- Preparation method of PF-06651600 intermediate
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The invention relates to a preparation method of a PF-06651600 intermediate, and belongs to the field of medicinal chemistry. According to the method, 3-amino-6-methylpyridine can be used as a raw material, and a target compound is obtained through amino protection, quaternization, reduction, ketone formation, imine formation, reduction and amino protection. The method has the advantages of mild conditions, readily available reagents, high product purity, high yield and safe operation, and can be used for industrial production.
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Paragraph 0052-0054
(2021/02/10)
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- Preparation method of key intermediate of JAK3 enzyme inhibitor
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The invention relates to a preparation method of a key intermediate ((3R,6S)-1-benzyl-6-methyl piperidine-3-amine) of a JAK3 enzyme inhibitor, and particularly relates to a method for preparing the required intermediate by taking 6-methyl piperidine-3-amine as an initial raw material through Boc protection, catalytic hydrogenation, benzyl protection, trifluoroacetic acid Boc de-protection, salt forming and splitting, and dissociation. The salt forming and splitting method comprises the following steps: mixing a racemic mixture containing a compound enantiomer with a structure shown in the formula with a splitting reagent with definite stereo-specificity in a solvent to form a solution, wherein the splitting agent is capable of binding at least one but not all of said enantiomers to form a precipitate containing the at least one the stereo-specific form of enantiomers; and collecting and purifying the precipitate , or collecting a solution containing other enantiomers and recrystallizing the enantiomers contained in the solution. The preparation method has the advantages of cheap and easily available raw materials, mild reaction conditions, high reaction controllability and good industrial application prospect.
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Paragraph 0017-0018
(2021/07/17)
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- PYRROLO[2,3-D]PYRIMIDINE TOSYLATE SALT, CRYSTALLINE FORM THEREOF AND MANUFACTURING PROCESS AND INTERMEDIATES THERETO
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The present invention discloses a novel p-toluenesulfonic acid salt and a crystalline polymorphic Form 1 of said salt of 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one, pharmaceutical composition containing the same, as well as preparations and uses thereof. The present invention also discloses a novel phosphoric acid salt of 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one, pharma-ceutical composition containing the same, as well as preparations and uses thereof.
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Page/Page column 16-17
(2020/05/29)
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- PYRROLO [2,3-d] PYRIMIDINE TOSYLATE, CRYSTALLINE FORMS THEREOF, AND PREPARATION METHOD AND INTERMEDIATE THEREOF
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PROBLEM TO BE SOLVED: To provide a drug molecule in a novel or purer polymorphic form. SOLUTION: In the present invention, disclosed is a novel p-toluenesulfonate of 1-((2S,5R)-5-((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino)-2-methyl piperidin-1-yl) prop-2-en-1-one and a crystalline polymorphic form 1 thereof, a pharmaceutical composition comprising the same, and their preparation and use. In the present invention, also disclosed is a novel phosphate of 1-((2S,5R)-5-((7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino)-2-methyl piperidin-1-yl) prop-2-en-1-one, a pharmaceutical composition comprising the same, and their preparation and use. SELECTED DRAWING: Figure 1 COPYRIGHT: (C)2020,JPOandINPIT
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Paragraph 0052; 0053; 0056
(2020/05/29)
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- Process Development and Scale up of a Selective JAK3 Covalent Inhibitor PF-06651600
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A scalable process for PF-06651600 (1) has been developed through successful enabling of the first generation syntheis. The synthesis highlights include the following: (1) replacement of costly PtO2 with a less expensive 5% Rh/C catalyst for a pyridine hydrogenation, (2) identification of a diasteroemeric salt crystallization to isolate the enantiomerically pure cis-isomer directly from a racemic mixture of cis/trans isomers, (3) a high yielding amidation via Schotten-Baumann conditions, and (4) critical development of a reproducible crystallization procedure for a stable crystalline salt (1·TsOH), which is suitable for long-term storage and tablet formulation. All chromatographic purifications, including two chiral SFC chromatographic separations, were eliminated. Combined with other improvements in each step of the synthesis, the overall yield was increased from 5% to 14%. Several multikilogram batches of the API have been delivered to support clinical studies.
- Tao, Yong,McWilliams, J. Christopher,Wiglesworth, Kristin E.,Girard, Kevin P.,Makowski, Teresa M.,Sach, Neal W.,Mustakis, Jason G.,Mehta, Ruchi,Trujillo, John I.,Chen, Xiaofeng,Li, Tangqing,Shi, Feng,Xie, Chengfu,Zhang, Qing
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p. 1872 - 1880
(2019/08/20)
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- Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans
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Significant work has been dedicated to the discovery of JAK kinase inhibitors resulting in several compounds entering clinical development and two FDA approved NMEs. However, despite significant effort during the past 2 decades, identification of highly s
- Thorarensen, Atli,Dowty, Martin E.,Banker, Mary Ellen,Juba, Brian,Jussif, Jason,Lin, Tsung,Vincent, Fabien,Czerwinski, Robert M.,Casimiro-Garcia, Agustin,Unwalla, Ray,Trujillo, John I.,Liang, Sidney,Balbo, Paul,Che, Ye,Gilbert, Adam M.,Brown, Matthew F.,Hayward, Matthew,Montgomery, Justin,Leung, Louis,Yang, Xin,Soucy, Sarah,Hegen, Martin,Coe, Jotham,Langille, Jonathan,Vajdos, Felix,Chrencik, Jill,Telliez, Jean-Baptiste
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p. 1971 - 1993
(2017/03/20)
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- INHIBITORS OF BRUTON'S TYROSINE KINASE
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Disclosed herein are reversible and irreversible inhibitors of Bruton's tyrosine kinase (Btk). Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are describeded, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.
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Paragraph 001090
(2016/12/22)
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- Discovery of imidazopyridazines as potent Pim-1/2 kinase inhibitors
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High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers, suggesting that inhibition of Pim signaling could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal using a screening hit (rac-1) as a starting point. Modification of the indazole ring resulted in the discovery of a series of imidazopyridazine-based Pim inhibitors exemplified by compound 22m, which was found to be a subnanomolar inhibitor of the Pim-1 and Pim-2 isoforms (IC50values of 0.024?nM and 0.095?nM, respectively) and to potently inhibit the phosphorylation of BAD in a cell line that expresses high levels of all Pim isoforms, KMS-12-BM (IC50?=?28?nM). Profiling of Pim-1 and Pim-2 expression levels in a panel of multiple myeloma cell lines and correlation of these data with the potency of compound 22m in a proliferation assay suggests that Pim-2 inhibition would be advantageous for this indication.
- Wurz, Ryan P.,Sastri, Christine,D'Amico, Derin C.,Herberich, Brad,Jackson, Claire L.M.,Pettus, Liping H.,Tasker, Andrew S.,Wu, Bin,Guerrero, Nadia,Lipford, J. Russell,Winston, Jeffrey T.,Yang, Yajing,Wang, Paul,Nguyen, Yen,Andrews, Kristin L.,Huang, Xin,Lee, Matthew R.,Mohr, Christopher,Zhang,Reid, Darren L.,Xu, Yang,Zhou, Yihong,Wang, Hui-Ling
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p. 5580 - 5590
(2016/11/09)
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- PYRROLO[2,3-D]PYRIMIDINYL, PYRROLO[2,3-B]PYRAZINYL AND PYR-ROLO[2,3-D]PYRIDINYL ACRYLAMIDES
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The present invention provides pharmaceutically active pyrrolo[2,3-d]pyrimidinyl and pyrrolo[2,3-d]pyridinyl acrylamides and analogues thereof. Such compounds are useful for inhibiting Janus Kinase (JAK). This invention also is directed to compositions comprising methods for making such compounds, and methods for treating and preventing conditions mediated by JAK.
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Paragraph 0270
(2015/06/17)
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- HETEROCYCLIC TYROSINE KINASE INHIBITORS
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The present invention provides compounds useful as inhibitors of Tec family kinases, compositions thereof, and methods of using the same. In certain embodiments, the present invention provides pharmaceutical formulations comprising provided compounds. In certain embodiments, the present invention provides a method of decreasing enzymatic activity of a Tec kinase family member. In some embodiments, such methods include contacting a Tec kinase family member with an effective amount of a Tec kinase family member inhibitor. In certain embodiments, the present invention provides a method of treating a disorder responsive to Tec kinase family inhibition in a subject in need thereof.
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Page/Page column 165-166
(2012/05/19)
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- BICYCLIC PYRIDAZINE COMPOUNDS AS PIM INHIBITORS
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The invention relates to bicyclic compounds of formulas I and I', and salts thereof. In some embodiments, the invention relates to inhibitors or modulators of Pim-1 and/or Pim-2, and/or Pim-3 protein kinase activity or enzyme function. In still further embodiments, the invention relates to pharmaceutical compositions comprising compounds disclosed herein, and their use in the prevention and treatment of Pim kinase related conditions and diseases, preferably cancer.
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Page/Page column 113; 114
(2012/11/13)
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- N -pyridyl and pyrimidine benzamides as KCNQ2/Q3 potassium channel openers for the treatment of epilepsy
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A series of N-pyridyl benzamide KCNQ2/Q3 potassium channel openers were identified and found to be active in animal models of epilepsy and pain. The best compound 12 [ICA-027243, N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzamide] has an EC50 of 0.38 μM and is selective for KCNQ2/Q3 channels. This compound was active in several rodent models of epilepsy and pain but upon repeated dosing had a number of unacceptable toxicities that prevented further development. On the basis of the structure-activity relationships developed around 12, a second compound, 51, [N-(2-chloro-pyrimidin-5-yl)-3,4-difluoro- benzamide, ICA-069673], was prepared and advanced into a phase 1 clinical study. Herein, we describe the structure-activity relationships that led to the identification of compound 12 and to the corresponding pyrimidine 51.
- Amato, George,Roeloffs, Rosemarie,Rigdon, Greg C.,Antonio, Brett,Mersch, Theresa,McNaughton-Smith, Grant,Wickenden, Alan D.,Fritch, Paul,Suto, Mark J.
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supporting information; experimental part
p. 481 - 484
(2011/08/22)
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- Pd-catalyzed amidation of aryl(Het) halides with tert-butyl carbamate
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Pd-catalyzed cross-coupling reaction of tert-butyl carbamate with various aryl(Het) halides with Cs2CO3 as base in 1,4-dioxane as solvent was investigated, which resulted in the formation of the desired compounds in moderate to excellent yields.
- Qin, Lijin,Cui, Hongmeng,Zou, Dapeng,Li, Jingya,Wu, Yangjie,Zhu, Zhiwu,Wu, Yusheng
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experimental part
p. 4445 - 4448
(2010/09/12)
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- 6 SUBSTITUTED 2-HETEROCYCLYLAMINO PYRAZINE COMPOUNDS AS CHK-1 INHIBITORS
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The present invention is directed to compounds of formula (I), and pharmaceutically acceptable salts thereof, their synthesis, and their use as CHK-1 inhibitors.
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Page/Page column 135-136
(2010/04/03)
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- PYRAZOLE DERIVATIVE
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A compound represented by Formula (I): wherein Ar1 represents Formula (II): Ar2 represents a 5- or 6-membered aromatic heterocyclic group which may be substituted; and X represents Formula (III): a salt thereof, or a solvate of the compound or the salt. A potent platelet aggregation suppressant which does not inhibit COX-1 and COX-2 is provided.
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Page/Page column 29-30
(2010/11/27)
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- AMIDOPYRAZOLE DERIVATIVE
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A platelet coagulation inhibitor which inhibits neither COX-1 nor COX-2 is provided. The inhibitor is a compound represented by general formula (I): wherein Ar1 and Ar2 independently represent a 5- or 6-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents, or a phenyl group optionally substituted with 1 to 3 substituents; R1 represents a lower acyl group, carboxyl group, a lower alkoxycarbonyl group, a lower alkoxy group, a lower alkyl group optionally substituted with 1 or 2 substituents, a carbamoyl group optionally substituted with 1 or 2 substituents, an oxamoyl group optionally substituted with 1 or 2 substituents, an amino group optionally substituted with 1 or 2 substituents, a 4- to 7-membered alicyclic heterocyclic group optionally substituted with 1 or 2 substituents, a phenyl group optionally substituted with 1 to 3 substituents, or a 5- or 6-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents; and R2 represents hydrogen atom, a halogeno group, or the like.
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Page/Page column 46
(2010/11/23)
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- Analysis of structure-activity relationships for the 'A-region' of N-(4-t-butylbenzyl)-N′-[4-(methylsulfonylamino)benzyl]thiourea analogues as TRPV1 antagonists
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The structure-activity relationships for the 'A-region' of N-(4-t-butylbenzyl)-N′-[4-(methylsulfonylamino)benzyl]thiourea analogues have been investigated as TRPV1 receptor antagonists. The 2-halogen analogues showed enhanced antagonism compared to the prototype antagonist.
- Lee, Jeewoo,Kang, Sang-Uk,Kil, Min-Jung,Shin, Myoungyoup,Lim, Ju-Ok,Choi, Hyun-Kyung,Jin, Mi-Kyoung,Kim, Su Yeon,Kim, Sung-Eun,Lee, Yong-Sil,Min, Kyung-Hoon,Kim, Young-Ho,Ha, Hee-Jin,Tran, Richard,Welter, Jacqueline D.,Wang, Yun,Szabo, Tamas,Pearce, Larry V.,Lundberg, Daniel J.,Toth, Attila,Pavlyukovets, Vladimir A.,Morgan, Matthew A.,Blumberg, Peter M.
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p. 4136 - 4142
(2007/10/03)
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- A potent, long-acting, orally active (2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide: A novel muscarinic M3 receptor antagonist with high selectivity for M3 over M2 receptors
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A novel series of (2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamides was designed and synthesized based on the structure and biological profiles of an active metabolite 2 of our prototype muscarinic M3 receptor selective antagon
- Mitsuya,Kobayashi,Kawakami,Satoh,Ogino,Kakikawa,Ohtake,Kimura,Hirose,Sato,Numazawa,Hasegawa,Noguchi,Mase
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p. 5017 - 5029
(2007/10/03)
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