WO2017184412A1 - Agoniste cannabinoïde de la purine pour traiter la stéatohépatite non alcoolique et la fibrose - Google Patents

Agoniste cannabinoïde de la purine pour traiter la stéatohépatite non alcoolique et la fibrose Download PDF

Info

Publication number
WO2017184412A1
WO2017184412A1 PCT/US2017/027306 US2017027306W WO2017184412A1 WO 2017184412 A1 WO2017184412 A1 WO 2017184412A1 US 2017027306 W US2017027306 W US 2017027306W WO 2017184412 A1 WO2017184412 A1 WO 2017184412A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
purine
piperazin
pyran
tetrahydro
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/US2017/027306
Other languages
English (en)
Inventor
Zhiming Ding
Bei Betty ZHANG
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.)
Lilly China Research and Development Co Ltd
Eli Lilly and Co
Original Assignee
Lilly China Research and Development Co Ltd
Eli Lilly and Co
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
Priority claimed from PCT/CN2016/079541 external-priority patent/WO2017181317A1/fr
Priority claimed from PCT/CN2017/072622 external-priority patent/WO2018137176A1/fr
Application filed by Lilly China Research and Development Co Ltd, Eli Lilly and Co filed Critical Lilly China Research and Development Co Ltd
Publication of WO2017184412A1 publication Critical patent/WO2017184412A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

  • Nonalcoholic steatohepatitis is a liver disease with an etiological constellation characterized by macrovesicular hepatic steatosis, inflammation hepatocyte ballooning and fibrosis.
  • Nonalcoholic steatohepatitis occurs in people who drink little or no alcohol and is often comorbid with obesity, type II diabetes, elevated levels of cholesterol, and triglycerides.
  • Nonalcoholic steatohepatitis may lead to cirrhosis and liver failure. It has been established that patients with nonalcoholic steatohepatitis are more likely to develop cirrhosis, and have a higher risk of cardiovascular mortality, and hepatocyte carcinoma.
  • the stage of disease can be defined, for example, by the nonalcoholic steatohepatitis CRN (Clinical Research Network) fibrosis staging which measures the amount and pattern of nonalcoholic steatohepatitis fibrosis, as well as parenchymal architectural remodeling in a patient.
  • Nonalcoholic steatohepatitis is
  • liver biopsy typically diagnosed in a human patient using liver biopsy.
  • the present invention provides a pharmaceutical treatment for nonalcoholic steatohepatitis comprising administering an effective amount of the compound, 8-(2- Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H- purine to a patient.
  • Compounds of WO 2010/080306 are stated to be agonists of the cannabinoid receptor 2 (CB2 receptor) in vitro and useful for treatment or prevention of pain.
  • CB2 receptor cannabinoid receptor 2
  • the present invention provides a method for treating nonalcoholic steatohepatitis, comprising administering an effective amount of 8-(2-Chloro-phenyl)-2-methyl-6-(4- methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H-purine, or a pharmaceutically acceptable salt thereof, to a patient.
  • the present invention provides a method for treating nonalcoholic steatohepatitis and fibrosis, comprising administering an effective amount of 8-(2-Chloro-phenyl)-2- methyl-6-(4-methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H-purine, or a pharmaceutically acceptable salt thereof, to a patient.
  • the present invention provides a method for treating nonalcoholic steatohepatitis, comprising administering an effective amount of 8-(2-Chloro-phenyl)-2-methyl-6-(4- methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H-purine to a patient.
  • the present invention provides the compound 8-(2-Chloro-phenyl)-2-methyl-6-(4- methyl-piperazin- 1 -yl)-9-(tetrahydro-pyran-4-yl)-9H-purine, or pharmaceutically acceptable salt thereof, for use in treating nonalcoholic steatohepatitis in a patient.
  • the present invention provides the compound 8-(2-Chloro-phenyl)-2-methyl-6-(4- methyl-piperazin- 1 -yl)-9-(tetrahydro-pyran-4-yl)-9H-purine, or pharmaceutically acceptable salt thereof, for use in treating nonalcoholic steatohepatitis and fibrosis in a patient.
  • the present invention provides the compound 8-(2-Chloro-phenyl)-2-methyl-6-(4- methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H-purine, for use in treating nonalcoholic steatohepatitis in a patient.
  • the present invention provides the compound 8-(2-Chloro-phenyl)-2-methyl-6-(4- methyl-piperazin- 1 -yl)-9-(tetrahydro-pyran-4-yl)-9H-purine, or pharmaceutically acceptable salt thereof, for use in treating hepatic fibrosis in a mammal.
  • the present invention provides a pharmaceutical composition for use in the treatment of nonalcoholic steatohepatitis comprising 8-(2-Chloro-phenyl)-2-methyl-6-(4- methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H-purine, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • the present invention provides a pharmaceutical composition for use in the treatment of nonalcoholic steatohepatitis and fibrosis comprising 8-(2-Chloro-phenyl)-2- methyl-6-(4-methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H-purine, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • the present invention provides the use of 8-(2-Chloro-phenyl)-2-methyl-6-(4- methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H-purine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of nonalcoholic steatohepatitis.
  • the present invention provides the use of 8-(2-Chloro-phenyl)-2-methyl-6-(4- methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H-purine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of nonalcoholic steatohepatitis and fibrosis.
  • the present invention provides the use of 8-(2-Chloro-phenyl)-2-methyl-6-(4- methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H-purine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of hepatic fibrosis.
  • the present invention provides a method for treating hepatic fibrosis, comprising administering an effective amount of 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl- piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H-purine, or a pharmaceutically acceptable salt thereof, to a mammal.
  • the compound, 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9- (tetrahydro-pyran-4-yl)-9H-purine 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin- l-yl)-9-(tetrahydro-pyran-4-yl)-9H-purine, has the following structural formula:
  • treating refers to restraining, slowing, or stopping the progression or alleviating the severity of the stated condition to be treated.
  • the term "effective amount” refers to the amount or dose of 8-(2- Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H- purine, or a pharmaceutically acceptable salt thereof which upon single or multiple dose administration to the patient, provides the desired effect in the patient. It will be understood that the amount of active agent actually administered will be determined by a physician, in light of the relevant circumstances.
  • patient refers to a mammal in need of treatment for
  • nonalcoholic steatohepatitis In a preferred embodiment, the patient is a mammal.
  • mammal is a human. In a preferred embodiment the mammal is a human in need of treatment for nonalcoholic steatohepatitis and fibrosis.
  • 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4- yl)-9H-purine is preferably formulated as a pharmaceutical composition administered by any route which makes the compound bioavailable. Most preferably, such composition is for oral administration.
  • Such pharmaceutical compositions and processes for preparing the same are well known in the art. See, e.g., Remington: The Science and Practice of Pharmacy (D.B. Troy, Editor, 21st Edition, Lippincott, Williams & Wilkins, 2006).
  • mice Male C57BL/6N mice are fed with D09100301 diet (Research Diets, 40% fat, 2% cholesterol, 24% fructose, 3H diet) for 150 days. Each mouse is then singly housed after 5 days of acclimation period. Plasma alanine aminotransferase (ALT) and CK18 (cytokeratin 18) are measured. After one week of acclimation, the mice are randomized into groups by their ALT, CK18 and body weight.
  • D09100301 diet Research Diets, 40% fat, 2% cholesterol, 24% fructose, 3H diet
  • CK18 cytokeratin 18
  • Animals of each group are administrated either vehicle (0.5% methylcellulose (MC) + 0.25% Tween 80 in distilled water) or the compound of 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9- (tetrahydro-pyran-4-yl)-9H-purine (at a 1, 3, 10, and 30 mg/kg dose) once daily in a volume of 5 ml/kg for 11 weeks.
  • vehicle 0.5% methylcellulose (MC) + 0.25% Tween 80 in distilled water
  • 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9- (tetrahydro-pyran-4-yl)-9H-purine at a 1, 3, 10, and 30 mg/kg dose
  • mice treated with the compound of 8-(2-Chloro-phenyl)- 2-methyl-6-(4-methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H-purine for 76 days 2 hours after the last dose.
  • Compound levels in the plasma are analyzed by mass spectroscopy. The results are listed below in Table 1. Treated mice exhibit a dose- dependent increase in plasma compound levels.
  • the animals are sacrificed and their livers excised. Two sections of the left and right lobes are fixed in neutral buffered 10% formalin. Liver tissue slides are stained with hematoxylin and eosin (H&E), Sirius red, and Masson's Trichrome to prepare slides for pathological analysis. All specimens are examined microscopically and scored as a modified Brunt score system. Scores are based on the grading scheme and end-points as described in Brunt E. M, et al. , "Histopathology of nonalcoholic fatty liver disease," World J. of Gastroenterol, 2010, 16(42), 5286-5296. Group means are then calculated for each individual end-point.
  • mice that received 8-(2- Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H- purine exhibit a significant decrease in hepatic inflammation
  • mice that received 3 mg/kg and higher doses of 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9- (tetrahydro-pyran-4-yl)-9H-purine exhibit a significant decrease in macrovesicular vaculation and perisinusoidal fibrosis
  • mice that received 10 and 30 mg/kg of 8-(2- Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H- purine also exhibit a significant decrease in portal fibrosis.
  • Plasma Levels of 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9- (tetrahydro-pyran-4-yl)-9H-purine Dose Number of Plasma Compound (mg/kg) Animals Level (ng/ml)
  • Nonparametric test is applied to compare scores between compound treatment groups and vehicle group. Scores for left and right laterals are compared separately.
  • HFD high fat diet
  • mice that received 30 mg/kg of 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l- yl)-9-(tetrahydro-pyran-4-yl)-9H-purine exhibit a significant decrease in ALT and AST after 33 weeks of compound treatment.
  • mice After 20 weeks of treatment, mice are sacrificed (un-fasted). The liver is isolated and total liver weight is determined. The medial lobe is isolated, fixed in formalin and embedded in paraffin for histological evaluation. Formalin-fixed and paraffin-embedded cross- sections (3 ⁇ ) are stained with haematoxylin and eosin and are scored blindly by a board-certified pathologist using an adapted grading method for human nonalcoholic steatohepatitis (Liang et al, "Establishment of a General NAFLD Scoring System for Rodent Models and Comparison to Human Liver Pathology," PLoS ONE, 9(12), 2014, 1- 17).
  • fibrosis is assessed histochemically by Picro-Sirius Red staining (Chroma, WALDECK-Gmbh, Miinster, Germany). The development of fibrosis is assessed by a pathologist to gain insight into the distribution pattern of the collagen and to quantify the percentage of pericellular fibrosis specifically.
  • mice treated with the compound of 8- (2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H- purine is provided in Table 5.
  • the results indicate that the mice that received 30 mg/kg of 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9-(tetrahydro-pyran-4-yl)-9H- purine exhibit a significant decrease in hepatic inflammation, macrovesicular vacuolation and fibrosis.
  • ANOVA test is applied to compare scores between compound treatment groups and vehicle group.
  • IU refers to international units
  • ANOVA test is applied to compare scores between compound treatment groups and vehicle group.
  • the total collagen content is determined by quantitative analysis of
  • results from this method can be useful to support that 8-(2-Chloro-phenyl)-2-methyl-6-(4-methyl-piperazin-l-yl)-9- (tetrahydro-pyran-4-yl)-9H-purine significantly reduces liver fibrosis and total collagen in the nonalcoholic steatohepatitis model at a 30 mg/kg /day food mixture dosing.

Landscapes

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

Abstract

La présente invention concerne une méthode de traitement de la stéatohépatite non alcoolique comprenant l'administration d'une quantité efficace de 8-(2-chlorophényl)-2-méthyl-6-(4-méthylpipérazin-1-yl)-9-(tétrahydro-pyran-4-yl)-9H-purine, ou d'un sel pharmaceutiquement acceptable de celui-ci, à un patient.
PCT/US2017/027306 2016-04-18 2017-04-13 Agoniste cannabinoïde de la purine pour traiter la stéatohépatite non alcoolique et la fibrose Ceased WO2017184412A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CNPCT/CN2016/079541 2016-04-18
PCT/CN2016/079541 WO2017181317A1 (fr) 2016-04-18 2016-04-18 Traitement de la stéatohépatite non alcoolique et de la fibrose
CNPCT/CN2017/072622 2017-01-25
PCT/CN2017/072622 WO2018137176A1 (fr) 2017-01-25 2017-01-25 Traitement de la fibrose et de la stéatohépatite non alcoolique

Publications (1)

Publication Number Publication Date
WO2017184412A1 true WO2017184412A1 (fr) 2017-10-26

Family

ID=59298510

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2017/027306 Ceased WO2017184412A1 (fr) 2016-04-18 2017-04-13 Agoniste cannabinoïde de la purine pour traiter la stéatohépatite non alcoolique et la fibrose

Country Status (1)

Country Link
WO (1) WO2017184412A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1725223A2 (fr) * 2004-03-09 2006-11-29 Inserm Utilisation d'antagonistes des récepteurs cb1 pour la fabrication d'un médicament destiné au traitement des maladies hépatiques
WO2010080306A1 (fr) 2008-12-18 2010-07-15 Eli Lilly And Company Composés purines
WO2017039643A1 (fr) * 2015-09-01 2017-03-09 Arena Pharmaceuticals, Inc. Internalisation de récepteur cb2

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1725223A2 (fr) * 2004-03-09 2006-11-29 Inserm Utilisation d'antagonistes des récepteurs cb1 pour la fabrication d'un médicament destiné au traitement des maladies hépatiques
WO2010080306A1 (fr) 2008-12-18 2010-07-15 Eli Lilly And Company Composés purines
WO2017039643A1 (fr) * 2015-09-01 2017-03-09 Arena Pharmaceuticals, Inc. Internalisation de récepteur cb2

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BRUNT E. M ET AL.: "Histopathology of nonalcoholic fatty liver disease", WORLD J. OF GASTROENTEROL, vol. 16, no. 42, 2010, pages 5286 - 5296
BRUNT, E. M ET AL.: "Nonalcoholic steatohepatitis: A proposal for grading and staging the histological lesions", AM J GASTROENTEROLOGY, vol. 94, no. 9, 1999, pages 2467 - 2474, XP055215446, DOI: doi:10.1111/j.1572-0241.1999.01377.x
BRUNT, E. M.: "Histopathology of nonalcoholic fatty liver disease", CLIN LIVER DIS., vol. 13, 2009, pages 533 - 544
D.B. TROY: "Remington: The Science and Practice of Pharmacy, 21st ed", 2006, LIPPINCOTT, WILLIAMS & WILKINS
LIANG ET AL.: "Establishment of a General NAFLD Scoring System for Rodent Models and Comparison to Human Liver Pathology", PLOS ONE, vol. 9, no. 12, 2014, pages 1 - 17
ROSSELLA GUIDETTI ET AL: "The SAR development of substituted purine derivatives as selective CB2 agonists for the treatment of chronic pain", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 24, no. 24, 1 December 2014 (2014-12-01), AMSTERDAM, NL, pages 5572 - 5575, XP055379448, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2014.11.006 *

Similar Documents

Publication Publication Date Title
Li et al. Salidroside improves high-fat diet-induced non-alcoholic steatohepatitis by regulating the gut microbiota–bile acid–farnesoid X receptor axis
Wang et al. Inhibitory effects of quercetin on the progression of liver fibrosis through the regulation of NF-кB/IкBα, p38 MAPK, and Bcl-2/Bax signaling
EP3280421B1 (fr) Compositions pharmaceutiques pour thérapie combinée
TWI667025B (zh) 治療肝臟疾病之方法
Kismet et al. Does propolis have any effect on non-alcoholic fatty liver disease?
TW201733582A (zh) Fxr促效劑及arb之組合醫藥
Bian et al. Celastrol confers ferroptosis resistance via AKT/GSK3β signaling in high-fat diet-induced cardiac injury
Lin et al. Differential action of TGR5 agonists on GLP-2 secretion and promotion of intestinal adaptation in a piglet short bowel model
Chen et al. Strobilanthes sarcorrhiza root phenolic extract prevent diabetic nephropathy in mice by regulating NF-κB/IL-1β signaling and glycerophospholipid metabolism
Dang et al. Zishen Yutai pills restore fertility in premature ovarian failure through regulating arachidonic acid metabolism and the ATK pathway
Zheng et al. Geniposide via enema alleviates colitis by modulating intestinal flora and bile acid metabolites, inhibiting S100A8/S100A9/NF-κB, and promoting TGR5 inhibition of NLRP3 inflammasome
Liu et al. Myricetin alleviates high-fat diet-induced atherosclerosis in ApoE−/− mice by regulating bile acid metabolism involved in gut microbiota remodeling
Chinese Society of Gastroenterology, Cancer Collaboration Group of Chinese Society of Gastroenterology, Chinese Medical Association Chinese consensus on prevention of colorectal neoplasia (2021, S hanghai)
Chang et al. Metabolism profiles of tannins in Phyllanthus emblica L. and its immunotherapeutic potential against hepatocellular carcinoma by re-educating tumor microenvironment
Cheng et al. Bioinformatic and biochemical findings disclosed anti-hepatic steatosis mechanism of calycosin
Niu et al. ACT001 alleviates MASLD through gut microbiota–bile acid–FXR axis in mice
WO2018137176A1 (fr) Traitement de la fibrose et de la stéatohépatite non alcoolique
Li et al. Qingtong Treatment Principle alleviates opioid-induced constipation by regulating bile acid homeostasis via an FXR-dependent manner
JP7756126B2 (ja) 脂肪性肝疾患の治療薬
CN113368107B (zh) 包含小檗碱和苦参碱的药物组合物及其治疗或预防非酒精性脂肪性肝病的用途
CN103599108B (zh) 齐墩果酸在制备预防和治疗胆汁淤积症药物中的应用
CN116270695A (zh) 一种预防或治疗代谢相关脂肪性肝病的药物组合物
WO2017181320A1 (fr) Traitement de la stéatohépatite non alcoolique et de la fibrose
WO2017181317A1 (fr) Traitement de la stéatohépatite non alcoolique et de la fibrose
CN111356458A (zh) 用于治疗肝疾病的fxr激动剂

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

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

Ref document number: 17737398

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17737398

Country of ref document: EP

Kind code of ref document: A1