PT98476A - Processo para preparacao de derivados da indolina de n-sulfonilo - Google Patents

Processo para preparacao de derivados da indolina de n-sulfonilo

Info

Publication number: PT98476A
Authority: PT; Portugal
Prior art keywords: denotes; alkyl; group; trifluoromethyl; naphthyl
Prior art date: 1990-07-31

Application number

PT98476A

Other languages

English (en)

Other versions

PT98476B (pt

Inventor

Dino Nisato

Jean Wagnon

Paul De Cointet

Claude Plouzane

Claudine Serradeil-Legal

Original Assignee

Sanofi Sa

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.)

1990-07-31

Filing date

1991-07-29

Publication date

1992-05-29

1991-07-29 Application filed by Sanofi Sa filed Critical Sanofi Sa

1992-05-29 Publication of PT98476A publication Critical patent/PT98476A/pt

1997-10-31 Publication of PT98476B publication Critical patent/PT98476B/pt

Links

125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 6
-1 5-dimethylamino-1-naphthyl Chemical group 0.000 abstract 4
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract 3
125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
125000003545 alkoxy group Chemical group 0.000 abstract 2
125000003277 amino group Chemical group 0.000 abstract 2
150000001875 compounds Chemical class 0.000 abstract 2
229910052736 halogen Inorganic materials 0.000 abstract 2
150000002367 halogens Chemical class 0.000 abstract 2
125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 2
125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 2
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract 2
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 2
125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 1
125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 abstract 1
125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 abstract 1
125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 abstract 1
101800000989 Oxytocin Proteins 0.000 abstract 1
102400000050 Oxytocin Human genes 0.000 abstract 1
GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 abstract 1
108010004977 Vasopressins Proteins 0.000 abstract 1
102000002852 Vasopressins Human genes 0.000 abstract 1
125000004453 alkoxycarbonyl group Chemical group 0.000 abstract 1
125000000217 alkyl group Chemical group 0.000 abstract 1
125000004414 alkyl thio group Chemical group 0.000 abstract 1
KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 abstract 1
125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 abstract 1
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 abstract 1
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 abstract 1
125000005392 carboxamide group Chemical group NC(=O)* 0.000 abstract 1
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract 1
125000004093 cyano group Chemical group *C#N 0.000 abstract 1
150000001925 cycloalkenes Chemical class 0.000 abstract 1
125000000753 cycloalkyl group Chemical group 0.000 abstract 1
125000005843 halogen group Chemical group 0.000 abstract 1
229910052739 hydrogen Inorganic materials 0.000 abstract 1
239000001257 hydrogen Substances 0.000 abstract 1
125000003884 phenylalkyl group Chemical group 0.000 abstract 1
150000003839 salts Chemical class 0.000 abstract 1
125000001424 substituent group Chemical group 0.000 abstract 1
229960003726 vasopressin Drugs 0.000 abstract 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- 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
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
- C07C311/13—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings the carbon skeleton containing six-membered aromatic rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
General Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Public Health (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)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
Engineering & Computer Science (AREA)
Cardiology (AREA)
Heart & Thoracic Surgery (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Urology & Nephrology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Indole Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Peptides Or Proteins (AREA)

PT98476A 1990-07-31 1991-07-29 Processo para preparacao de derivados da indolina de n-sulfonilo PT98476B (pt)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
FR9009778A FR2665441B1 (fr)	1990-07-31	1990-07-31	Derives de la n-sulfonyl indoline, leur preparation, les compositions pharmaceutiques en contenant.

Publications (2)

Publication Number	Publication Date
PT98476A true PT98476A (pt)	1992-05-29
PT98476B PT98476B (pt)	1997-10-31

Family

ID=9399281

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
PT98476A PT98476B (pt)	1990-07-31	1991-07-29	Processo para preparacao de derivados da indolina de n-sulfonilo

Country Status (17)

Country	Link
EP (1)	EP0469984B1 (pt)
JP (1)	JP3195381B2 (pt)
KR (1)	KR100211434B1 (pt)
AT (1)	ATE129236T1 (pt)
AU (2)	AU645585B2 (pt)
CA (1)	CA2048139C (pt)
DE (1)	DE69113911T2 (pt)
ES (1)	ES2080922T3 (pt)
FI (1)	FI97224C (pt)
FR (1)	FR2665441B1 (pt)
HU (1)	HU220765B1 (pt)
IE (1)	IE73452B1 (pt)
IL (2)	IL99012A (pt)
NO (1)	NO175254C (pt)
NZ (1)	NZ239182A (pt)
PT (1)	PT98476B (pt)
ZA (1)	ZA916031B (pt)

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US5338755A (en) *	1990-07-31	1994-08-16	Elf Sanofi	N-sulfonylindoline derivatives, their preparation and the pharmaceutical compositions in which they are present
US5481005A (en) *	1990-07-31	1996-01-02	Sanofi	N-sulfonylindoline derivatives, their preparation and the pharmaceutical compositions in which they are present
FR2679903B1 (fr) *	1991-08-02	1993-12-03	Elf Sanofi	Derives de la n-sulfonyl indoline portant une fonction amidique, leur preparation, les compositions pharmaceutiques en contenant.
US5686454A (en) *	1993-07-16	1997-11-11	Merck & Co., Inc.	Camphorcarbonyl
AU691829B2 (en) *	1993-07-16	1998-05-28	Merck & Co., Inc.	Benzoxazinone and benzopyrimidinone piperidinyl tocolytic oxytocin receptor antagonists
FR2708606B1 (fr) *	1993-07-30	1995-10-27	Sanofi Sa	Dérivés du N-phénylalkylindol-2-one, leur préparation, les compositions pharmaceutiques en contenant.
FR2708608B1 (fr) *	1993-07-30	1995-10-27	Sanofi Sa	Dérivés de N-sulfonylbenzimidazolone, leur préparation, les compositions pharmaceutiques en contenant.
FR2714378B1 (fr) *	1993-12-24	1996-03-15	Sanofi Sa	Dérivés de l'indol-2-one substitués en 3 par un groupe azoté, leur préparation, les compositions pharmaceutiques en contenant.
GB9918684D0 (en)	1999-08-09	1999-10-13	Novartis Ag	Organic compounds
AU1401902A (en)	2000-10-17	2002-04-29	Applied Research Systems	Pharmaceutically active sulfanilide derivatives
GB0115515D0 (en) *	2001-06-25	2001-08-15	Ferring Bv	Oxytocin agonisys
GB0116594D0 (en)	2001-07-06	2001-08-29	Cancer Res Ventures Ltd	Therapeutic compounds
IL162615A0 (en)	2001-12-20	2005-11-20	Applied Research Systems	Triazole derivatives, their preparation and pharmaceutical compositions containing them
AU2003248549B2 (en) *	2002-05-24	2010-04-08	Millennium Pharmaceuticals, Inc.	CCR9 inhibitors and methods of use thereof
ES2330205T3 (es)	2002-12-20	2009-12-07	Cancer Research Technology Limited	Compuestos de 4-1-(sulfonil)-1h-indol-2-yl)-4-hydroxi-ciclohexa-2,5-dienona y analogos de los mismos como agentes terapeuticos.
FR2853650B1 (fr) *	2003-04-10	2006-07-07	Merck Sante Sas	Procede de dedoublement d'amines utiles pour le traitement de desordres associes au syndrome d'insulino-resistance
FR2880023B1 (fr)	2004-12-23	2007-02-23	Sanofi Aventis Sa	Derives de n-[(4,5-diphenyl-3-alkyl-2-thienyl) methyl] amine leur preparation et leur application en therapeutique
FR2927625B1 (fr)	2008-02-19	2010-03-12	Sanofi Aventis	Nouveaux derives de 3-aminoalkyl-1,3-dihydro-2h-indol-2-one, leur preparation et leur application en therapeutique
FR2930249B1 (fr)	2008-04-21	2010-05-14	Sanofi Aventis	Nouveaux derives de 3-aminoalkyl-1,3-dihydro-2h-indol-2-one, leur preparation et leur application en therapeutique.
CN116514868A (zh) *	2022-01-20	2023-08-01	华创合成制药股份有限公司	一种用于治疗的磺酰胺类化合物其及制备方法和用途
CN122374291A (zh)	2023-12-12	2026-07-10	爱杜西亚药品有限公司	作为食欲素受体调节剂的芳基砜及砜酮衍生物
WO2025132542A1 (en)	2023-12-19	2025-06-26	Idorsia Pharmaceuticals Ltd	Macrocyclic orexin agonists
WO2025224168A1 (en)	2024-04-24	2025-10-30	Idorsia Pharmaceuticals Ltd	Aryl sulfone and sulfanone derivatives as orexin receptor modulators

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US3838167A (en) *	1972-08-01	1974-09-24	Lilly Co Eli	Process for preparing indoles
US4479963A (en) *	1981-02-17	1984-10-30	Ciba-Geigy Corporation	1-Carboxyalkanoylindoline-2-carboxylic acids
DE3705934A1 (de) *	1987-02-25	1988-09-08	Nattermann A & Cie	Indolyl-derivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
GB8820129D0 (en) *	1988-08-24	1988-09-28	Schering Agrochemicals Ltd	Fungicides
FR2679903B1 (fr) *	1991-08-02	1993-12-03	Elf Sanofi	Derives de la n-sulfonyl indoline portant une fonction amidique, leur preparation, les compositions pharmaceutiques en contenant.

1990
- 1990-07-31 FR FR9009778A patent/FR2665441B1/fr not_active Expired - Fee Related
1991
- 1991-07-29 FI FI913614A patent/FI97224C/fi not_active IP Right Cessation
- 1991-07-29 PT PT98476A patent/PT98476B/pt not_active IP Right Cessation
- 1991-07-30 NZ NZ239182A patent/NZ239182A/en unknown
- 1991-07-30 ES ES91402123T patent/ES2080922T3/es not_active Expired - Lifetime
- 1991-07-30 DE DE69113911T patent/DE69113911T2/de not_active Expired - Fee Related
- 1991-07-30 CA CA002048139A patent/CA2048139C/en not_active Expired - Fee Related
- 1991-07-30 AT AT91402123T patent/ATE129236T1/de not_active IP Right Cessation
- 1991-07-30 IL IL9901291A patent/IL99012A/en not_active IP Right Cessation
- 1991-07-30 EP EP91402123A patent/EP0469984B1/fr not_active Expired - Lifetime
- 1991-07-30 NO NO912970A patent/NO175254C/no not_active IP Right Cessation
- 1991-07-31 ZA ZA916031A patent/ZA916031B/xx unknown
- 1991-07-31 KR KR1019910013249A patent/KR100211434B1/ko not_active Expired - Fee Related
- 1991-07-31 JP JP19207891A patent/JP3195381B2/ja not_active Expired - Fee Related
- 1991-07-31 IE IE269691A patent/IE73452B1/en not_active IP Right Cessation
- 1991-07-31 AU AU81478/91A patent/AU645585B2/en not_active Ceased
- 1991-07-31 HU HU9102552A patent/HU220765B1/hu not_active IP Right Cessation
1993
- 1993-11-05 AU AU50473/93A patent/AU664491B2/en not_active Ceased
1995
- 1995-08-15 IL IL11493495A patent/IL114934A0/xx unknown

Also Published As

Publication number	Publication date
FR2665441A1 (fr)	1992-02-07
IL99012A0 (en)	1992-07-15
DE69113911D1 (de)	1995-11-23
ATE129236T1 (de)	1995-11-15
NO175254C (no)	1994-09-21
CA2048139C (en)	2002-02-12
FI97224C (fi)	1996-11-11
AU664491B2 (en)	1995-11-16
AU645585B2 (en)	1994-01-20
JP3195381B2 (ja)	2001-08-06
IL114934A0 (en)	1995-12-08
NO175254B (no)	1994-06-13
PT98476B (pt)	1997-10-31
FI913614A0 (fi)	1991-07-29
NZ239182A (en)	1995-07-26
IE912696A1 (en)	1992-02-12
FI913614L (fi)	1992-02-01
KR920002537A (ko)	1992-02-28
JPH04234361A (ja)	1992-08-24
ES2080922T3 (es)	1996-02-16
FR2665441B1 (fr)	1992-12-04
DE69113911T2 (de)	1996-03-28
EP0469984B1 (fr)	1995-10-18
HUT59669A (en)	1992-06-29
EP0469984A2 (fr)	1992-02-05
NO912970L (no)	1992-02-03
HU220765B1 (hu)	2002-05-28
NO912970D0 (no)	1991-07-30
CA2048139A1 (en)	1992-02-01
ZA916031B (en)	1992-04-29
EP0469984A3 (fr)	1992-03-11
AU8147891A (en)	1992-02-06
FI97224B (fi)	1996-07-31
HU912552D0 (en)	1992-01-28
AU5047393A (en)	1994-01-13
IE73452B1 (en)	1997-06-04
IL99012A (en)	1996-07-23
KR100211434B1 (ko)	1999-08-02

Legal Events

Date	Code	Title	Description
1992-05-29	BB1A	Laying open of patent application	Effective date: 19920128
1997-10-31	FG3A	Patent granted, date of granting	Effective date: 19970708
2000-09-29	PC3A	Transfer or assignment	Free format text: 20000704 SANOFI-SYNTHELABO FR
2005-03-31	MM3A	Annulment or lapse	Free format text: LAPSE DUE TO NON-PAYMENT OF FEES Effective date: 20050110

Publication	Publication Date	Title
NO912970D0 (no)	1991-07-30	Fremgangsmaate for fremstilling av derivater av n-sylfonylindolin.
ES2037015T5 (es)	1995-08-16	Procedimiento para la obtencion de 3,4,5,6-tetrahidroftalimidas n-substituidas y sus precursores.
ATE275545T1 (de)	2004-09-15	Arylpiperazinderivate von indol als liganden der rezeptoren 5 ht1-like, 5 ht1b und 5 ht1d
ES2147223T3 (es)	2000-09-01	Derivados de indol como agonistas de tipo 5-ht1.
DE69728544D1 (de)	2004-05-13	Totalsynthese von acylfulvenen mit antitumorwirkung
DE10199016I2 (de)	2006-04-06	Indol derivate zur Behandlung von Migraene
CA2152902A1 (fr)	1994-07-21	Ligands selectifs des recepteurs 5-ht1d-5ht1b derives d'indole-piperazine utiles comme medicaments
HUP0001165A2 (hu)	2000-11-28	NK1 és NK2 antagonista hatású acil-amino-alkil-amid-származékok, a vegyületeket tartalmazó gyógyszerkészítmények, eljárás előállításukra
UY25970A1 (es)	2001-08-27	Derivado de indol para tratamiento de superproducción de dihidrotestosterona
DK0646110T3 (da)	1996-11-18	N-substituerede 3-azabicyclo(3.2.0) heptanderivater som neuroleptika
ATE162191T1 (de)	1998-01-15	Azanoradamantane
NZ221004A (en)	1989-07-27	2,6-piperazinediones and pharamceutical compositions
EP0739903A4 (en)	1998-07-08	CARBAMOYL METHYL URINE DERIVATIVES
ZA941334B (en)	1995-08-25	Amide derivative .
CO4750832A1 (es)	1999-03-31	Nuevos derivados de quinolina
ES2194690T3 (es)	2003-12-01	Procedimiento de preparacion de oxazoles trisustituidos.
CO4920233A1 (es)	2000-05-29	Acidos aminobutiricos gamma substituidos como agentes farmaceuticos
CO4761068A1 (es)	1999-04-27	Nuevos antagonistas nk-2/nk-3