[go: up one dir, main page]

WO2015185499A1 - Inhibiteurs pde9 présentant un squelette 1-benzyl-2,5,6,8-tétrahydro-3-oxo-2,7-naphtyridine-4-carbonitrile - Google Patents

Inhibiteurs pde9 présentant un squelette 1-benzyl-2,5,6,8-tétrahydro-3-oxo-2,7-naphtyridine-4-carbonitrile Download PDF

Info

Publication number
WO2015185499A1
WO2015185499A1 PCT/EP2015/062140 EP2015062140W WO2015185499A1 WO 2015185499 A1 WO2015185499 A1 WO 2015185499A1 EP 2015062140 W EP2015062140 W EP 2015062140W WO 2015185499 A1 WO2015185499 A1 WO 2015185499A1
Authority
WO
WIPO (PCT)
Prior art keywords
benzyl
oxo
tetrahydro
naphthyridine
compound
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.)
Ceased
Application number
PCT/EP2015/062140
Other languages
English (en)
Inventor
Klaus Bæk SIMONSEN
Niels PLATH
Tenna Juul SCHRØDER
Niels Svenstrup
Kate Xin WEN
Zhigang Li
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.)
H Lundbeck AS
Original Assignee
H Lundbeck AS
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 H Lundbeck AS filed Critical H Lundbeck AS
Publication of WO2015185499A1 publication Critical patent/WO2015185499A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C07D471/02—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 two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the present invention relates to cyclic guanylate monophosphate (cGMP)-specific phosphodiesterase type 9 inhibitors (hereinafter referred to as PDE9 inhibitors) with an 1-benzyl-2,5,6,8-tetrahydro-3-oxo-2,7-naphthyridine-4-carbonitrile backbone and their use as a medicament.
  • PDE9 inhibitors cyclic guanylate monophosphate
  • PDE9 inhibitors 1-benzyl-2,5,6,8-tetrahydro-3-oxo-2,7-naphthyridine-4-carbonitrile backbone
  • a pharmaceutical composition comprising compounds with a 1-benzyl-2,5,6,8-tetrahydro-3-oxo-2,7-naphthyridine-4-carbonitrile backbone, as well as a process for preparation of the compounds.
  • PDEs Phosphodiesterases
  • PDEs are a family of enzymes degrading cyclic nucleotides and thereby regulating the cellular levels of second messengers throughout the entire body. PDEs represent attractive drug targets, as proven by a number of compounds that have been introduced to clinical testing and the market, respectively. PDEs are encoded by 21 genes that are functionally separated into 11 families differing with respect to kinetic properties, substrate selectivity, expression, localization pattern, activation, regulation factors and inhibitor sensitivity.
  • PDEs The function of PDEs is the degradation of the cyclic nucleotide monophosphates cyclic Adenosine Monophosphate (cAMP) and/or Guanosine Monophosphate (cGMP), which are important intracellular mediators involved in numerous vital processes including the control of neurotransmission and smooth muscle contraction and relaxation.
  • cAMP cyclic Adenosine Monophosphate
  • cGMP Guanosine Monophosphate
  • PDE9 is cGMP specific (Km cAMP is >1000x for cGMP) and is hypothesized to be a key player in regulating cGMP levels as it has the lowest Km among the PDEs for this nucleotide.
  • PDE9 is expressed throughout the brain at low levels with the potential for regulating basal cGMP.
  • cGMP acts as a central second messenger involved in several signalling cascades shown to regulate synaptic transmission, neuroprotection and neuroinflammation. The inhibition of PDE9 leads to increased cGMP levels which is proposed to result in pro-cognitive processes.
  • the PDE9 inhibitors of the present invention may be used in the treatment of numerous diseases and indications related to the peripheral nervous system (peripheral indications) including benign prostate hyperplasia, urinary tract dysfunctional epithelium disease, erectile dysfunction, sickle cell disease (SCD) and type 2 diabetes.
  • peripheral indications including benign prostate hyperplasia, urinary tract dysfunctional epithelium disease, erectile dysfunction, sickle cell disease (SCD) and type 2 diabetes.
  • PDE9 expression pattern and modulatory capabilities within specific regions as well as literature evidence are supportive of PDE9 inhibitors' therapeutic potential is peripheral indications as described below.
  • Benign prostate hyperplasia is one of the most prevalent conditions in the aging male population and represents a major health problem (Ueckert S et al., Expert Rev Clin Pharmacol. 2013 May;6(3):323-32). BPH results in the formation of large nodules in the periurethral region of the prostate, which could lead to urinary tract obstruction. BPH is predominantly the result of a stromal proliferative process, and a significant component of prostatic enlargement results from smooth-muscle proliferation.
  • the current pharmacological treatment of BPH includes a1 adrenergic blockers, 5-a-reductase inhibitors and more recently the PDE5 inhibitor tadalafil. PDE5 inhibitors are known to mediate smooth muscle relaxation via increased cGMP levels. The cGMP specific PDE9 is expressed at high levels in the prostate and PDE9 inhibition may thus offer potential antiproliferative benefits for BPH.
  • PDE9 is widely distributed in the urothelial epithelium of human lower urinary tract and PDE9 inhibition may be beneficial in lower urinary tract dysfunctional epithelium (LUDE) disease (Nagasaki et al., BJU Int. 2012 Mar; 109(6):934-40).
  • Dysfunctional lower urinary tract epithelium can affect the bladder, urethra, labia or vaginal introitus in women, and the prostatic ducts and urethra in men (Parsons LC et al., 2002).
  • PDE9 expression has been shown in murine corpus cavernosum and chronic PDE9 inhibition was demonstrated to result in amplified NO-cGMP mediated cavernosal responses and thereby opening for potential benefit in erectile dysfunction (DaSilva et al., Int J Impot Res. 2013 Mar- Apr;25(2):69-73).
  • Currently approved treatment for erectile dysfunction is the class of PDE5 inhibitors, increasing cGMP in the smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis.
  • SCD is a genetic disorder in the haemoglobin gene resulting in the production of red blood cells assuming an abnormal sickle shape leading to vaso-occlusive processes responsible for much of the mortality in SCD patients.
  • the only currently approved treatment for SCD is hydroxyurea, which increases fetal hemoglobin production thereby inhibiting the formation of sickle hemoglobin aggregates.
  • the mechanism of action of hydroxyurea is hypothesized to be via increased nitric oxide levels causing rise in cGMP and the activation of the gamma globin chain synthesis necessary for fetal hemoglobin production.
  • the cGMP specific PDE9 is shown to be expressed in human haematopoietic cells including neutrophils, reticulocytes erythroid and erythroleukaemic cells with PDE9 expression being significantly higher in the reticulocytes and neutrophils of SCD individuals (Almeida et al., Br J Haematol. 2008 Sep;142(5):836-44). PDE9 inhibition results in the reversal of the increased adhesive properties of SCD neutrophils (Miguel et al., Inflamm Res. 201 1 Jul;60(7):633-42).
  • PDE9 inhibitors including oxo-quinazoline derivatives as disclosed in WO2008018306.
  • the compounds of the invention are PDE9 inhibitors which only pass the blood-brain-barrier (BBB) to a very limited extent opening for the therapeutic potential in various peripheral indications such as those discussed aboved without or with very limited side effects on the CNS system. DESCRIPTION OF THE FIGURES
  • Figure 1 describes the effect of compound b and alfuzosin on PHE-induced contractions of human prostatic strips from BPH patients.
  • the data are mean ⁇ SEM of N experiments using prostate samples from N different BPH patients.
  • Figure 2 describes the effect of compound b and alfuzosin on KCI-induced contractions of human prostatic strips from BPH patients.
  • the data are mean ⁇ SEM of N experiments using prostate samples from N different BPH patients.
  • Figure 3 describes the effect of compound b and alfuzosin on EFS-induced contractions of human prostatic strips from BPH patients.
  • the data are mean ⁇ SEM of N experiments using prostate samples from N different BPH patients.
  • Ci-C 6 -alkyl refers to a straight-chain or branched saturated hydrocarbon having from one to six carbon atoms, inclusive. Examples of such groups include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-1 -butyl, and n-hexyl.
  • Ci-C 6 -alkoxy refers to a straight-chain or branched saturated alkoxy group having from one to six carbon atoms, inclusive, with the open valency on the oxygen.
  • the present invention relates to a 1 -benzyl-2, 5,6, 8-tetrahydro-3-oxo- 2,7-naphthyridine-4-carbonitrile compound of the formula I:
  • R is -COCH 2 R 2 , COO-C 1-6 -alkyl, CH 2 CONR 3 R 4 , pyridinyl, pyrimidinyl or d-e-alkyl which is optionally substituted with Ci_ 6 -alkoxy, wherein R 2 is morpholinyl or piperazinyl optionally substituted with d-6-alkyl,
  • R 3 and R 4 are independently selected from Ci_ 6 -alkyl, and benzyl or R 3 and R 4 together with nitrogen to which they are attached form a morpholinyl or piperazinyl optionally substituted with d-e-alkyl, and pharmaceutically acceptable acid addition salts thereof.
  • the compound is selected from the group consisting of:
  • the present invention relates to a compound of any one of embodiments 1 or 2 for use as a medicament.
  • the present invention relates to a compound of any one of embodiments 1 or 2 for use in the treatment of a disease or condition selected from the group comprising benign prostate hyperplasia, urinary tract dysfunctional epithelium disease, erectile dysfunction, sickle cell disease and type 2 diabetes.
  • the present invention relates to a compound of any one of embodiments 1 or 2 for the preparation of a medicament for use in the treatment of a disease or condition selected from the group comprising benign prostate hyperplasia, urinary tract dysfunctional epithelium disease, erectile dysfunction, sickle cell disease and type 2 diabetes.
  • a disease or condition selected from the group comprising benign prostate hyperplasia, urinary tract dysfunctional epithelium disease, erectile dysfunction, sickle cell disease and type 2 diabetes.
  • the present invention relates to a method of treating a subject suffering from a disease or condition selected from the group comprising benign prostate hyperplasia, urinary tract dysfunctional epithelium disease, erectile dysfunction, sickle cell disease and type 2 diabetes comprising administering a compound of any one of embodiments 1 or 2.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of embodiments 1 or 2, and one or more pharmaceutically acceptable carriers, diluents and excipients.
  • Table 1 Exemplary compounds of the invention.
  • Compound PDE9 IC50 B/P litra Compound name (nM) screening a 1-Benzyl-7-methyl-3-oxo-2,5,6,8-tetrahydro-2,7- naphthyridine-4-carbonitrile 150 n.a.
  • the present invention also comprises salts of the compounds, typically, pharmaceutically acceptable salts.
  • Such salts include pharmaceutically acceptable acid addition salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids.
  • suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-tol
  • the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
  • the present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.
  • the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one of the specific compounds disclosed in the Experimental Section herein and a pharmaceutically acceptable carrier or diluent.
  • the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in either single or multiple doses.
  • pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • compositions may be specifically formulated for administration by any suitable route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. It will be appreciated that the route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient.
  • compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, the compositions may be prepared with coatings such as enteric coatings or they may be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.
  • Other suitable administration forms include, but are not limited to, suppositories, sprays, ointments, creams, gels, inhalants, dermal patches and implants.
  • Typical oral dosages range from about 0.001 to about 100 mg/kg body weight per day. Typical oral dosages also range from about 0.01 to about 50 mg/kg body weight per day. Typical oral dosages further range from about 0.05 to about 10 mg/kg body weight per day. Oral dosages are usually administered in one or more dosages, typically, one to three dosages per day. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • a typical unit dosage form for oral administration may contain from about 0.01 to about 1000 mg, from about 0.05 to about 500 mg, or from about 0.5 mg to about 200 mg.
  • the present invention also provides a process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of a compound of formula (I) and at least one pharmaceutically acceptable carrier or diluent.
  • the compound utilized in the aforementioned process is one of the specific compounds disclosed in the Experimental Section herein.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • One example is an acid addition salt of a compound having the utility of a free base.
  • salts are prepared in a conventional manner by treating a solution or suspension of a free base of formula (I) with a molar equivalent of a pharmaceutically acceptable acid.
  • suitable organic and inorganic acids are described above.
  • solutions of the compounds of formula (I) in sterile aqueous solution aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the compounds of formula (I) may be readily incorporated into known sterile aqueous media using standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • sustained release material such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and optionally a suitable excipient.
  • the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion.
  • the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it may be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will range from about 25 mg to about 1 g per dosage unit.
  • the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the pharmaceutical compositions of the invention may be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine prepare tablets.
  • adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatin, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colorings, flavorings, preservatives etc. may be used provided that they are compatible with the active ingredients.
  • Example 10 1-Benzyl-3-oxo-7-pyrimidin-2-yl-2,5,6,8-tetrahydro-2,7-naphthyridine- 4-carbonitrile (j) The procedure was similar to the preparation of compound (i) starting from compound 5 and 2- bromopyrimidine.
  • a PDE9 assay may for example, be performed as follows: The assay is performed in 60 uL samples containing a fixed amount of the relevant PDE enzyme (sufficient to convert 20-25% of the cyclic nucleotide substrate), a buffer (50 mM HEPES7.6; 10mM MgCI 2 ; 0.02% Tween20), 0.1 mg/ml BSA, 225 pCi of 3 H-labelled cyclic nucleotide substrate, tritium labeled cAMP to a final concentration of 5 nM and varying amounts of inhibitors.
  • Reactions are initiated by addition of the cyclic nucleotide substrate, and reactions are allowed to proceed for one hr at room temperature before being terminated through mixing with 15 uL 8 mg/mL yttrium silicate SPA beads (Amersham). The beads are allowed to settle for one hr in the dark before the plates are counted in a Wallac 1450 Microbeta counter. The measured signal can be converted to activity relative to an uninhibited control (100 %) and IC 50 values can be calculated using the Xlfit extension to EXCEL.
  • the assay was performed in 60 uL assay buffer (50 mM HEPES pH 7.6; 10mM MgCI 2 ; 0.02% Tween20) containing enough PDE9 to convert 20-25% of 10 nM 3 H-cAMP and varying amounts of inhibitors. Following a 1 hour incubation the reactions were terminated by addition of 15 uL 8 mg/mL yttrium silicate SPA beads (Amersham). The beads were allowed to settle for one hr in the dark before the plates were counted in a Wallac 1450 Microbeta counter. IC 5 o values were calculated by non linear regression using XLfit (IDBS).
  • Brain disposition has been assessed in mouse after oral administration of 10mg/kg of the test item. Thirty minutes post-dose the animals were sacrificed; plasma and brain samples were collected for exposure determination. The test compound was extracted with acetonitrile from plasma and homogenized brain tissues and the extracts analyzed by LC-MS to quantify the test. The results were expressed in ng/ml for plasma samples and ng/g for brain and the ratio between brain concentration and plasma concentration was expressed as the brain to plasma ratio.
  • the a1-receptor agonist PE induced contractions of human BPH tissue.
  • Compound b and alfuzosin treatment was demonstrated to result in a significant concentration dependent relaxation ( Figure 1 ).
  • the effect of compound b was less efficient than alfuzosin but compound b exhibited greater potency (Table 1 ).
  • Table 1 Potency (pD2) and maximum response (Emax) obtained using nonlinear logistic regression for compound b or alfuzosin-induced relaxation on PHE-induced contractions of human prostatic strips from BPH patients.
  • ⁇ p ⁇ 0.01 Student's t-test, CRC to alfuzosin versus CRC to compound b
  • ⁇ p ⁇ 0.001 Student's t-test, CRC to alfuzosin versus CRC to compound b.
  • KCL-induced contractions do not involve adrenergic receptors but are dependent on Ca2+ influx and K+ efflux independent of the signaling pathways activated by agonist stimulation-induced contraction (Martin DJ, et al. 1997).
  • alfuzosin which may be the result of non specific activity independent from its anti-adrenergic properties ( Figure 2).
  • Compound b treatment exerted a greater relaxing effect than alfuzosin but the Emax of both compounds was not found to be significantly different.
  • EFS 32 Hz, 5ms pulse duration, 5 sec train duration at 300mA
  • PA1 and PA10 and pD2 value of compound b for experiments PA1 could not be included because nonlinear regression performed by Graph Pad Prism was aberrant or could not be calculated.
  • compound b exerted a significant inhibitory effect on PE, KCL and EFS-induced contractions of prostatic strips from BPH patients.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Reproductive Health (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé de 1-benzyl-2,5,6,8-tétrahydro-3-oxo-2,7-naphtyridine-4-carbonitrile de formule (I), dans laquelle R1 représente -COCH2R2, COO-C1-6-alkyle, CH2CONR3R4, pyridinyle, pyrimidinyle ou C1-6-alkyle qui est éventuellement substitué par C1-6-alcoxy, R2 représentant morpholinyle ou pipérazinyle éventuellement substitué par C1-6-alkyle, R3 et R4 étant choisis, indépendamment, parmi C1-6-alkyle et benzyle ou R3 et R4 formant, conjointement avec l'atome d'azote auquel ils sont liés, morpholinyle ou pipérazinyle, éventuellement substitué par C1-6-alkyle, et des sels d'addition d'acide pharmaceutiquement acceptables correspondants.
PCT/EP2015/062140 2014-06-06 2015-06-01 Inhibiteurs pde9 présentant un squelette 1-benzyl-2,5,6,8-tétrahydro-3-oxo-2,7-naphtyridine-4-carbonitrile Ceased WO2015185499A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2014079398 2014-06-06
CNPCT/CN2014/079398 2014-06-06

Publications (1)

Publication Number Publication Date
WO2015185499A1 true WO2015185499A1 (fr) 2015-12-10

Family

ID=53366008

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2015/062140 Ceased WO2015185499A1 (fr) 2014-06-06 2015-06-01 Inhibiteurs pde9 présentant un squelette 1-benzyl-2,5,6,8-tétrahydro-3-oxo-2,7-naphtyridine-4-carbonitrile

Country Status (1)

Country Link
WO (1) WO2015185499A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109475556A (zh) * 2016-07-06 2019-03-15 伊马拉公司 用于治疗外周疾病的pde9抑制剂
US11608342B2 (en) 2015-07-07 2023-03-21 H. Lundbeck A/S PDE9 inhibitors with imidazo triazinone backbone and imidazo pyrazinone backbone for treatment of peripheral diseases
US12006319B2 (en) 2018-05-25 2024-06-11 Cardurion Pharmaceuticals, Inc. Monohydrate and crystalline forms of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one
US12213975B2 (en) 2018-08-31 2025-02-04 Cardurion Pharmaceuticals, Inc. PDE9 inhibitors for treating sickle cell disease

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006125554A1 (fr) * 2005-05-27 2006-11-30 Bayer Healthcare Ag Utilisation de cyanopyrimidines pour traiter des troubles cardio-vasculaires
EP2050739A1 (fr) * 2006-08-08 2009-04-22 ASKA Pharmaceutical Co., Ltd. Dérivé quinazoline

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006125554A1 (fr) * 2005-05-27 2006-11-30 Bayer Healthcare Ag Utilisation de cyanopyrimidines pour traiter des troubles cardio-vasculaires
EP2050739A1 (fr) * 2006-08-08 2009-04-22 ASKA Pharmaceutical Co., Ltd. Dérivé quinazoline

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHUNG C WU ET AL: "Discovery of 3-hydroxy-4-cyano-isoquinolines as novel, potent, and selective inhibitors of human 11-hydroxydehydrogenase 1 (11-HSD1)", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, AMSTERDAM, NL, vol. 21, no. 22, 15 September 2011 (2011-09-15), pages 6693 - 6698, XP028320720, ISSN: 0960-894X, [retrieved on 20110921], DOI: 10.1016/J.BMCL.2011.09.058 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11608342B2 (en) 2015-07-07 2023-03-21 H. Lundbeck A/S PDE9 inhibitors with imidazo triazinone backbone and imidazo pyrazinone backbone for treatment of peripheral diseases
CN109475556A (zh) * 2016-07-06 2019-03-15 伊马拉公司 用于治疗外周疾病的pde9抑制剂
US12006319B2 (en) 2018-05-25 2024-06-11 Cardurion Pharmaceuticals, Inc. Monohydrate and crystalline forms of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one
US12466832B2 (en) 2018-05-25 2025-11-11 Cardurion Pharmaceuticals, Inc. Monohydrate and crystalline forms of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl-7H-imidazo[1,5-a]pyrazin-8-one
US12213975B2 (en) 2018-08-31 2025-02-04 Cardurion Pharmaceuticals, Inc. PDE9 inhibitors for treating sickle cell disease

Similar Documents

Publication Publication Date Title
CA2743257C (fr) Nouveau derive tricyclique ou ses sels pharmaceutiquement acceptables, son procede de preparation, et composition pharmaceutique le contenant
TWI676620B (zh) 離胺酸特異性去甲基酶-１之抑制劑
US6087368A (en) Quinazolinone inhibitors of cGMP phosphodiesterase
JP4287649B2 (ja) Ｈｉｖインテグラーゼ阻害薬として有用なアザ−およびポリアザ−ナフタレニルカルボキサミド類
KR101860583B1 (ko) 피라졸로퀴놀린 화합물
CN116410207B (zh) 一类泛素化特异性蛋白酶抑制剂及其制备方法与应用
JP6431622B2 (ja) 結晶性ｆｇｆｒ４阻害剤化合物およびその使用
KR20170018913A (ko) 리신 특이적 데메틸라제-1의 억제제
KR20130098269A (ko) 테트라히드로카르볼린 유도체
CA2368023A1 (fr) Composes fusionnes de pyridopyridazine inhibiteurs de la cgmp phosphodiesterase
CN101679272B (zh) 作为腺苷a3受体配体的三唑并[1,5-a]喹啉类
CN107001358A (zh) 调节组蛋白赖氨酸脱甲基酶(kdm)催化活性的新型吡啶并嘧啶酮化合物
WO2015185499A1 (fr) Inhibiteurs pde9 présentant un squelette 1-benzyl-2,5,6,8-tétrahydro-3-oxo-2,7-naphtyridine-4-carbonitrile
KR101335770B1 (ko) 사치환된 피리다진 헷지호그 경로 길항제
HK1244278B (zh) 喹唑啉衍生物的盐及其制备方法
Hong et al. Synthesis and Cytotoxicity Studies of Cyclohepta [b] indoles, Benzo [6, 7] Cyclohepta [1, 2‐b] Indoles, Indeno [1, 2‐b] Indoles, and Benzo [a] Carbazoles
CN112521386B (zh) 具有抗病毒作用的多环吡啶酮化合物及其药物组合和用途
JP2009500451A (ja) ピラノピリジン化合物
EP4242207A1 (fr) Inhibiteurs de kras pour le traitement de cancers
CN1334732A (zh) 嘧啶衍生物在预防和治疗脑缺血中的应用
CA2493854A1 (fr) Inhibiteur de phosphodiesterase
CN106749045A (zh) 一种新型d‑氨基酸氧化酶抑制剂及其制法和应用
WO2010037249A1 (fr) Composé de type 5,8-disubstitué-1,6- naphthyridine-7-amide carbonylé, son procédé de préparation, son composé et son utilisation
RU2496769C2 (ru) Производные бензоциклогептана и бензоксепина
CN116217561A (zh) 一类具有二甲基异吲哚酮结构的新型激酶抑制剂及其制备方法和用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15727621

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15727621

Country of ref document: EP

Kind code of ref document: A1