cas 148546-99-0, 3-(4-Methylpiperazin-1-yl)aniline

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NOTCH INHIBITORS AND USES THEREOF
Disclosed herein, inter alia, are compounds for inhibiting Notch and uses thereof.
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(2021/11/26)

PYRIMIDINE COMPOUND, PREPARATION METHOD THEREOF AND MEDICAL USE THEREOF
The present invention discloses a pyrimidine compound, a preparation method thereof and a medical use thereof. Specifically, the present invention discloses a pyrimidine compound represented by formula (I), pharmaceutically acceptable salts thereof, a preparation method thereof, and a use thereof as a cyclin-dependent kinase 9 (CDK9) inhibitor, particularly for the treatment of cancer. The definition of each group in formula (I) is the same as that in the specification.
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(2021/04/10)

Discovery of novel 4-azaaryl-N-phenylpyrimidin-2-amine derivatives as potent and selective FLT3 inhibitors for acute myeloid leukaemia with FLT3 mutations
Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3) is one of the most pursued targets in the treatment of acute myeloid leukaemia (AML) as its gene amplification and mutations, particularly internal tandem duplication (ITD), contribute to the pa
Long, Yi,Yu, Mingfeng,Ochnik, Aleksandra M.,Karanjia, Jasmine D.,Basnet, Sunita KC.,Kebede, Alemwork A.,Kou, Lianmeng,Wang, Shudong
(2021/02/03)

Combining structure- and property-based optimization to identify selective FLT3-ITD inhibitors with good antitumor efficacy in AML cell inoculated mouse xenograft model
FLT3 mutation is among the most common genetic mutations in acute myeloid leukemia (AML), which is also related with poor overall survival and refractory in AML patients. Recently, FLT3 inhibitors have been approved for AML therapy. Herein, a series of new compounds with pyrazole amine scaffold was discovered, which showed potent inhibitory activity against FLT3-ITD and significant selectivity against both FLT3-ITD and AML cells expressing FLT3-ITD. Compound 46, possessing the most promising cellular activity, blocked the autophosphorylation of FLT3 pathway in MV4-11 cell line. Furthermore, the apoptosis and downregulation of P-STAT5 were also observed in tumor cells extracted from the MV4-11 cell xenografts model upon compound 46 treatment. Compound 46 was also metabolically stable in vitro and suppressed tumor growth significantly in MV4-11 xenografts model in vivo. Compound 46 showed no toxicity to the viscera of mice and caused no decrease in body weight of mice. In conclusion, the results of this study could provide valuable insights into discovery of new FLT3 inhibitors, and compound 46 was worthy of further development as potential drug candidate to treat AML.
Heng, Hao,Wang, Zhijie,Li, Hongmei,Huang, Yatian,Lan, Qingyuan,Guo, Xiaoxing,Zhang, Liang,Zhi, Yanle,Cai, Jiongheng,Qin, Tianren,Xiang, Li,Wang, Shuxian,Chen, Yadong,Lu, Tao,Lu, Shuai
p. 248 - 267
(2019/05/21)

Catalyst-Directed Chemoselective Double Amination of Bromo-chloro(hetero)arenes: A Synthetic Route toward Advanced Amino-aniline Intermediates
A chemoselective sequential one-pot coupling protocol was developed for preparing several amino-anilines in high yield as building blocks for active pharmaceutical ingredients (APIs). Site (Cl vs Br on electrophile) and nucleophile (amine vs imine) selectivity is dictated by the catalyst employed. A Pd-crotyl(t-BuXPhos) precatalyst selectively coupled the Ar-Br of the polyhaloarene with benzophenone imine, even in the presence of a secondary amine, while Pd-based RuPhos or (BINAP)Pd(allyl)Cl coupled the Ar-Cl site with secondary amines.
Mikhailine, Alexandre A.,Grasa Mannino, Gabriela A.,Colacot, Thomas J.
supporting information
p. 2301 - 2305
(2018/04/30)

SAR study on: N 2, N 4-disubstituted pyrimidine-2,4-diamines as effective CDK2/CDK9 inhibitors and antiproliferative agents
Cyclin-dependent kinases (CDKs) are pivotal kinases in cell cycle transition and gene transcription. A series of N2,N4-diphenylpyrimidine-2,4-diamines were previously identified as potent CDK2/CDK9 inhibitors. To explore the SAR of this structural prototype, twenty-four novel N2,N4-disubstituted pyrimidine-2,4-diamines were designed and synthesized. Among them, twenty-one compounds exhibited potent inhibitory activities against both CDK2/cyclin A and CDK9/cyclin T1 systems, and the most potent CDK2 and CDK9 inhibitors, 3g and 3c, showed IC50 values of 83 nM and 65 nM respectively. Most of these compounds displayed significant inhibition against the tested tumor cell lines in the SRB assay, and in particular, remained active against the triple-negative breast cancer (TNBC) cell line MDA-MB-231. Flow cytometer analysis of compounds 2a, 2d and 3b in MDA-MB-231 cells indicated that these compounds induced cell cycle arrest in G2/M phase. Docking studies on compound 3g were performed, which provided conducive clues for further molecular optimization.
Jing, Liandong,Tang, Yanbo,Goto, Masuo,Lee, Kuo-Hsiung,Xiao, Zhiyan
p. 11871 - 11885
(2018/04/12)

DIARYLUREAS AS CB1 ALLOSTERIC MODULATORS
The present invention provides novel diarylurea derivatives (compounds of formula (I)) and their uses. The compounds of the present invention are demonstrated to be allosteric modulators of the CB1 receptor, and therefore useful for the treatment of diseases and conditions mediated by CB1.
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Paragraph 69; 126; 164

(2018/12/02)

Discovery of Potent, Selective Stem Cell Factor Receptor/Platelet Derived Growth Factor Receptor Alpha (c-KIT/PDGFRα) Dual Inhibitor for the Treatment of Imatinib-Resistant Gastrointestinal Stromal Tumors (GISTs)
Stem cell factor receptor (c-KIT) and platelet derived growth factor receptor alpha (PDGFRα) kinases play an important role in gastrointestinal stromal tumors (GISTs). Here, we have discovered an c-KIT/PDGFRα dual inhibitor, compound 31, with single-digit nanomolar potency against c-KIT and PDGFRα. Compared to Imatinib (1), 31 showed better antiproliferative efficacy against various TEL-c-KIT/PDGFRα-BaF3 isogenic cells, including three 1-resistant BaF3 cell lines, as well as against GIST-T1 and GIST-882 cell lines. Furthermore, compound 31 showed a good KinomeScan selectivity (468 kinases) (S score (1) = 0.01 at 1 μM concentration), good metabolic stability in liver microsomes, and no hERG inhibitory activity. It was worth noting that 31 inhibited GIST-T1 tumor growth (TGI = 81.5%) and even the BaF3-TEL-cKIT-T670I tumor progression (TGI = 41.9%, 1-resistant GISTs) at a dosage of 100 mg/kg/day without exhibiting apparent toxicity.
Lu, Yanli,Mao, Fei,Li, Xiaokang,Zheng, Xinyu,Wang, Manjiong,Xu, Qing,Zhu, Jin,Li, Jian
p. 5099 - 5119
(2017/06/28)

N-SUBSTITUTED HETEROCYCLIC DERIVATIVES AS KINASE INHIBITORS
The present invention provides N-substituted novel heterocyclic derivatives of formula (I) as protein kinase inhibitors, in which R1, R2 and 'n' have the same meanings given in the specification, and pharmaceutically acceptable salts
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(2014/09/03)

2, 4 -DIAMINOPYRIMIDINE DERIVATIVES AS PROTEIN KINASE INHIBITORS
The present invention relates to novel pyrimide derivatives of formula (I): that are useful as kinase inhibitors. More particularly, the present invention relates to novel pyrimidine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative disorders.
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(2012/05/20)

Synthesis and SAR of (piperazin-1-yl-phenyl)-arylsulfonamides: A novel series of atypical antipsychotic agents
(Piperazin-1-yl-phenyl)-arylsulfonamides were synthesized and identified to show high affinities for both 5-HT2C and 5-HT6 receptors. Among them, naphthalene-2-sulfonic acid isopropyl-[3-(4-methyl-piperazin-1-yl)- phenyl]-amide (6b) exhibits the highest affinity towards both 5-HT2C (IC50 = 4 nM) and 5-HT6 receptors (IC50 = 3 nM) with good selectivity over other serotonin (5-HT1A, 5-HT 2A, and 5-HT7) and dopamine (D2-D4) receptor subtypes. In 5-HT2C and 5-HT6 receptor functional assays, this compound showed considerable antagonistic activity for both receptors.
Park, Chul Min,Kim, So Young,Park, Woo Kyu,Choi, Jung Hwan,Seong, Churl Min
supporting information; experimental part
p. 5221 - 5224
(2010/10/01)

COMPOUNDS AND COMPOSITIONS AS KINASE INHIBITORS
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Page/Page column 32-33

(2008/12/07)

Antiprion activity of functionalized 9-aminoacridines related to quinacrine
A library of functionalized 6-chloro-2-methoxy-(N9-substituted)acridin-9-amines structurally related to quinacrine were synthesized and evaluated for antiprion activity on four different cell models persistently infected with scrapie prion strains (ScN2a, N167, Ch2) or a human disease prion strain (F3). Most of the compounds were distinguished by the side chain attached to 9-amino of the acridine ring. These were dialkylaminoalkyl and phenyl with basic groups on the phenyl ring. The most promising compound was 6-chloro-2-methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)acridin-9-amine (15) which had submicromolar EC50 values (0.1-0.7 μM) on all cell models, was able to clear PrPSc at non-toxic concentrations of 1.2-2.5 μM, and was more active than quinacrine in terms of EC50 values. Other promising compounds were 14 (a regioisomer of 15) and 17 which had a 1-benzylpiperidin-4-yl substituent attached to the 9-amino function. Activity was strongly dependent on the presence of a substituted acridine ring, which in this library comprised 6-chloro-2-methoxy substituents on the acridine ring. The side chains of 14, 15, and 17 have not been previously associated with antiprion activity and are interesting leads for further optimization of antiprion activity.
Nguyen Thi, Hanh Thuy,Lee, Chong-Yew,Teruya, Kenta,Ong, Wei-Yi,Doh-ura, Katsumi,Go, Mei-Lin
p. 6737 - 6746
(2008/12/21)

COMPOUNDS
A compound of formula (I): compositions and medicaments containing the same as well as processes for the preparation and use of such compounds, compositions and medicaments, particularly in diseases associated with inappropriate Aurora activity.
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Page/Page column 96-97

(2010/11/26)

5-Oxo-5,8-dihydro-pyrido-pyrimidines as inhibitors of c-fms kinase
The invention addresses the current need for selective and potent protein tyrosine kinase inhibitors by providing potent inhibitors of c-fms kinase. The invention is directed to the novel compounds of Formula I: or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein: W, A, Y, Z, R101 and R200 are described in the specification.
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Page/Page column 48

(2010/11/26)

ARYL-AMINO SUBSTITUTED PYRROLOPYRIMIDINE MULTI-KINASE INHIBITING COMPOUNDS
Compounds represented by Formula (I): or stereoisomers or pharmaceutically acceptable salts thereof, are inhibitors of least two of the Abl, Aurora-A, Blk, c-Raf, cSRC, Src, PRK2, FGFR3, Flt3, Lck, Mekl, PDK-1, GSK3?, EGFR, p70S6K, BMX, SGK, CaMKII, Tie-2
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Page/Page column 158

(2008/06/13)

HETEROCYCLIC AMIDES WITH ANTI-TUBERCULOSIS ACTIVITY
Compounds having the general structure (I) : wherein A is selected from the group consisting of oxygen, sulfur, and NR15, and R15 is selected from the group consisting of H, alkyl, aryl, substituted alkyl, and substituted aryl; B, D, and E are each independently selected from the group consisting of CH, nitrogen, sulfur and oxygen; R1 is selected from the group consisting of nitro, halo, alkyl ester, phenylsulfanyl, phenylsulfinyl, phenylsulfonyl and sulfonic acid; t is an integer from 1 to 3; and X is a substituted amide and methods of using the novel compounds for treating infections caused microorganisms, including Mycobacterium tuberculosis.
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Page 66

(2010/02/10)

2-AMINO-4-HYDROXY-5-PYRIMIDINECARBOXAMIDE DERIVATIVES AND RELATED COMPOUNDS AS INHIBITORS OF T CELL ACTIVATION FOR THE TREATMENT OF INFLAMMATORY DISEASES
The present invention relates to pyrimidine or pyridine carboxamides or pharmaceutically-acceptable salts thereof. Also included is a method of treatment of inflammation, inhibition of T cell activation and proliferation, arthritis, rheumatoid arthritis,
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Page/Page column 73

(2008/06/13)

Heterocyclic amides with anti-tuberculosis activity
Compounds having the general structure: wherein A is selected from the group consisting of oxygen, sulfur, and NR15, and R15 is selected from the group consisting of H, alkyl, aryl, substituted alkyl, and substituted aryl; B,D, and E are each independently selected from the group consisting of CH, nitrogen, sulfur and oxygen; R1 is selected from the group consisting of nitro, halo, alkyl ester, arylsulfanyl, arylsulfinyl, arylsulfonyl and sulfonic acid; t is an integer from 1 to 3; and X is a substituted amide, and methods of using the novel compounds for treating infections caused by microorganisms, including Mycobacterium tuberculosis.
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(2008/06/13)

2-AMINOPYRIMIDINE AND 2-AMINOPYRIDINE-4-CARBAMATES FOR USE IN THE TREATMENT OF AUTOIMMUNE DISEASES
The present invention relates to pyrimidine or pyridine carbamate compounds having the general Formula (1) and pharmaceutically acceptable salts or derivatives thereof. Also included are methods of treatment of various diseases and conditions, including inflammation, inhibition of T cell activation and proliferation, arthritis, organ transplant, ischemic or reperfusion injury, myocardial infarction, stroke, multiple sclerosis, inflammatory bowel disease, Crohn's disease, lupus, hypersensitivity, type 1 diabetes, psoriasis, dermatitis, Hashimoto's thyroiditis, Sjogren's syndrome, autoimmune hyperthyroidism, Addison's disease, autoimmune diseases, glomerulonephritis, allergic diseases, asthma, hayfever, eczema, cancer, colon carcinoma, thymoma, just to name a few, in a mammal, the methods comprising administering a therapeutically-effective amount a compound of Formula I, or a salt or derivative form thereof, as described above.
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Page 84

(2010/02/10)

SUBSTITUTED HETEROCYCLIC COMPOUNDS AND METHODS OF USE
The present invention relates to tetracyclic pyrimidines or pyridines or pharmaceutically-acceptable salts or derivatives thereof. Also included are methods of use of the tetracyclic pyrimidines or pyridines including use related to treating inflammation,
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Page/Page column 80

(2010/02/11)

SUBSTITUTED HETEROCYCLIC COMPOUNDS AND METHODS OF USE
The present invention relates to hydroxybenzimidazole pyrimidines or pyridines or pharmaceutically-acceptable salts thereof. Also included is a method of treatment of inflammation, inhibition of T cell activation and proliferation, arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, organ transplant, acute transplant or heterograft or homograft rejection, transplantation tolerance induction, ischemic or reperfusion injury, myocardial infarction, stroke, multiple sclerosis, inflammatory bowel disease, including ulcerative colitis, Crohn's disease, lupus, contact hypersensitivity, delayed-type hypersensitivity, and gluten-sensitive enteropathy, type 1 diabetes, psoriasis, contact dermatitis, Hashimoto's thyroiditis, Sjogren's syndrome, autoimmune hyperthyroidism, Addison's disease, autoimmune polyglandular disease, autoimmune alopecia, pernicious anemia, vitiligo, autoimmune hypopituatarism, Guillain-Barre syndrome, glomerulonephritis, serum sickness, uticaria, allergic diseases, asthma, hayfever, allergic rhinitis, scleracielma, mycosis fungoides, dermatomyositis, alopecia areata, chronic actinic dermatitis, eczema, Behcet's disease, Pustulosis palmoplanteris, Pyoderma gangrenum, Sezary's syndrome, atopic dermatitis, systemic schlerosis, morphea, atopic dermatitis, colon carcinoma or thymoma in a mammal comprising administering a therapeutically-effective amount a compound as described above.
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Page/Page column 84

(2010/02/11)

Synthesis and evaluation of cyclic secondary amine substituted phenyl and benzyl nitrofuranyl amides as novel antituberculosis agents
In an ongoing effort to develop new and potent antituberculosis agents, a second-generation series of nitrofuranyl amides was synthesized on the basis of the lead compound 5-nitrofuran-2-carboxylic acid 3,4-dimethoxybenzylamide. The primary design consideration was to improve the solubility and consequently the bioavailability of the series by the addition of hydrophilic rings to the benzyl and phenyl B ring core. The synthesis of 27 cyclic, secondary amine substituted phenyl and benzyl nitrofuranyl amides is described and their activity against Mycobacterium tuberculosis reported. The series showed a strong structure-activity relationship as the benzyl nitrofuranyl amides were significantly more active than similarly substituted phenyl nitrofuranyl amides. Para-substituted benzyl piperazines showed the most antituberculosis activity. Compounds in the series were subsequently selected for bioavailability and in vivo testing. This study led to the successful discovery of novel compounds with increased antituberculosis activity in vitro and a better understanding of the requisite pharmacological properties to advance this class.
Tangallapally, Rajendra P.,Yendapally, Raghunandan,Lee, Robin E.,Lenaerts, Anne J. M.,Lee, Richard E.
p. 8261 - 8269
(2007/10/03)

Compounds and compositions as inhibitors of receptor tyrosine kinase activity
The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with cSRC, Lck, FGFR3, Flt3, TrkB, Bmx, and/or PFGFRα kinase
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Page/Page column 12

(2010/02/11)

PHENYL-[4-(3-PHENYL-1H-PYRAZOL-4-YL)-PYRIMIDIN-2-Yl)-AMINE DERIVATIVES
The invention relates to phenyl-[4-(3-phenyl-1H-pyrazol-4-yl)-pyrimidin-2-yl)-amine derivatives and to processes for the preparation thereof, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives - alone or in combination with one or more other pharmaceutically active compounds - for the preparation of pharmaceutical compositions for the treatment especially of a proliferative disease, such as a tumour.
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Page 46

(2010/11/30)

1, 3, 4-BENZOTRIAZEPIN-2-ONE SALTS AND THEIR USE AS CCK RECEPTOR LIGANDS
This invention relates to pharmaceutically acceptable salts of compounds of formula (I) wherein: W is N or N+-O-; R2 is an optionally substituted C1 to C18 hydrocarbyl group wherein up to three C atoms may optionally be replaced by N, O and/or S atoms. R3 is -(CR11R12)m-X-(CR13R14)p-R9; m is 0, 1, 2, 3 or 4; p is 0, 1 or 2; X is a bond, -CR15=CR16-, -C≡C-, C(O)NH, NHC(O), C(O)NMe, NMeC(O), C(O)O, NHC(O)NH, NHC(O)O, OC(O)NH, NH, O, CO, SO2, SO2NH, C(O)NHNH, R9 is H ; C1 to C6 alkyl ; or phenyl, naphthyl, pyridyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolinyl, isoindolinyl, indolyl, isoindolyl or 2-pyridonyl substituted with -L-Q. R4 is an optionally substituted C1 to C18 hydrocarbyl group wherein up to three C atoms may optionally be replaced by N, O and/or S atoms ; and Such salts are useful, for example, for the treatment of gastrin related disorders.
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Page 95

(2008/06/13)

HAIR DYES COMPRISING M-PHENYLENEDIAMINE DERIVATIVES AS COUPLING COMPONENTS
The invention relates to agents for dyeing keratin fibers, especially human hair, containing at least one m-phenylenediamine derivative of formula (I) or one of the physiologically acceptable salts thereof as a coupling component in a cosmetically accepta
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Page/Page column 43

(2010/02/06)

Substituted amine derivatives and methods of use
Selected amines are effective for prophylaxis and treatment of diseases, such as angiogenesis mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
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(2008/06/13)

Substituted alkylamine derivatives and methods of use
Selected heterocyclic compounds are effective for prophylaxis and treatment of diseases, such as angiogenesis mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
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(2008/06/13)

Substituted alkylamine derivatives and methods of use
Selected amines are effective for prophylaxis and treatment of diseases, such as angiogenesis mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
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Page 81; 123

(2010/02/05)

PYRROLO-TRIAZINE ANILINE COMPOUNDS USEFUL AS KINASE INHIBITORS
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Page/Page column 84-85

(2008/06/13)

Structure-affinity relationships of a unique nicotinic ligand: N1-dimethyl-N4-phenylpiperazinium iodide (DMPP)
DMPP is a well-known nicotinic agonist that does not fit any proposed pharmacophore for nicotinic binding and represents a unique ligand among the hundreds of nicotinic agonists studied in the past decades. A systematic modulation of the chemical structure of DMPP, aimed to establish its structure-affinity relationships, is reported. The research has allowed to identify molecules such as 11c, 13c, 14c, and 28c, with affinities for α4β2 receptors in the low nanomolar range, some 2 orders of magnitude lower than the lead compound. The agonistic properties of the most interesting compounds have been assessed by measuring their analgesic activity on mice (hot-plate test). Another result of the research was the identification of DMPP analogues, such as 3a (Ki = 90 nM) and 14b (Ki = 180 nM), that maintain affinity for the central nicotinic receptor when the ammonium function is changed into an aminic one and are therefore possible leads for drug development in neurodegenerative diseases.
Romanelli,Manetti,Scapecchi,Borea,Dei,Bartolini,Ghelardini,Gualtieri,Guandalini,Varani
p. 3946 - 3955
(2007/10/03)

Benzodiazepine derivatives
Compounds of Formula (I), and salts and prodrugs thereof, wherein R1 represents H, optionally substituted C1-6 alkyl or C3-7 cycloalkyl; R2 is NHR12 or (CH2)s R13 where 5 is 0, 1 or 2; R3 represents C1-6 alkyl, halo or NR6 R7 ; R4 and R5 are H, C1-12 alkyl optionally substituted by NR9 R9' or an azacyclic or azabicyclic group, optionally substituted C4-9 cycloalkyl, C4-9 cycloalkyl C1-4 alkyl, aryl, arylC1-6 alkyl or azacyclic or azabicyclic groups, or R4 and R5 together form the residue of an optionally substituted azacyclic or azabicyclic ring system; x is 0, 1, 2 or 3; R12 is optionally substituted phenyl or pyridyl; R13 represents a group (A) wherein R14 is H or C1-6 alkyl; R15 is H, C1-6 alkyl, halo or NR6 R7 ; and the dotted line is an optional covalent bond; are CCK and/or gastrin antagonists useful in therapy. STR1
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(2008/06/13)