl, phenyl,
  • substituted phenyl and “substituted phenylalkyl” as used herein refer to phenyl or
  • phenylalkyl moieties in which the phenyl ring is substituted by one or more substituents selected from alkyl, hydroxy, alkoxy, halogen, alkylamino,
  • cycloalkyl refers to cycloalkyl rings of 3 to 10 carbon atoms and includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantane, norbornane and the like which may optionally be substituted by 1 or more substituents selected from alkyl, hydroxy, alkoxy, and halogen.
  • halogen refers to chlorine, bromine, fluorine, and iodine.
  • salts capable of being formed with the compounds of the present invention, e.g., when R represents OH, NR 5 R 6 when R 6 is Alk-NR 8 R 9 or heterocyclealkyl without materially altering the covalent chemical structure thereof.
  • Such salts include inorganic and organic base or acid addition salts, such as sodium, potassium, calcium, ammonium, alkylammonium, quaternary ammonium, triethanolamine, lysine, hydrochloride, hydrobromide, phosphate, citrate, etc. well known to those skilled in the art.
  • the foregoing salts are prepared in the conventional manner by neutralization of the compounds of formula I with the desired base or acid.
  • the compounds of the present invention can be administered to a patient in such oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, or syrups as well as aerosols for inhalation.
  • administration may be effected
  • the preferred form of administration is oral.
  • An effective but non-toxic amount of the compound is employed in treatment.
  • the dosage regimen utilizing the present compounds is selected in accordance with a variety of factors including the type, age, weight, sex, and medical condition of the patient; the severity of the condition to be ameliorated; and the route of administration.
  • a physician of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, treat or arrest the progress of the condition.
  • the effective amount for administration is ordinarily that amount which is required to assure that the mammalian neutrophils involved in the generation of superoxide will be exposed to a sufficient concentration of drug to either inhibit superoxide generation or stimulate superoxide generation as the case may be.
  • Dosages of the compounds of the present invention will range generally between 0.1 mg/kg/day to about 100 mg/kg/day and preferably between about 0.5 mg/kg of body weight per day to about 50 mg/kg of body weight per day when administered to patients suffering from inflammation or allergic or hypersensitivity reactions.
  • a unit dose form of the compounds of the invention will contain from about 1.75 to about 750 mg of compound.
  • the compound may be administered in divided dosages, e.g. two or more times daily.
  • the compounds may also be administered transdermally or topically to treat proliferative skin conditions such as psoriasis.
  • the daily dosage may be administered in a single dose or in equal divided doses three or four times daily.
  • Unit dosage forms such as tablets and capsules can contain any suitable, predetermined, therapeutically effective amount of one or more active agent and a pharmaceutically acceptable carrier or diluent.
  • inventions which inhibit cyclooxygenase and/or 5-lipoxygenase will contain from 1.75 to 750 mg per tablet of drug as the effective 5-lipoxygenase and/or cyclooxygenase inhibiting amount of the compound.
  • a topical preparation of a compound of this invention to the affected area three or four times daily.
  • the compounds may be administered either on a chronic basis, or as symptoms appear.
  • the active agent on a chronic basis.
  • inhibitors they may conveniently be administered in a unit dosage form or may be administered separately.
  • a typical tablet of this invention can have the following compositions:
  • compositions and methods of the present invention at least one of the active compounds of the invention or a pharmaceutically acceptable salt thereof will typically be administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups, and the like, and consistent with conventional pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients, or carriers
  • suitable pharmaceutical diluents, excipients, or carriers suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups, and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, cellulose, magnesium
  • the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier such as ethanol and the like.
  • suitable binders such as ethanol and the like.
  • Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol, and waxes.
  • Lubricants for use in these dosage forms include boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, guar gum, and the like.
  • the compounds of the invention are prepared from readily available starting materials by any of the following alternate processes in a conventional manner.
  • the following reaction schemes describe methods which can be .employed for preparing the compounds of formula I, including starting materials, intermediates, and reaction conditions.
  • a mercaptan (V) can be reacted with an oxabicyclo compound (VI) to give the intermediate (III) which may then be reacted with a monohaloacid or protected monohaloacid in a base or alternatively with a thiol acid in an acid to obtain a product acid of type (VII).
  • Epoxides of type (VI) are readily prepared by oxidation of a double bond with peroxides such as m-chloro-perbenzoic acid, peracetic acid, pertrifluoroacetic acids, hydrogen peroxide, t- butyl hydroperoxide and the like.
  • epoxides can be used as
  • halohydrins which can also be used to produce compounds of type III, following reaction with, for example, a mercaptan.
  • Most bases can be used for the preparation of III, for example, hydroxides, tert-amines, heterocyclic amines, dimethylaminopyridines, hydrides, lithium alkyls, lithium amides and the like, since the thiolate anion is an exceptional nucleophile.
  • Non-nucleophilic bases are preferred for the conversion of III into VII in the presence of an electrophilic reagent such as a
  • Epoxides of Formula VI can be converted into thioepoxides (the sulfur analog) by, for example, the method described by E. E. Van Tamelin, Organic
  • Thioepoxides can be used in place of epoxides allowing the order of addition of substituents to be varied, especially in the case where A is sulfur.
  • Compound III may also be converted into VII via conversion into a halo compound (Scheme C), an
  • Non-nucleophilic acids are preferred and include, for example, trifluoroacetic acid, toluene sulfonic acid, perfluorobutyric acid, triflie acid, phosphoric acid, sulfuric acid, boron trifloride, aluminum chloride and the like.
  • the carboxylic acid may be treated with the appropriate alcohol with or without added solvent in the presence of an acid (see above) to provide the product ester.
  • a salt of the carboxylic acid may be prepared by treatment with a base (see above) and the salt then treated with an electrophilic group with displacement of, for example, a halide, tosylate and the like.
  • Acid halides can be made by mixing, for example, thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentabromide, oxalyl chloride and the like with the acid.
  • Mixed anhydrides with, e.g., isobutyl chloroformate are prepared in the standard manner with the acid being treated with isobutyl chloroformate in the presence of a base or from a preformed carboxylate salt.
  • the same type of salt either prepared in the reaction or preformed, can be treated with for example, N-chlorosuccinimide, to form the succinimide activated ester.
  • Treatment of either of these intermediates with the appropriate amine, alcohol, mercaptan or
  • the acylating agent can be an acid halide or anhydride.
  • Scheme C illustrates yet another method for the preparation of the intermediates and compounds of this invention.
  • An alpha-halo ketone, substituted or unsubstituted, is treated with a oxygen or sulfur nucleophile generated as described above.
  • the valuable intermediate, XV, is reduced directly with, for
  • a hydride reducing agent such as sodium borohydride, lithium aluminum hydride, sodium cyano borohydride and the like or borane, to provide the alcohols III and XI.
  • a hydride reducing agent such as sodium borohydride, lithium aluminum hydride, sodium cyano borohydride and the like or borane.
  • reagents such as phosphorus pentasulfide or 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent). Reduction of the thioketone as discussed above for the ketones provides the mercaptan analogs of III and XI and it is used similarly.
  • the sulfone and sulfoxide compounds of the present invention are readily prepared by oxidation of the sulfides with, for example, m-chloroperoxybenzoic acid or sodium metaperiodate.
  • the compounds of the invention are evaluated with respect to superoxide modulating activity according to the following assay procedure:
  • ferricytochrome C (5 mM, stock) were added and preincubated for 3 minutes at 37° C. Absorption measurements at 550 ran were recorded at start of preincubation. Fifty ul FMLP (6 uM, stock) was added to initiate reaction. A plateau was reached within 3 minutes and this reading minus the initial reading (before addition of FMLP) was used to calculate nanomoles of superoxide generated based on a molar extinction coefficient of 2.1 ⁇ 10 4 cm -1 mole -1 .
  • Human neutrophils were isolated from freshly drawn blood of healthy donors. Two ml of 5% dextran (MW 200,000-300,000) in saline was added to 10 ml aliquots of blood, mixed and placed upright for 45 min. at 37° C.
  • the compounds of the present invention evaluated with respect to cyclooxygenase inhibition according to the following assay procedure.
  • the assay was based on oxygen consumption during conversion of arachidonic acid to prostaglandin G 2 catalyzed by cyclooxygenase Biochem. 11:3276-3285
  • the compounds of the invention are evaluated with respect to 5-lipoxygenase inhibition according to the following assay procedure.
  • Basophilic Leukemia Cell Homogenate serves as a 5-lipoxygenase enzyme source.
  • the enzyme is incubated with [1- 14 C)-arachidonic acid and Ca++ in the presence and absence of test compound.
  • the product of 5-lipoxygenase is incubated with [1- 14 C)-arachidonic acid and Ca++ in the presence and absence of test compound.
  • 5-hydroxyeicosatetraenoic acid (5-HETE) is separated by thin-layer chromatography and
  • the compound of Formula XX inhibited both superoxide generation and 5-lipoxygenase whereas the compound of Example 16 inhibited 5-lipoxygenase and stimulated superoxide generation.
  • This data indicates that superoxide generation is not dependent on 5- lipoxygenase and that the ability of a compound to inhibit 5-lipoxygenase is not related to its ability to simulate superoxide generation.
  • Complement C5a induced superoxide generation may also.be stimulated or inhibited by compounds of the present invention.
  • reaction mixture (50 ml) was added over 10 minutes. The reaction mixture was stirred at room temperature for 30 minutes then at 50°C for 1.5 hours. After cooling to room temperature, the reaction mixture was poured into cold (0°C) water (100 ml) containing potassium
  • Example 2 Purified by chromatography on silica gel and used directly in the next Example 2.
  • Example 2
  • Example 1 The compound of Example 1 (42 g, 0.143 moles) was heated to 300°C in a round bottom flask with a heating mantle for 2 hours. After cooling to room temperature the material was dissolved in ethylene glycol (100 ml) . A solution of potassium hydroxide (12.0 g, 0.214 moles) in water (20 ml) was added and the reaction mixture was heated to 123°C for 3.5 hrs. After stirring at room temperature for 20 hours, the reaction mixture was cooled to 0°C with an ice bath, and 10% hydrochloric acid was added slowly to adjust the pH to 2.0. The reaction mixture was extracted twice with 100 ml of ethyl acetate.
  • Example 2 3,5-Bis(1,1-dimethylethyl)benzenethiol (Example 2) (5.0 g, 0.0225 moles) was added to freshly prepared sodium ethoxide (0.0230 moles) in absolute ethyl alcohol (50 ml). After stirring for 1 hour,
  • cyclohexene oxide (2.2 g; 0.0225 moles) was added by syringe over 5 minutes, and the reaction mixture was stirred for 60 hours at room temperature.
  • Methyl thioglycolate (2.65 g, 0.025 moles) was added by syringe to a solution of trans-2-[[3,5- bis(1,1-dimethylethyl)phenyl]thio]cyclohexanol
  • Example 8 Using the method of Example 8 and substituting meta-phenyl phenol for meta-t-butyl phenol the title compound was prepared. The structure was supported by NMR.
  • Oxalyl chloride (0.19 g, 0.0015 moles) was added by syringe to a cold (10°C) solution of trans-[[2- [[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexyl]-thio]acetic acid (Example 5) (0.55 g, 0.0014 moles) in benzene (50 ml).
  • the cold bath was removed and the reaction mixture was stirred at room temperature for 20 hours.
  • the reaction mixture was concentrated to an oil using a rotary evaporator. The oil was dissolved in toluene (50 ml) and concentrated to an oil.
  • the reaction is cooled to room temperature and poured into water (125 ml).
  • the solution is made acidic with 1N hydrochloric acid and extracted 3 times with 100 ml of diethyl ether.
  • the combined diethyl ether extracts are dried over anhydrous magnesium sulfate, filtered and concentrated with a rotary evaporator.
  • the product is purified by silica gel chromatography.
  • the reaction mixture is concentrated to an oil with a gentle flow of nitrogen gas.
  • the residue is dissolved in diethyl ether (75 ml), washed twice with 50 ml of 0.25N hydrochloric acid and once with 25 ml of brine, dried over anhydrous magnesium sulfate, filtered and concentrated with a gentle flow of nitrogen gas.
  • the product is purified by silica gel chromatography.
  • Oxalyl chloride (18mg, 0.000142 mole) was added to a solution of trans-2-[([1,1'-biphenyl]-3- yl)thio]cyclohexanol(24 mg, 0.000071 mole) in toluene (25ml) and stirred magnetically for 20 hours at room temperature. The solution was concentrated to an oil. The oil was dissolved in toluene (25ml) and
  • Oxalyl chloride (55mg, 0.00043 mole) was added to a solution of trans-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexyl]thio]acetic acid (85 mg, 0.000215 mole) in toluene (50 ml) and was stirred at room temperature for 20 hours. The solution was concentrated to an oil. The oil was redissolved in toluene (50 ml) and concentrated to an oil.
  • Example 58 Starting with 2-[[3,5-bis(1,1(dimethylethyl)- phenyl]thio]cyclooctanone and following the procedure described in Example 52 gives the title compounds.
  • Example 58 Starting with 2-[[3,5-bis(1,1(dimethylethyl)- phenyl]thio]cyclooctanone and following the procedure described in Example 52 gives the title compounds.
  • trans-2-[[3,5-bis(1,1-dimethylethyl)-phenyl]thio]cyclohexanol for trans-2-[( [ 1 ,1'-biphenyl]-3-yl)]thio]cyclohexanol used therein and also
  • Example 23 and following the procedure described therein gives trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)-phenyl]thio]cyclohexyl]thio]-N-[3-(diethylamino)-propyl]acetamide.
  • Example 23 and following the procedure described therein gives trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexyl]thio]-N-[(dimethylamino)ethyl]-N-methylacetamide.

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Abstract

La présente invention se rapporte à des composés de la formule (I) et aux sels pharmaceutiquement acceptables de ceux-ci, dans laquelle R1, R2 et R10 sont identiques ou différents et représentent indépendamment alkyle, alcoxy, hydroxy, phényle, halogène, trifluorométhyle, cyano ou hydrogène; q est 0 ou 1; R3 représente hydrogène, alkyle, alcoxy, ou hydroxy; X représente O, S ou (CH2)m où m est un nombre entier de 0 à 4; A représente 0 ou S(O)n, n est 0, 1, ou 2; Alk1 est alkyle à chaîne droite ou ramifiée ayant de 1 à 6 atomes de carbone; p est 0 ou 1; et R représente: (a) alkyle; (b) OH; (c) OR4 où R4 est alkyle ayant de 1 à 6 atomes de carbone; (d) NR5 R6 où R5 est hydrogène ou alkyle, et R6 est hydrogène, alkyle, alcoxyalkyle, hétérocyclealkyle, hétérocyclealkyle substitué, cycloalkyle, cycloalkyle substitué, phényle, phényle substitué, phénylalkyle, phénylalkyle substitué, ou Alk-NR8R9 où Alk est alkyle ayant de 1 à 10 atomes de carbone, et R8 et R9 sont indépendamment l'un de l'autre hydrogène ou alkyle; ou NR5R6 forment ensemble un hétérocycle qui peut être éventuellement substitué; ou (e) (CH2)tCOOR7 où t est un nombre entier de 1 à 4 et R7 est hydrogène ou alkyle de 1 à 4 atomes de carbones. Les composés sont des inhibiteurs ou des stimulateurs de production de superoxyde.
EP92924323A 1991-11-18 1992-11-17 Derives de thioethers phenoliques cycliques utilises comme inhibiteurs ou stimulateurs de production de superoxyde Withdrawn EP0613463A1 (fr)

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