ATE533762T1 - Chinolin- oder isochinolinsubstituierte p2x7- antagonisten - Google Patents
Chinolin- oder isochinolinsubstituierte p2x7- antagonistenInfo
- Publication number
- ATE533762T1 ATE533762T1 AT09735472T AT09735472T ATE533762T1 AT E533762 T1 ATE533762 T1 AT E533762T1 AT 09735472 T AT09735472 T AT 09735472T AT 09735472 T AT09735472 T AT 09735472T AT E533762 T1 ATE533762 T1 AT E533762T1
- Authority
- AT
- Austria
- Prior art keywords
- quinoline
- antagonists
- compounds
- isoquinoline substituted
- isoquinoline
- Prior art date
Links
Classifications
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- 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
- 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
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—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
- C07D491/02—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
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP08154909 | 2008-04-22 | ||
PCT/US2009/041249 WO2009132000A1 (en) | 2008-04-22 | 2009-04-21 | Quinoline or isoquinoline substituted p2x7 antagonists |
Publications (1)
Publication Number | Publication Date |
---|---|
ATE533762T1 true ATE533762T1 (de) | 2011-12-15 |
Family
ID=39462005
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AT09735472T ATE533762T1 (de) | 2008-04-22 | 2009-04-21 | Chinolin- oder isochinolinsubstituierte p2x7- antagonisten |
Country Status (10)
Country | Link |
---|---|
US (1) | US8431704B2 (de) |
EP (1) | EP2285800B1 (de) |
JP (1) | JP5369173B2 (de) |
KR (1) | KR101598397B1 (de) |
CN (1) | CN102066360B (de) |
AT (1) | ATE533762T1 (de) |
AU (1) | AU2009239471B2 (de) |
CA (1) | CA2722035C (de) |
ES (1) | ES2376092T3 (de) |
WO (1) | WO2009132000A1 (de) |
Families Citing this family (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013521002A (ja) | 2010-03-05 | 2013-06-10 | プレジデント アンド フェロウズ オブ ハーバード カレッジ | 誘導樹状細胞組成物及びその使用 |
WO2012110190A1 (en) | 2011-02-17 | 2012-08-23 | Affectis Pharmaceuticals Ag | Novel p2x7r antagonists and their use |
WO2012163792A1 (en) | 2011-05-27 | 2012-12-06 | Affectis Pharmaceuticals Ag | Novel p2x7r antagonists and their use |
WO2012163456A1 (en) | 2011-05-27 | 2012-12-06 | Affectis Pharmaceuticals Ag | Novel p2x7r antagonists and their use |
ES2574840T3 (es) | 2011-07-22 | 2016-06-22 | Actelion Pharmaceuticals Ltd. | Derivados de amidas heterocíclicas como antagonistas de receptores p2x7 |
EP2804865B1 (de) | 2012-01-20 | 2015-12-23 | Actelion Pharmaceuticals Ltd. | Heterocyclische amidderivate als p2x7-rezeptorantagonisten |
MX346147B (es) | 2012-03-07 | 2017-03-09 | Inst Of Cancer Research: Royal Cancer Hospital (The) | Compuestos de 3-aril-5-substituido-isoquinolin-1-ona y su uso terapeutico. |
TW201427947A (zh) | 2012-10-12 | 2014-07-16 | Lundbeck & Co As H | 環狀胺 |
TWI598325B (zh) * | 2012-10-12 | 2017-09-11 | H 朗德貝克公司 | 苯甲醯胺類 |
BR112015013463B1 (pt) | 2012-12-12 | 2022-06-14 | Idorsia Pharmaceuticals Ltd | Derivados de carboxamida indol como antagonistas do receptor de p2x7 |
AR094053A1 (es) | 2012-12-18 | 2015-07-08 | Actelion Pharmaceuticals Ltd | Derivados de indol carboxamida como antagonistas del receptor p2x₇ |
ES2616114T3 (es) | 2013-01-22 | 2017-06-09 | Actelion Pharmaceuticals Ltd. | Derivados de amida heterocíclica como antagonistas del receptor P2X7 |
CA2897459C (en) | 2013-01-22 | 2021-03-02 | Actelion Pharmaceuticals Ltd | Heterocyclic amide derivatives as p2x7 receptor antagonists |
JO3509B1 (ar) | 2013-03-14 | 2020-07-05 | Janssen Pharmaceutica Nv | معدلات p2x7 |
US9096596B2 (en) | 2013-03-14 | 2015-08-04 | Janssen Pharmaceutica Nv | P2X7 modulators |
US9040534B2 (en) | 2013-03-14 | 2015-05-26 | Janssen Pharmaceutica Nv | [1,2,4]triazolo[4,3-a]pyrazines as P2X7 modulators |
JO3773B1 (ar) | 2013-03-14 | 2021-01-31 | Janssen Pharmaceutica Nv | معدلات p2x7 |
CA2922469A1 (en) | 2013-09-11 | 2015-03-19 | Institute Of Cancer Research: Royal Cancer Hospital (The) | 3-aryl-5-substituted-isoquinolin-1-one compounds and their therapeutic use |
EP2905282A1 (de) | 2014-02-05 | 2015-08-12 | AXXAM S.p.A. | Substituierte Thiazole oder Oxazole als P2X7-Rezeptorantagonisten |
US9399623B2 (en) * | 2014-06-05 | 2016-07-26 | Merck Patent Gmbh | Quinoline derivatives and their use in neurodegenerative diseases |
JP6592510B2 (ja) | 2014-09-12 | 2019-10-16 | ヤンセン ファーマシューティカ エヌ.ベー. | P2x7調節因子 |
US9592186B2 (en) | 2014-09-30 | 2017-03-14 | Avon Products, Inc. | Topical compositions and methods for skin lightening |
EP3290416A1 (de) | 2016-08-31 | 2018-03-07 | AXXAM S.p.A. | Substituierte n-[2-(4-phenoxypiperidin-1-yl)-2-(1,3-thiazol-5-yl)ethyl]benzamid- und n-[2-(4-benzyloxypiperidin-1-yl)-2-(1,3-thiazol-5-yl)ethyl]benzamid- derivate und ihre verwendung als p2x7 rezeptor antagonist |
EP3290417A1 (de) | 2016-08-31 | 2018-03-07 | AXXAM S.p.A. | 2-chloro-n-[2-(1,3-thiazol-5-yl)ethyl]-5-(5-fluoropyrimidin-2-yl)-benzamide und ihre verwendung als p2x7 rezeptor antagonisten |
WO2018170203A1 (en) | 2017-03-16 | 2018-09-20 | Celgene Car Llc | Mk2 inhibitors, synthesis thereof, and intermediates thereto |
EP3398941A1 (de) | 2017-05-03 | 2018-11-07 | AXXAM S.p.A. | Heterozyklische p2x7-antagonisten |
WO2018224455A1 (en) | 2017-06-07 | 2018-12-13 | Basf Se | Substituted cyclopropyl derivatives |
WO2018234488A1 (en) | 2017-06-23 | 2018-12-27 | Basf Se | SUBSTITUTED CYCLOPROPYL DERIVATIVES |
WO2019078040A1 (ja) * | 2017-10-18 | 2019-04-25 | 国立大学法人大阪大学 | 化合物またはその結合物、及び有機半導体材料 |
WO2019121143A1 (en) | 2017-12-20 | 2019-06-27 | Basf Se | Substituted cyclopropyl derivatives |
US20200102311A1 (en) | 2018-09-28 | 2020-04-02 | Janssen Pharmaceutica Nv | Monoacylglycerol Lipase Modulators |
EP3856178A1 (de) | 2018-09-28 | 2021-08-04 | Janssen Pharmaceutica NV | Monoacylglycerin-lipase-modulatoren |
MA55805A (fr) | 2019-05-03 | 2022-03-09 | Flagship Pioneering Innovations V Inc | Métodes de modulation de l'activité immunitaire |
EP4038070A1 (de) | 2019-09-30 | 2022-08-10 | Janssen Pharmaceutica NV | Radiomarkierte mgl-pet-liganden |
KR20220157999A (ko) | 2020-03-26 | 2022-11-29 | 얀센 파마슈티카 엔.브이. | 모노아실글리세롤 리파아제 조절제 |
CN111285812A (zh) * | 2020-04-08 | 2020-06-16 | 安徽昊帆生物有限公司 | 2-芳氨基-5-甲酰基-嘧啶的制备方法 |
EP4015039A1 (de) | 2020-12-18 | 2022-06-22 | AXXAM S.p.A. | Heterocyclische derivate als p2x7-rezeptor-antagonisten |
CN117881675A (zh) | 2021-09-03 | 2024-04-12 | 布雷耶疗法有限公司 | 2,4-二氢-3h-1,2,4-三唑-3-酮p2x7拮抗剂 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0312609D0 (en) | 2003-06-02 | 2003-07-09 | Astrazeneca Ab | Novel compounds |
JP2008528580A (ja) * | 2005-01-27 | 2008-07-31 | アストラゼネカ・アクチエボラーグ | P2x7受容体の阻害剤である新規二環式芳香族化合物 |
US7402596B2 (en) | 2005-03-24 | 2008-07-22 | Renovis, Inc. | Bicycloheteroaryl compounds as P2X7 modulators and uses thereof |
WO2006110516A1 (en) | 2005-04-11 | 2006-10-19 | Abbott Laboratories | Acylhydrazide p2x7 antagonists and uses thereof |
-
2009
- 2009-04-21 CN CN2009801246595A patent/CN102066360B/zh not_active Expired - Fee Related
- 2009-04-21 AU AU2009239471A patent/AU2009239471B2/en not_active Ceased
- 2009-04-21 US US12/988,891 patent/US8431704B2/en active Active
- 2009-04-21 WO PCT/US2009/041249 patent/WO2009132000A1/en active Application Filing
- 2009-04-21 JP JP2011506394A patent/JP5369173B2/ja not_active Expired - Fee Related
- 2009-04-21 ES ES09735472T patent/ES2376092T3/es active Active
- 2009-04-21 KR KR1020107026043A patent/KR101598397B1/ko active IP Right Grant
- 2009-04-21 CA CA2722035A patent/CA2722035C/en not_active Expired - Fee Related
- 2009-04-21 EP EP09735472A patent/EP2285800B1/de active Active
- 2009-04-21 AT AT09735472T patent/ATE533762T1/de active
Also Published As
Publication number | Publication date |
---|---|
CN102066360A (zh) | 2011-05-18 |
ES2376092T3 (es) | 2012-03-08 |
CN102066360B (zh) | 2013-10-30 |
AU2009239471B2 (en) | 2013-01-24 |
JP2011518226A (ja) | 2011-06-23 |
AU2009239471A1 (en) | 2009-10-29 |
WO2009132000A1 (en) | 2009-10-29 |
EP2285800B1 (de) | 2011-11-16 |
US20110092481A1 (en) | 2011-04-21 |
CA2722035C (en) | 2016-10-11 |
KR20110010732A (ko) | 2011-02-07 |
US8431704B2 (en) | 2013-04-30 |
CA2722035A1 (en) | 2009-10-29 |
EP2285800A1 (de) | 2011-02-23 |
JP5369173B2 (ja) | 2013-12-18 |
KR101598397B1 (ko) | 2016-02-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ATE533762T1 (de) | Chinolin- oder isochinolinsubstituierte p2x7- antagonisten | |
CY1123365T1 (el) | Ενωσεις που εχουν δραστικοτητα ανταγωνιστη μουσκαρινικου υποδοχεα και αγωνιστη βητα2 αδρενεργικου υποδοχεα | |
MY165113A (en) | Piperidinone carboxamide azaindane cgrp receptor antagonists | |
MX2012002179A (es) | Compuestos heterociclicos de oxima. | |
UA107188C2 (uk) | Карбоксамідні похідні хіназолінів або хінолінів та фармацевтична композиція на їх основі | |
TN2015000250A1 (en) | Novel benzimidazole derivatives as ep4 antagonists | |
MX348422B (es) | Inhibidores de arginasa y sus aplicaciones terapeuticas. | |
TR201904614T4 (tr) | Novel pyrazole derivative. | |
MX2011009847A (es) | Agentes antihelminticos y su uso. | |
BRPI1014902A2 (pt) | composto antagonista de p2x7r, sua composição e seus usos | |
ME01532B (me) | Jedinjenja | |
EA201691461A1 (ru) | Определенные триазолопиридины и триазолопиразины, их композиции и способы их применения | |
NZ590650A (en) | Buprenorphine analogs | |
EA201400553A1 (ru) | Производные 2-(1,2,3-триазол-2-ил)бензамида и 3-(1,2,3-триазол-2-ил)пиколинамида | |
BR112013021675A2 (pt) | compostos de triazolopiridina como inibidores de pim cinase | |
MX2013012652A (es) | Derivados de n-[(1h-pirazol-1-il)aril]-1h-indol o 1h-indazol-3-carboxamida, su preparacion y su uso como antagonistas p2y12. | |
PH12014502241A1 (en) | Pharmaceutical formulations comprising ccr3 antagonists | |
BR112014001908A2 (pt) | derivados aza heterocíclicos substituídos | |
WO2009021965A3 (en) | Substituted quinoline derivatives as h1 receptor antagonists | |
DK2081572T3 (da) | Benzimidazol-cannabinoid-agonister med en substitueret heterocyklisk gruppe | |
EA201300436A1 (ru) | Совместные кристаллы и соли ингибиторов ccr3 | |
ATE542795T1 (de) | Benzylpiperazinderivate als motilin- rezeptorantagonisten | |
EA201400623A1 (ru) | Новые 2h-индазолы в качестве антагонистов рецептора ep | |
IN2012DN00953A (de) | ||
DE602007012313D1 (de) | Als a2b-adenosinrezeptorantagonisten geeignete 5-phenyl-6-pyridin-4-yl-1,3-dihydro-2h-imidazoä4,5-büpyridin-2-onderivate |