DE69918590D1 - Substituierte Karbazole, Verfahren zu ihrer Herstellung und ihre Verwendung als sPLA2-Inhibitoren - Google Patents

Substituierte Karbazole, Verfahren zu ihrer Herstellung und ihre Verwendung als sPLA2-Inhibitoren

Info

Publication number
DE69918590D1
DE69918590D1 DE69918590T DE69918590T DE69918590D1 DE 69918590 D1 DE69918590 D1 DE 69918590D1 DE 69918590 T DE69918590 T DE 69918590T DE 69918590 T DE69918590 T DE 69918590T DE 69918590 D1 DE69918590 D1 DE 69918590D1
Authority
DE
Germany
Prior art keywords
processes
preparation
spla2 inhibitors
substituted carbazoles
carbazoles
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.)
Expired - Lifetime
Application number
DE69918590T
Other languages
English (en)
Other versions
DE69918590T2 (de
Inventor
Nicholas James Bach
Jolie Anne Bastian
Gary Alan Hite
Michael Dean Kinnick
Edward David Mihelich
John Michael Morin Jr
Daniel Jon Sall
Robert Theodore Vasileff
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.)
Eli Lilly and Co
Original Assignee
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
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Application granted granted Critical
Publication of DE69918590D1 publication Critical patent/DE69918590D1/de
Publication of DE69918590T2 publication Critical patent/DE69918590T2/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56Ring systems containing three or more rings
    • C07D209/80[b, c]- or [b, d]-condensed
    • C07D209/82Carbazoles; Hydrogenated carbazoles
    • C07D209/88Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56Ring systems containing three or more rings
    • C07D209/58[b]- or [c]-condensed
    • C07D209/70[b]- or [c]-condensed containing carbocyclic rings other than six-membered
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/06Antiasthmatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
DE69918590T 1998-04-17 1999-04-16 Substituierte Karbazole, Verfahren zu ihrer Herstellung und ihre Verwendung als sPLA2-Inhibitoren Expired - Lifetime DE69918590T2 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6232898A 1998-04-17 1998-04-17
US62328 1998-04-17

Publications (2)

Publication Number Publication Date
DE69918590D1 true DE69918590D1 (de) 2004-08-19
DE69918590T2 DE69918590T2 (de) 2005-07-21

Family

ID=22041763

Family Applications (2)

Application Number Title Priority Date Filing Date
DE69917833T Expired - Lifetime DE69917833T2 (de) 1998-04-17 1999-04-16 Substituierte Karbazole, Verfahren zu ihrer Herstellung und ihre Verwendung als sPLA2- Inhibitoren
DE69918590T Expired - Lifetime DE69918590T2 (de) 1998-04-17 1999-04-16 Substituierte Karbazole, Verfahren zu ihrer Herstellung und ihre Verwendung als sPLA2-Inhibitoren

Family Applications Before (1)

Application Number Title Priority Date Filing Date
DE69917833T Expired - Lifetime DE69917833T2 (de) 1998-04-17 1999-04-16 Substituierte Karbazole, Verfahren zu ihrer Herstellung und ihre Verwendung als sPLA2- Inhibitoren

Country Status (30)

Country Link
EP (2) EP0952149B1 (de)
JP (2) JPH11322713A (de)
KR (2) KR100586761B1 (de)
CN (1) CN1149193C (de)
AR (2) AR018186A1 (de)
AT (2) ATE271037T1 (de)
AU (2) AU753547B2 (de)
BR (2) BR9901279A (de)
CA (2) CA2269262A1 (de)
CO (2) CO5011054A1 (de)
CZ (2) CZ137099A3 (de)
DE (2) DE69917833T2 (de)
DK (1) DK0950657T3 (de)
DZ (1) DZ2769A1 (de)
EA (2) EA002347B1 (de)
ES (2) ES2226286T3 (de)
HU (2) HUP9901220A3 (de)
ID (2) ID23287A (de)
IL (2) IL129483A0 (de)
NO (2) NO314400B1 (de)
NZ (3) NZ335251A (de)
PE (2) PE20000432A1 (de)
PL (2) PL332566A1 (de)
PT (1) PT950657E (de)
SG (2) SG81976A1 (de)
SI (1) SI0950657T1 (de)
TR (2) TR199900853A3 (de)
TW (1) TWI238160B (de)
YU (2) YU18999A (de)
ZA (2) ZA992771B (de)

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2301586A1 (en) * 1997-08-28 1999-03-04 William Louis Macias Method for treatment of non-rheumatoid arthritis
DZ2769A1 (fr) * 1998-04-17 2003-12-01 Lilly Co Eli Composés tricycliques substitués.
WO2000037022A2 (en) * 1998-12-21 2000-06-29 Eli Lilly And Company Combination therapy for the treatment of sepsis
JP2003505372A (ja) * 1999-07-19 2003-02-12 イーライ・リリー・アンド・カンパニー sPLA2インヒビター
US6706752B1 (en) 1999-07-19 2004-03-16 Eli Lilly And Company sPLA2 inhibitors
AU2001267825A1 (en) 2000-06-29 2002-01-08 Shionogi And Co., Ltd. Remedies for cirrhosis
TW583000B (en) * 2000-06-29 2004-04-11 Shionogi & Co X-type sPLA2 inhibitor as a cancer therapeutical agent
WO2002000257A1 (fr) * 2000-06-29 2002-01-03 Shionogi & Co., Ltd. Remedes a la maladie d'alzheimer
AU2001272915A1 (en) * 2000-07-14 2002-01-30 Eli Lilly And Company Method for treating sepsis
CA2431028A1 (en) * 2000-12-18 2002-06-27 Ho-Shen Lin Tetracyclic carbazole derivates and their use as spla2 inhibitors
DE60218155D1 (de) * 2001-03-28 2007-03-29 Lilly Co Eli Substituierte carbazole als inhibitoren von spla2
AUPS282602A0 (en) 2002-06-07 2002-06-27 Garvan Institute Of Medical Research Method of inhibiting cell proliferation
DE10249055A1 (de) 2002-10-22 2004-05-06 Bayer Cropscience Ag 2-Phenyl-2-substituierte-1,3-diketone
JO3598B1 (ar) 2006-10-10 2020-07-05 Infinity Discovery Inc الاحماض والاسترات البورونية كمثبطات اميد هيدروليز الحامض الدهني
EP1988098A1 (de) * 2007-04-27 2008-11-05 AEterna Zentaris GmbH Neue Tetrahydrocarbazolderivate als Liganden von G-Protein-gekoppelten Rezeptoren
WO2009119534A1 (ja) 2008-03-26 2009-10-01 第一三共株式会社 新規テトラヒドロイソキノリン誘導体
AR072249A1 (es) 2008-04-09 2010-08-18 Infinity Pharmaceuticals Inc Inhibidores de amida hidrolasa de acido graso. usos. metodos.
WO2010084402A2 (en) * 2009-01-22 2010-07-29 Orchid Research Laboratories Ltd. Heterocyclic compounds as phosphodiesterase inhibitors
AU2010234449A1 (en) 2009-04-07 2011-11-03 Infinity Pharmaceuticals, Inc. Inhibitors of fatty acid amide hydrolase
EP2416660B1 (de) 2009-04-07 2014-07-02 Infinity Pharmaceuticals, Inc. Fettsäureamidhydrolase-hemmer
CN102834401B (zh) 2010-02-03 2016-08-24 无限药品股份有限公司 脂肪酸酰胺水解酶抑制剂
AR088377A1 (es) 2011-10-20 2014-05-28 Siena Biotech Spa Proceso para la preparacion de 6-cloro-2,3,4,9-tetrahidro-1h-carbazol-1-carboxamida y compuestos intermedios de esta
CN102816107B (zh) * 2012-08-20 2015-06-03 东南大学 咔唑衍生物及其制备方法与用途
CA2892485A1 (en) 2012-11-30 2014-06-05 Ge Healthcare Limited Crystallization process of tricyclic indole derivatives
MX2015006864A (es) * 2012-11-30 2015-09-16 Ge Healthcare Ltd Proceso de ciclizacion mediado con haluro de cinc que conduce a indoles triciclicos.
WO2016116527A1 (de) * 2015-01-20 2016-07-28 Cynora Gmbh Organische moleküle, insbesondere zur verwendung in optoelektronischen bauelementen
CN108707104A (zh) * 2018-08-07 2018-10-26 北京恒信卓元科技有限公司 2-氯-1h-咔唑-1,4(9h)-二酮的合成方法

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3579534A (en) * 1969-05-09 1971-05-18 American Cyanamid Co Tetrahydrocarbazolecarboxylates
US3939177A (en) * 1972-11-22 1976-02-17 Sterling Drug Inc. 4-Aminomethyl-9-benzyl-1,2,3,4-tetrahydrocarbazoles
US3979391A (en) * 1972-11-22 1976-09-07 Sterling Drug Inc. 1,2,3,4-Tetrahydrocarbazoles
US5420289A (en) * 1989-10-27 1995-05-30 American Home Products Corporation Substituted indole-, indene-, pyranoindole- and tetrahydrocarbazole-alkanoic acid derivatives as inhibitors of PLA2 and lipoxygenase
PT95692A (pt) * 1989-10-27 1991-09-13 American Home Prod Processo para a preparacao de derivados de acidos indole-,indeno-,piranoindole- e tetra-hidrocarbazole-alcanoicos, ou quais sao uteis como inibidores de pla2 e da lipoxigenase
WO1993001169A2 (en) * 1991-07-05 1993-01-21 Merck Sharp & Dohme Limited Aromatic compounds, pharmaceutical compositions containing them and their use in therapy
MY110227A (en) * 1991-08-12 1998-03-31 Ciba Geigy Ag 1-acylpiperindine compounds.
IL109311A0 (en) * 1993-04-16 1994-07-31 Lilly Co Eli 1H-indole-3-acetamide sPla2 inhibitors
IL109309A (en) * 1993-04-16 2000-06-29 Lilly Co Eli 1-H-indole-3-acetic acid hydrazide SPLA2 inhibitors and pharmaceutical compositions containing them
ES2151993T3 (es) * 1995-06-23 2001-01-16 Lilly Co Eli 1,2,3,4-tetrahidro-9h-carbazoles 6-sustituidos y 10h-ciclohepta(7,6-b)indoles 7-sustituidos.
PT779271E (pt) * 1995-12-13 2001-11-30 Lilly Co Eli Naftilacetamidas como inibidores da spla2
WO1998018464A1 (en) * 1996-10-30 1998-05-07 Eli Lilly And Company Substituted tricyclics
WO1999016453A1 (en) * 1997-09-26 1999-04-08 Eli Lilly And Company Method for the treatment of cystic fibrosis
AU1407399A (en) * 1997-11-14 1999-06-07 Eli Lilly And Company Treatment for alzheimer's disease
DZ2769A1 (fr) * 1998-04-17 2003-12-01 Lilly Co Eli Composés tricycliques substitués.

Also Published As

Publication number Publication date
EA199900301A2 (ru) 1999-10-28
AU2381799A (en) 1999-10-28
DE69918590T2 (de) 2005-07-21
AR018593A1 (es) 2001-11-28
TR199900853A2 (xx) 1999-11-22
YU18999A (sh) 2002-08-12
KR19990083233A (ko) 1999-11-25
ZA992771B (en) 2002-04-18
PT950657E (pt) 2004-11-30
JPH11322713A (ja) 1999-11-24
EA199900303A2 (ru) 1999-10-28
NZ335253A (en) 2000-11-24
TR199900843A2 (xx) 2000-02-21
NO312240B1 (no) 2002-04-15
EP0950657A2 (de) 1999-10-20
ATE268756T1 (de) 2004-06-15
CO5011054A1 (es) 2001-02-28
ZA992772B (en) 2002-07-16
SG81976A1 (en) 2001-07-24
NZ507564A (en) 2002-10-25
IL129483A0 (en) 2000-02-29
CZ136999A3 (cs) 1999-11-17
KR19990083232A (ko) 1999-11-25
PE20000476A1 (es) 2000-06-02
CO5031247A1 (es) 2001-04-27
DE69917833T2 (de) 2005-07-14
NO991822L (no) 1999-10-18
EA199900303A3 (ru) 2000-04-24
EP0950657A3 (de) 2001-08-16
DK0950657T3 (da) 2004-11-22
ES2226286T3 (es) 2005-03-16
CN1149193C (zh) 2004-05-12
HUP9901220A3 (en) 2001-11-28
CA2269246A1 (en) 1999-10-17
TWI238160B (en) 2005-08-21
SI0950657T1 (en) 2005-02-28
NO991821L (no) 1999-10-18
CA2269246C (en) 2009-08-25
KR100586761B1 (ko) 2006-06-08
NO314400B1 (no) 2003-03-17
EP0952149A2 (de) 1999-10-27
ID23287A (id) 2000-04-05
SG81977A1 (en) 2001-07-24
IL129485A0 (en) 2000-02-29
PL332565A1 (en) 1999-10-25
EA002816B1 (ru) 2002-10-31
DE69917833D1 (de) 2004-07-15
BR9901279A (pt) 2000-05-02
CZ137099A3 (cs) 1999-11-17
DZ2769A1 (fr) 2003-12-01
AU753436B2 (en) 2002-10-17
AU2381999A (en) 1999-10-28
HU9901220A (hu) 2000-04-28
ATE271037T1 (de) 2004-07-15
PL332566A1 (en) 1999-10-25
PE20000432A1 (es) 2000-05-23
CA2269262A1 (en) 1999-10-17
HUP9901221A3 (en) 2001-11-28
EP0952149B1 (de) 2004-06-09
HU9901221A (hu) 2000-04-28
NO991822D0 (no) 1999-04-16
YU19199A (sh) 2002-08-12
HU9901220D0 (en) 1999-06-28
BR9902365A (pt) 2001-04-24
NO991821D0 (no) 1999-04-16
HU9901221D0 (en) 1999-06-28
EA002347B1 (ru) 2002-04-25
AU753547B2 (en) 2002-10-24
ID23761A (id) 2000-05-11
EA199900301A3 (ru) 2000-04-24
TR199900853A3 (tr) 1999-11-22
JP2000026416A (ja) 2000-01-25
AR018186A1 (es) 2001-10-31
EP0952149A3 (de) 2001-08-16
NZ335251A (en) 2000-11-24
JP4435330B2 (ja) 2010-03-17
CN1253948A (zh) 2000-05-24
ES2222663T3 (es) 2005-02-01
EP0950657B1 (de) 2004-07-14

Similar Documents

Publication Publication Date Title
DE69918590D1 (de) Substituierte Karbazole, Verfahren zu ihrer Herstellung und ihre Verwendung als sPLA2-Inhibitoren
DE60033028D1 (de) 5-pyridyl-1,3-azol-derivate, verfahren zu ihrer herstellung und ihre verwendung
DE69925145D1 (de) 2-aminothiazolederivate, verfahren zu ihrer herstellung und ihre verwendung als antitumormittel
DE69922086D1 (de) Funktionsangepasste Legierung, ihre Verwendung und Verfahren zu ihrer Herstellung
DE50208960D1 (de) Diarylcycloalkylderivate, verfahren zu ihrer herstellung und ihre verwendung als ppar-aktivatoren
DE10393704D2 (de) Nancomposite, Verfahren zu ihrer Herstellung und ihre Verwendung
DE10399006I2 (de) Tetracyclische Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung.
DE122006000035I2 (de) Nd verfahren zu seiner herstellung
DE69931289D1 (de) Selbstnivellierender sehr hoher Leistungsbeton, Verfahren zu seiner Herstellung und seine Verwendung
DE69708411T2 (de) Phosphite, Verfahren zu ihrer Herstellung und ihre Verwendung
ATE327981T1 (de) Arylisoxazolin-derivative, verfahren zu ihrer herstellung und ihre verwendung als schädlingsbekämpfungsmittel
DE59913771D1 (de) Beschichtungsmittel und Klebstoffe, ihre Verwendung und Verfahren zu ihrer Herstellung
DE69706690D1 (de) Acryloyl-substituierte distamycin-derivate, verfahren zu ihrer herstellung und ihre verwendung als antitumor- und antivirale mittel
DE50008845D1 (de) Substituierte benzoylketone, verfahren zu ihrer herstellung und ihre verwendung als herbizide
DE69832784D1 (de) Fluorpolymere, verfahren zu ihrer herstellung und ihre verwendung
DE69908371D1 (de) Thioethergruppen enthaltende distamycin-derivate, verfahren zu ihrer herstellung und ihre verwendung als antitumormittel
DE60032381D1 (de) Polierzusammensetzung und verfahren zu ihrer verwendung
DE59908394D1 (de) Wasserlösliche Monoazoverbindungen, Verfahren zu ihrer Herstellung und ihre Verwendung als Farbstoffe
DE59610666D1 (de) Mehrlagenfolie, verfahren zu ihrer herstellung und ihre verwendung
DE60116063D1 (de) Memno-peptide, verfahren zu ihrer herstellung und ihre verwendung
DE59800568D1 (de) Benzoxazindionderivate, Verfahren zu ihrer Herstellung und ihre Verwendung
DE50107787D1 (de) Acesulfam-Metall-Komplexe, Verfahren zu ihrer Herstellung und ihre Verwendung
DE69912871D1 (de) Ethylenpolymerzusammensetzung, Verfahren zu ihrer Herstellung und ihre Verwendung
DE59911949D1 (de) Substituierte sulfonylcyanamide, verfahren zu ihrer herstellung und ihre verwendung als medikament
DE59700950D1 (de) 5-Z-Octenylester, Verfahren zu ihrer Herstellung und ihre Verwendung

Legal Events

Date Code Title Description
8364 No opposition during term of opposition
8328 Change in the person/name/address of the agent

Representative=s name: KROHER, STROBEL RECHTS- UND PATENTANWAELTE, 80336

8328 Change in the person/name/address of the agent

Representative=s name: DR. SCHOEN & PARTNER, 80336 MUENCHEN