US20110152233A1 - Pyrrolidine compounds - Google Patents

Pyrrolidine compounds Download PDF

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Publication number
US20110152233A1
US20110152233A1 US12/964,769 US96476910A US2011152233A1 US 20110152233 A1 US20110152233 A1 US 20110152233A1 US 96476910 A US96476910 A US 96476910A US 2011152233 A1 US2011152233 A1 US 2011152233A1
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United States
Prior art keywords
fluoro
phenyl
carbonyl
pyrrolidin
ethyl
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Abandoned
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US12/964,769
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English (en)
Inventor
Henner Knust
Andreas Koblet
Matthias Nettekoven
Hasane Ratni
Claus Riemer
Walter Vifian
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Hoffmann La Roche Inc
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Hoffmann La Roche Inc
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Assigned to F. HOFFMANN-LA ROCHE AG reassignment F. HOFFMANN-LA ROCHE AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KNUST, HENNER, KOBLET, ANDREAS, NETTEKOVEN, MATTHIAS, RATNI, HASANE, RIEMER, CLAUS, VIFIAN, WALTER
Assigned to HOFFMANN-LA ROCHE, INC. reassignment HOFFMANN-LA ROCHE, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: F. HOFFMANN-LA ROCHE AG
Publication of US20110152233A1 publication Critical patent/US20110152233A1/en
Priority to US13/798,583 priority Critical patent/US9346786B2/en
Abandoned legal-status Critical Current

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • 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

Definitions

  • the three main mammalian tachykinins, substance P(SP), neurokinin A (NKA) and neurokinin B (NKB) belong to the family of neuropeptides sharing the common COOH-terminal pentapeptide sequence of Phe-X-Gly-Leu-Met-NH 2 .
  • SP neurokinin A
  • NKB neurokinin B
  • NK-1, NK-2 and NK-3 three distinct neurokinin (NK) receptors termed as NK-1, NK-2 and NK-3.
  • SP binds preferentially to the NK-1 receptor, NKA to the NK-2 and NKB to the NK-3 receptor.
  • the NK-3 receptor is characterized by a predominant expression in CNS and its involvement in the modulation of the central monoaminergic system has been shown. These properties make the NK-3 receptor a potential target for central nervous system disorders such as anxiety, depression, bipolar disorders, Parkinson's disease, schizophrenia and pain ( Neurosci. Letters, 2000, 283, 185-188 ; Exp. Opin. Ther. Patents 2000, 10, 939-960 ; Neuroscience, 1996, 74, 403-414 ; Neuropeptides, 1998, 32, 481-488).
  • Schizophrenia is one of the major neuropsychiatric disorders, characterized by severe and chronic mental impairment. This devastating disease affects about 1% of the world's population. Symptoms begin in early adulthood and are followed by a period of interpersonal and social dysfunction. Schizophrenia manifests as auditory and visual hallucinations, paranoia, delusions (positive symptoms), blunted affect, depression, anhedonia, poverty of speech, memory and attention deficits as well as social withdrawal (negative symptoms).
  • an appropriate multireceptor affinity profile might be required for efficacy against positive and negative signs and symptoms.
  • an ideal drug against schizophrenia would preferably have a low dosage allowing once-per-day dosage, due to the low adherence of schizophrenic patients.
  • Osanetant (SR 142,801) from Sanofi-Synthelabo was the first identified potent and selective non-peptide antagonist described for the NK3 tachykinin receptor for the potential treatment of schizophrenia, which was reported in the literature ( Current Opinion in Investigational Drugs, 2001, 2(7), 950-956 and Psychiatric Disorders Study 4 , Schizophrenia , June 2003, Decision Recources, Inc., Waltham, Mass.).
  • the proposed drug SR 142,801 has been shown in a phase II trial as active on positive symptoms of schizophrenia, such as altered behaviour, delusion, hallucinations, extreme emotions, excited motor activity and incoherent speech, but inactive in the treatment of negative symptoms, which are depression, anhedonia, social isolation or memory and attention deficits.
  • the neurokinin-3 receptor antagonists have been described as useful in pain or inflammation, as well as in schizophrenia, Exp. Opinion. Ther. Patents (2000), 10(6), 939-960 and Current Opinion in Investigational Drugs, 2001, 2(7), 950-956 956 and Psychiatric Disorders Study 4 , Schizophrenia , June 2003, Decision Recources, Inc., Waltham, Mass.).
  • the invention includes all stereoisomeric forms, including individual diastereoisomers and enantiomers of the compound of formula (I) as well as racemic and non-racemic mixtures thereof.
  • the present invention provides novel compounds of formula I, their manufacture, pharmaceutical compositions containing them and methods for producing such compositions.
  • the present compounds are high potential NK-3 receptor antagonists for the treatment of depression, pain, bipolar disorders, psychosis, Parkinson's disease, schizophrenia, anxiety and attention deficit hyperactivity disorder (ADHD).
  • the preferred indications using the compounds of the present invention are depression, psychosis, Parkinson's disease, schizophrenia, anxiety and attention deficit hyperactivity disorder (ADHD).
  • lower alkyl and C 2-7 -alkyl denote a straight- or branched-chain hydrocarbon group containing from 2-7 carbon atoms, for example, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like.
  • Preferred lower alkyl groups are groups with 2-4 carbon atoms.
  • lower alkoxy denotes a lower alkyl group as defined above which is connected with an oxygen atom.
  • lower alkyl substituted by halogen denotes a lower alkyl group as defined above, wherein at least one hydrogen atom is replaced by halogen, for example —CF 3 , —CHF 2 , —CH 2 F, —CH 2 CF 3 , —C(CH 3 ) 2 CF 3 , —CH(CH 3 )CH 2 CF 3 , —CH(CH 3 )CF 3 , —CH 2 CH 2 CF 3 , —CH 2 CH 2 CH 2 CF 3 , —CH 2 CH 2 CF 2 CF 3 , —CH 2 CH 2 CH 2 CF 2 CF 3 , —CH 2 CH 2 CH 2 CF 2 CF 3 , —CH 2 CH 2 CH 2 CF 2 CF 3 , —CH 2 CF 2 CF 3 and the like.
  • Preferred lower alkyl substituted by halogen groups are groups having 1-5 carbon atoms.
  • halogen denotes chlorine, iodine, fluorine and bromine.
  • lower alkyl substituted by hydroxy denotes a lower alkyl group as defined above, wherein at least one hydrogen atom is replaced by a hydroxyl group.
  • cycloalkyl denotes a saturated carbon ring containing from 3-6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • aryl denotes a cyclic aromatic hydrocarbon radical consisting of one or more fused rings containing 6-14 carbon atoms in which at least one ring is aromatic in nature, for example phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl or indanyl. Preferred is the phenyl group.
  • heteroaryl denotes a cyclic aromatic radical consisting of one or more fused rings containing 5-14 ring atoms, preferably containing 5-10 ring atoms, in which at least one ring is aromatic in nature, and which contains at least one heteroatom, selected from N, O and S, for example quinoxalinyl, dihydroisoquinolinyl, pyrazinyl, pyrazolyl, 2,4-dihydro-pyrazol-3-one, pyridinyl, isoxazolyl, benzo[1,3]dioxol, [1.3.4]thiadiazol, pyridazinyl, pyrimidinyl, benzotriazol-5-yl, benzoimidazol-5-yl, [1,3,4]-oxadiazol-2-yl, [1,2,4]triazol-1-yl, [1,6]naphthyridin-2-yl, imidazo[4,5-b]pyridine-6
  • heterocycloalkyl denotes a cyclic nonaromatic ring, containing one or two heteroatoms selected from N, S and O, for example the following groups: tetrahydropyranyl, 1,1-dioxo-hexahydro-1 ⁇ 6 -thiopyranyl, 1,1-dioxo-tetrahydro-1 ⁇ 6 -thiophenyl, oxetanyl, morpholinyl, [1,4]diazepam-1-yl, piperazinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidin-4-yl or 1,1-dioxo- ⁇ 6 -thiomorpholinyl.
  • “Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
  • pharmaceutically acceptable acid addition salts embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
  • “Therapeutically effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
  • a preferred aryl group is phenyl.
  • R 1 is hydrogen, halogen, cyano, lower alkyl or lower alkyl substituted by halogen; n is 1, 2 or 3, wherein when n is 2 or 3, each R 1 is the same or different; R 2 is C 2-7 -alkyl or C 3-6 -cycloalkyl; R 3 is a non aromatic heterocyclic group
  • X is CH
  • Y is —N(R 7 )—
  • R 6 is hydrogen; o and m are each independently 0, 1 or 2; p is 0 or 1; R 7′ is hydrogen, —C(O)-lower alkyl, —C(O)O-lower alkyl, S(O) 2 -lower alkyl, —C(O)CH 2 O-lower alkyl, or is cycloalkyl, —CH 2 -cycloalkyl or —C(O)-cycloalkyl, wherein the cycloalkyl groups are optionally substituted by lower alkyl, CF 3 , halogen or cyano, or is —C(O)-heterocycloalkyl, heterocycloalkyl, heteroaryl, —C(O)-heteroaryl, —C(O)-aryl, or aryl, which heterocycloalkyl, heteroaryl or aryl groups are optionally substituted by halogen, lower alkyl, lower alkoxy, lower alkyl substitute
  • Z is —O—
  • R 4 is (CH 2 ) q -aryl or is (CH 2 ) q -heteroaryl, which aryl or heteroaryl rings are optionally substituted by halogen, hydroxy, lower alkyl, lower alkyl substituted by halogen, S(O) 2 -lower alkyl, cyano or by lower alkoxy; q is 0 or 1; or to a pharmaceutically active salt thereof.
  • the 3,4-disubstituted pyrrolidine VI is prepared via a stereo specific 1,3-dipolar cycloaddition between the 2-nitrostyrene compound IV and the azomethine ylide generated in situ from the N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine V in the presence of a catalytic amount of acid, such as TFA.
  • a catalytic amount of acid such as TFA.
  • Reduction of the nitro moiety of VI using standard conditions for example SnCl 2 .H 2 O yields VII.
  • the amino moiety of VII is subsequently alkylated to produce VIII.
  • the secondary amine of the intermediates VII can be protected, for instance with a Boc group to afford a compound of formula X, followed by a selective debenzylation to produce XI. Then a coupling with a suitable carbamoyl chloride, acid chloride or carboxylic acid gives XII. Deprotection with TFA affords the free amine XIII, which after reaction with an acid anhydride, chloroformate or a mixture of triphosgene and an alcohol or amine in the presence of a base affords compounds of formula I.
  • racemic material was subjected to separation on CHIRALPAK AD eluting with i-propanol/heptane.
  • hNK3 receptor binding experiment were performed using [ 3 H]SR142801 (Catalog No. TRK1035, specific activity: 74.0 Ci/mmol, Amersham, GE Healthcare UK limited, Buckinghamshire, UK) and membrane isolated from HEK293 cells transiently expressing recombinant human NK3 receptor. After thawing, the membrane homogenates were centrifuged at 48,000 ⁇ g for 10 min at 4° C., the pellets were resuspended in the 50 mM Tris-HCl, 4 mM MnCl 2 , 1 ⁇ M phosphoramidon, 0.1% BSA binding buffer at pH 7.4 to a final assay concentration of 5 ⁇ g protein/well.
  • membranes were incubated with [ 3 H]SR142801 at a concentration equal to K D value of radioligand and 10 concentrations of the inhibitory compound (0.0003-10 ⁇ M) (in a total reaction volume of 500 ⁇ l) for 75 min at room temperature (RT).
  • RT room temperature
  • membranes were filtered onto unitfilter (96-well white microplate with bonded GF/C filter preincubated 1 h in 0.3% PEI+0.3% BSA, Packard BioScience, Meriden, Conn.) with a Filtermate 196 harvester (Packard BioScience) and washed 4 times with ice-cold 50 mM Tris-HCl, pH 7.4 buffer.
  • Nonspecific binding was measured in the presence of 10 ⁇ M SB222200 for both radioligands.
  • the radioactivity on the filter was counted (5 min) on a Packard Top-count microplate scintillation counter with quenching correction after addition of 45 ⁇ l of microscint 40 (Canberra Packard S. A., Zürich, Switzerland) and shaking for 1 h.
  • the compounds of formula I as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations.
  • the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions.
  • the administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
  • the compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragées and hard gelatine capsules.
  • Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols etc.
  • Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.
  • Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.
  • Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.
  • the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case.
  • a daily dosage of about 10 to 1000 mg per person of a compound of general formula I should be appropriate, although the above upper limit can also be exceeded when necessary.
  • the active substance, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine.
  • the mixture is returned to the mixer, the talc is added thereto and mixed thoroughly.
  • the mixture is filled by machine into hard gelantine capsules.
  • the suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to 45° C. Thereupon, the finely powdered active substance is added thereto and stirred until it has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to cool, the suppositories are then removed from the moulds and packed individually in wax paper or metal foil.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Rheumatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US12/964,769 2009-12-18 2010-12-10 Pyrrolidine compounds Abandoned US20110152233A1 (en)

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US (2) US20110152233A1 (ja)
EP (1) EP2513084B1 (ja)
JP (1) JP5551267B2 (ja)
KR (1) KR101490004B1 (ja)
CN (1) CN102656157B (ja)
BR (1) BR112012014576A2 (ja)
CA (1) CA2781495A1 (ja)
ES (1) ES2546833T3 (ja)
HK (1) HK1169992A1 (ja)
MX (1) MX2012006293A (ja)
RU (1) RU2561271C2 (ja)
WO (1) WO2011073160A1 (ja)

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US20120178761A1 (en) * 2011-01-07 2012-07-12 Henner Knust Pyrrolidine derivatives

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US8022099B2 (en) * 2008-11-03 2011-09-20 Hoffmann-La Roche Inc. N-benzyl pyrrolidine derivatives
US20110144081A1 (en) * 2009-12-15 2011-06-16 Henner Knust Pyrrolidine derivatives
RU2606131C2 (ru) * 2011-05-13 2017-01-10 Эррэй Биофарма Инк. СОЕДИНЕНИЯ ПИРРОЛИДИНИЛМОЧЕВИНЫ И ПИРРОЛИДИНИЛТИОМОЧЕВИНЫ КАК ИНГИБИТОРЫ КИНАЗЫ TrkA
CN107011229B (zh) * 2012-01-06 2019-11-05 诺华股份有限公司 杂环化合物和它们的使用方法

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