US3324122A - Series of 4-substituted-2-(5-nitro-2-furyl) quinazolines - Google Patents

Series of 4-substituted-2-(5-nitro-2-furyl) quinazolines Download PDF

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Publication number
US3324122A
US3324122A US418311A US41831164A US3324122A US 3324122 A US3324122 A US 3324122A US 418311 A US418311 A US 418311A US 41831164 A US41831164 A US 41831164A US 3324122 A US3324122 A US 3324122A
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US
United States
Prior art keywords
mole
compound
mixture
furyl
solution
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Expired - Lifetime
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US418311A
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English (en)
Inventor
Homer A Burch
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Warner Chilcott Pharmaceuticals Inc
Original Assignee
Norwich Pharmacal Co
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 Norwich Pharmacal Co filed Critical Norwich Pharmacal Co
Priority to US418311A priority Critical patent/US3324122A/en
Priority to IL24359A priority patent/IL24359A/xx
Priority to ES0318292A priority patent/ES318292A1/es
Priority to DE19651620076 priority patent/DE1620076A1/de
Priority to SE13375/65A priority patent/SE325579B/xx
Priority to DK535765AA priority patent/DK117902B/da
Priority to NL6513634A priority patent/NL6513634A/xx
Priority to AT1028165A priority patent/AT255424B/de
Priority to NO160494A priority patent/NO118066B/no
Priority to BE672504A priority patent/BE672504A/xx
Priority to FR41817A priority patent/FR4910M/fr
Priority to FR41816A priority patent/FR1460221A/fr
Priority to GB52914/65A priority patent/GB1101179A/en
Priority to CH1713065A priority patent/CH448110A/de
Priority to GB4532167A priority patent/GB1101180A/en
Priority to BR175667/65A priority patent/BR6575667D0/pt
Application granted granted Critical
Publication of US3324122A publication Critical patent/US3324122A/en
Assigned to NORWICH EATON PHARMACEUTICALS, INC., A CORP. OF OH reassignment NORWICH EATON PHARMACEUTICALS, INC., A CORP. OF OH ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: MORTON-NORWICH PRODUCTS, INC., A CORP. OF DE
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Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim

Definitions

  • X represents in which R is selected from the group consisting of hydrogen, lower alkyl, hydroxy (lower) alkyl, lower alkoxyalkyl and amino; and R is selected from the group consisting of hydroxy (lower) alkyl, lower alkoxyalkyl and morpholinopropyl.
  • the compounds of this invention bearing the group, in which R and R have the significance above related, in the 4-position are particularly distinguished by their ability to inhibit the growth of microorganisms.
  • Representative of the very high order of antimicrobial activity resident in the members of this series is the effect elicited by the compound 4-[ bis-(2 hydroxyethyl)amino] 2-(5-nitro-2-furyl)quinazoline against a broad spectrum of gram-positive and gram-negative organisms under the commonly employed serial dilution technique:
  • these compounds are adapted to be combined with suitable carriers in the form of dusts, suspensions, ointment, sprays and the like to provide compositions designed to prevent and eradicate bacterial contamination.
  • the compounds of this invent-ion having the substituent are also capable of suppressing systemic infection in animals provoked by Staphylococcus aureus. When administered perorally in a dose of from 50-200 mgL/kg. to mice lethally infected with that bacterium, protect-ion against mortality is secured.
  • an inert solvent in which the desired end product has low solubility such as water or petroleum ether, is conveniently added to the mixture to evoke the separation of solid material, which is secured by filtration and purified, if necessary or desirable, to yield the desired end product.
  • the prodnot (208 g.) is purified by Soxhlet extraction with toluene.
  • the toluene solution is chilled and filtered.
  • the product is obtained as long, yellow needles melting at 196.5-198.5 in ayield of 106 g.
  • EXAMPLE II 4- [Z-lzydroxyethyl(Z-hydro-xy propyl) amino] -2- (S-nirro- Z-fmyl) quinazoline (NF-1174)
  • the solution is heated on a steam bath for 1 hour.
  • the solution is diluted with water until a solid begins to separate.
  • EXAMPLE III 4-b1's(2-hydr0xypr0pyl)amino-2-(5-nitr0-2-furyl) quinazoline (NF-1144)
  • a 1 l., three-neck flask, fitted with a stirrer, is charged with 40 g. (0.145 mole) of the compound of Example I, B., and 40 g. (0.3 mole) of 1,1-iminodi-2-propanol in 500 ml. of dimethylformamide.
  • the solution is heated on a steam bath for 2 hours.
  • the solution is diluted with water until a solid begins to separate.
  • the mixture is cooled; the crude product is collected by filtration, and recrystallized from isopropyl alcohol.
  • the product separates as yellow needles melting at 169170 (corr.) in a yield of 39 g. (73%).
  • EXAMPLE V 4 -bis- 2 -hydroxyethyl amino-2 5 -n itro-Z-fruyl quinazoline (NF -1 088)
  • NF -1 088 A 500 ml., three-neck flask, fitted with a stirrer, was charged with 30.2 g. (0.11 mole) of the compound of Example I, B., and 26.3 g. (0.25 mole) of diethanolamine in 300 ml. of dimethylformamide.
  • the solution is heated on a steam bath for 2 hours.
  • the solution is diluted with water until a solid begins to separate.
  • the mixture is cooled and the crude product is collected by filtration and recrystallized from ethanol.
  • the product separates as yellow platelets melting at 162.5164.5 (corr.) in a yield of 22 g. (58%).
  • EXAMPLE VI 4 2 -hydr0xyethyl methylam in0-2- 5 -nitr0-2-furyl quinazoline (NF-1081 A mixture of 50 g. (0.182 mole) of the compound of Example I, B., and 34 g. (0.45 mole) of N-methylethanol- EXAMPLE VII 4-(Zanethoxyethyl)amino-2-(5-nitro-2-fulyl) quinazoline (NF-1175) A 2 1., three-neck flask, fitted with a stirrer, condenser, and a stopper, is charged with 40 g. (0.145 mole) of the compound of Example I, B., and 22.5 g.
  • EXAMPLE VIII 4-(3-methoxypropylamino)2-(5-nitr0-2-furyl) quinazoline (NF-1145)
  • a 1 1., three-neck flask, fitted with a stirrer, is charged with 35 g. (0.127 mole) of the compound of Example I, B., and 23.1 g. (0.26 mole) of methoxypropylamine in 500 ml. of dimethylformamide.
  • the solution is heated on a steam bath for 2 hours.
  • the solution is diluted with Water until a solid begins to separate.
  • the mixture is cooled; the crude product is collected by filtration, and recrystallized from isopropyl alcohol.
  • the product separates as yellow platelets melting at 143-145 (corr.) in a yield of 33 g. (82%).
  • EXAMPLE IX 4 -bis( Z-ethoxyethyl am ino-Z 5 -nitr0-2 -fwyl quinazoline (NF-1127) A 2 l., three-neck flask, fitted with a stirrer, is charged with 35 g. (0.127 mole) of the compound of Example I, B., and 42 g. (0.26 mole) of diethoxyethylamine in 1 l. of dimethylformamide. The solution is heated on a steam bath, with stirring, for 2 hours. The solution is diluted with water until a solid begins to separate. The mixture is cooled; the crude product is collected by filtration, and recrystallized from isopropyl alcohol. The product separates as yellow needles melting at 6061 (corr.) in a yield of 40 g. (79%).
  • a yellow solid is collected by filtration, slurried in.cold water and made basic with sodium hydroxide solution.
  • the free base, melting at 164-166, is collected by filtration in a yield of 42 g. (100%). Recrystallization from ethanol gives the product as yellow platelets melting at 170-1715 (corn).
  • the free base (40 g., 0.104 mole) is dissolved in 500 ml. of glacial acetic acid and anhydrous hydrogen chloride is bubbled into the solution until saturated. The mixture is cooled and diluted with anhydrous ether. A yellow solid is collected by filtration and recrystallized from ethanot to give the hydrochloride as a yellow solid melting at 211213 in a yield of 30 g. (63.5%).
  • EXAMPLE XIV 4-[ (Z-hydroxyethyl) isopropylamino] -2-(5-nitr0-2-furyl) quinazoline (NF-1192 A 1 l., three-neck flask, fitted with a stirrer is charged with 35 g. (0.127 mole) of the compound of Example I, B., and 25 g. (0.242 mole) of N-isopropylethanolamine in 500 ml. of dimethylformamide. The solution is heated on a steam bath for 2 hours. The solution is diluted with water until a solid separates and the mixture is cooled. The product is collected by filtration and recrystallized from isopropyl alcohol. The product separates as yellow platelets melting at l48150 in a yield of 21 g. (48%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
US418311A 1964-12-14 1964-12-14 Series of 4-substituted-2-(5-nitro-2-furyl) quinazolines Expired - Lifetime US3324122A (en)

Priority Applications (16)

Application Number Priority Date Filing Date Title
US418311A US3324122A (en) 1964-12-14 1964-12-14 Series of 4-substituted-2-(5-nitro-2-furyl) quinazolines
IL24359A IL24359A (en) 1964-12-14 1965-09-23 4-substituted-2-(5-nitro-2-furyl)-quinazolines and a process for their production
ES0318292A ES318292A1 (es) 1964-12-14 1965-10-08 Metodo de preparacion de 2-(5-nitro-2-furil) quinazolinas 4sustituidas.
DE19651620076 DE1620076A1 (de) 1964-12-14 1965-10-13 Verfahren zur Herstellung von neuen 2-(5-Nitro-2-furyl)-chinazolinen
SE13375/65A SE325579B (de) 1964-12-14 1965-10-15
DK535765AA DK117902B (da) 1964-12-14 1965-10-20 Fremangsmåde til fremstilling af 4-substituerede 2-(5-nitro-2-furyl)-kinazoliner eller syreadditionssalte deraf.
NL6513634A NL6513634A (de) 1964-12-14 1965-10-21
AT1028165A AT255424B (de) 1964-12-14 1965-11-15 Verfahren zur Herstellung von neuen 2-(5-Nitro-2-furyl)-chinazolinen
NO160494A NO118066B (de) 1964-12-14 1965-11-16
BE672504A BE672504A (de) 1964-12-14 1965-11-18
FR41817A FR4910M (de) 1964-12-14 1965-12-10
FR41816A FR1460221A (fr) 1964-12-14 1965-12-10 Nouvelles quinazolines substituées par un radical nitrofurannique
GB52914/65A GB1101179A (en) 1964-12-14 1965-12-13 Improvements in or relating to nitrofuryl quinazolines
CH1713065A CH448110A (de) 1964-12-14 1965-12-13 Verfahren zur Herstellung von neuen 2-(5-Nitro-2-furyl)-chinazolinen
GB4532167A GB1101180A (en) 1964-12-14 1965-12-13 Improvements in or relating to nitrofuryl quinazolines
BR175667/65A BR6575667D0 (pt) 1964-12-14 1965-12-14 Processo de preparacao de 2-(5-nitro-2-turil)-quinazolinas substituidas na posicao 4

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US418311A US3324122A (en) 1964-12-14 1964-12-14 Series of 4-substituted-2-(5-nitro-2-furyl) quinazolines

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US3324122A true US3324122A (en) 1967-06-06

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US418311A Expired - Lifetime US3324122A (en) 1964-12-14 1964-12-14 Series of 4-substituted-2-(5-nitro-2-furyl) quinazolines

Country Status (14)

Country Link
US (1) US3324122A (de)
AT (1) AT255424B (de)
BE (1) BE672504A (de)
BR (1) BR6575667D0 (de)
CH (1) CH448110A (de)
DE (1) DE1620076A1 (de)
DK (1) DK117902B (de)
ES (1) ES318292A1 (de)
FR (2) FR1460221A (de)
GB (1) GB1101179A (de)
IL (1) IL24359A (de)
NL (1) NL6513634A (de)
NO (1) NO118066B (de)
SE (1) SE325579B (de)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3542784A (en) * 1968-04-05 1970-11-24 Norwich Pharma Co 4-(hydroxyanilino)-2-(5-nitro-2-furyl)quinazolines
US4055642A (en) * 1975-05-12 1977-10-25 Sandoz Ltd. Imidazolyl-2-quinazoline derivatives
US5436233A (en) * 1992-07-15 1995-07-25 Ono Pharmaceutical Co., Ltd. 4-aminoquinazoline derivatives
WO2005014585A1 (en) * 2003-08-08 2005-02-17 Ulysses Pharmaceutical Products Inc. Halogenated quinazolinyl nitrofurans as antibacterial agents
US20080146562A1 (en) * 2003-08-08 2008-06-19 Ulysses Pharmaceutical Products Inc., Halogenated quinazolinyl nitrofurans as antibacterial agents

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3705898A (en) * 1970-01-26 1972-12-12 Morton Norwich Products Inc Certain 4 - amino - 2-(5-nitro-2-thienyl) quinazolines and the intermediate 4 - chloro-(5 - nitro-2-thienyl)quinazolines therefor

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3184462A (en) * 1960-06-09 1965-05-18 Mead Johnson & Co Certain 4-substituted quinazolines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3184462A (en) * 1960-06-09 1965-05-18 Mead Johnson & Co Certain 4-substituted quinazolines

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3542784A (en) * 1968-04-05 1970-11-24 Norwich Pharma Co 4-(hydroxyanilino)-2-(5-nitro-2-furyl)quinazolines
US4055642A (en) * 1975-05-12 1977-10-25 Sandoz Ltd. Imidazolyl-2-quinazoline derivatives
US5436233A (en) * 1992-07-15 1995-07-25 Ono Pharmaceutical Co., Ltd. 4-aminoquinazoline derivatives
WO2005014585A1 (en) * 2003-08-08 2005-02-17 Ulysses Pharmaceutical Products Inc. Halogenated quinazolinyl nitrofurans as antibacterial agents
US20060258693A1 (en) * 2003-08-08 2006-11-16 Suzanne Chamberland Halogenated quinazolinyl nitrofurans as antibacterial agents
US20080146562A1 (en) * 2003-08-08 2008-06-19 Ulysses Pharmaceutical Products Inc., Halogenated quinazolinyl nitrofurans as antibacterial agents
US7410974B2 (en) 2003-08-08 2008-08-12 Ulysses Pharmaceutical Products, Inc. Halogenated Quinazolinyl nitrofurans as antibacterial agents

Also Published As

Publication number Publication date
SE325579B (de) 1970-07-06
BR6575667D0 (pt) 1973-09-06
NL6513634A (de) 1966-06-15
FR1460221A (fr) 1966-06-17
ES318292A1 (es) 1967-03-01
CH448110A (de) 1967-12-15
BE672504A (de) 1966-03-16
AT255424B (de) 1967-07-10
DK117902B (da) 1970-06-15
NO118066B (de) 1969-11-03
GB1101179A (en) 1968-01-31
DE1620076A1 (de) 1970-02-12
FR4910M (de) 1967-03-13
IL24359A (en) 1969-01-29

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Owner name: NORWICH EATON PHARMACEUTICALS, INC., 17 EATON AVE.

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:MORTON-NORWICH PRODUCTS, INC., A CORP. OF DE;REEL/FRAME:004085/0126

Effective date: 19820609