US3886158A - 6H-pyrimido{8 1,2-c{9 {8 1,3,5{9 {0 benzoxadiazepines - Google Patents

6H-pyrimido{8 1,2-c{9 {8 1,3,5{9 {0 benzoxadiazepines Download PDF

Info

Publication number
US3886158A
US3886158A US382803A US38280373A US3886158A US 3886158 A US3886158 A US 3886158A US 382803 A US382803 A US 382803A US 38280373 A US38280373 A US 38280373A US 3886158 A US3886158 A US 3886158A
Authority
US
United States
Prior art keywords
compounds
compound
mixture
hours
give
Prior art date
Legal status (The legal status 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 status listed.)
Expired - Lifetime
Application number
US382803A
Other languages
English (en)
Inventor
Harry Louis Yale
Ramesh B Petigara
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ER Squibb and Sons LLC
Original Assignee
ER Squibb and Sons LLC
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 ER Squibb and Sons LLC filed Critical ER Squibb and Sons LLC
Priority to US382803A priority Critical patent/US3886158A/en
Priority to CA203,723A priority patent/CA1051427A/fr
Priority to GB2953374A priority patent/GB1476124A/en
Priority to DE2435383A priority patent/DE2435383A1/de
Priority to JP49086508A priority patent/JPS5041893A/ja
Priority to FR7426131A priority patent/FR2238492B1/fr
Priority to US05/556,510 priority patent/US3965101A/en
Application granted granted Critical
Publication of US3886158A publication Critical patent/US3886158A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom

Definitions

  • the compounds of the present invention have the fol lowing formulae RI N,CH (CH o (R rfl J ⁇ wherein m may be 1 or 2; when m is l, R occupies either position -4 or -5 of the original 2-aminopyrimidine, but when R is halogen it occupies only position -5; when m is 2, the two Rs occupy the 4- and 5- positions of the original Z-aminopyrimidine, but only one of the two R-substituents can be halogen and it must occupy the 5-position;
  • R may be the same or different and may be hydrogen, halogen (F, C1, or Br), alkyl of from 1 to 4 carbons, benzyl, phenyl, or mono-substituted phenyl wherein the substituent may be halogen (F, Cl, Br or I), alkyl of from 1 to 4- carbons, alkoxy of from 1 to 4 carbons, or trifluoromethyl;
  • R may be hydrogen, halogen (F, Cl, Br or l), alkyl of from 1 to 4 carbons, alkylsulfonyl wherein. the alkyl radical has from 1 to 4 carbons, dialk ylamidosulfonyl wherein each alkyl radical may have from 1 to 4 carbons, trifluoromethyl;
  • n may be 0 or 1;
  • R" may be alkyl of from 1 to 4 carbons, or hy drogen
  • the foregoing compounds possess central nervous system stimulating properties and act as muscle relaxants.
  • R is as previously defined with an o bromophenoxyalkylene halide lll wherein R" is as previously defined and X is chlorine or bromine.
  • This reaction takes place in any solvent or solvent mixture in which the reactants can be dissolved and which has a boiling point of at least about C.
  • Typical solvents are aromatic hydrocarbons, others, aliphatic alcohols or aryhsubstituted aliphatic alcohols. Toluene and xylene are examples of suitable aromatic hydrocarbons.
  • Monomethyl ether of diethylene glycol, dirnethyl ether of diethylene glycol (diglyme), monornethyl ether of ethylene glycol or dimethyl ether of ethylene glycol (glyrne) are examples of suitable ethers.
  • n-Arnyl alcohol is an example of a suitable aliphatic alcohol
  • benzyl alcohol is an example of a suitable arylsubstituted aliphatic alcohol.
  • Heating compounds ii and ill in a solvent as described above, or a mixture thereof, at temperatures from about 100 to about 140%: for a period of several hours, typically from about 3 to about 24 hours produces a pyrimidiniurn compound W.
  • the latter is converted to an imino compound V by treating with a water miscible alcohol and an alkali metal alkoxide of up to 3 carbon atoms or an alkali metal carbonate.
  • the reaction takes place at room temperature over a period of from about 1 to about 4 hours.
  • Qompound V may be converted to the final compound I by treating with a water miscible alcohol and an alkali metal alkoxide of up to 3 carbons in the presence of copper at a temperature of from about 60 to about 126 for about 4 to 10 days, typically from about 6 to about 8 days.
  • lV may be converted directly to l by heating at a temperature of from about 60 to about 126T for about 4 to 10 days, typically from about 6 to about 8 days in the presence of potassium carbonate and copper in a solvent such as dimethyltormamide, dirnethylacetamide, dichlorobenzene, trichlorobenzene, or diethylbenzene.
  • a solvent such as dimethyltormamide, dirnethylacetamide, dichlorobenzene, trichlorobenzene, or diethylbenzene.
  • IV may be converted directly to l by heating at a temperature of from about 60 to about C for about 4 to 10 days, typically from about 6 to about 8 days in the presence of an alkali metal hydroxide, alkali metal carbonate, tris-alkali metal phosphate, alkali metal metaborate or alkali metal tetraborate in a solvent comprising a mixture or? water and a water miscible alcohol in the presence of copper.
  • an alkali metal hydroxide, alkali metal carbonate, tris-alkali metal phosphate, alkali metal metaborate or alkali metal tetraborate in a solvent comprising a mixture or? water and a water miscible alcohol in the presence of copper.
  • suitable compounds include LiOl-l, NaOH, KOH, RbUH, CsOli, Na 'CO K CO Rb CO Cs CO Na PO K PO Rb PO (3 11 0,, Na B O Na B,0 X 8 0 and K 8 0
  • the ratios of water and alcohol in the mixture of water and a water miscible alcohol are such that a homogeneous single phase system results.
  • the intermediates of formula III wherein n is 0 may be prepared by refluxing about equimolar amounts of a 1,l-dibromoalkane or a l-bromo-l-chloroalkane of l to 4 carbons VI with a saturated solution of Na SO for a period of from about 40 to about 120 hours.
  • the resulting l-bromoalkane-l-sodium sulfonate VII is then reacted by heating with about equimolar amounts of an o-bromophenol VIII in the presence of aqueous alkali illustrated by the following equations:
  • the compounds of the present invention may be administered to mammalian species as central nervous system stimulants and as muscle relaxants.
  • responses to the stimulant activity of the compounds of the present invention include increased activity and body tremors.
  • the muscle relaxant properties manifest themselves by responses that include decreased limb tone, decreased grip strength, and limb paralysis.
  • the dosage range varies from about 6.25 to about 50 mg/kg for both activities, while in humans the dosage range varies from about 40 to about 2000 mg. daily in about four divided doses for both activities.
  • the pyrimidinium compounds of formula l ⁇ / are themselves effective bactericides.
  • Microbial bioassays as described in The Microbial World, by R. Y. Stanier, 'M. Doudoroff and E. A. Adelberg, Prentice-Hall, lnc., Englewood Cliffs, Ni, 3rd Ed, p. 858, are employed to determine the bactericidal properties of the pyrimidinium compounds IV of this invention.
  • the bacteria employed include Staphylococcus aureus, 1, Streptococcus pyogenes, 2, Salmonella schottmuelleri, 3, Salmonella gallinarum, 4, Pseu domonas aeruginosa, 5, Proteus vulgaris, 6, Escherichia coli, 7, Pasturella mullocida, 8, and Mycobacterium tuberculosis, 9.
  • a sterile agar plate is seeded with the test organism, and then a number of glass cylinders are placed on its surface, forming a series of little cups.
  • a known dilution of the compounds of this invention is added to each cup and the entire plate is then incubated until significant bacterial growth has occurred.
  • the compounds of this invention diffuse out of the cup into the surrounding agar and produce a zone of inhibition. In this fashion it is possible to find the minimum inhibiting concentration (mic), of the compound that produces a recognizable zone of inhibition.
  • the compounds of the present invention in the tie scribed dosages may be administered orally; however, other routes such as intraperitoneally, subcutaneously, intramuscularly or intravenously may be employed.
  • the active compounds of the present invention are orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
  • the active compounds of this invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, and the like.
  • the amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained.
  • the tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of Wintergreen, or cherry flavoring.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermin
  • any material may be present as coatings or to otherwise modify the physical form of the dosage unit, for instance, tablets, pills or capsules may be coated with shellac, sugar, or both.
  • a syrup or elixir may contain the active compounds, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • Acids useful for preparing these acid-addition salts include, inter alia, inorganic acids, such as the hydrohalic acids (cg, hydrochloric and hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as rnaleic, fumaric, tartaric, citric, acetic, benzoic, 2-acetoxybenzoic, salicylic, succinic acid, theophylline, fl-chlorothcophylline, p-aminobenzoic, pacetamidobenzoic, or methanesulfonic.
  • inorganic acids such as the hydrohalic acids (cg, hydrochloric and hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid
  • organic acids such as rnaleic, fumaric, tartaric, citric, acetic, benzoic, 2-acetoxybenzoic, salicylic, succinic acid, theophylline,
  • aqueous phase is concentrated to 600 ml and cooled.
  • the crystalline solid is filtered and dried in vacuo to give 63.3 g of the product, which is recrystallized from 600 ml of 90 percent aqueous ethanol to furnish about 57.5 g of the title product, mp about 282284.
  • C. o-Bromo-a-chloroanisole A mixture of 29.0 g of (o-bromophenoxy)methane sulfonic acid, sodium salt and 50.0 g of PCl are thoroughly blended in a mortar. After about minutes of continuous mixing, the mixture partly melts, a vigorous reaction occurs, and the whole turns to a liquid.
  • 2-Chloro-6Hpyrimido[ 1,2- 0] 1 ,3,5 ]benzoxadiazepine hydrochloride A mixture of 14.0 g of 2-amino-l-[(2-brom0-4- chlorophenoxy)methyl]pyrimidinium chloride, 1 1.1 g of micronized, anhydrous potassium carbonate, 0.4 g of copper bronze, and 350 ml of anhydrous n-propanol is stirred and heated under reflux for about 8 hours, filtered hot, and the deep yellow filtrate is concentrated to dryness in vacuo. Workup gives about 6.8 g of 2- chloro-6H-pyrimido[ l,2-c][ 1 ,3,5 l-benzoxadiazepine.
  • Example 1 41. l, l-d ibromoethane 42 l l-d ibromoisobutane 43 l l-dibromopropane 44. l l-dibromopentane 45 l l-dibromobutane 46 l l-d ibromoisopentane EXAMPLE 47 6,7-Dihydro-7-methyll -phenylpyrimido[ 1,2- d][ l,4,6]-benzoxadiazocine A.
  • o-Bromophenyl 2-chloropropyl ether To a solution of 23.0 g of sodium metal in 500 ml of absolute ethanol is added in about 0.5 hour a solution of 173.0 g of o-bromophenol in 250 ml of absolute ethanol. The mixture is stirred and heated under reflux for about 0.5 hours, cooled to 0, and treated, dropwise, with 157.5 g of l-bromo-2-chloropropane. The last addition requires about 1 hour.
  • EXAMPLE 49 Preparation of tablet formulation
  • the active ingredient, lactose and corn starch (for mix) are blended together.
  • the corn starch (for paste) is suspended in water at a ratio of 10 grams of corn starch per 80 milliliters of water and heated with stirring to form a paste.
  • This paste is then used to granulate the mixed powders.
  • the wet granules are passed through a No. 8 screen and dried at F.
  • the dry granules are passed through a No. 16 screen.
  • the mixture is lubricated with magnesium stearate and compressed into tablets in a suitable tableting machine. Each tablet contains 300 milligrams of active ingredient.
  • R is the same or different and is hydrogen, F, Cl, Br, alkyl of from 1 to 4 carbons, benzyl, phenyl, or mono-substituted phenyl wherein the substituent is F, Cl, Br, 1, alkyl of from 1 to 4 carbons, alkoxy of from 1 to 4 carbons, or trifluoromethyl with the proviso that R may not be adjacent tertiary alkyl;
  • R is hydrogen, F, Cl, Br, I, alkyl of from 1 to 4 carbons, alkylsulfonyl wherein the alkyl has from 1 to 4 carbons, dialkylamidosulfonyl wherein each alkyl has from l to 4 carbons, trifluoromethyl; n is O or 1;
  • R" is hydrogen or alkyl of from 1 to 4 carbons
  • R, R, and R" being hydrogen; and pharmaceutically acceptable acid-addition salts thereof.
  • a compound of claim 11 having the name 6E- pyrimido-[ l ,2-c] 1,3 ,5 ]benzoxadiazepine.
  • a compound of claim 1 having the name 2-chloro- 6g-pyrimido[ 1,2-c] 1 ,3 ,5 ]benzoxadia2epine.
  • a compound of claim 1 having the name 6,7- dihydro-7-methyl-10-phenylpyrimido[ 1,2- d][ l,4,6]benzoxadiazocine.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
US382803A 1973-07-26 1973-07-26 6H-pyrimido{8 1,2-c{9 {8 1,3,5{9 {0 benzoxadiazepines Expired - Lifetime US3886158A (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
US382803A US3886158A (en) 1973-07-26 1973-07-26 6H-pyrimido{8 1,2-c{9 {8 1,3,5{9 {0 benzoxadiazepines
CA203,723A CA1051427A (fr) 1973-07-26 1974-06-28 6-h-pyrimido- (1,2-c) (1,3,5) benzoxadiazepines
GB2953374A GB1476124A (en) 1973-07-26 1974-07-03 Fused-ring benzoxadiazepine and benzoxadiazocine derivatives
DE2435383A DE2435383A1 (de) 1973-07-26 1974-07-23 Pyrimidobenzoxadiazepine und pyrimidobenzoxadiazocine, verfahren zu ihrer herstellung und arzneimittel
JP49086508A JPS5041893A (fr) 1973-07-26 1974-07-26
FR7426131A FR2238492B1 (fr) 1973-07-26 1974-07-26
US05/556,510 US3965101A (en) 1973-07-26 1975-03-07 1-(O-Bromo-phenoxyalkyl)-1,2-dihydro-2-iminopyrimidines

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US382803A US3886158A (en) 1973-07-26 1973-07-26 6H-pyrimido{8 1,2-c{9 {8 1,3,5{9 {0 benzoxadiazepines

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US05/556,510 Division US3965101A (en) 1973-07-26 1975-03-07 1-(O-Bromo-phenoxyalkyl)-1,2-dihydro-2-iminopyrimidines

Publications (1)

Publication Number Publication Date
US3886158A true US3886158A (en) 1975-05-27

Family

ID=23510470

Family Applications (1)

Application Number Title Priority Date Filing Date
US382803A Expired - Lifetime US3886158A (en) 1973-07-26 1973-07-26 6H-pyrimido{8 1,2-c{9 {8 1,3,5{9 {0 benzoxadiazepines

Country Status (6)

Country Link
US (1) US3886158A (fr)
JP (1) JPS5041893A (fr)
CA (1) CA1051427A (fr)
DE (1) DE2435383A1 (fr)
FR (1) FR2238492B1 (fr)
GB (1) GB1476124A (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3833588A (en) * 1972-04-25 1974-09-03 Sandoz Ag Unsaturated-substituted tricyclic quinazolinones

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3833588A (en) * 1972-04-25 1974-09-03 Sandoz Ag Unsaturated-substituted tricyclic quinazolinones

Also Published As

Publication number Publication date
FR2238492A1 (fr) 1975-02-21
GB1476124A (en) 1977-06-10
DE2435383A1 (de) 1975-02-13
FR2238492B1 (fr) 1978-07-28
JPS5041893A (fr) 1975-04-16
CA1051427A (fr) 1979-03-27

Similar Documents

Publication Publication Date Title
US4256748A (en) Imidazo[2,1-b]quinazolin-2(3H)-ones and pharmaceutical compositions for treatment and prophylaxis of cardiac insufficiency and cardiac failure
US5834462A (en) Tricyclic heterocyclic sulfonamide and sulfonic ester derivatives
CY1662A (en) Substituted benzamides
CS266310B2 (en) Process for preparing derivatives of benzmide
US3875162A (en) Certain 6H-pyrimido{8 1,2-c{9 {8 1,3,5{9 benzothiadiaza compounds
US3621099A (en) Therapeutic compositions and methods for stimulating the central nervous system
US3886158A (en) 6H-pyrimido{8 1,2-c{9 {8 1,3,5{9 {0 benzoxadiazepines
KR910003151B1 (ko) 벤조퀴놀리진의 제조방법
US3965101A (en) 1-(O-Bromo-phenoxyalkyl)-1,2-dihydro-2-iminopyrimidines
US3911129A (en) Pyrazolo-pyridine biologically active compounds
US3530137A (en) Certain alkyl and aryl ethers and thioethers of tropine and derivatives thereof
US3995042A (en) Pyridine containing compounds
CS229692B2 (en) Manufacturing process of derivate 4-phenylquinazoline
US3985760A (en) Amino derivatives of 6-phenylisoxazolo[5,4-b]pyridines
US3868374A (en) Therapeutic compounds and intermediates therefor
US4134975A (en) Stimulating the central nervous system
US3966733A (en) Intermediates for certain benzothiadiazepine and benzothiadiazocine compounds
US4108894A (en) Amidines
US5071849A (en) Dihydropyrimidothiazine derivatives
US3752820A (en) Substituted-1,2,3,4-tetrahydrobenzothieno(3,2-c)pyridine derivatives
US4062846A (en) Hydroxy pyrimido compounds
US3957806A (en) Intermediates for use in preparing therapeutic compounds
US3957799A (en) Sulfur containing amino and imino pyridines
US3957787A (en) 1,2-dihydro-2-imino-1-(bromophenylalkyl)pyrimidines
US3804836A (en) N-phenyl-n'-dialkylphosphinylalkyl-piperazines