WO2008061968A1 - Dérivés de benzimidazolone utiles dans le traitement de l'hypertension artérielle pulmonaire - Google Patents

Dérivés de benzimidazolone utiles dans le traitement de l'hypertension artérielle pulmonaire Download PDF

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Publication number
WO2008061968A1
WO2008061968A1 PCT/EP2007/062537 EP2007062537W WO2008061968A1 WO 2008061968 A1 WO2008061968 A1 WO 2008061968A1 EP 2007062537 W EP2007062537 W EP 2007062537W WO 2008061968 A1 WO2008061968 A1 WO 2008061968A1
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WO
WIPO (PCT)
Prior art keywords
use according
pah
formula
compound
acid addition
Prior art date
Application number
PCT/EP2007/062537
Other languages
English (en)
Inventor
Angelo Ceci
Marcus Schindler
Original Assignee
Boehringer Ingelheim International Gmbh
Boehringer Ingelheim Pharma Gmbh & Co. Kg
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International Gmbh, Boehringer Ingelheim Pharma Gmbh & Co. Kg filed Critical Boehringer Ingelheim International Gmbh
Publication of WO2008061968A1 publication Critical patent/WO2008061968A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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

Definitions

  • the invention relates to the use of benzimidazolone derivatives of formula (I) for preparing a medicament for treating diseases in which the use of therapeutic effective amounts of compounds displaying affinity for the 5-HT 2B -receptor display a therapeutic benefit.
  • R 1 , R 2 , R 3 , and R 4 denote hydrogen or hydroxy with the proviso that R 1 , R 2 , R 3 , and R 4 cannot simultaneously represent hydrogen.
  • Preferred compounds according to the invention are those of general formula (I) wherein two or three of the four radicals R1 , R2, R3, and R4 denote hydrogen. Also preferred are compounds of general formula (I) wherein one of the radicals R1 , R2, R3, and R4 denotes hydroxy, whilst the other radicals represent hydrogen.
  • 5-HT1 A and 5-HT2-receptor show affinity for the 5-HT1 A and 5-HT2-receptor. They may be of value in the treatment of those diseases where an altered functioning of neurosignal transmission is present. Examples of these CNS disorders include depression, schizophrenia, Parkinson, anxiety, sleep disturbances, sexual and mental disorders and age associated memory impairment (WO 01/21593 A1 ).
  • the compounds of formula (I) ⁇ optionally in form of the free base or in form of the pharmacologically acceptable acid addition salts thereof show affinity for the 5-HT 2B -receptor with antagonistic activity.
  • the instant invention relates to the use of one or more, preferably one compound of formula (I) ⁇ _, optionally in form of the free base or in form of the pharmacologically acceptable acid addition salts thereof for the preparation of a medicament for preventing and/or treating diseases in which the use of therapeutic effective amounts of compounds displaying affinity for the 5-HT 2B -receptor display a therapeutic benefit.
  • the instant invention relates to the use of one or more, preferably one compound of formula (I) ⁇ _, optionally in form of the free base or in form of the pharmacologically acceptable acid addition salts thereof for the preparation of a medicament for preventing and/or treating diseases in which the use of therapeutic effective amounts of compounds displaying antagonistic activity to the 5-HT 2B -receptor display a therapeutic benefit.
  • Pulmonary arterial hypertension is the clinical term used to describe a condition associated with progressive elevation in pulmonary arterial pressure (by 10-15 mmHg). PAH occurs more commonly secondary to collagen vascular disease, congenital systemic to pulmonary shunt, portal hypertension, human immunodeficiency virus infection, chronic obstructive lung diseases, interstitial fibrosis and high left-sided filling pressures.
  • pulmonary vascular tone is regulated by a balance between the effects of vasodilators/antiproliferative agents such as prostacyclin and nitric oxide and vasoconsthctors/co-mitogens such as 5-HT (5-Hydroxytryptamin). Alterations in 5-HT turnover lead to an increased availability of free 5-HT in the vicinity of the pulmonary artery wall. Under normal conditions, the lung vascular bed is not exposed to excessive 5-HT levels, because of its position as a secondary filter located downstream from the liver and because of the ability of platelets to store large amounts of 5-HT.
  • vasodilators/antiproliferative agents such as prostacyclin and nitric oxide
  • vasoconsthctors/co-mitogens such as 5-HT (5-Hydroxytryptamin). Alterations in 5-HT turnover lead to an increased availability of free 5-HT in the vicinity of the pulmonary artery wall.
  • the lung vascular bed is not exposed to excessive 5-HT levels, because of its position as a
  • the invention relates to the use of one or more, preferably one compound of formula (I) ⁇ _, optionally in form of the free base or in form of the pharmacologically acceptable acid addition salts thereof for the preparation of a medicament for preventing and/or treating Pulmonary arterial hypertension (PAH).
  • PAH Pulmonary arterial hypertension
  • the invention relates to the use of one or more, preferably one compound of formula (I) ⁇ _, optionally in form of the free base or in form of the pharmacologically acceptable acid addition salts thereof for the preparation of a medicament for preventing and/or treating PAH secondary to collagen vascular disease.
  • the invention relates to the use of one or more, preferably one compound of formula (I) ⁇ _, optionally in form of the free base or in form of the pharmacologically acceptable acid addition salts thereof for the preparation of a medicament for preventing and/or treating PAH congenital systemic to pulmonary shunt.
  • the invention relates to the use of one or more, preferably one compound of formula (I) ⁇ _, optionally in form of the free base or in form of the pharmacologically acceptable acid addition salts thereof for the preparation of a medicament for preventing and/or treating PAH secondary to portal hypertension.
  • the invention relates to the use of one or more, preferably one compound of formula (I) ⁇ _, optionally in form of the free base or in form of the pharmacologically acceptable acid addition salts thereof for the preparation of a medicament for preventing and/or treating PAH secondary to human immunodeficiency virus infection.
  • the invention relates to the use of one or more, preferably one compound of formula (I) ⁇ _, optionally in form of the free base or in form of the pharmacologically acceptable acid addition salts thereof for the preparation of a medicament for preventing and/or treating PAH secondary to chronic obstructive lung diseases.
  • the invention relates to the use of one or more, preferably one compound of formula (I) ⁇ _, optionally in form of the free base or in form of the pharmacologically acceptable acid addition salts thereof for the preparation of a medicament for preventing and/or treating PAH secondary to interstitial fibrosis.
  • the invention relates to the use of one or more, preferably one compound of formula (I) ⁇ _, optionally in form of the free base or in form of the pharmacologically acceptable acid addition salts thereof for the preparation of a medicament for preventing and/or treating PAH secondary to high left-sided filling pressures.
  • Another embodiment of the invention relates to a method for preventing and/or treating of any of the aforementioned conditions, comprising the administration of a therapeutically effective amount of one or more, preferably one compound of formula (I) 1, optionally in form of the free base or in form of the pharmacologically acceptable acid addition salts thereof.
  • the present invention relates to any of the above mentioned uses and methods wherein 1_ is selected from the group consisting of
  • the compounds of formula (I) l and the compounds (I. a), (l.b), (l.c), (l.d), (l.e), (l.f), (l.g) and (l.h) can be used either as free base or in form of its pharmaceutically acceptable acid addition salts.
  • the term ..acceptable acid addition salts includes both organic and inorganic acids such as maleic, citric, tartaric, methanesulphonic, acetic, benzoic, succinic, gluconic, isethionic, glycinic, lactic, malic, mucoic, glutamic, sulphamic and ascorbic acid; inorganic acids include hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acid. Mixtures of the above mentioned acid addition salts may also be used.
  • the present invention includes within its scope prodrugs of the compounds ⁇ _.
  • prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound.
  • terapéuticaally effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.
  • the compounds of formula (I) l and the compounds (I. a), (l.b), (l.c), (l.d), (l.e), (l.f), (l.g) and (l.h), optionally in form of the free base or in form of the pharmacologically acceptable acid addition salts thereof., may be incorporated into the conventional pharmaceutical preparation in solid, liquid or spray form.
  • the composition may, for example, be presented in a form suitable for oral, rectal, parenteral administration or for nasal inhalation: preferred forms includes for example, capsules, tablets, coated tablets, ampoules, suppositories and nasal spray.
  • the compounds of formula (I) l and the compounds (I. a), (l.b), (l.c), (l.d), (l.e), (l.f), (l.g) and (l.h), may be incorporated in excipients or carriers conventionally used in pharmaceutical compositions such as, for example, talc, arabic gum, lactose, gelatine, magnesium stearate, corn starch, acqueous or non acqueous vehicles, polyvynil pyrrolidone, semisynthetic glicerides of fatty acids, benzalconium chloride, sodium phosphate , EDTA, polysorbate 80.
  • excipients or carriers conventionally used in pharmaceutical compositions such as, for example, talc, arabic gum, lactose, gelatine, magnesium stearate, corn starch, acqueous or non acqueous vehicles, polyvynil pyrrolidone, semisynthetic glicerides of fatty
  • compositions are advantageously formulated in dosage units, each dosage unit being adapted to supply a single dose of the active ingredient.
  • the dose range applicable per day is between 0.1 to 400, preferably between 1.0 to 300, more preferably between 2 to 200 mg of the compounds of formula (I) l and the compounds (I. a), (l.b), (l.c), (l.d), (l.e), (l.f), (l.g) and (l.h).
  • Each dosage unit may conveniently contain from 0,01 mg to 100 mg of the compounds of formula (I) 1, preferably from 0,1 to 50 mg.
  • the dosage units are administered to the patient 1 , 2, 3, or 4 times daily. It is preferred that the dosage units are administered either three or fewer times, more preferably once or twice daily consecutively over a period of time.
  • the dose is administered to a patient in the morning and the evening, more preferably once in the morning and once in the evening, most preferably once in the evening only consecutively over a period of time.
  • Suitable tablets may be obtained, 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 gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • the tablets may also comprise several layers. Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number or layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
  • excipients for example inert
  • Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g of. a flavouring such as vanilline or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
  • a sweetener such as saccharine, cyclamate, glycerol or sugar
  • a flavour enhancer e.g of. a flavouring such as vanilline or orange extract.
  • suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
  • Solutions for injection are prepared in the usual way, e.g of. with the addition of preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, and transferred into injection vials or ampoules.
  • preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid
  • Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
  • Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
  • the finely ground active substance, lactose and some of the corn starch are mixed together.
  • the mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried.
  • the granules, the remaining corn starch and the magnesium stearate are screened and mixed together.
  • the mixture is compressed to produce tablets of suitable shape and size.
  • the finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened.
  • the sodium-carboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.
  • the active substance, corn starch, lactose and polyvinylpyrrolidone are thoroughly mixed and moistened with water.
  • the moist mass is pushed through a screen with a 1 mm mesh size, dried at about 45°C and the granules are then passed through the same screen.
  • convex tablet cores with a diameter of 6 mm are compressed in a tablet-making machine .
  • the tablet cores thus produced are coated in known manner with a covering consisting essentially of sugar and talc.
  • the finished coated tablets are polished with wax.
  • the substance and corn starch are mixed and moistened with water.
  • the moist mass is screened and dried.
  • the dry granules are screened and mixed with magnesium stearate.
  • the finished mixture is packed into size 1 hard gelatine capsules.
  • the active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic.
  • the solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion.
  • the hard fat is melted.
  • the ground active substance is homogeneously dispersed. It is cooled to 38°C and poured into slightly chilled suppository moulds.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de dérivés de benzimidazolone représentés par la formule (I) en vue de la préparation d'un médicament destiné à traiter des maladies dans lesquelles l'utilisation de quantités thérapeutiquement efficaces de composés présentant une affinité pour le récepteur 5-HT2B présente un bénéfice thérapeutique.
PCT/EP2007/062537 2006-11-22 2007-11-20 Dérivés de benzimidazolone utiles dans le traitement de l'hypertension artérielle pulmonaire WO2008061968A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP06124577 2006-11-22
EP06124577.5 2006-11-22

Publications (1)

Publication Number Publication Date
WO2008061968A1 true WO2008061968A1 (fr) 2008-05-29

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/062537 WO2008061968A1 (fr) 2006-11-22 2007-11-20 Dérivés de benzimidazolone utiles dans le traitement de l'hypertension artérielle pulmonaire

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WO (1) WO2008061968A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2184276A1 (fr) 2008-11-07 2010-05-12 Universite Paul Cezanne Aix-Marseille Iii Procédé de préparation de nouvelles 1H-benzo(d) imidazol-2(3h)-ones substituées, de nouveaux intermédiaires et leur utilisation en tant qu'inhibiteurs de bace 1
CN103467596A (zh) * 2012-06-06 2013-12-25 北京大学 一个治疗肺动脉高压的新靶点

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001021593A1 (fr) * 1999-09-22 2001-03-29 Boehringer Ingelheim Italia S.P.A. Nouveaux derives de benzimidazolone possedant une affinite mixte envers les recepteurs de serotonine et de dopamine
US20050222176A1 (en) * 2003-03-31 2005-10-06 Dhanoa Dale S Piperidinylamino-thieno[2,3-D] pyrimidine compounds
US20060120972A1 (en) * 2004-11-09 2006-06-08 Peter Engels 9-(N-methyl-piperidyliden-4)-thioxanthene for treatment of pulmonary hypertension

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001021593A1 (fr) * 1999-09-22 2001-03-29 Boehringer Ingelheim Italia S.P.A. Nouveaux derives de benzimidazolone possedant une affinite mixte envers les recepteurs de serotonine et de dopamine
US20050222176A1 (en) * 2003-03-31 2005-10-06 Dhanoa Dale S Piperidinylamino-thieno[2,3-D] pyrimidine compounds
US20060120972A1 (en) * 2004-11-09 2006-06-08 Peter Engels 9-(N-methyl-piperidyliden-4)-thioxanthene for treatment of pulmonary hypertension

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2184276A1 (fr) 2008-11-07 2010-05-12 Universite Paul Cezanne Aix-Marseille Iii Procédé de préparation de nouvelles 1H-benzo(d) imidazol-2(3h)-ones substituées, de nouveaux intermédiaires et leur utilisation en tant qu'inhibiteurs de bace 1
US7906541B2 (en) 2008-11-07 2011-03-15 Universite Paul Cezanne-Aix Marseille Iii Process to prepare new substituted 1H-benzo[d]imidazol-2(3H)-ones, new intermediates and their use as BACE 1 inhibitors
CN103467596A (zh) * 2012-06-06 2013-12-25 北京大学 一个治疗肺动脉高压的新靶点

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