BR112018073579A2 - tratamento de transtornos neurológicos - Google Patents

tratamento de transtornos neurológicos

Info

Publication number
BR112018073579A2
BR112018073579A2 BR112018073579-5A BR112018073579A BR112018073579A2 BR 112018073579 A2 BR112018073579 A2 BR 112018073579A2 BR 112018073579 A BR112018073579 A BR 112018073579A BR 112018073579 A2 BR112018073579 A2 BR 112018073579A2
Authority
BR
Brazil
Prior art keywords
treatment
neurological disorders
tautomers
solvates
metabolites
Prior art date
Application number
BR112018073579-5A
Other languages
English (en)
Other versions
BR112018073579A8 (pt
Inventor
Rageot Denise
Hebeisen Paul
Beaufils Florent
Fabbro Doriano
Hillmann-Wuellner Petra
Huu Phuc Nguyen Hoa
Löscher Wolfgang
BRANDT Claudia
Markus SELE Alexander
Original Assignee
Piqur Therapeutics Ag
Universität Basel
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 Piqur Therapeutics Ag, Universität Basel filed Critical Piqur Therapeutics Ag
Publication of BR112018073579A2 publication Critical patent/BR112018073579A2/pt
Publication of BR112018073579A8 publication Critical patent/BR112018073579A8/pt

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/153—Ortho-condensed systems the condensed system containing two rings with oxygen as ring hetero atom and one ring with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

a presente invenção refere-se a um composto de fórmula (i), em que x1, x2 e x3 são, independentemente um do outro, n ou ch; com a condição de que pelo menos dois de x1, x2 e x3 sejam n; y é n ou ch; r1 e r2 são independentes um do outro; e profármacos, metabólitos, tautômeros, solvatos e sais farmaceuticamente aceitáveis dos mesmos, para uso na prevenção ou no tratamento de um transtorno neurológico em um indivíduo.
BR112018073579A 2016-05-18 2017-05-17 Uso de inibidores específicos de mtor ou inibidores duplos de pi3k/mtor, e composição farmacêutica BR112018073579A8 (pt)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP16170107.3 2016-05-18
EP16170107 2016-05-18
PCT/EP2017/025136 WO2017198346A1 (en) 2016-05-18 2017-05-17 Treatment of neurological disorders

Publications (2)

Publication Number Publication Date
BR112018073579A2 true BR112018073579A2 (pt) 2019-03-19
BR112018073579A8 BR112018073579A8 (pt) 2023-01-10

Family

ID=56024138

Family Applications (1)

Application Number Title Priority Date Filing Date
BR112018073579A BR112018073579A8 (pt) 2016-05-18 2017-05-17 Uso de inibidores específicos de mtor ou inibidores duplos de pi3k/mtor, e composição farmacêutica

Country Status (25)

Country Link
US (2) US20190284178A1 (pt)
EP (1) EP3458067B1 (pt)
JP (1) JP6991158B2 (pt)
KR (1) KR102472461B1 (pt)
CN (1) CN109475560B (pt)
AU (1) AU2017265383B2 (pt)
BR (1) BR112018073579A8 (pt)
CA (1) CA3022753A1 (pt)
CY (1) CY1124051T1 (pt)
DK (1) DK3458067T3 (pt)
ES (1) ES2863250T3 (pt)
HR (1) HRP20210477T1 (pt)
HU (1) HUE053494T2 (pt)
IL (1) IL263080B (pt)
LT (1) LT3458067T (pt)
MX (1) MX2018014168A (pt)
PL (1) PL3458067T3 (pt)
PT (1) PT3458067T (pt)
RS (1) RS61655B1 (pt)
RU (1) RU2765868C2 (pt)
SG (1) SG11201809792TA (pt)
SI (1) SI3458067T1 (pt)
TW (1) TWI753912B (pt)
WO (1) WO2017198346A1 (pt)
ZA (1) ZA201807393B (pt)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2018014167A (es) 2016-05-18 2019-08-16 Piqur Therapeutics Ag Tratamiento de lesiones de la piel.
AU2018371168A1 (en) * 2017-11-23 2020-04-30 Torqur Ag Treatment of skin disorders
EP4320115A1 (en) * 2021-04-09 2024-02-14 Universität Basel Triazine derivative as reversible and irreversible covalent inhibitors of pi3k

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JO2660B1 (en) * 2006-01-20 2012-06-17 نوفارتيس ايه جي Pi-3 inhibitors and methods of use
JP5398268B2 (ja) 2006-02-09 2014-01-29 アルバ セラピューティクス コーポレーション タイトジャンクション・エフェクター用製剤
MX2008013584A (es) * 2006-04-26 2009-03-23 Genentech Inc Compuestos farmaceuticos.
US8022205B2 (en) 2006-08-08 2011-09-20 Chugai Seiyaku Kabushiki Kaisha Pyrimidine derivatives as PI3K inhibitor and use thereof
US8173647B2 (en) * 2007-02-06 2012-05-08 Gordana Atallah PI 3-kinase inhibitors and methods of their use
GEP20125589B (en) * 2008-05-23 2012-07-25 Wyeth Llc TRIAZINE COMPOUNDS AS P13 KINASE AND mTOR INHIBITORS
GB2465405A (en) * 2008-11-10 2010-05-19 Univ Basel Triazine, pyrimidine and pyridine analogues and their use in therapy
MX364558B (es) 2013-10-04 2019-04-29 Univ Basel INHIBIDORES DE PI3K Y mTOR CONFORMACIONALMENTE RESTRINGIDOS.
MA40933A (fr) * 2014-11-11 2017-09-19 Piqur Therapeutics Ag Difluorométhyl-aminopyridines et difluorométhyl-aminopyrimidines
CA3022758C (en) 2016-05-18 2024-02-06 Piqur Therapeutics Ag Treatment of skin lesions
MX2018014167A (es) * 2016-05-18 2019-08-16 Piqur Therapeutics Ag Tratamiento de lesiones de la piel.

Also Published As

Publication number Publication date
KR102472461B1 (ko) 2022-11-30
US11878972B2 (en) 2024-01-23
HRP20210477T1 (hr) 2021-05-14
RU2765868C2 (ru) 2022-02-04
RU2018140013A (ru) 2020-06-18
TWI753912B (zh) 2022-02-01
CA3022753A1 (en) 2017-11-23
IL263080A (en) 2018-12-31
US20190284178A1 (en) 2019-09-19
MX2018014168A (es) 2019-04-29
RU2018140013A3 (pt) 2020-07-09
EP3458067B1 (en) 2020-12-30
ES2863250T3 (es) 2021-10-11
CY1124051T1 (el) 2022-05-27
WO2017198346A1 (en) 2017-11-23
PT3458067T (pt) 2021-04-07
EP3458067A1 (en) 2019-03-27
BR112018073579A8 (pt) 2023-01-10
TW201808944A (zh) 2018-03-16
SG11201809792TA (en) 2018-12-28
AU2017265383A1 (en) 2018-12-13
CN109475560B (zh) 2023-05-02
IL263080B (en) 2022-02-01
SI3458067T1 (sl) 2021-07-30
AU2017265383B2 (en) 2022-07-28
ZA201807393B (en) 2023-10-25
JP2019519507A (ja) 2019-07-11
DK3458067T3 (da) 2021-04-06
CN109475560A (zh) 2019-03-15
HUE053494T2 (hu) 2021-06-28
US20220135551A1 (en) 2022-05-05
RS61655B1 (sr) 2021-04-29
PL3458067T3 (pl) 2021-12-13
JP6991158B2 (ja) 2022-02-10
KR20190008294A (ko) 2019-01-23
LT3458067T (lt) 2021-04-26

Similar Documents

Publication Publication Date Title
BR112018072570A2 (pt) piperidinas como inibidores de menina
ECSP20069418A (es) Compuestos heterocíclicos como inmunomoduladores
EA201792214A1 (ru) Соединения замещенного хиназолина
BR112018070859A2 (pt) degradantes da proteína de bet
PH12018500041A1 (en) Substituted aza compoounds as irak-4 inhibitors
BR112016024057A2 (pt) inibidores de quinases heterocíclicos
EA201890307A1 (ru) Индазольные и азаиндазольные соединения как ингибиторы irak-4
CL2016000466A1 (es) Compuestos derivados de 2-amino pirimidina sustituida, inhibidores de bmi-1 composicion farmaceutica y uso en el tratamiento del cancer.
EA201792116A1 (ru) Ингибитор янус-киназы
BR112016015983A2 (pt) Compostos de indazol como inibidores de irak4, seus usos, e composição farmacêutica
BR112015032693A2 (pt) inibidores de bromodomínio
GT201500092A (es) Moduladores de quinolinillo unidos a fenilo de ror-gamma-t
BR112019003932A2 (pt) composto, composição farmacêutica, combinação, método de tratamento de uma doença ou desordem e uso do composto
ECSP20018487A (es) Activadores de piruvato quinasas para usar en el tratamiento de trastornos en la sangre
EA201692268A1 (ru) Ингибиторы фосфатидилинозитол-3-киназы
DOP2016000291A (es) Composiciones y métodos para modular la expresión del factor b del complemento
EA201992147A1 (ru) Ингибиторы тирозинкиназы брутона
EA202191519A1 (ru) Модуляторы trex1
UY36875A (es) Composiciones inhibidoras de bromodominios para el tratamiento de diversas enfermedades
MX2021003905A (es) Composicion de liberacion modificada de orlistat y acarbosa para el tratamiento de la obesidad y trastornos metabolicos relacionados.
BR112017022958A2 (pt) métodos para tratamento de câncer com inibidor da via da stat3 e inibidor de quinase
BR112017022158A2 (pt) compostos, composições farmacêuticas e uso de um composto
BR112018073579A2 (pt) tratamento de transtornos neurológicos
CL2021000292A1 (es) Benzimidazoles sustituidos como inhibidores de pad4.
EA202191051A1 (ru) Ингибитор аврора-киназы a для применения для лечения нейробластомы

Legal Events

Date Code Title Description
B350 Update of information on the portal [chapter 15.35 patent gazette]
B06W Patent application suspended after preliminary examination (for patents with searches from other patent authorities) chapter 6.23 patent gazette]
B25A Requested transfer of rights approved

Owner name: UNIVERSITAET BASEL (CH) ; TORQUR AG (CH)

B06A Patent application procedure suspended [chapter 6.1 patent gazette]