EP1824854A2 - Pteridines substituees destinees au traitement de maladies inflammatoires - Google Patents

Pteridines substituees destinees au traitement de maladies inflammatoires

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Publication number
EP1824854A2
EP1824854A2 EP05823962A EP05823962A EP1824854A2 EP 1824854 A2 EP1824854 A2 EP 1824854A2 EP 05823962 A EP05823962 A EP 05823962A EP 05823962 A EP05823962 A EP 05823962A EP 1824854 A2 EP1824854 A2 EP 1824854A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
group
conh
cycloalkyl
formula
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.)
Withdrawn
Application number
EP05823962A
Other languages
German (de)
English (en)
Inventor
Horst Dollinger
Domnic Martyres
Juergen Mack
Peter Nickolaus
Birgit Jung
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.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
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Filing date
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Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Publication of EP1824854A2 publication Critical patent/EP1824854A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
    • C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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
    • A61P27/16—Otologicals
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to novel pteridines which are suitable for the treatment of respiratory or gastrointestinal complaints or diseases,
  • Pteridines are known as drugs with antiproliferative action from the prior art. Merz et al. describe in the Journal of Medicinal Chemistry 1998, 41, 4733-4743 the preparation of 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidinopteridine and derivatives thereof, which are free of positional isomers. It has been shown that the compounds produced can inhibit the growth of tumor cells. In DE 3540952 2-piperazino-pteridines are described, which are substituted in the 6-position with a halogen atom selected from a fluorine, chlorine or bromine atom. These compounds were shown to inhibit the activity of tumor cells and human platelets in vitro.
  • DE 3323932 discloses 2-piperazino-pteridines which carry in the 4-position a dialkylamino, piperidino, morpholino, thiomorpholino or 1-oxidothiomorpholino group. These compounds were shown to inhibit the activity of tumor cells and human platelets in vitro.
  • pteridines are described with a large number of different substituents in the 2-, 4-, 6- and 7-position, wherein compounds having a 2-piperazino group on the pteridine skeleton are suitable as inhibitors for tumor growth and antithrombotic and metastasis-inhibiting properties exhibit.
  • Tri- and tetrasubstituted pteridine derivatives are disclosed in US Pat. No.
  • the object of the present invention is to provide novel compounds which are suitable for the prevention or treatment of respiratory or gastrointestinal complaints or diseases, inflammatory diseases of the joints, the skin or the eyes, disorders of the peripheral or central nervous system, or cancers, in particular those compounds characterized by less side effects, especially emesis and nausea.
  • R 1 is a saturated or unsaturated, five-, six- or seven-membered heterocyclic ring which may contain one nitrogen atom and one further atom selected from the group consisting of nitrogen, sulfur and oxygen;
  • R 2 is a five, six or seven membered heterocyclic ring
  • Nitrogen atom and another atom selected from the group consisting of nitrogen, sulfur and oxygen may contain;
  • R 3 is a group of the formula ai
  • n 0.1, 2 or 3;
  • R 311 is H, d-6 alkyl
  • R 312 is H, d-6 alkyl
  • R is a radical selected from the group consisting of C 2 - 6 -alkyl
  • R 3 2 1 H 1 C 1 ⁇ -AlkYl; R 3 22 H, Cz- ⁇ -alkyl;
  • R 1 is a saturated or unsaturated, five- or six-membered heterocyclic ring which may contain one nitrogen atom and one further atom selected from the group consisting of nitrogen and sulfur;
  • R 2 is a five- or six-membered heterocyclic ring which may contain one or two nitrogen atoms;
  • R 1 is a saturated or unsaturated, five- or six-membered heterocyclic ring containing one nitrogen atom and optionally one further sulfur atom;
  • R 2 is a six-membered heterocyclic ring containing two nitrogen atoms
  • R 3 is a group of formula ai wherein m is 1,2 or 3; n is 0.1, 2 or 3;
  • t31 a radical selected from the group consisting of Ci- 6 alkyl, C 3 -6 cycloalkyl, Ph, COOR 311, CONR 311 R 312, CN, d- ⁇ -haloalkyl, OR 311, OC 3 - 6 cycloalkyl, Od-alkylene-Cs-e-cycloalkyl, O-Ci- 4 -alkylene-CONH 2 ,
  • R 311 is H, d-6 alkyl; R 312 Hd-6-alkyl;
  • R 32 is a radical selected from the group consisting of C 2 . 6- alkyl,
  • R 322 is H, C 2 - 6 alkyl; R 323 Hd- ⁇ -alkyl;
  • R 3 is a group of formula ai, in which m is 1,2 or 3; n is 0.1, 2 or 3;
  • R 31 is selected, a radical from the group consisting of C 1-4 alkyl, C 3 - 6 cycloalkyl, Ph, COOR 311, CONR 311 R 312, CN, C 1-4 haloalkyl, OR 311,
  • OC 3-6 -cycloalkyl O-Ci- 4 alkylene-C 3 - 6 cycloalkyl, O-Ci-4 alkylene CONH 2, O-Ci- 4 alkylene-NH 2, O-Ci -4 - Haloalkyl, NR 311 R 312 , NHCOR 311 , SO 2 R 311 , SO 2 NR 311 R 312 , halogen,
  • R 311 is H, d-4 alkyl
  • R 312 is H, d-4 alkyl
  • R 32 is a radical selected from the group consisting of C 2-4 alkyl
  • R 321 is H, d-4 alkyl;
  • R 322 is H, C 2 _ 4 alkyl;
  • R 323 is H, d-4 alkyl
  • R 3 is a group of formula ai, in which
  • R 32 is a radical selected from the group consisting of ethyl, propyl, OEt, OPr, F, Br, CN, NH 2 , NHCOMe, COOH, COOMe, CONH 2 , SO 2 Me, SO 2 NH 2 , SO 2 NMe 2 , Ph, OH, OCHF 2 , OCF 3 , CF 3 , cyclopropyl, cyclopentyl, OCH 2 CONH 2 , OCH 2 CH 2 NH 2 , O-cyclopentyl, OCH 2 -cyclopropyl,
  • R 3 is a group of formula ai, in which
  • n is O, 1, 2 or 3;
  • R 3 1 is a radical selected from among C 1 -C 4 -alkyl
  • R 32 is a radical selected from the group consisting of C 2 . 4- alkyl,
  • R 3 is a group of formula ai, in which
  • n 0, 1, 2 or 3;
  • R 3 1 is a radical selected from the group consisting of methyl, / so-propyl,
  • OMe, F, Cl, CN NHCOMe, CONH 2 , SO 2 Me, SO 2 NH 2 , Ph, OH, OCHF 2 , OCF 3 , CF 3 , i-Pr, cyclopropyl, OCH 2 CONH 2 , OCH 2 CH 2 NH 2 , O-cyclopentyl, OCH 2 -cyclopropyl
  • R 32 is a radical selected from the group consisting of CN, NHCOMe,
  • R 1 is pyrrolidine
  • R 3 is a radical selected from the group consisting of
  • VI may have the meaning of 2-ToIyI, 3-ToIyI, 4-ToIyI and benzyl.
  • pharmacologically acceptable acid addition salts are meant, for example, those salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, Hydrobenzoate and hydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate and hydromethanesulfonate.
  • de-alkyl (including those which are part of other radicals) are branched and unbranched alkyl groups having 1 to 6 carbon atoms, by the term “C 2 - 6 alkyl” branched and unbranched alkyl groups having 2 to 6 carbon atoms and lower the term branched and "Ci- 4 alkyl" unbranched
  • alkyl groups having 1 to 4 carbon atoms having 1 to 4 carbon atoms.
  • alkyl groups having 1 to 4 carbon atoms include: methyl, ethyl, n-propyl, / so-propyl, n-butyl, / so-butyl, sec-butyl, tert-butyl, n-pentyl, / so-pentyl, neo-pentyl or hexyl.
  • the abbreviations Me, Et, n-Pr, / -Pr, n-Bu, / -Bu, t-Bu, etc. are also used for the abovementioned groups.
  • propyl includes n-propyl and / so-propyl
  • butyl includes / so-butyl, sec-butyl and tert-butyl, etc.
  • 4 -alkylene D (including those which are part of other groups) are meant branched and unbranched alkylene groups with 1 to 4 carbon atoms.
  • propylene and butylene include all conceivable isomeric forms of the respective radicals of the same carbon number.
  • propyl also includes 1-methylethylene and butylene includes 1-methylpropylene, 1, 1 - Dimethylethylene, 1, 2-dimethylethylene.
  • C 3 - 6 -cycloalkyl (including those which are part of other groups) cyclic alkyl groups having 3 to 6 carbon atoms are understood. Examples include: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Unless otherwise specified, the cyclic alkyl groups may be substituted with one or more radicals selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluoro, chloro, bromo and iodo.
  • Halogen is in the context of the present invention for fluorine, chlorine, bromine or iodine. Unless otherwise indicated, fluorine, chlorine and bromine are preferred halogens.
  • de-haloalkyl (including those which are part of other radicals) are meant branched and unbranched alkyl groups having 1 to 6 carbon atoms which are substituted by one or more halogen atoms.
  • C 1-6 -alkyl is meant branched and unbranched alkyl groups having from 1 to 4 carbon atoms substituted with one or more halogen atoms. Preferred are alkyl groups having 1 to 4 carbon atoms. For example: CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 .
  • aryl (even if they are part of other radicals) are understood as meaning aromatic ring systems having 6 or 10 carbon atoms. For example: phenyl or naphthyl, more preferably aryl is phenyl. Unless otherwise stated, the aromatics may be substituted with one or more radicals selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
  • heterocyclic rings or “Het” are meant five-, six- or seven-membered, saturated or unsaturated heterocyclic rings or 5-10 membered, bicyclic hetero rings, the one, two or three heteroatoms selected from the group consisting of oxygen, sulfur and In this case, the ring may be linked to the molecule via a carbon atom or, if present, via a nitrogen atom.
  • heterocyclic rings examples include:
  • a heterocyclic ring may be provided with a keto group. As an example for this are called.
  • the compounds according to the invention can be prepared by methods known per se from the literature, as described, for example, in DE 3540952.
  • EXAMPLE 37a a) 3-Cyclopropylmethoxy-4-difluoromethoxybenzaldehyde: 4.70 g (24.98 mmol) of 4-difluoromethoxy-3-hydroxybenzaldehyde are initially charged in 50 ml of dimethylformamide, 4.00 g (29.63 mmol) of bromomethylcyclopropane and 3.50 g (25.32 mmol) of potassium carbonate. The reaction mixture is heated at 100 0 C for 20 hours, then the dimethylformamide evaporated. The residue is extracted with ethyl acetate and water, the organic phase is dried and evaporated to dryness. Yield: 5.83 g (96% of theory)
  • Example 38 a) 3-Cyclopropylmethoxy-4-difluoromethoxybenzaldehyde oxime: 4.50 g (18.58 mmol) of 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde are initially charged in 50 ml of acetonitrile, 3.00 ml (22, 00 mmol) of triethylamine and 1.50 g (22.00 mmol) of hydroxylamine hydrochloride were added. The reaction mixture is stirred under reflux for 4 hours and at room temperature for 16 hours. The mixture is then evaporated to the residue. This is extracted with ethyl acetate and water, the organic phase dried and evaporated to dryness. Yield: 4.56 g (95% of theory)
  • Example 41 a) 3-Cyclopentyloxy-4-methoxybenzaldehyde: 2.00 g of 3-hydroxy-4-methylbenzaldehyde are initially charged in 20 ml of dimethylformamide, 2.20 ml (20.67 mmol)
  • the compounds of formula 1 are characterized by a variety of possible applications in the therapeutic field. Worth mentioning are those applications for which the compounds of formula 1 according to the invention can preferably be used as a PDE4 inhibitor due to their pharmaceutical activity. Examples include his respiratory or gastrointestinal diseases or disorders, inflammatory diseases of the joints, the skin or the eyes, cancers, as well as diseases of the peripheral or central nervous system.
  • respiratory or lung diseases which are associated with increased mucus production, inflammation and / or obstructive diseases of the respiratory tract.
  • examples include his, acute, allergic or chronic bronchitis, chronic obstructive pulmonary disease (COPD), cough, pulmonary emphysema, allergic or non-allergic rhinitis or sinusitis, chronic rhinitis or sinusitis, asthma, alveolitis, farmers ' disease, hyperrespiratory airways, infectious bronchitis or pneumonitis, pediatric asthma, bronchiectasis, pulmonary fibrosis, ARDS (acute adult respiratory distress syndrome), bronchial edema, pulmonary edema, bronchitis, pneumonia or interstitial pneumonia triggered by various causes such as aspiration, inhalation of toxic gases or bronchi
  • inflammatory diseases of the gastrointestinal tract examples of this are its called, acute or chronic inflammatory changes in gallbladder inflammation, Crohn's disease, ulcerative colitis, inflammatory pseudopolyps, juvenile polyps, colitis cystica profunda, pneumatosis cystoides intestinales, diseases of the bile ducts and gallbladder, e.g. Gallstones and conglomerates for the treatment of inflammatory diseases of the joints such as rheumatoid arthritis or inflammatory diseases of the skin and eyes.
  • gliomas such as oligodendroglioma and glioblastoma.
  • Depression bipolar or manic depression, acute and chronic anxiety, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis or acute and chronic pain, and brain damage caused by stroke, hypoxia or traumatic brain injury.
  • the present invention relates to the use of compounds of formula 1 for the manufacture of a medicament for the treatment of inflammatory or obstructive diseases of the upper and lower respiratory organs, including the lung, such as allergic rhinitis, chronic rhinitis, bronchiectasis, cystic fibrosis, idiopathic pulmonary fibrosis, fibrosing alveolitis, COPD, chronic bronchitis, chronic sinusitis, asthma, Crohn's disease, ulcerative colitis, especially COPD, chronic bronchitis and asthma.
  • the compounds of formula 1 for the treatment of inflammatory and obstructive diseases such as COPD, chronic bronchitis, chronic sinusitis, asthma, Crohn's disease, ulcerative colitis, especially COPD, chronic bronchitis and asthma.
  • COPD inflammatory and obstructive diseases
  • chronic bronchitis chronic sinusitis
  • asthma Crohn's disease
  • ulcerative colitis especially COPD, chronic bronchitis and asthma.
  • the compounds of formula 1 for the treatment of diseases of the peripheral or central nervous system such as depression, bipolar or manic depression, acute and chronic anxiety, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis or acute and chronic pain as well as brain damage caused by stroke, hypoxia or craniocerebral trauma.
  • diseases of the peripheral or central nervous system such as depression, bipolar or manic depression, acute and chronic anxiety, schizophrenia, Alzheimer's disease, Parkinson's disease, acute and chronic multiple sclerosis or acute and chronic pain as well as brain damage caused by stroke, hypoxia or craniocerebral trauma.
  • An outstanding aspect of the present invention is the reduced profile of side effects.
  • this is understood as being able to administer a dose of a pharmaceutical composition without inducing vomiting in the patient, preferably nausea, particularly preferably malaise.
  • administration of a therapeutically effective amount of substance without inducing emesis or nausea is at any stage of the disease process.
  • the compounds of the formula 1 can be used alone or in combination with other active compounds of the formula 1 according to the invention.
  • the compounds of formula 1 can also be used in combination with other pharmacologically active ingredients.
  • Preferred active substances are those which are selected, for example, from the group consisting of betamimetics, anticholinergics, corticosteroids, other PDE4 inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, H1 antihistamines, PAF antagonists and PI3 Kinase inhibitors or two or three combinations thereof, such as combinations of
  • PDE4 inhibitors with EGFR inhibitors or LTD4 antagonists PDE4 inhibitors with EGFR inhibitors or LTD4 antagonists
  • a further aspect of the invention is medicaments for the treatment of respiratory diseases which contain one or more of the abovementioned pteridines of the formula 1 which are used in combination with one or more additional active substances selected from the group of betamimetics, anticholinergics, corticosteroids, PI3-kinase inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, H1 antihistamines or PAF antagonists, preferably betamimetics, anticholinergics or corticosteroids are used together or sequentially, for simultaneous, sequential or separate administration.
  • additional active substances selected from the group of betamimetics, anticholinergics, corticosteroids, PI3-kinase inhibitors, LTD4 antagonists, EGFR inhibitors, dopamine agonists, H1 antihistamines or PAF antagonists, preferably betamimetics, anticholinergics or corticosteroids are used together or sequentially, for simultaneous, sequential or separate administration.
  • Suitable application forms are, for example, tablets, capsules, solutions, juices, emulsions or inhalable powders or aerosols.
  • the proportion of the pharmaceutically active compound (s) in each case in the range of 0.1 to 90 wt .-%, preferably 0.5 to 50 wt .-% of the total composition, i. in amounts sufficient to reach the dosage range given below.
  • Oral administration may be in the form of a tablet, as a powder, as a powder in a capsule (e.g., hard gelatin capsule), as a solution or suspension.
  • the active substance combination can be carried out as a powder, as an aqueous or aqueous-ethanolic solution or by means of a propellant gas formulation.
  • compositions are preferably characterized by the content of one or more compounds of formula 1 according to the above preferred embodiments. It is particularly preferred if the compounds of the formula 1 are administered orally, it is particularly preferred if the administration takes place once or twice daily.
  • Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents to obtain the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • the tablets can also consist of several layers.
  • Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core can also consist of several layers.
  • the dragee sheath to achieve a depot effect of several layers may consist of the above mentioned in the tablets excipients can be used.
  • Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetening agent, such as saccharin, cyclamate, glycerol or sugar, and a taste-improving agent, e.g. Flavorings such as vanillin or orange extract. They may also contain suspending aids or thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • a sweetening agent such as saccharin, cyclamate, glycerol or sugar
  • a taste-improving agent e.g. Flavorings such as vanillin or orange extract.
  • suspending aids or thickening agents such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • the capsules containing one or more active ingredients or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules.
  • suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.
  • auxiliaries for example, water, pharmaceutically acceptable organic solvents such as paraffins (eg petroleum fractions), oils of vegetable origin (eg peanut or sesame oil), mono- or polyfunctional alcohols (eg ethanol or glycerol), excipients such as natural minerals (eg kaolin, Clays, talc, chalk) synthetic minerals (eg finely divided silicic acid and silicates), sugars (eg pipe, milk and dextrose) emulsifiers (eg lignin, liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and Sodium lauryl sulfate).
  • paraffins eg petroleum fractions
  • oils of vegetable origin eg peanut or sesame oil
  • mono- or polyfunctional alcohols eg ethanol or glycerol
  • excipients such as natural minerals (eg kaolin, Clays, talc, chalk
  • the tablets may also contain additives other than those mentioned.
  • Sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like.
  • lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tableting.
  • the active ingredients may be added to the abovementioned excipients with various flavor enhancers or dyes.
  • the compounds of the formula 1 are administered by inhalation, it being particularly preferred if the administration is carried out once or twice daily.
  • the compounds of formula 1 must be provided in inhaled dosage forms.
  • Suitable inhalable dosage forms are inhalable powders, propellant-containing metered-dose inhalers or propellant-free inhalable solutions which, if appropriate, are present in admixture with conventional physiologically compatible excipients.
  • propellant-free inhalable solutions also includes concentrates or sterile, ready-to-use inhalable solutions.
  • the administration forms which can be used in the context of the present invention will be described in detail in the following part of the description.
  • the inhalable powders according to the invention can be used to prepare them the following physiologically acceptable excipients are used: monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, sucrose, maltose), oligo- and polysaccharides (eg dextrans), polyalcohols (eg sorbitol, mannitol, xylitol), salts (eg sodium chloride , Calcium carbonate) or mixtures of these excipients with each other.
  • monosaccharides eg glucose or arabinose
  • disaccharides eg lactose, sucrose, maltose
  • oligo- and polysaccharides eg dextrans
  • polyalcohols eg sorbitol, mannitol, xylitol
  • salts eg sodium chloride , Calcium carbonate
  • lactose preferably lactose monohydrate
  • Methods for producing the inhalable powders according to the invention by grinding and micronizing as well as by final mixing of the constituents are known from the prior art.
  • the propellant-containing inhalable aerosols which can be used in the context of the use according to the invention can be dissolved in the propellant gas or in dispersed form.
  • the propellant gases which can be used for the preparation of the inhalation aerosols are known from the prior art. Suitable propellant gases are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • the abovementioned propellant gases can be used alone or in mixtures thereof.
  • propellant gases are fluorinated alkane derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,3,3,3,3-heptafluoropropane) and mixtures thereof.
  • the propellant-containing inhalation aerosols which can be used in the context of the use according to the invention can also contain further constituents, such as co-solvents, stabilizers, surfactants, antioxidants, lubricants and agents for adjusting the pH. All of these ingredients are known in the art.
  • Suitable solvents for this purpose are aqueous or alcoholic, preferably ethanolic solutions.
  • the solvent may be water only or it may be a mixture of water and ethanol.
  • the solutions or suspensions are with suitable acids to a pH of 2 to 7, preferably from 2 to 5 set.
  • acids selected from inorganic or organic acids can be used.
  • particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid.
  • particularly suitable organic acids are:
  • Ascorbic acid citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others.
  • Preferred inorganic acids are hydrochloric acid, sulfuric acid. It is also possible to use the acids which already form an acid addition salt with one of the active substances.
  • organic acids ascorbic acid, fumaric acid and citric acid are preferable.
  • mixtures of said acids may also be employed, particularly in the case of acids which, in addition to their acidification properties, also possess other properties, e.g. as flavorants, antioxidants or complexing agents, such as citric acid or ascorbic acid.
  • Hydrochloric acid is particularly preferably used according to the invention for adjusting the pH.
  • Co-solvents and / or further auxiliaries can be added to the propellant-free inhalable solutions which can be used in the context of the inventive use.
  • Preferred co-solvents are those which contain hydroxyl groups or other polar groups, for example alcohols - in particular isopropyl alcohol, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
  • auxiliaries and additives are understood as meaning any pharmacologically acceptable substance which is not an active substance but together with the substance (s).
  • Active ingredient (s) can be formulated in the pharmacologically suitable solvent to improve the qualitative properties of the drug formulation. These substances preferably do not develop any appreciable or at least no undesirable pharmacological effect in the context of the intended therapy.
  • the auxiliaries and additives include, for example, surfactants such as soybean lecithin, oleic acid, sorbitan esters such as polysorbates, polyvinylpyrrolidone other stabilizers, complexing agents, antioxidants and / or preservatives that ensure or prolong the useful life of the finished drug formulation, flavorings, vitamins and / or Other known in the art Additives.
  • the additives also include pharmacologically acceptable salts such as sodium chloride as isotonants.
  • Preferred excipients include antioxidants, such as ascorbic acid, if not already used for pH adjustment, vitamin A, vitamin E, tocopherols, and similar vitamins or provitamins found in the human organism.
  • Preservatives may be used to protect the formulation from contamination by germs. Suitable preservatives are those known in the art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art.
  • ready-to-use packs of a medicament for the treatment of respiratory disorders including an enclosed description containing, for example, the words respiratory disease, COPD or asthma, a pteridine and one or more combination partners selected from the group described above, are provided.

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Abstract

L'invention concerne de nouvelles ptéridines, appropriées au traitement d'affections ou de maladies gastro-intestinales ou des voies respiratoires, de maladies inflammatoires des articulations, de la peau ou des yeux, de maladies du système nerveux central ou périphérique ou encore de maladies cancéreuses. Ladite invention concerne également des compositions pharmaceutiques contenant ces composés.
EP05823962A 2004-11-29 2005-11-25 Pteridines substituees destinees au traitement de maladies inflammatoires Withdrawn EP1824854A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004057595A DE102004057595A1 (de) 2004-11-29 2004-11-29 Substituierte Pteridine zur Behandlung von entzündlichen Erkrankungen
PCT/EP2005/056246 WO2006058869A2 (fr) 2004-11-29 2005-11-25 Pteridines substituees destinees au traitement de maladies inflammatoires

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EP1824854A2 true EP1824854A2 (fr) 2007-08-29

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US (1) US7750009B2 (fr)
EP (1) EP1824854A2 (fr)
JP (1) JP2008521774A (fr)
AR (1) AR054991A1 (fr)
CA (1) CA2587269A1 (fr)
DE (1) DE102004057595A1 (fr)
TW (1) TW200635597A (fr)
WO (1) WO2006058869A2 (fr)

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DE102004057618A1 (de) * 2004-11-29 2006-06-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Substituierte Pteridine zur Behandlung von entzündlichen Erkrankungen
DE102004057594A1 (de) * 2004-11-29 2006-06-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg Substitueirte Pteridine zur Behandlung von entzündlichen Erkrankungen
DE102004057645A1 (de) * 2004-11-29 2006-06-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Substituierte Pteridine zur Behandlung von entzündlichen Erkrankungen
CA2652840C (fr) 2006-05-24 2014-09-09 Boehringer Ingelheim International Gmbh 2-piperazino-6-chloro-pteridines en tant qu'inhibiteurs de la pde-4 pourle traitement des maladies inflammatoires
WO2008003149A2 (fr) * 2006-07-06 2008-01-10 Gilead Sciences , Inc. Ptéridines substituées pour le traitement et la prévention d'infections virales
US10144736B2 (en) 2006-07-20 2018-12-04 Gilead Sciences, Inc. Substituted pteridines useful for the treatment and prevention of viral infections
JP5592265B2 (ja) * 2007-11-01 2014-09-17 アキュセラ インコーポレイテッド 眼の疾患及び障害治療用のアミン誘導体化合物
UA123090C2 (uk) 2015-03-04 2021-02-17 Гіліад Сайєнсіз, Інк. 4,6-ДІАМІНОПІРИДО[3,2-d]ПІРИМІДИНОВІ СПОЛУКИ, ЯКІ МОДУЛЮЮТЬ TOLL-ПОДІБНІ РЕЦЕПТОРИ
WO2018045150A1 (fr) 2016-09-02 2018-03-08 Gilead Sciences, Inc. Dérivés de 4,6-diamino-pyrido [3,2-d] pyrimidine en tant que modulateurs du récepteur de type toll
EP3507276B1 (fr) 2016-09-02 2021-11-03 Gilead Sciences, Inc. Composés modulateurs du recepteur de type toll
KR20200075864A (ko) 2017-10-23 2020-06-26 베링거 인겔하임 인터내셔날 게엠베하 진행성 섬유화 간질성 폐 질환(pf-ild)의 치료를 위한 활성 제제들의 신규한 배합
TWI751517B (zh) 2019-04-17 2022-01-01 美商基利科學股份有限公司 類鐸受體調節劑之固體形式
TW202210480A (zh) 2019-04-17 2022-03-16 美商基利科學股份有限公司 類鐸受體調節劑之固體形式
TW202115056A (zh) 2019-06-28 2021-04-16 美商基利科學股份有限公司 類鐸受體調節劑化合物的製備方法
TW202342050A (zh) 2021-12-09 2023-11-01 德商百靈佳殷格翰國際股份有限公司 用於治療進行性纖維化間質性肺病之新穎治療組合
US20230181590A1 (en) 2021-12-09 2023-06-15 Boehringer Ingelheim International Gmbh New oral pharmaceutical composition and dose regimen for the therapy of progressive fibrosing interstitial lung diseases
WO2024068386A1 (fr) 2022-09-28 2024-04-04 Boehringer Ingelheim International Gmbh Utilisation de biomarqueurs dans le traitement d'états fibrotiques avec inhibiteur de la pde4b

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TW200635597A (en) 2006-10-16
WO2006058869A3 (fr) 2006-10-26
US20060116373A1 (en) 2006-06-01
CA2587269A1 (fr) 2006-08-06
DE102004057595A1 (de) 2006-06-08
US7750009B2 (en) 2010-07-06
WO2006058869A2 (fr) 2006-06-08
AR054991A1 (es) 2007-08-01
JP2008521774A (ja) 2008-06-26
WO2006058869A8 (fr) 2007-01-18

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