US3840537A - Imidazo(5,1-f)triazinones - Google Patents

Imidazo(5,1-f)triazinones Download PDF

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Publication number
US3840537A
US3840537A US00300749A US30074972A US3840537A US 3840537 A US3840537 A US 3840537A US 00300749 A US00300749 A US 00300749A US 30074972 A US30074972 A US 30074972A US 3840537 A US3840537 A US 3840537A
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Prior art keywords
amino
triazin
dihydro
oxo
benzyl
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Expired - Lifetime
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US00300749A
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English (en)
Inventor
S Garside
D Hartley
H Lunts
A Oxford
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Allen and Hanburys Ltd
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Allen and Hanburys Ltd
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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)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
US00300749A 1971-11-19 1972-10-25 Imidazo(5,1-f)triazinones Expired - Lifetime US3840537A (en)

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GB5375071A GB1400999A (en) 1971-11-19 1971-11-19 Imidazo-triazine compounds and their use in therapeutic compositions

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JP (1) JPS563873B2 (enrdf_load_stackoverflow)
AT (1) AT321923B (enrdf_load_stackoverflow)
AU (1) AU472127B2 (enrdf_load_stackoverflow)
BE (1) BE791025A (enrdf_load_stackoverflow)
CA (1) CA990292A (enrdf_load_stackoverflow)
CH (1) CH594671A5 (enrdf_load_stackoverflow)
DE (1) DE2255172A1 (enrdf_load_stackoverflow)
DK (1) DK138691B (enrdf_load_stackoverflow)
ES (1) ES408736A1 (enrdf_load_stackoverflow)
FR (1) FR2160407B1 (enrdf_load_stackoverflow)
GB (1) GB1400999A (enrdf_load_stackoverflow)
IE (1) IE37046B1 (enrdf_load_stackoverflow)
IL (1) IL40686A (enrdf_load_stackoverflow)
NL (1) NL7215646A (enrdf_load_stackoverflow)
PH (1) PH9669A (enrdf_load_stackoverflow)
SE (1) SE402915B (enrdf_load_stackoverflow)
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Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3887552A (en) * 1973-03-23 1975-06-03 Boehringer Sohn Ingelheim 5-Oxo-2,3-dihydro-imidazo(1,2-a)-s-triazines
US3928345A (en) * 1973-07-11 1975-12-23 Hoechst Ag Bis-triazinobenzimidazoles and their preparation
US3941785A (en) * 1973-01-04 1976-03-02 Allen & Hanburys Limited Imidazo [5,1-f]-as-triazines
US4107307A (en) * 1977-02-03 1978-08-15 American Cyanamid Company Imidazo [1,5-d]-as-triazine-4(3H)-ones and thiones
US4107308A (en) * 1977-10-18 1978-08-15 American Cyanamid Company Imidazo[1,5-d]-as-triazines
US4115572A (en) * 1977-02-03 1978-09-19 American Cyanamid Company Imidazo-[1,5-d]-as-triazin-1(2H)-ones and method of ameliorating asthma
USRE30511E (en) * 1977-02-03 1981-02-10 American Cyanamid Company Imidazo[1,5-d]-as-triazine-4(3H)-ones and thiones
US4395547A (en) * 1982-02-10 1983-07-26 American Cyanamid Co. Process for preparing 1-substituted-6-n-propyl-8-methylimidazo[1,5-d]-as-triazin-4(3H)-ones
US4469692A (en) * 1981-11-18 1984-09-04 Alkaloida Vegyeszeti Gyar Spiro derivatives of the pyrazolo [1,5-d] [1,2,4] triazine ring system and a process for the preparation thereof
WO2001013953A3 (en) * 1999-08-21 2001-09-20 Byk Gulden Lomberg Chem Fab Synergistic combination of pde inhibitors and beta 2 adrenoceptor agonist
US6362178B1 (en) 1997-11-12 2002-03-26 Bayer Aktiengesellschaft 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
WO2002098873A1 (en) * 2001-06-01 2002-12-12 Bayer Healthcare Ag 2-heteroaryl-imidazotriazinones and their use in the treatment of inflammatory or immune diseases
WO2002098879A1 (en) * 2001-06-01 2002-12-12 Bayer Healthcare Ag Imidazotriazinones derivatives and their use against inflammatory processes and/or immune diseases
US6555583B2 (en) 1998-08-26 2003-04-29 Smithkline Beecham Corporation Therapies for treating pulmonary diseases
US6624181B1 (en) * 1997-02-28 2003-09-23 Altana Pharma Ag Synergistic combination
US20040152700A1 (en) * 2001-05-09 2004-08-05 Ulrich Niewohner Novel use of 2-phenyl-substituted imidazotriazinones
US20050049250A1 (en) * 1998-06-20 2005-03-03 Bayer Aktiengesellschaft 7-Aikyl and cycloalkyl-substituted imidazotriazinones
US20060111354A1 (en) * 2002-07-16 2006-05-25 Peter Serno Medicaments containing vardenafil hydrochloride trihydrate
US20060217382A1 (en) * 2003-04-01 2006-09-28 Mui Cheung Imidazotriazine compounds
US20080249096A1 (en) * 2005-03-01 2008-10-09 Bayer Healthcare Ag Pharmaceutical Forms with Improved Pharmacokinetic Properties
US20080280914A1 (en) * 2005-01-15 2008-11-13 Bayer Healthcare Ag Intravenous Formulations of Pde Inhibitors
US20090017122A1 (en) * 2005-03-01 2009-01-15 Bayer Healthcare Ag Drug Forms Having Controlled Bioavailability
US20090186896A1 (en) * 2005-09-29 2009-07-23 Bayer Healthcare Ag PDE Inhibitors and Combinations Thereof for the Treatment of Urological Disorders
US20100184769A1 (en) * 2007-06-13 2010-07-22 Bayer Schering Pharma Aktiengesellschaft Pde inhibitors for the treatment of hearing impairment
US20110190496A1 (en) * 2005-11-17 2011-08-04 Osi Pharmaceuticals, Inc. FUSED BICYCLIC mTOR INHIBITORS
US8513415B2 (en) 2009-04-20 2013-08-20 OSI Pharmaceuticals, LLC Preparation of C-pyrazine-methylamines
CN103374002A (zh) * 2012-04-19 2013-10-30 山东轩竹医药科技有限公司 磷酸二酯酶-5抑制剂
US8653268B2 (en) 2004-04-02 2014-02-18 OSI Pharmaceuticals, LLC 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors
WO2017003895A1 (en) * 2015-07-01 2017-01-05 Merck Sharp & Dohme Corp. Bicyclic heterocyclic compounds as pde2 inhibitors

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK109578A (da) * 1977-03-25 1978-09-26 Allen & Hanburys Ltd Fremgangsmaade til fremstilling af heterocycliske forbindelser
US4308384A (en) * 1978-09-18 1981-12-29 Glaxo Group Limited Production of triazinones
AU622330B2 (en) * 1989-06-23 1992-04-02 Takeda Chemical Industries Ltd. Condensed heterocyclic compounds having a nitrogen atom in the bridgehead for use as fungicides
DE10135815A1 (de) 2001-07-23 2003-02-06 Bayer Ag Verwendung von 2-Alkoxyphenyl-substituierten Imidazotriazinonen
JP2018508555A (ja) * 2015-03-16 2018-03-29 大日本住友製薬株式会社 二環性イミダゾロ誘導体
WO2017204316A1 (ja) * 2016-05-27 2017-11-30 塩野義製薬株式会社 ５－オキソ－１，２，４－トリアジン誘導体およびその医薬組成物

Cited By (64)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3941785A (en) * 1973-01-04 1976-03-02 Allen & Hanburys Limited Imidazo [5,1-f]-as-triazines
US3887552A (en) * 1973-03-23 1975-06-03 Boehringer Sohn Ingelheim 5-Oxo-2,3-dihydro-imidazo(1,2-a)-s-triazines
US3928345A (en) * 1973-07-11 1975-12-23 Hoechst Ag Bis-triazinobenzimidazoles and their preparation
US4107307A (en) * 1977-02-03 1978-08-15 American Cyanamid Company Imidazo [1,5-d]-as-triazine-4(3H)-ones and thiones
US4115572A (en) * 1977-02-03 1978-09-19 American Cyanamid Company Imidazo-[1,5-d]-as-triazin-1(2H)-ones and method of ameliorating asthma
USRE30511E (en) * 1977-02-03 1981-02-10 American Cyanamid Company Imidazo[1,5-d]-as-triazine-4(3H)-ones and thiones
US4107308A (en) * 1977-10-18 1978-08-15 American Cyanamid Company Imidazo[1,5-d]-as-triazines
US4469692A (en) * 1981-11-18 1984-09-04 Alkaloida Vegyeszeti Gyar Spiro derivatives of the pyrazolo [1,5-d] [1,2,4] triazine ring system and a process for the preparation thereof
US4395547A (en) * 1982-02-10 1983-07-26 American Cyanamid Co. Process for preparing 1-substituted-6-n-propyl-8-methylimidazo[1,5-d]-as-triazin-4(3H)-ones
US6624181B1 (en) * 1997-02-28 2003-09-23 Altana Pharma Ag Synergistic combination
US6566360B1 (en) 1997-11-12 2003-05-20 Bayer Aktiengesellschaft 2-phenyl substituted imidatriazinones as phosphodiesterase inhibitors
US7314871B2 (en) 1997-11-12 2008-01-01 Bayer Aktiengesellschaft 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors, for treatment of hypertension
US20110009367A1 (en) * 1997-11-12 2011-01-13 Bayer Schering Pharma Aktiengesellschaft 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
US7704999B2 (en) 1997-11-12 2010-04-27 Bayer Schering Pharma Aktiengesellschaft 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
US7696206B2 (en) 1997-11-12 2010-04-13 Bayer Schering Pharma Aktiengesellschaft 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
US6362178B1 (en) 1997-11-12 2002-03-26 Bayer Aktiengesellschaft 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
US20060189615A1 (en) * 1997-11-12 2006-08-24 Bayer Aktiengesellschaft 2-Phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
US20040067945A1 (en) * 1997-11-12 2004-04-08 Ulrich Niewohner 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
US7122540B2 (en) 1997-11-12 2006-10-17 Bayer Healthcare Ag 2-Phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
CN100430396C (zh) * 1997-11-12 2008-11-05 拜耳医药保健股份公司 用作磷酸二酯酶抑制剂的2-苯基取代的咪唑并三嗪酮
US20100016323A1 (en) * 1997-11-12 2010-01-21 Bayer Schering Pharma Aktiengesellschaft 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
US20050070541A1 (en) * 1997-11-12 2005-03-31 Bayer Aktiengesellschaft 2-Phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
US6890922B2 (en) 1997-11-12 2005-05-10 Bayer Healthcare Ag 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
US20040034087A1 (en) * 1998-02-24 2004-02-19 Altana Pharma Ag Synergistic combination
US20060079539A1 (en) * 1998-02-24 2006-04-13 Altana Pharma Ag Synergistic combination
US20060205806A1 (en) * 1998-02-24 2006-09-14 Altana Pharma Ag Synergistic combination
US7056936B2 (en) 1998-02-24 2006-06-06 Altana Pharma Ag Synergistic combination
US20050049250A1 (en) * 1998-06-20 2005-03-03 Bayer Aktiengesellschaft 7-Aikyl and cycloalkyl-substituted imidazotriazinones
US6943163B2 (en) 1998-06-20 2005-09-13 Bayer Aktiengesellschaft 7-Alkyl and cycloalkyl-substituted imidazotriazinones
US6555583B2 (en) 1998-08-26 2003-04-29 Smithkline Beecham Corporation Therapies for treating pulmonary diseases
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CH594671A5 (enrdf_load_stackoverflow) 1978-01-13
JPS563873B2 (enrdf_load_stackoverflow) 1981-01-27
AT321923B (de) 1975-04-25
GB1400999A (en) 1975-07-16
PH9669A (en) 1976-02-10
ZA727532B (en) 1973-07-25
JPS4857993A (enrdf_load_stackoverflow) 1973-08-14
ES408736A1 (es) 1976-03-01
FR2160407B1 (enrdf_load_stackoverflow) 1975-10-17
SE402915B (sv) 1978-07-24
IE37046L (en) 1973-05-19
NL7215646A (enrdf_load_stackoverflow) 1973-05-22
IE37046B1 (en) 1977-04-27
AU4819172A (en) 1974-05-16
AU472127B2 (en) 1976-05-20
CA990292A (en) 1976-06-01
IL40686A (en) 1975-12-31
BE791025A (fr) 1973-05-07
DK138691B (da) 1978-10-16
DK138691C (enrdf_load_stackoverflow) 1979-03-26
DE2255172A1 (de) 1973-05-24
IL40686A0 (en) 1972-12-29
FR2160407A1 (enrdf_load_stackoverflow) 1973-06-29

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