CO2023012903A2 - Derivados de pirimidina útiles como inhibidores de la proteína cinasa de repetición 2 rica en leucina (lrrk2) - Google Patents

Derivados de pirimidina útiles como inhibidores de la proteína cinasa de repetición 2 rica en leucina (lrrk2)

Info

Publication number
CO2023012903A2
CO2023012903A2 CONC2023/0012903A CO2023012903A CO2023012903A2 CO 2023012903 A2 CO2023012903 A2 CO 2023012903A2 CO 2023012903 A CO2023012903 A CO 2023012903A CO 2023012903 A2 CO2023012903 A2 CO 2023012903A2
Authority
CO
Colombia
Prior art keywords
lrrk2
inhibitors
leucine
protein kinase
pyrimidine derivatives
Prior art date
Application number
CONC2023/0012903A
Other languages
English (en)
Inventor
David J Bearss
John Sai Keong Kauwe Iii
Alexis Henri Abel Mollard
Original Assignee
Halia Therapeutics Inc
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 Halia Therapeutics Inc filed Critical Halia Therapeutics Inc
Publication of CO2023012903A2 publication Critical patent/CO2023012903A2/es

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • 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
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • 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
    • A61P25/14—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
    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D403/02—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 two hetero rings
    • C07D403/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • 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
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Se proporcionan compuestos que tienen actividad como inhibidores de cinasa LRRK2. Los compuestos tienen la Estructura (I): (I) o una sal farmacéuticamente aceptable, estereoisómero o profármaco del mismo, en donde A, B, R1a, R1b, R2 y L son como se definen en la presente. También se proporcionan métodos asociados con la preparación y el uso de estos compuestos, composiciones farmacéuticas que comprenden estos compuestos y métodos para modular la actividad de la cinasa LRRK2.
CONC2023/0012903A 2021-03-23 2023-09-28 Derivados de pirimidina útiles como inhibidores de la proteína cinasa de repetición 2 rica en leucina (lrrk2) CO2023012903A2 (es)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163164804P 2021-03-23 2021-03-23
PCT/US2022/021573 WO2022204299A1 (en) 2021-03-23 2022-03-23 Pyrimidine derivatives useful as lrrk2 kinase inhibitors

Publications (1)

Publication Number Publication Date
CO2023012903A2 true CO2023012903A2 (es) 2023-10-09

Family

ID=81328290

Family Applications (1)

Application Number Title Priority Date Filing Date
CONC2023/0012903A CO2023012903A2 (es) 2021-03-23 2023-09-28 Derivados de pirimidina útiles como inhibidores de la proteína cinasa de repetición 2 rica en leucina (lrrk2)

Country Status (12)

Country Link
US (3) US11578061B2 (es)
EP (1) EP4313955A1 (es)
JP (1) JP2024512024A (es)
KR (1) KR20230170684A (es)
CN (1) CN117355507A (es)
AU (1) AU2022246081A1 (es)
BR (1) BR112023019388A2 (es)
CA (1) CA3214360A1 (es)
CO (1) CO2023012903A2 (es)
IL (1) IL306008A (es)
MX (1) MX2023011027A (es)
WO (1) WO2022204299A1 (es)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR112023019388A2 (pt) * 2021-03-23 2023-11-07 Halia Therapeutics Inc Derivados de pirimidina úteis como inibidores de quinase lrrk2

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0619343D0 (en) 2006-09-30 2006-11-08 Vernalis R&D Ltd New chemical compounds
TW201024281A (en) 2008-11-24 2010-07-01 Boehringer Ingelheim Int New compounds
AU2010331927B2 (en) 2009-12-17 2013-10-10 Merck Canada Inc. Aminopyrimidines as Syk inhibitors
EP2512246B1 (en) 2009-12-17 2015-09-30 Merck Sharp & Dohme Corp. Aminopyrimidines as syk inhibitors
CN105837519A (zh) 2010-06-04 2016-08-10 霍夫曼-拉罗奇有限公司 作为lrrk2调节剂的氨基嘧啶衍生物
PL3004079T3 (pl) 2013-06-04 2018-07-31 Acturum Real Estate Ab Związki pirymidyny i ich zastosowanie jako modulatorów sekretazy gamma
JP6474826B2 (ja) 2014-01-29 2019-02-27 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ 化合物
EP3144292B1 (en) 2014-04-14 2020-08-26 Shanghai Haiyan Pharmaceutical Technology Co., Ltd 2,3,4,6-tetra-substituted benzene-1,5-diamine derivatives, preparation method therefor and medicinal use thereof
WO2017087905A1 (en) 2015-11-20 2017-05-26 Denali Therapeutics Inc. Compound, compositions, and methods
US11028080B2 (en) * 2016-03-11 2021-06-08 Denali Therapeutics Inc. Substituted pyrimidines as LRKK2 inhibitors
WO2019074810A1 (en) 2017-10-11 2019-04-18 Merck Sharp & Dohme Corp. INDAZOLYL-SPIRO [2,3] HEXANE-CARBONITRILE DERIVATIVES AS INHIBITORS OF LRRK2, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF
TW202017918A (zh) 2017-12-19 2020-05-16 美商必治妥美雅史谷比公司 作為lpa拮抗劑之環己基酸三唑吖
CN110872277B (zh) 2019-11-14 2021-06-04 浙江大学 N-取代芳环-2-氨基嘧啶类化合物及用途
BR112023019388A2 (pt) * 2021-03-23 2023-11-07 Halia Therapeutics Inc Derivados de pirimidina úteis como inibidores de quinase lrrk2

Also Published As

Publication number Publication date
CA3214360A1 (en) 2022-09-29
WO2022204299A1 (en) 2022-09-29
US20230183217A1 (en) 2023-06-15
US11866423B2 (en) 2024-01-09
BR112023019388A2 (pt) 2023-11-07
MX2023011027A (es) 2023-09-27
KR20230170684A (ko) 2023-12-19
US20220324845A1 (en) 2022-10-13
IL306008A (en) 2023-11-01
AU2022246081A1 (en) 2023-10-12
EP4313955A1 (en) 2024-02-07
US11578061B2 (en) 2023-02-14
US20240190848A1 (en) 2024-06-13
CN117355507A (zh) 2024-01-05
JP2024512024A (ja) 2024-03-18

Similar Documents

Publication Publication Date Title
CL2019002777A1 (es) Compuestos que inhiben la proteína mcl-1.
CL2022001625A1 (es) Derivados de pirazolilo útiles como agentes anti-cancerígenos
UY38196A (es) Inhibidores de cinasa dependientes de ciclina
ECSP20070854A (es) Compuestos heteroaril tetracíclicos
CO2018007052A2 (es) Compuestos y metodos para modulación de la quinasa, e indicaciones de los mismos
ECSP21038390A (es) Compuestos, composiciones farmacéuticas y métodos de preparación de compuestos y de su uso como inhibidores de la cinasa atr
UY31068A1 (es) Ligandos purinoreceptores p2x, metodos para la prparacion de los mismos, composiciones farmaceuticas que los contienen y sus usos 570
ECSP17007208A (es) Derivados de indano e indolina y el uso de los mismos como activadores de la guanilato ciclasa soluble
CO2022017622A2 (es) Inhibidores de quinasa nek7
NI201900077A (es) Inhibidores selectivos de jak1
CO2020004977A2 (es) Compuestos bicíclicos para su uso como inhibidores de la ripi quinasa
CO2023012903A2 (es) Derivados de pirimidina útiles como inhibidores de la proteína cinasa de repetición 2 rica en leucina (lrrk2)
CO2022019131A2 (es) Inhibidores de la quinasa nek7
CL2020001020A1 (es) Derivados de bencimidazol y sus usos.
CO2020012353A2 (es) Compuestos de pirazol sustituidos con heteroarilo y uso farmacéutico de los mismos
UY38786A (es) Agonistas de receptores tipo toll
DOP2019000100A (es) Derivados de naftiridinona y su uso en el tratamiento de la arritmia
UY38892A (es) Moduladores de sting (estimulador de genes de interferón)
CO2023001407A2 (es) Compuestos de tetrahidropirazolo-pirazinil-dihidroimidazolona o tetrahidropirazolo-piridinil-dihidroimidazolona y métodos de uso de los mismos
CO2023014204A2 (es) Inhibidores de la cinasa relacionada con el gen nunca en mitosis a 7 (nek7)
UY38006A (es) Inhibidores de la quinasa mtor, composiciones farmacéuticas que los contienen, y al uso en terapia de tales compuestos y composiciones
ECSP23070418A (es) Moduladores de sting (estimulador de genes de interferón)
BR112022026275A2 (pt) Piridina-1,5-dionas que exibem inibição de mnk e seus métodos de uso
UY38133A (es) Nuevos inhibidores de cdk8/19
AR120156A1 (es) Compuestos quiméricos de somatostatina-dopamina estables de almacenamiento y las formas salinas de estos