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US20020183326A1 - 1,2,4-triazolo[4,3-B]pyrido[3,2-D]pyridazine derivatives and pharmaceutical compositions containing them - Google Patents

1,2,4-triazolo[4,3-B]pyrido[3,2-D]pyridazine derivatives and pharmaceutical compositions containing them Download PDF

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US20020183326A1
US20020183326A1 US10/038,777 US3877702A US2002183326A1 US 20020183326 A1 US20020183326 A1 US 20020183326A1 US 3877702 A US3877702 A US 3877702A US 2002183326 A1 US2002183326 A1 US 2002183326A1
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Jordi Ferrer
M. Crespo Crespo
Armando Vega Noverola
Andres Fernandez Garcia
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Almirall SA
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Almirall Prodesfarma SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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

Definitions

  • This invention relates to new therapeutically useful heterocyclic compounds, to process for their preparation and to pharmaceutical compositions containing them.
  • PDE 4 phosphodiesterase 4
  • EP-A-85,840 discloses a series of triazolo-phthalazine derivatives of formula:
  • the present invention provides a compound which is a heterocycle of formula (I):
  • R 1 represents a hydrogen atom or a —(CH 2 ) m —Y group, wherein m is an integer from 0 to 4 and Y represents an alkyl, haloalkyl (preferably trifluoromethyl), alkoxy, alkoxycarbonyl, C 3 -C 7 cycloalkyl, norbornyl (preferably 2-norbornyl) or phenylalkenyl group, or an aromatic group (preferably phenyl or pyridyl) which aromatic group Y may optionally be substituted by one or more halogen atoms;
  • R 2 represents an aromatic group (preferably phenyl, naphthyl or thienyl) which aromatic group may optionally be substituted by one or more halogen atoms or alkyl, alkoxy, C 3 -C 6 cycloalkoxy, methylenedioxy, nitro, dialkylamino or trifluoromethyl groups; and
  • R 3 represents a hydrogen or halogen atom (preferably chloro) or an alkyl group
  • alkyl, haloalkyl, alkenyl or alkynyl groups and moieties such as in the alkoxy groups, mentioned in relation to the groups R 1 —R 3 in compounds of the invention are usually “lower” alkyl, that is containing up to 6 and particularly up to 4 carbon atoms, the hydrocarbon chain being branched or straight.
  • alkyl groups and moieties are CH 3 , C 2 H 5 , C 3 H 7 , i-C 3 H 7 , n—C 4 H 9 , i—C 4 H 9 , isoamyl and neopentyl.
  • R 1 are the preferred alkyl groups mentioned above, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl and cyclopenthylmethyl.
  • R 2 examples are phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl and 3-nitrophenyl.
  • R 3 are hydrogen, alkyl or chloro, preferably in the 8- or 9-positions.
  • heterocyclic compounds of formula (I) can be prepared from the corresponding hydrazine derivative of formula (II):
  • R 2 and R 3 are as defined above, by reaction with a reactive derivative of a carboxylic acid of the general formula (III):
  • R 1 is as defined above.
  • the reactive derivative of the said carboxylic acid may be, for example, a halide (preferably chloride), an anhydride or a mixed anhydride.
  • the reaction is preferably carried out in an inert organic solvent such as methylene chloride, dioxane or tetrahydrofuran, in the presence of an organic nitrogen-containing base, e.g. triethylamine and at a temperature between ⁇ 10° C. and +60° C.
  • an organic nitrogen-containing base e.g. triethylamine
  • the hydrazine derivative of formula (II) may be prepared by:
  • R 2 and R 3 are as defined above and R 4 is an alkyl group, with a phosphorus halide or phosphorus oxyhalide (preferably phosphorus oxychloride), to form the intermediate compound of formula (VI):
  • R 2 and R 3 are as defined above and X is a chlorine or bromine atom;
  • R 5 is an alkyl group
  • R 2 , R 3 and R 5 are as defined above;
  • reaction of (VI) with the alkyl carbazate of formula (VII) to obtain the corresponding alkoxycarbonylhydrazine derivative (VIII), is preferably carried out in the presence of an organic solvent as tetrahydrofuran or dioxan at a temperature of from 60° C. to the boiling point of the reaction medium.
  • the alkoxycarbonylhydrazine derivative (VIII) may, for example, be transformed into the hydrazine derivative (II) at room temperature in hydrogen chloride-ethanol saturated solution.
  • hydrazone derivatives of formula (V) are known compounds which can be prepared from the corresponding 2-acylnicotinic acid by known methods described in the literature.
  • Compound A is 3-isobutyl-6-phenyl-1,2,4-triazolo[3,4-a]phthalazine, a compound included in EP-A-8-5,840.
  • the compounds of formula (I) are cyclic phosphodiestrerase inhibitors, in particular type 4 cyclic AMP phosphodiesterase inhibitors.
  • the compounds are also capable of blocking the production of some pro-inflammatory cytokines such as, for example, TNF ⁇ .
  • pro-inflammatory cytokines such as, for example, TNF ⁇ .
  • they can be used in the treatment of allergic, inflammatory and immunological diseases, as well as those disease or conditions where the blockade of pro-inflammatory cytokines or the selective inhibition of PDE 4 could be of benefit.
  • These diseases states include asthma, rheumatoid arthritis, osteoarthritis, osteoporosis, bone-formation disorders, glomerulonephritis, multiple sclerosis, Graves ophtalmopathy, myasthenia gravis, insulin-dependent diabetes mellitus, graft rejection, gastrointestinal disorders such as ulcerative colitis or Crohn disease, septic shock, adult distress respiratory syndrome, and skin diseases such as atopic dermatitis, contact dermatitis, acute dermatomyositis and psoriasis.
  • the compounds of the present invention are also of benefit when administered in combination with other drugs such as steroids and immunosuppressive agents, such as cyclosporin A, rapamycin or T-cell receptor blockers.
  • other drugs such as steroids and immunosuppressive agents, such as cyclosporin A, rapamycin or T-cell receptor blockers.
  • the administration of the compounds allows a reduction of the dosage of the other drugs, thus preventing the appearance of the undesired side effects associated with both steroids and immunosuppressants.
  • the compounds of the invention have also shown their efficacy in blocking, after preventive and/or curative treatment, the erosive and ulcerogenic effects induced by a variety of etiological agents, such as antiinflammatory drugs (steroidal or non-steroidal antiinflammatory agents), stress, ammonia, ethanol and concentrated acids. They can be used alone or in combination with antacids and/or antisecretory drugs in the preventive and/or curative treatment of gastrointestinal pathologies like drug-induced ulcers, peptic ulcers, H. Pylori -related ulcers, esophagitis and gastro-esophageal reflux disease.
  • antiinflammatory drugs steroidal or non-steroidal antiinflammatory agents
  • stress erosive and ulcerogenic effects induced by a variety of etiological agents
  • antacids and/or antisecretory drugs in the preventive and/or curative treatment of gastrointestinal pathologies like drug-induced ulcers, peptic ulcers, H. Pylori -related ulcers, es
  • the present invention also provides a heterocyclic compound of formula (I) for use in a method of treatment of the human or animal body by therapy, particularly for use as a PDE 4 inhibitor or to block the production of a pro-inflammatory cytokine such as TNF ⁇ .
  • the present invention additionally provides a pharmaceutical composition which comprises, as active ingredient, at least one heterocyclic compound of formula (I), and a pharmaceutically acceptable carrier or diluent.
  • compositions are in a form suitable for oral, inhalation, rectal, transdermal, nasal, topical or parenteral administration.
  • compositions of this invention are well known per se and the actual excipients used depend inter alia on the intended method of administration of the compositions.
  • compositions of this invention are preferably adapted for administration per os.
  • the compositions for oral administration may take the form of tablets, capsules, lozenges or effervescent granules or liquid preparations such as elixirs, syrups or suspensions, all containing one or more compounds of the invention.
  • Such preparations may be made by methods well known in the art, for instance by mixing the heterocyclic compound of formula (I) with the pharmaceutically acceptable carrier or diluent.
  • the diluents which may be used in the preparation of the compositions include those liquid and solid diluents which are compatible with the active ingredient, together with colouring or flavouring agents if desided.
  • Tablets or capsules may conveniently contain from 1 to 100 mg and preferably from 5 to 50 mg of active ingredient.
  • the compounds may also be incorporated into pellets coated with appropriate natural or synthetic polymers known in the art to produce sustained release characteristics or incorporated with polymers into tablet form to produce the same characteristics.
  • the liquid compositions adapted for oral use may be in the form of solutions, suspensions or aerosols.
  • the solutions may be aqueous or aqueous-alcoholic solutions in association with, for example, sucrose or sorbitol to form a syrup.
  • the suspensions may comprise an insoluble or microencapsulated form of an active compound of the invention in association with water and other acceptable solvents together with a suspending agent or flavouring agent.
  • compositions for inhalation administration may be in the form of solutions, suspensions or micronized powder, contained in an appropriate inhaler.
  • compositions for parenteral injection may be prepared, which may or may not be freeze-dried and which may be dissolved in water or an appropriate parenteral injection fluid.
  • the doses of the heterocyclic compound depend on the desired effect and duration of the treatment; adult doses are generally from 1 mg to 100 mg per day. In general the physician will decide the posology, taking into account the age and weight of the patient being treated.
  • microcrystalline suspension prepared with these ingredients was introduced in the inhalation-flasks at a volume of 20 ml per flask with a filling machine.
  • the flasks were furnished with an appropriate valve which released 0.2 ml of suspension for each activation (0.4 mg of active compound).

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  • Hematology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Obesity (AREA)
  • Biomedical Technology (AREA)
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  • Nitrogen Condensed Heterocyclic Rings (AREA)
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Abstract

Heterocyclic compounds of formula (I),
Figure US20020183326A1-20021205-C00001
wherein R1 represents a hydrogen atom or a —(CH2)M—Y group, wherein m is an integer from 0 to 4 and Y represents an alkyl, haloalkyl, alkoxy, alkoxycarbonyl, C3-C7 cycloalkyl, norbornyl or phenylalkenyl group, or an aromatic group which aromatic group ^ may optionally be substituted by one or more halogen atoms; R2 represents an aromatic group which aromatic group may optionally be substituted by one or more halogen atoms or alkyl, alkoxy, C3-C6 cycloalkoxy, methylenedioxy, nitro, dialkylamino or trifluoromethyl groups, and R3 represents a hydrogen or halogen atom or an alkyl group, and pharmaceutically acceptable salts thereof, processes for preparing the same. The compounds are phosphodiesterase 4 inhibitors.

Description

  • This invention relates to new therapeutically useful heterocyclic compounds, to process for their preparation and to pharmaceutical compositions containing them. [0001]
  • It is known that inhibitors of phosphodiesterase 4 (PDE 4) are useful in the treatment of inflammatory and allergic processes such as asthma, non-steroidal antiinflammatory drugs-induced gastrointestinal damage and atopic dermatitis. [0002]
  • EP-A-85,840 discloses a series of triazolo-phthalazine derivatives of formula: [0003]
    Figure US20020183326A1-20021205-C00002
  • which are useful as anxiolytic agents. [0004]
  • We have now found that the presence of a pyridine ring instead of the benzo ring in the above structure, provides new compounds which inhibit cyclic phosphodiesterases, in particular type 4 cyclic phosphodiesterases and have a very low emetic activity (10-100 times less active than rolipram in inducing emesis in dogs). [0005]
  • Accordingly, the present invention provides a compound which is a heterocycle of formula (I): [0006]
    Figure US20020183326A1-20021205-C00003
  • wherein: [0007]
  • R[0008] 1 represents a hydrogen atom or a —(CH2)m—Y group, wherein m is an integer from 0 to 4 and Y represents an alkyl, haloalkyl (preferably trifluoromethyl), alkoxy, alkoxycarbonyl, C3-C7 cycloalkyl, norbornyl (preferably 2-norbornyl) or phenylalkenyl group, or an aromatic group (preferably phenyl or pyridyl) which aromatic group Y may optionally be substituted by one or more halogen atoms;
  • R[0009] 2 represents an aromatic group (preferably phenyl, naphthyl or thienyl) which aromatic group may optionally be substituted by one or more halogen atoms or alkyl, alkoxy, C3-C6 cycloalkoxy, methylenedioxy, nitro, dialkylamino or trifluoromethyl groups; and
  • R[0010] 3 represents a hydrogen or halogen atom (preferably chloro) or an alkyl group,
  • and pharmaceutically acceptable salts thereof. [0011]
  • The alkyl, haloalkyl, alkenyl or alkynyl groups and moieties, such as in the alkoxy groups, mentioned in relation to the groups R[0012] 1—R3 in compounds of the invention are usually “lower” alkyl, that is containing up to 6 and particularly up to 4 carbon atoms, the hydrocarbon chain being branched or straight. Examples of alkyl groups and moieties are CH3, C2H5, C3H7, i-C3H7, n—C4H9, i—C4H9, isoamyl and neopentyl.
  • When any of the groups, such as R[0013] 1 or R2 has a chiral centre, the compounds of formula (I) exhibit optical isomerism and the isomers are within the scope of the present invention.
  • Examples of R[0014] 1 are the preferred alkyl groups mentioned above, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl and cyclopenthylmethyl.
  • Examples of R[0015] 2 are phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl and 3-nitrophenyl.
  • Examples of R[0016] 3 are hydrogen, alkyl or chloro, preferably in the 8- or 9-positions.
  • The most preferred compounds of the invention are [0017]
  • 6-(4-fluorophenyl)-3-isobutyl-1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine, 3-cyclopropylmethyl-6-(3-nitrophenyl)-1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine, 3-cyclopropyl-6-phenyl-1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine, and 3-cyclobutylmethyl-6-(3-nitrophenyl)-1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine. [0018]
  • According to a further feature of the present invention, the heterocyclic compounds of formula (I) can be prepared from the corresponding hydrazine derivative of formula (II): [0019]
    Figure US20020183326A1-20021205-C00004
  • wherein [0020]
  • R[0021] 2 and R3 are as defined above, by reaction with a reactive derivative of a carboxylic acid of the general formula (III):
  • HOOC—R1  (III)
  • wherein R[0022] 1 is as defined above. The reactive derivative of the said carboxylic acid may be, for example, a halide (preferably chloride), an anhydride or a mixed anhydride.
  • The reaction is preferably carried out in an inert organic solvent such as methylene chloride, dioxane or tetrahydrofuran, in the presence of an organic nitrogen-containing base, e.g. triethylamine and at a temperature between −10° C. and +60° C. In the reaction, the corresponding hydrazide of general formula (IV) is first formed: [0023]
    Figure US20020183326A1-20021205-C00005
  • wherein R[0024] 1, R2 and R3 are as defined above. A suspension of this hydrazide (IV) in an organic solvent such as dioxane, tetrahydrofuran, isopropanol or n-butanol, is heated, for example at the boiling point of the solvent, to give the corresponding heterocyclic compound of formula (I).
  • The hydrazine derivative of formula (II) may be prepared by: [0025]
  • 1) reacting a hydrazone of formula (V): [0026]
    Figure US20020183326A1-20021205-C00006
  • wherein R[0027] 2 and R3 are as defined above and R4 is an alkyl group, with a phosphorus halide or phosphorus oxyhalide (preferably phosphorus oxychloride), to form the intermediate compound of formula (VI):
    Figure US20020183326A1-20021205-C00007
  • wherein R[0028] 2 and R3 are as defined above and X is a chlorine or bromine atom;
  • 2) reacting compound (VI) with an alkyl carbazate (preferably t-butyl carbazate) of formula (VII): [0029]
  • H2N—NH—COOR5  (VII)
  • wherein R[0030] 5 is an alkyl group, to give the alkoxycarbonylhydrazine derivative (VIII):
    Figure US20020183326A1-20021205-C00008
  • wherein R[0031] 2, R3 and R5 are as defined above; and
  • 3) treating compound (VIII) with hydrogen chloride in an anhydrous solvent as ethanol. [0032]
  • The reaction between the hydrazone of formula (V) and a phosphorus halide or phosphorus oxyhalide is carried out with an excess of reagent at a temperature from 80° C. to 120° C., then removed the excess of reagent and poured into cold water. In this way the compound (VI) is obtained. [0033]
  • The reaction of (VI) with the alkyl carbazate of formula (VII) to obtain the corresponding alkoxycarbonylhydrazine derivative (VIII), is preferably carried out in the presence of an organic solvent as tetrahydrofuran or dioxan at a temperature of from 60° C. to the boiling point of the reaction medium. [0034]
  • The alkoxycarbonylhydrazine derivative (VIII) may, for example, be transformed into the hydrazine derivative (II) at room temperature in hydrogen chloride-ethanol saturated solution. [0035]
  • The hydrazone derivatives of formula (V) are known compounds which can be prepared from the corresponding 2-acylnicotinic acid by known methods described in the literature. [0036]
  • The inhibition of cyclic nucleotide phosphodiesterase 4 from guinea-pig hearts was performed using 96-well microtiter plates as described by Verghese et al., (Molecular Pharmacology, 47, 1164-1171 (1995)). [0037]
  • The results from such test are shown in Table 1. [0038]
    TABLE 1
    PDE4
    Compound * IC50 (μM)
    A 10
    6 2
    7 0.3
    12 3
    31 0.2
    47 0.7
    55 0.2
    60 0.1
    61 2
    109 0.04
    112 0.7
    113 0.2
  • Compound A is 3-isobutyl-6-phenyl-1,2,4-triazolo[3,4-a]phthalazine, a compound included in EP-A-8-5,840. [0039]
  • As it can be seen from Table 1, the compounds of formula (I) are cyclic phosphodiestrerase inhibitors, in particular type 4 cyclic AMP phosphodiesterase inhibitors. The compounds are also capable of blocking the production of some pro-inflammatory cytokines such as, for example, TNFα. Thus, they can be used in the treatment of allergic, inflammatory and immunological diseases, as well as those disease or conditions where the blockade of pro-inflammatory cytokines or the selective inhibition of PDE 4 could be of benefit. [0040]
  • These diseases states include asthma, rheumatoid arthritis, osteoarthritis, osteoporosis, bone-formation disorders, glomerulonephritis, multiple sclerosis, Graves ophtalmopathy, myasthenia gravis, insulin-dependent diabetes mellitus, graft rejection, gastrointestinal disorders such as ulcerative colitis or Crohn disease, septic shock, adult distress respiratory syndrome, and skin diseases such as atopic dermatitis, contact dermatitis, acute dermatomyositis and psoriasis. [0041]
  • They can also be used as improvers of cerebrovascular function as well as in the treatment of other CNS related diseases such as dementia, Alzheimer's disease, depression, and as nootropic agents. [0042]
  • The compounds of the present invention are also of benefit when administered in combination with other drugs such as steroids and immunosuppressive agents, such as cyclosporin A, rapamycin or T-cell receptor blockers. In this case the administration of the compounds allows a reduction of the dosage of the other drugs, thus preventing the appearance of the undesired side effects associated with both steroids and immunosuppressants. [0043]
  • The compounds of the invention have also shown their efficacy in blocking, after preventive and/or curative treatment, the erosive and ulcerogenic effects induced by a variety of etiological agents, such as antiinflammatory drugs (steroidal or non-steroidal antiinflammatory agents), stress, ammonia, ethanol and concentrated acids. They can be used alone or in combination with antacids and/or antisecretory drugs in the preventive and/or curative treatment of gastrointestinal pathologies like drug-induced ulcers, peptic ulcers, [0044] H. Pylori-related ulcers, esophagitis and gastro-esophageal reflux disease.
  • They can also be used in the treatment of pathological situations where damage to the cells or tissues is produced through conditions like anoxia or the production of an excess of free radicals. Examples of such beneficial effects are the protection of cardiac tissue after coronary artery occlusion or the prolongation of cell and tissue viability when the compounds of the invention are added to preserving solutions intended for storage of transplant organs or fluids such as blood or sperm. They are also of benefit on tissue repair and wound healing. [0045]
  • The present invention also provides a heterocyclic compound of formula (I) for use in a method of treatment of the human or animal body by therapy, particularly for use as a PDE 4 inhibitor or to block the production of a pro-inflammatory cytokine such as TNFα. [0046]
  • The present invention additionally provides a pharmaceutical composition which comprises, as active ingredient, at least one heterocyclic compound of formula (I), and a pharmaceutically acceptable carrier or diluent. [0047]
  • Preferably the compositions are in a form suitable for oral, inhalation, rectal, transdermal, nasal, topical or parenteral administration. [0048]
  • The pharmaceutically-acceptable carriers or diluents which are admixed with the active compound or compounds to form the compositions of this invention are well known per se and the actual excipients used depend inter alia on the intended method of administration of the compositions. [0049]
  • Compositions of this invention are preferably adapted for administration per os. The compositions for oral administration may take the form of tablets, capsules, lozenges or effervescent granules or liquid preparations such as elixirs, syrups or suspensions, all containing one or more compounds of the invention. Such preparations may be made by methods well known in the art, for instance by mixing the heterocyclic compound of formula (I) with the pharmaceutically acceptable carrier or diluent. [0050]
  • The diluents which may be used in the preparation of the compositions include those liquid and solid diluents which are compatible with the active ingredient, together with colouring or flavouring agents if desided. Tablets or capsules may conveniently contain from 1 to 100 mg and preferably from 5 to 50 mg of active ingredient. The compounds may also be incorporated into pellets coated with appropriate natural or synthetic polymers known in the art to produce sustained release characteristics or incorporated with polymers into tablet form to produce the same characteristics. [0051]
  • The liquid compositions adapted for oral use may be in the form of solutions, suspensions or aerosols. The solutions may be aqueous or aqueous-alcoholic solutions in association with, for example, sucrose or sorbitol to form a syrup. The suspensions may comprise an insoluble or microencapsulated form of an active compound of the invention in association with water and other acceptable solvents together with a suspending agent or flavouring agent. [0052]
  • Compositions for inhalation administration may be in the form of solutions, suspensions or micronized powder, contained in an appropriate inhaler. [0053]
  • Compositions for parenteral injection may be prepared, which may or may not be freeze-dried and which may be dissolved in water or an appropriate parenteral injection fluid. [0054]
  • In human therapy, the doses of the heterocyclic compound depend on the desired effect and duration of the treatment; adult doses are generally from 1 mg to 100 mg per day. In general the physician will decide the posology, taking into account the age and weight of the patient being treated. [0055]
  • The following Examples further illustrate the invention.[0056]
    • EXAMPLE 1
  • a) A mixture of t-butoxycarbonylhydrazone of 2-benzoylnicotinic acid (45 g; 13.2 mols) in phosphorus oxychloride (500 ml) was boiled under reflux for one hour, then the excess of phosphorus oxychloride was removed under reduced pressure, the residue treated with ice-water and extracted twice with methylene chloride. The organic solution was washed with 4% sodium bicarbonate aqueous solution, with brine and after drying (Na[0057] 2SO4), the solvent removed in vacuo. The obtained solid was collected with a mixture of diethyl ether-petrol ether 1:1 to give 5-chloro-8-phenylpyrido[2,3-d]pyridazine as a red solid, (25.4 g; 80% yield).
  • b) To a suspension of the above compound (18.2; 0.075 mols) in anhydrous tetrahydrofuran (180 ml), t-butyl carbazate (10.0 g; 0.075 mols) was added and the mixture was boiled under reflux for one hour. After cooling the crystallized solid was collected by filtration when 5-t-butoxycarbonylhydrazino-8-phenylpyrido[2,3-d]pyridazine was obtained (28.5 g). This compound was solved in ethanol (150 ml), hydrogen chloride in ethanol saturated solution (100 ml) was added and the resulting mixture stirred at room temperature for 15 hours. A solid was formed which was collected by filtration and washed with diethyl ether to give 5-hydrazino-8-phenylpyrido[2,3-d]pyridazine dihydrochloride (21.6 g; 92% yield). [0058]
  • c) To a suspension of 5-hydrazino-8-phenylpyrido[2,3-d]pyridazine dihydrochloride (1.24 g; 0.004 mols) in methylene chloride (30 ml), triethylamine (1.9 ml; 0.013 mols) was added, then stirred at room temperature for 15 minutes and pivaloyl chloride (0.5 ml; 0.0044 moles) slowly added. After stirring at room temperature for two hours, water (30 ml) was added, the formed yellow solid, collected by filtration and washed with diethyl ether to give the intermediate hydrazide. This compound was suspended in n-butanol (30 ml), boiled under reflux for 15 hours and on cooling, crystallized a white solid which was collected by filtration and washed with diethyl ether. The obtained solid was purified by flash column chromatography with silica gel and methylene chloride-ethanol-ammonium hydroxide 200:8:1 as eluent. 3-t-butyl-6-phenyl-1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine was obtained (0.83 g; 69% yield), m.p. 188.1 (determined by Differential Scanning Calorimetry, Perkin-Elmer DSC-7 (compound 8 in Table 2). [0059]
  • The heterocyclic compounds of formula (I) in Table 2 were prepared according to the processes disclosed in this Example, but with the appropriate starting materials. [0060]
    TABLE 2
    Figure US20020183326A1-20021205-C00009
    Compound R1 R2 R3 m.p. ° C.
    1 H C6H5 H 215.8
    2 CH3 ″ ″ 215.9
    3 C2H5 ″ ″ 194.1
    4 C3H7 ″ ″ 168.1
    5 i-C3H7 ″ ″ 176.8
    6 n-C4H9 ″ ″ 162.9
    7 i-C4H9 ″ ″ 179.7
    8 t-C4H9 ″ ″ 188.1
    9 n-C5H11 ″ ″ 137.4
    10 neopentyl ″ ″ 216.3
    11 t-amyl ″ ″ 153
    12 cyclopropyl ″ ″ 244.3
    13 cyclobutyl ″ ″ 218
    14 cyclopentyl ″ ″ 202.4
    15 cyclohexyl ″ ″ 196.3
    16 cyclopropyl-CH2 ″ ″ 195
    17 cyclobutyl-CH2 ″ ″ 183
    18 cyclopentyl-CH2 ″ ″ 193
    19 cyclohexyl-CH2 ″ ″ 212.8
    20 2-norbornyl-CH2 ″ ″ 217
    21 C6H5 ″ ″ 304.1
    22 C6H5—CH2 ″ ″ 192
    23 C6H5—CH2CH2 ″ ″ 176
    24 C6H5—CH═CH ″ ″ 278
    25 CF3 ″ ″ 192.5
    26 H3CO—CH2 ″ ″ 159
    27 2-ClC6H4 ″ ″ 206
    28 4-pyridyl ″ ″ 333.4
    29 CH3 4-FC6H4 ″ 276
    30 n-C4H9 ″ ″ 111
    31 i-C4H9 ″ ″ 135
    32 t-C4H9 ″ ″ 195
    33 neopentyl ″ ″ 216
    34 cyclopropyl ″ ″ 245
    35 cyclohexyl ″ ″ 177
    36 cyclopropyl-CH2 ″ ″ 160
    37 cyclobutyl-CH2 ″ ″ 132
    38 cyclopentyl-CH2 ″ ″ 162
    39 2-norbornyl-CH2 ″ ″ 161
    40 C6H5—CH═CH ″ ″ 272
    41 C2H5OOC—CH2 ″ ″
    42 i-C4H9 3-FC6H4 ″ 147
    43 neopentyl ″ ″ 190
    44 cyclopropyl ″ ″ 222
    45 cyclopropyl-CH2 ″ ″ 174
    46 cyclobutyl-CH2 ″ ″ 139
    47 cyclopentyl-CH2 ″ ″ 145
    48 i-C4H9 2-FC6H4 ″ 202
    49 t-C4H9 ″ ″ 212
    50 neopentyl ″ ″ 235
    51 cyclopropyl ″ ″ 262
    52 cyclopropyl-CH2 ″ ″ 224
    53 i-C4H9 4-ClC6H4 ″ 133
    54 cyclopropyl ″ ″ 208
    55 i-C4H9 3-ClC6H4 ″ 113
    56 t-C4H9 ″ ″ 160
    57 neopentyl ″ ″ 177
    58 t-amyl ″ ″ 150
    59 cyclopropyl ″ ″ 189
    60 cyclopropyl-CH2 ″ ″ 136
    61 cyclobutyl-CH2 ″ ″ 156
    62 cyclopentyl-CH2 ″ ″ 147
    63 i-C4H9 2-ClC6H4 ″ 182
    64 neopentyl ″ ″ 216
    65 cyclopropyl ″ ″ 198
    66 i-C4H9 4-BrC6H4 ″ 135
    67 neopentyl ″ ″ 204
    68 cyclopropyl ″ ″ 208
    69 cyclopropyl-CH2 ″ ″ 140
    70 cyclopentyl-CH2 ″ ″ 187
    71 2-norbornyl-CH2 ″ ″ 174
    72 i-C4H9 3-BrC6H4 ″ 152
    73 t-C4H9 ″ ″ 160
    74 neopentyl ″ ″ 177
    75 cyclopropyl ″ ″ 186
    76 cyclopentyl-CH2 ″ ″ 143
    77 i-C4H9 3,4-diClC6H3 ″ 143
    78 neopentyl ″ ″ 215
    79 i-C4H9 3-CH3C6H4 ″ 119
    80 cyclopropyl ″ ″ 206
    81 i-C4H9 2-CH3C6H4 ″ 147
    82 neopentyl ″ ″ 191
    83 cyclopropyl ″ ″ 200
    84 i-C4H9 3,4-diCH3C6H3 ″ 165
    85 neopentyl ″ ″ 184
    86 cyclopropyl ″ ″ 182
    87 cyclohexyl ″ ″ 211
    88 cyclopentyl-CH2 ″ ″ 144
    89 i-C4H9 3-CF3C6H4 ″ 139
    90 cyclopropyl ″ ″ 172
    91 cyclopentyl-CH2 ″ ″ 141
    92 i-C4H9 4-CH3OC6H4 ″ 177
    93 cyclopropyl ″ ″ 164
    94 i-C4H9 3-CH3OC6H4 ″ 119
    95 neopentyl ″ ″ 155
    96 cyclopropyl ″ ″ 192
    97 i-C4H9 2-CH3OC6H4 ″ 181
    98 cyclopropyl ″ ″ 211
    99 ″ 3,4-diCH3OC6H3 ″ 177
    100 i-C4H9
    Figure US20020183326A1-20021205-C00010
         		″ 158
    101 t-C4H9
    Figure US20020183326A1-20021205-C00011
         		″ 251
    102 neopentyl
    Figure US20020183326A1-20021205-C00012
         		″ 208
    103 cyclopropyl
    Figure US20020183326A1-20021205-C00013
         		″ 208
    104 i-C4H9
    Figure US20020183326A1-20021205-C00014
         		″ 193
    105 t-C4H9
    Figure US20020183326A1-20021205-C00015
         		″ 210
    106 neopentyl
    Figure US20020183326A1-20021205-C00016
         		″ 219
    107 cyclopropyl
    Figure US20020183326A1-20021205-C00017
         		″ 162
    108 i-C3H7 3-NO2C6H4 ″ 176
    109 i-C4H9 ″ ″ 178
    110 neopentyl ″ ″ 229
    111 cyclopropyl ″ ″ 234
    112 cyclopropyl-CH2 ″ ″ 164
    113 cyclobutyl-CH2 ″ ″ 150
    114 cyclopentyl-CH2 ″ ″ 183
    115 cyclopropyl 3-(CH3)2NC6H4 ″ 213
    116 i-C4H9 2-naphthyl ″ 140
    117 cyclopropyl ″ ″ 212
    118 i-C4H9 2-thienyl ″ 196
    119 cyclopropyl ″ ″ 214
    120 i-C4H9 3-thienyl ″ 166
    121 cyclopropyl ″ ″ 183
    122 i-C4H9 C6H5 8-H3C 170
    123 neopentyl ″ ″ 221
    124 cyclopropyl ″ ″ 185
    125 cyclopentyl-CH2 ″ ″ 163
    126 2-norbornyl-CH2 ″ ″ 193
    127 i-C4H9 ″ 9-Cl 174
    128 cyclopropyl ″ ″ 149
    129 cyclopropyl-CH2 ″ ″ 175
    130 cyclopentyl-CH2 ″ ″ 175
  • The following Examples illustrate pharmaceutical compositions according to the invention. [0061]
    • EXAMPLE 2
  • 3,000 inhalation-flasks each containing 40 mg of 3-t-butyl-6-phenyl-1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine (active compound) were prepared as follows: [0062]
    Active compound 120 g
    Sorbitan trioleate 4 g
    propellent q.s. 60 l
  • Procedure [0063]
  • The microcrystalline suspension prepared with these ingredients was introduced in the inhalation-flasks at a volume of 20 ml per flask with a filling machine. The flasks were furnished with an appropriate valve which released 0.2 ml of suspension for each activation (0.4 mg of active compound). [0064]
    • EXAMPLE 3
  • 15,000 capsules each containing 20 mg of 3-t-butyl-6-phenyl-1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine (active compound) were prepared from the following formulation: [0065]
    Active compound 300 g
    Sodium carboxymethyl starch 330 g
    Talc 195 g
    Hydrogenated castor oil 165 g
    Corn starch 495 g
  • Procedure [0066]
  • The above ingredients were sieved through a 60 mesh sieve, then mixed in a suitable mixer and filled into 15,000 gelatine capsules. [0067]

Claims (12)

1. A compound of formula (I)
Figure US20020183326A1-20021205-C00018
wherein;
R1 represents a hydrogen atom or a —(CH2)m—Y group, wherein m is an integer from 0 to 4 and Y represents an alkyl, haloalkyl, alkoxy, alkoxycarbonyl, C3-C7 cycloalkyl, norbornyl or phenylalkenyl group, or an aromatic group which aromatic group Y may optionally be substituted by one or more halogen atoms;
R2 represents an aromatic group which aromatic group may optionally be substituted by one or more halogen atoms or alkyl, alkoxy, C3-C6 cycloalkoxy, methylenedioxy, nitro, dialkylamino or trifluoromethyl groups; and
R3 represents a hydrogen or halogen atom or an alkyl group,
and pharmaceutically acceptable salts thereof.
2. A compound according to claim 1 wherein the alkyl, haloalkyl and alkoxy groups have up to 6 carbon atoms, the alkoxycarbonyl groups have up to 7 carbon atoms and the phenylalkenyl groups have up to 12 carbon atoms.
3. A compound according to claim 1 or 2 wherein R1 represents —(CH2)m—Y wherein m is 0 or 1 and Y represents C1-6 alkyl or C3-7 cycloalkyl.
4. A compound according to any one of the preceding claims wherein R2 represents a phenyl group, naphthyl group or thienyl group which group R2 may optionally be substituted by one or more halogen atoms, methyl groups, methoxy groups, cyclopentoxy groups, nitro groups or dimethyl amino groups.
5. A compound according to claim 4 wherein R2 represents a phenyl, 3-chlorophenyl, 4-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl or 3-nitrophenyl group.
6. A compound according to any one of the preceding claims wherein R3 represents a hydrogen atom, a C1-6 alkyl group or a chlorine atom at the 8- or 9-position of the 1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine skeleton.
7. A compound according to claim 1 which is 6-(4-fluorophenyl)-3-isobutyl-1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine, 3-cyclopropylmethyl-6-(3-nitrophenyl)-1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine, 3-cyclopropyl-6-phenyl-1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine and 3-cyclobutylmethyl-6-(3-nitrophenyl)-1,2,4-triazolo[4,3-b]pyrido[3,2-d]pyridazine.
8. A process for preparing a compound of formula (I)
Figure US20020183326A1-20021205-C00019
wherein;
R1 represents a hydrogen atom or a —(CH2)m—Y group, wherein m is an integer from 0 to 4 and Y represents an alkyl, haloalkyl, alkoxy, alkoxycarbonyl, C3-C7 cycloalkyl, norbornyl or phenylalkenyl group, or an aromatic group which aromatic group Y may optionally be substituted by one or more halogen atoms;
R2 represents an aromatic group which aromatic group may optionally be substituted by one or more halogen atoms or alkyl, alkoxy, C3-C6 cycloalkoxy, methylenedioxy, nitro, dialkylamino or trifluoromethyl groups; and
R3 represents a hydrogen or halogen atom or an alkyl group,
which process comprises formation of the 1,2,4-triazine ring present in formula (I) by cyclisation of a hydrazide of formula (IV)
Figure US20020183326A1-20021205-C00020
wherein R1, R2 and R3 are as defined above.
9. A composition comprising a compound according to any one of claims 1 to 7 or pharmaceutically acceptable salt thereof mixed with a pharmaceutically acceptable diluent or carrier.
10. A compound according to anv one of claims 1 to 7 or pharmaceutically acceptable salt thereof or a composition according to claim 9 for use in a method of treatment of the human or animal body.
11. Use of a compound according to any one of claims 1 to 7 or pharmaceutically acceptable salt thereof or a composition according to claim 9 for the manufacture of a medicament for the treatment of a condition whose known treatment is to inhibit phosphodiesterase 4 including allergic reaction and disease states, inflammation, ulcers and immunological disease.
12. A method of treating a condition whose known treatment is to inhibit phosphodiesterase 4 which comprises administering to a human or animal subject in need of such treatment an effective amount of compound according to any one of claims 1 to 7 or pharmaceutically acceptable salt thereof or a composition according to claim 9.
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