Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
  • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
  • C07D253/06—1,2,4-Triazines
  • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
  • C07D253/07—1,2,4-Triazines having three 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
  • C07D253/075—Two hetero atoms, in positions 3 and 5
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/10—Antioedematous agents; Diuretics
• • 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
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
  • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
  • C07D253/06—1,2,4-Triazines

Definitions

• R R R R and R may be the same or diflerent and each represent a hydrogen atom or a straight or branched chain alkyl or alkenyl radical containing from 1 to 6 carbon atoms, which may optionally be substituted by one or more aryl groups.
• R in addition may represent an acyl (C -C group and R and R may independently represent a cycloalkyl, arylalkyl or aryl group. These compounds act as spasmolytics and phosphodiesterase inhibitors.
• This invention relates to certain heterocyclic compounds having pharmacological activity and to processes for the preparation thereof as well as pharmaceutical compositions containing them.
• imidazo [5,1-f] triazinones act as spasmolytics and phosphodiesterase inhibitors and have cardiotonic and diuretic properties. They are therefore particularly useful in the treatment of diseases involving constriction of bronchial muscle, for example asthma and bronchitis and also for the treatment of pulmonary oedema and congestive heart failure.
• the compounds may also be useful in the treatment of skin diseases, for example psoriasis.
• the present invention therefore provides compounds of the general formula I:
• R R R R and R may be the same or different and each represent a hydrogen atom or a straight or branched chain alkyl or alkenyl radical containing from 1 to 6 carbon atoms, which may optionally be substituted by one or more aryl groups.
• R in addition may represent an acyl (C -C group and R and R may independently represent a cycloalkyl, arylalkyl or aryl group.
• Preferred compounds are those in which R represents hydrogen or acyl (C R represents hydrogen, R represents hydrogen or lower alkyl (C R represents hydrogen or lower alkyl (C and R represents lower alkyl (C cycloalkyl (C aryl or arylalkyl (C alkyl). In a particular class of compounds R R and R all represent hydrogen. Preferred compounds are those whose preparation is described in the Examples.
• the compounds of the invention are inhibitors of the enzyme phosphodiesterase.
• hydrochloride is 8 times more potent than choline theophyllinate in inhibiting the degradative action of this enzyme on cyclic adenosine monophosphate, a humoral agent important in bronchodilator mechanisms.
• the compounds according to the invention may be formulated for use in human and veterinary medicine for therapeutic and prophylactic purposes. They will in general be used in the form of their physiologically acceptable salts. Preferred salts include the hydrochloride, sulphate, maleate, tartrate,. etc. Such compounds may be presented for use in the conventional manner with the aid of carriers or excipients and formulating agents as required, and with or without supplementary medicinal agents.
• compositions may include solid and liquid preparations for oral use, suppositories or injections, or forms suitable for administration by inhalation.
• Oral administration is most convenient in the form of tablets.
• Injections may be formulated with the aid of physiologically acceptable carriers and agents as solutions, suspensions or as dry products for reconstitution before use.
• the compounds according to the invention are conveniently delievered in the form of an aerosol spray presentation from pressurised packs or a nebuliser.
• the dosage unit may be determined by providing a valve to deliver a metered amount.
• a typical dose for treating asthma in humans is from 1-200 mg. depending on the age, weight and condition of the patient and the route of administration.
• the compounds according to the invention may be formulated in combination with compounds such as salbutamol and isoprenaline that have stimulant activity at B adrenoreceptors.
• These combinations as exemplified by Z-amino-S-methyl-7-propyl-imidazo[5,l-f] as triazin- 4(3H)-one and salbutamol, are more effective than the sum of the two active ingredients given separately and the compounds are therefore synergistic.
• the preceding combination was about 2.5 times more potent than pred-icted from the individual dose response curves.
• the provision of therapeutic compositions comprising as active ingredients, a compound according to the invention and a p-adrenoreceptor stimulant, in particular salbutamoi, represents an aspect of the present invention.
• the compounds according to the invention may be prepared by a number of processes.
• an amino guanidine II or an appropriate salt, e.g. hydrogen carbonate is condensed with an a-ketoester III to yield the as-triazinone ester -IV.
• the N-benzyl derivative V of the last mentioned compound is then converted into an amine VII, for example by Curtius degradation via the corresponding hydrazine VI or by Hofiman degradation of the amide.
• the amine VII may then be acylated by conventional procedures, e.g. using acid halides or anhydrides to give the intermediate VIII.
• This amide is then cyclised by refluxing with a cyclodehydrating agent e.g. phosphorus oxychloride, with concomitant removal of the protecting group. The sequence is shown in the chart.
• the final step can be carried out in two stages in which the benzyl group is first removed e.g. b'y hydrogenolysis in the presence of noble metal catalyst, and the triazinone VIIIa is then converted into IX by heating with a cyclodehydrating compound e.g. polyphosphoric acid.
• a cyclodehydrating compound e.g. polyphosphoric acid.
• R is other than hydrogen
• R X may be for example, halogen or tosylate in the presence of a strong base, for example sodium hydride and in a suitable solvent e.g. N,N-dimethylformamide.
• the resulting imine XIII then undergoes hydrogenolysis and cyclodehydration as before.
• EXAMPLE 3 3-Amino-2-benzyl-2,5-dihydro-a-methyl-5-oxoas-triazine-6-acetic acid, hydrazide 3-Amino 2 benzyl 2,5-dihydro-a-methyl-5-oxo-astriazine-6-acetic acid, ethyl ester (7.5 g.) in methanol (100 ml.) and hydrazine hydrate (100 ml.) was allowed to stand for 3 days. Evaporation of the solvents under reduced pressure and crystallisation of the residue from methanol yielded white needles, m.p. 246 C.
• N-[l-(3-amino-2-benzyl-2,5-dihydro--oxo-as-triazin-6-yl)ethylJisovaleramide gave N- [1-(3-amino-2,5-dihydro 5 oxo-as-triazin-6-yl)ethyl] isovaleramide, m.p.
• EXAMPLE 8 Z-Amino-S-methyl-7-propyl-imidazo[5,1-f] as-triazin- 4(3H)-one, hydrochloride Method A N-[1-(3-Arnino2,5-dihydro 5 oxo-as-triazin-G-yl) ethyl]butyramide g.) was stirred with polyphosphoric acid (70 g.) at 100 and the temperature was then raised to 140 for 1 hour. The hot yellow solution was poured into water (500 ml.) and neutralised with sodium carbonate to precipitate the imidazo-triazinone as a white solid, m.p. l254 (8.4 g.).
• N-[1-(3-amino-2,5-dihydro-S oxo-as-triazin 6- yl)ethyl]cyclopentanecarboxamide gave 2-amino-5 methyl-7-cyclopentyl-imidazo- [5,1-f]-as-triazin-4(3H)-one, m.p. 299302.
• N-[1-(3- amino-2,5-dihydro S-oxo-as-triazin 6-yl)ethyl]phenylacetamide gave 2-amino 7-benzyl-5-methyl-imidazo- [5,1-f]-as-triazin-4(3H)-one, m.p.
• N-[l-(3-amino-2-benzyl-2,5-dihydro-S-oxo-as-triazin 6 yl)ethyl]acetamide gave 2- amino-5,7-dimethyl-imidazo[5,1-f] as triazin-4(3H)- one, m.p. 380-384 (dec.); N-[1-(3-amino-2-benzyl-2,5- dihydro-5-oxo-as-triazin-6-yl)ethyl]valeramide gave 2- 8 amino-7-butyl 5 methyl-imidazo[5,1-f] -as-triazin-4- (3H)-one, m.p. 214215.
• This Example gives representative formulations containing as active ingredient 2-amino-5-methyl-7-propylimidazo[5,1-f]-as-triazin-4(3H)-one referred in the Examples as AH 8883.
• This compound is used in the form of the hydrochloride which is referred to as AH 8883A.
• Method of Manufacture Dissolve the AH 8883 and the sodium chloride in of the water for injections. When solution is complete make up to volume with further water for injections. Filter through a suitable clarifying tfilter.
• the solution can then either be packed into 1 ml. neutral glass snap-ring ampoules and sterilised by heating in an autoclave or by filtration or may be prepared aseptically.
• Final tablet Weight 200 Method of Manufacture Blend together the milled AH 8883A and Lactose. Prepare the requisite quantity of 5% Starch Paste and add to the mixed powder and mix until a uniform damp cohesive mass is formed. Granulate this mass by passing through a suitable mill or sieve to produce discrete granulates. Dry the granules in either a fluid bed drier or on trays in a hot air oven at a temperature of about 50 C. After drying pass the granules through a 30 mesh B.S. sieve to break up aggregates.
• the tablets containing 30 mg. AH 8883A each weigh about 200 mg. and are 8.0 mm. in diameter, those containing 10 mg. AH 8883A each weigh about 156 mg. and are 7.0 mm. in diameter.
• Inhalation Aerosol Formulation Mg./metered dose 1. AH 8883 base (micronised) 0.5 2. Sorbiton trioleate 0.5 3. Trichlorofluoromethane B.P. 23 4. Dichlorodifluoromethane B.P. 85
• Method of Manufacture Disperse the micronised AH 883 base in the trichlorofluoromethane with the Sorbitan trioleate. Fill the requisite volume of this dispersion into suitable aerosol cans and seal by means of a suitable metering valve. Pressurise the containers by injecting the dichlorofluoromethane through the valve.
• R and R may be the same or different and each represents a hydrogen atom or a straight or branched chain alkyl or alkenyl radical containing from 1 to 6 carbon atoms or such a radical substituted by at least one phenyl group, R is as defined for R and R or a C -C alkanoyl group, and R and R are as defined for R and R or a C -C cycloalkyl, or phenyl group.
• R represents hydrogen or C -C alk-anoyl
• R represents hydrogen, R represents hydrogen or C -C alkyl
• R represents hydrogen, or C -C :alkyl (C and R represents C -C alkyl, C -C cycloalkyl, phenyl or phenyl C -C alkyl.
• R and R may be the same or different and each represents a hydrogen atom or a straight or branched chain alkyl or alkenyl radical containing from 1 to 6 carbon atoms or such a radical substituted by at least one phenyl group, R is as defined for R and R or a C -C alkanoyl group and R and R are as defined for R and R or a C -C cycloalkyl, or phenyl group, which comprises, for the production of a compound in which R is hydrogen and R R R and R have the meanings given above, the cyclodehydration with phosphorous oxychloride or polyphosphoric acid of a compound of the formula 0 R4 0 R4 H 1 hi i NHCORa EN 1 NHCOR5 01 N N Rt 2NkN RiRzN N HzP 11 VIII VIIIB.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Cardiology (AREA)
• Hematology (AREA)
• Diabetes (AREA)
• Hospice & Palliative Care (AREA)
• Heart & Thoracic Surgery (AREA)
• Dermatology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Medicinal Preparation (AREA)
• Plural Heterocyclic Compounds (AREA)

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Publications (1)

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Cited By (29)

Families Citing this family (6)

• 0
  • BE BE791025D patent/BE791025A/xx unknown
• 1971
  • 1971-11-19 GB GB5375071A patent/GB1400999A/en not_active Expired
• 1972
  • 1972-10-23 IE IE1433/72A patent/IE37046B1/xx unknown
  • 1972-10-23 DK DK525172AA patent/DK138691B/da unknown
  • 1972-10-23 ZA ZA727532A patent/ZA727532B/xx unknown
  • 1972-10-25 US US00300749A patent/US3840537A/en not_active Expired - Lifetime
  • 1972-10-26 AU AU48191/72A patent/AU472127B2/en not_active Expired
  • 1972-10-27 IL IL40686A patent/IL40686A/xx unknown
  • 1972-11-01 CA CA155,720A patent/CA990292A/en not_active Expired
  • 1972-11-06 SE SE7214358A patent/SE402915B/xx unknown
  • 1972-11-08 FR FR7239498A patent/FR2160407B1/fr not_active Expired
  • 1972-11-10 DE DE2255172A patent/DE2255172A1/de not_active Withdrawn
  • 1972-11-16 PH PH14090*UA patent/PH9669A/en unknown
  • 1972-11-16 CH CH1668372A patent/CH594671A5/xx not_active IP Right Cessation
  • 1972-11-17 ES ES408736A patent/ES408736A1/es not_active Expired
  • 1972-11-17 NL NL7215646A patent/NL7215646A/xx not_active Application Discontinuation
  • 1972-11-17 JP JP11549572A patent/JPS563873B2/ja not_active Expired
  • 1972-11-17 AT AT982372A patent/AT321923B/de not_active IP Right Cessation

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