WO1991012000A1 - DERIVES ANILINIQUES DE CARBINOLS DE STYRYLE-α EN TANT QU'AGENTS ANTIFONGIQUES - Google Patents

DERIVES ANILINIQUES DE CARBINOLS DE STYRYLE-α EN TANT QU'AGENTS ANTIFONGIQUES Download PDF

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Publication number
WO1991012000A1
WO1991012000A1 PCT/US1991/000193 US9100193W WO9112000A1 WO 1991012000 A1 WO1991012000 A1 WO 1991012000A1 US 9100193 W US9100193 W US 9100193W WO 9112000 A1 WO9112000 A1 WO 9112000A1
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WIPO (PCT)
Prior art keywords
compound
mammal
fungal
effective amount
alkyl
Prior art date
Application number
PCT/US1991/000193
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English (en)
Inventor
Chia-Lin Jeffrey Wang
Original Assignee
E.I. Du Pont De Nemours And Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by E.I. Du Pont De Nemours And Company filed Critical E.I. Du Pont De Nemours And Company
Publication of WO1991012000A1 publication Critical patent/WO1991012000A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms

Definitions

  • This invention relates to aniline derivatives of ⁇ - styryl carbinols, pharmaceutical compositions containing them and methods of using such compounds for treating fungal infections in a mammal.
  • EP 251086 describes ⁇ -styryl carbinol antifungal agents useful in medicine and/or agriculture. Also described are certain compounds useful as herbicides and plant growth regulants. The compounds described therein have the formula:
  • E is a bond or -O-, provided that when E is -O-, R and R 1 are not halogen;
  • A is C1-C8 perfluoroalkyl, NMe 2 , OH, naphthyl
  • X is C, NR 10 or 0;
  • Q is H, halogen, -S(O)R 11 , -S-CO-NHR 12 , CHO, -CO-Me,
  • R 3 H, and A and B are phenyl optionally
  • n 0-4, provided that when A is NMe 2 or
  • R and R 1 independently are H, C1-C4 alkyl, halogen or phenyl, or together form C3-C7 cycloalkyl;
  • R 2 is H, allyl, propargyl, C1-C4 alkyl, -CO-R 7
  • R 3 and R 4 are H, F or C1-C4 alkyl
  • R 5 is C1-C4 alkyl
  • R e is phenyl optionally substituted by 1-3 of
  • R 7 is C1-C4 alkyl, phenyl or benzyl
  • R 8 and R 9 is H, C1-C4 alkyl, phenyl or benzyl;
  • R 10 is H, C1-C4 alkyl or acetyl
  • R 11 is C1-C4 alkyl, C1-C4 haloalkyl, -CH 2 CN, -CH 2 SCN,
  • R 12 is C1-C4 alkyl, allyl, or phenyl or benzyl both optionally substituted by 1 or 2 of the following halogen, methyl or methoxy; and R 13 is H or C1-C4 alkyl. Fungicides useful in both the medical and
  • R 2 is 4-Cl
  • R3 is H. 2).
  • R 2 and R 3 are 2,4-di-Cl.
  • R is alkyl, cycloalkyl or Ph, each group optionally substituted
  • Y is -COY 1 , its acetal or ketal derivatives, or
  • Y l is H, alkyl, alkenyl, alkynyl, cycloalkyl, Ph or benzyl, these last 3 groups, being optionally substituted;
  • Y 2 is H, alkyl, alkenyl, alkynyl, cycloalkyl or
  • Z is halogen, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy or haloalkylthio;
  • n and p are 0, 1 or 2.
  • R is alkyl, optionally substituted cycloalkyl, or optionally substituted phenyl
  • X is N or CH
  • Z is halogen, alkyl, cycloalkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted phenylalkyl or optionally substituted phenylalkoxy; and m is 0-3.
  • EP 129798 describes fungicides active against phytopathogenic fungi. These fungicides have the formula:
  • n 0-5;
  • R is H, halogen, alkyl, alkoxy, alkylthio,
  • R 1 is alkyl, cycloalkyl, cycloalkylalkyl or an optionally substituted aryl, aralkyl, aryloxy, benzyloxyalkyl, alkenyl or alkynyl group;
  • R 2 and R 3 are alkyl are taken together are (CH 2 ) m ; m is 2-7;
  • Az is 1, 2, 4-triazol-1-yl, 1, 2, 4-triazol-4-yl, 1- imidazolyl, 1-pyrazolyl or 1-benzimidazolyl;
  • Y is CO or C(R 4 )ORs
  • R 4 is H, C1-C4 alkyl, vinyl or allyl
  • R 5 is H, C1-C3 alkyl or optionally substituted
  • alkenyl alkynyl or benzyl
  • EP 117578 describes orally active antimycotic agents as well as fungicides for agricultural use.
  • A is CO, CHOH or C(C1-C5 alkyl) (OH);
  • Q is imidazolyl or 1-H or 4H-1,2,4-triazol-l-yl;
  • R 1 H, C1-C5 alkyl, or C1-C8 acyl;
  • R 2 and R 3 are C1-C5 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, benzyl optionally substituted with 1-3 halogens, pyridyl, furyl, thienyl, or phenyl optionally substituted by 1-3 halogens, C1-C3 alkyl or C1-C3 alkoxy.
  • Azole derivatives and their acid addition salts are described in EP 40345. These compounds are described as being useful as fungicides and as plant grooth
  • R is alkyl or optionally substituted cycloalkyl or phenyl
  • X is N or CH
  • Z is halo, alkyl (optionally substituted by halo), cycloalkyl, alkoxy or alkylthio (both optionally substituted by halo), or optionally substandard phenyl, phenoxy, phenylalkyl or phenylalkoxy;
  • m 0-3.
  • GB 2175301 describes triazole and imidazole compounds useful as plant regulating agents. These triazole and imidazole compounds have the formula:
  • R 1 is alkyl, alkenyl, alkynyl, cycloalkyl or
  • R 2 is alkyl, alkenyl, alkynyl, alkynylalkenyl,
  • R 3 and R 4 are H (but not both H), C1-C4 alkyl, C1-C4 alkoxy, OCF 3 , CF 3 or halo; or R 3 and R 4 taken together are a C3-C6-membered ring; and
  • Y is CH or N; provided that all hydrocarbyl moieties (including cycloalkyl, cycloalkenyl and cycloalkylalkyl) contain up to 8C unless otherwise stated.
  • antifungal compounds having the formula:
  • R 1 is H or C1-C4 alkyl
  • R 3 is H, C1-C4 alkyl or CH 2 X;
  • X is Cl or Br
  • Ar is 2,4-F 2 C 6 H 3 , 4-ClC 6 H 4 , 2,4-Cl 2 C 6 H 3 ;
  • n 0 or 1.
  • Preferred compounds of this invention are those compounds of formula (I) or their pharmaceutically acceptable salts, wherein:
  • R 1 and R 2 independently are H or C1-C3 alkyl; and/or n is 0; and/or
  • Ar is 2,4-F 2 C 6 H 3 or 4-CIC 6 H 4 ;
  • R 1 R 2 N is substituted at the 4-or 5-position
  • X is 2-Cl or 2-Br. More preferred compounds of the present invention are those compounds of formula (I) or their
  • R 1 and R 2 independently are H or C1-C3 alkyl; and/or n is 0; and/or
  • Ar is 2,4-F 2 C 6 H 3 ;
  • R 1 R 2 N is substituted at the 4-or 5-position; and/or X is 2-Cl.
  • Specifically preferred compounds of the present invention are those more preferred compounds wherein: a) R 1 R 2 N is 5(CH 3 ) 2 N.
  • R 1 R 2 N is 4-H 2 N.
  • compositions comprising an antifungal effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • a method of treating a fungal infection in a mammal comprising administering to the mammal an anti-fungal effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • aldehydes of Formula (III) in ethereal solvents, such as tetrahydrofuran (THF) or diethyl ether, at a temperature ranging from about -78° to 60°C, preferably 0° to 40°C, for 0.5 to 24 hours.
  • ethereal solvents such as tetrahydrofuran (THF) or diethyl ether
  • Formula (II) are prepared using standard procedures from the corresponding chlorides, bromides or iodides.
  • the aldehydes of Formula (III) are known, or can be prepared using methods known to one skilled in the art.
  • the compounds of Formula (IV) are converted to the keto-oxiranes of Formula (VII) by either (1) Swern oxidation, (2) basic hydrogen peroxide epoxidation of the resulting enones of Formula (V) in an aqueous alcoholic solvent such as methanol or ethanol at 0°C to room temperature for 1 to 24 hours; or (1) m- chloroperbenzoic acid epoxidation in methylene chloride or benzene at 0°C to room temperature for 10 to 30 hours, (2) Swern oxidation of the resulting epoxy- alcohols of Formula (VI).
  • keto-oxiranes of Formula (VII) are olefinated with, for example, Wittig reagents, which provide epoxy- olefins of Formula (VIII).
  • Wittig reagents which provide epoxy- olefins of Formula (VIII).
  • Benzene, toluene, THF or diethyl ether can be used as a solvent.
  • n-Butyllithium or potassium t-butoxide can be used as a base and the temperature of this reaction can be ranging from about -20° to 80°C. The reaction time is 0.5-10 hours.
  • salts of compounds of Formula (I) can be prepared in a number of ways known in the art.
  • the salts include those resulting from
  • Methyltriphenylphosphonium bromide (8.57 g, 24 mmol) was heated at 75°C under high vacuum for 1 hour. It was then cooled to room temperature and THF (40 mL) was added. To this mixture at 0°C was added n- butyllithium (1.6 M, 14.99 mL, 24 mmol) and the
  • Example 15 By using the procedures described in Example 1, the following compounds (where n is 0) in Table I were prepared or can be prepared.
  • Example 1 Part H, 4.4 g (52%) of the product was obtained from 8.5 g (24.18 mmol) of 2-(2,4- difluorophenyl)-2-(2-chloro-4-acetamidobenzoyl) oxirane from Step G and 19 g (53.2 mmol) of
  • In vitro activity (Table V) is expressed in terms of the minimal inhibitory concentration (MIC) of the test compound which inhibits the growth of yeasts and fungi.
  • Candida albicans ATCC 11651 and Aspergillus fumigatus ATCC 28214 are standardized, [V. Bezjak, J. Clinical Micro . , 21 509-512 ( 1984 ) ] to a concentration of 107 organisms/mL and maintained at -70° until use.
  • Test compounds are solubilized in dimethyl sulfoxide (DMSO) and diluted in Eagle's Minimum
  • the in vitro assay utilizes a microtiter broth dilution technique [L. Polonelli and G. Morace,
  • Test compounds are serially diluted in EMEM to give graded concentrations ranging from 100 to 0.4 ⁇ g/mL.
  • the appropriate wells are inoculated with the required organism (C. albicans at 1 x 10 4 organisms/mL and
  • A. fumigatus at 5 x 10 5 organisms/mL and the assay incubated at 30° for 24 hours.
  • the extent of fungal growth is determined at an optical density equal to 540 nm using a scanning spectrophotometer (Flow ® MCC) and MIC values, representing the minimal concentration of a compound which inhibited growth, are determined, [V. Grenta, et al. Antimicrob. Ag. and Chemo., 22, 151-153 (1982)].
  • test compounds The in vivo activity of test compounds is based on the percent (%) survival of infected animals receiving test or standard agent compared to that in an infected untreated group (Table VI).
  • the in vivo assays are chronic systemic infections lethal to mice within 7 days post infection, [J. Barnes, et al. Lab Investigation, 49 460-467 (1963), and T. Rogers and E. Balish, Infection and Immunity, 14 33-38 (1976) ] .
  • Candida albicans ATCC 11651 from a frozen stock culture (10 9 organisms/mL) maintained at -70°, is diluted in saline to 1 x 10 7 organisms/mL and 0.2 mL inoculated intravenously (caudal vein) into 20.0 gm CF-1 female mice (Charles River).
  • Test compounds are routinely solubilized in 0.25% (w/v) methylcellulose (Methocel®) but for those
  • Emulophor® (EL620 GAF Corp.) is used.
  • the standard antifungal agents, amphotericin B (Fungizone ® ) in water and ketoconazole (Nizoral ® ) in Methocel ® are administered at 1.0 mg/kg/day and 150 mg/kg/day, respectively.
  • mice (10 per group) are mice (10 per group).
  • mice infected with C . albicans receive test compounds at 50 or 150 mg/kg/day via the subcutaneous route. Animals are dosed with the test compound at 1 and 6 hour postinfection and then once daily for the next three days. Survival of mice in each group is recorded for 21 days.
  • Example C albicans A. fumigatus
  • Ketoconazole* ⁇ 0.1 11.0 ⁇ 5.0
  • Ketoconazole 100 80 50 NT not tested
  • antifungal agents of this invention can be administered by any means that effects contact of the active ingredient with the agent's site of action in the body.
  • the compounds can be administered by any means that effects contact of the active ingredient with the agent's site of action in the body.
  • the compounds can be administered by any combination thereof
  • the dosage administered will, of course, vary depending on the use and known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration: age, health, and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired.
  • a daily dose of active ingredient can be about 10 to 50 milligrams per kilogram of body weight.
  • composition of the invention may be in a conventional pharmaceutical form suitable for oral administration, for example a tablet, a capsule, an emulsion or an aqueous or oily solution or suspension, or suitable for topical application, for example a cream, ointment or gel. It can also be administered parenterally in sterile liquid dosage forms.
  • Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective
  • ointments, creams and gels can, for example, contain the usual diluents, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these
  • diluents e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these
  • water a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • saline aqueous dextrose (glucose)
  • glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents and if necessary, buffer substances.
  • Antioxidizing agents such as sodium
  • bisulfite, sodium sulfite or ascorbic acid are suitable stabilizing agents.
  • compositions according to the invention can also contain coloring and flavoring to increase patient acceptance.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl or propyl-paraben, and chlorobutanol.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences. (1985) 17th Edition, A. Osol, a standard reference text in this field.
  • a large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
  • a mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive
  • the capsules are washed and dried.
  • the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose.
  • Appropriate coatings may be applied to increase the dosage unit.
  • administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume
  • An aqueous suspension is prepared for oral
  • each 5 milliliters contain 100 administration so that each 5 milliliters contain 100 milligrams of finely divided active ingredient, 100 milligrams of sodium carboxymethyl cellulose, 5
  • a cream for topical application is prepared by incorporating 100 milligrams of the finely pulverized active ingredient in 5 grams of a cream base which comprises 40% white petrolatum, 3% microcrystalline wax, 10% lanolin, 5% Span ® 20, 0.3% Tween ® 20 and 41.7% water.

Abstract

On a mis au point de nouveaux dérivés aniliniques des carbinols de styryle-α, des compositions pharmaceutiques les contenant, et des procédés d'utilisation de ces composés en tant qu'agents antifongiques.
PCT/US1991/000193 1990-02-13 1991-01-17 DERIVES ANILINIQUES DE CARBINOLS DE STYRYLE-α EN TANT QU'AGENTS ANTIFONGIQUES WO1991012000A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US48881390A 1990-02-13 1990-02-13
US488,813 1990-02-13

Publications (1)

Publication Number Publication Date
WO1991012000A1 true WO1991012000A1 (fr) 1991-08-22

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PCT/US1991/000193 WO1991012000A1 (fr) 1990-02-13 1991-01-17 DERIVES ANILINIQUES DE CARBINOLS DE STYRYLE-α EN TANT QU'AGENTS ANTIFONGIQUES

Country Status (5)

Country Link
AU (1) AU7184891A (fr)
IE (1) IE910456A1 (fr)
IL (1) IL97201A0 (fr)
NZ (1) NZ237088A (fr)
WO (1) WO1991012000A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TR27402A (tr) * 1993-04-10 1995-02-28 Degussa Kaplanmis, sodyum perkarbonat tanecikleri, bunlari üretmeye mahsus bir yöntem ve bunlari ihtiva eden deterjan, temizleyici ve agartici terkipleri.
WO1995007896A1 (fr) * 1993-09-16 1995-03-23 Bayer Aktiengesellschaft Derives de butenol-triazolyle, leur preparation et leur utilisation comme microbicides
EP3421460A1 (fr) 2018-03-15 2019-01-02 Bayer Aktiengesellschaft Fongicides de 2-[(4-alkylphenoxy)-pyridinyl]-1-(1,2,4-triazol-1-yl)alkan-2-ol
WO2019162228A1 (fr) 2018-02-21 2019-08-29 Bayer Aktiengesellschaft Dérivés de 1-(imidazol-1-yl à substitution en position 5)but-3-ène et leur utilisation en tant que fongicides

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4243405A (en) * 1976-08-19 1981-01-06 Imperial Chemical Industries Limited Fungicidal compounds
US4655820A (en) * 1982-06-14 1987-04-07 Imperial Chemical Industries Plc Triazole alkanols having fungicidal and plant growth regulating properties
US4980367A (en) * 1987-12-17 1990-12-25 E. I. Du Pont De Nemours And Company Antifungal carbinols

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4243405A (en) * 1976-08-19 1981-01-06 Imperial Chemical Industries Limited Fungicidal compounds
US4655820A (en) * 1982-06-14 1987-04-07 Imperial Chemical Industries Plc Triazole alkanols having fungicidal and plant growth regulating properties
US4980367A (en) * 1987-12-17 1990-12-25 E. I. Du Pont De Nemours And Company Antifungal carbinols

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TR27402A (tr) * 1993-04-10 1995-02-28 Degussa Kaplanmis, sodyum perkarbonat tanecikleri, bunlari üretmeye mahsus bir yöntem ve bunlari ihtiva eden deterjan, temizleyici ve agartici terkipleri.
WO1995007896A1 (fr) * 1993-09-16 1995-03-23 Bayer Aktiengesellschaft Derives de butenol-triazolyle, leur preparation et leur utilisation comme microbicides
TR27956A (tr) * 1993-09-16 1995-11-06 Bayer Ag Hidroksietil-azolil türevleri.
WO2019162228A1 (fr) 2018-02-21 2019-08-29 Bayer Aktiengesellschaft Dérivés de 1-(imidazol-1-yl à substitution en position 5)but-3-ène et leur utilisation en tant que fongicides
EP3421460A1 (fr) 2018-03-15 2019-01-02 Bayer Aktiengesellschaft Fongicides de 2-[(4-alkylphenoxy)-pyridinyl]-1-(1,2,4-triazol-1-yl)alkan-2-ol

Also Published As

Publication number Publication date
AU7184891A (en) 1991-09-03
NZ237088A (en) 1993-12-23
IL97201A0 (en) 1992-05-25
IE910456A1 (en) 1991-08-14

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