cas 50-35-1, Thalidomide | Articles data

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A Metal-Organic Framework (MOF)-Based Multifunctional Cargo Vehicle for Reactive-Gas Delivery and Catalysis
The efficient delivery of reactive and toxic gaseous reagents to organic reactions was studied using metal-organic frameworks (MOFs). The simultaneous cargo vehicle and catalytic capabilities of several MOFs were probed for the first time using the examples of aromatization, aminocarbonylation, and carbonylative Suzuki–Miyaura coupling reactions. These reactions highlight that MOFs can serve a dual role as a gas cargo vehicle and a catalyst, leading to product formation with yields similar to reactions employing pure gases. Furthermore, the MOFs can be recycled without sacrificing product yield, while simultaneously maintaining crystallinity. The reported findings were supported crystallographically and spectroscopically (e.g., diffuse reflectance infrared Fourier transform spectroscopy), foreshadowing a pathway for the development of multifunctional MOF-based reagent-catalyst cargo vessels for reactive gas reagents as an attractive alternative to the use of toxic pure gases or gas generators.
Chen, Donna A.,Corkill, Ryan E.,Garashchuk, Sophya,Jayaweera, H. D. A. Chathumal,Karakalos, Stavros G.,Kittikhunnatham, Preecha,Lauterbach, Jochen,Leith, Gabrielle A.,Martin, Corey R.,Mathur, Abhijai,McCullough, Katherine,Naglic, Jennifer K.,Park, Kyoung Chul,Shustova, Natalia B.,Smith, Mark D.
(2022/02/01)

Discovery of triazolyl thalidomide derivatives as anti-fibrosis agents
Fibrosis with excessive accumulation of extracellular matrix (ECM) often causes progressive organ dysfunction and results in many inflammatory and metabolic diseases, including systemic sclerosis, pulmonary fibrosis, advanced liver disease and advanced kidney disease. The store-operated calcium entry (SOCE) pathway and the related signaling pathway were both found to be the important routes for fibrogenesis. Our aim in this study was to discover novel compounds to inhibit fibrogenesis. A number of triazolyl thalidomide derivatives were synthesized and evaluated for their anti-fibrosis activities. Compounds 7b-e, 8c-d, 10a-b and 10e inhibited intracellular Ca2+ activation and showed no cytotoxicity. Among them, 6-{4-[(3-(1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}hexanoic acid (10e) with the most potent inhibitory effect was chosen for further examination. The results revealed that compound 10e, a SOCE inhibitor, reversed the migratory ability of TGF-β1-induced myofibroblasts, dedifferentiated myofibroblasts to fibroblasts due to cytoskeleton remodeling, and restrained myofibroblast activation by targeting Orai1 and TGF-β1/SMAD2/3 signaling pathways. The in silico study indicated that compound 10e, with the appropriate lipophilic carbon chain and carboxylic acid, showed a good drug-likeness model score. Conclusively, the SOCE inhibitor, compound 10e, is used as a promising lead compound for the development of a new treatment for fibrosis. This journal is
Tang, Kai-Wei,Hsu, Wen-Li,Chen, Cheng-Ru,Tsai, Ming-Hsien,Yen, Chia-Jung,Tseng, Chih-Hua
p. 3589 - 3599
(2021/03/03)

Facile Synthesis of Thalidomide
We report a simple and facile procedure for the preparation of thalidomide in two steps with a high overall yield (56%). The preparation was composed of a reaction between anhydride phthalic and l-glutamic acid to form N-phthaloyl-dl-glutamic acid (IV), and a cyclization step using IV reacted with ammonium acetate in diphenyl ether to create thalidomide. Reaction parameters reaction time, temperature, solvent, and molar ratio of reagents in the procedure are optimized so that the reaction performance is highest while ensuring environmental friendliness. Moreover, this process has great potential for the industrial scale of thalidomide. These compounds were identified through IR, MS, 1H NMR, and 13C NMR.
Vu, Binh Duong,Ho Ba, Ngoc Minh,Phan, Dinh Chau
supporting information
p. 1374 - 1377
(2019/08/12)

Synthesis method of thalidomide
The invention relates to an industrial synthesis method of thalidomide, and specifically discloses a method, which comprises: directly synthesizing a crude product thalidomide by using phthalic anhydride and L-glutamic acid as raw materials through a two-step reaction one-pot method, and then carrying out refining purifying to obtain a finished product. According to the present invention, thalidomide is synthesized by using the two-step reaction one-pot method, microwave heating and other special equipment are not required, and the synthesis of the thalidomide anhydride intermediate is not required, such that the intermediate reaction process is eliminated, the use of acetic anhydride is avoided, the operation is simplified, the labor intensity is reduced, the production efficiency is improved, the environmental protection is achieved, and the method has high economic and social value.
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Paragraph 0078-0091

(2019/08/01)

IMIDE-BASED MODULATORS OF PROTEOLYSIS AND METHODS OF USE
The description relates to imide-based compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.
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Page/Page column 224; 225

(2019/08/12)

Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships
The immunomodulatory drugs (IMiDs) thalidomide, pomalidomide, and lenalidomide have been approved for the treatment of multiple myeloma for many years. Recently, their use as E3 ligase recruiting elements for small-molecule-induced protein degradation has led to a resurgence in interest in IMiD synthesis and functionalization. Traditional IMiD synthesis follows a stepwise route with multiple purification steps. Herein we describe a novel one-pot synthesis without purification that provides rapid access to a multitude of IMiD analogues. Binding studies with the IMiD target protein cereblon (CRBN) reveals a narrow structure–activity relationship with only a few compounds showing sub-micromolar binding affinity in the range of pomalidomide and lenalidomide. However, anti-proliferative activity as well as Aiolos degradation could be identified for two IMiD analogues. This study provides useful insight into the structure–degradation relationships for molecules of this type as well as a rapid and robust method for IMiD synthesis.
Burslem, George M.,Ottis, Philipp,Jaime-Figueroa, Saul,Morgan, Alicia,Cromm, Philipp M.,Toure, Momar,Crews, Craig M.
p. 1508 - 1512
(2018/07/31)

Homo-PROTACs for the Chemical Knockdown of Cereblon
The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide, all approved for the treatment of multiple myeloma, induce targeted ubiquitination and degradation of Ikaros (IKZF1) and Aiolos (IKZF3) via the cereblon (CRBN) E3 ubiquitin ligase. IMiD-based proteolysis-targeting chimeras (PROTACs) can efficiently recruit CRBN to a protein of interest, leading to its ubiquitination and proteasomal degradation. By linking two pomalidomide molecules, we designed homobifunctional, so-called homo-PROTACs and investigated their ability to induce self-directed ubiquitination and degradation. The homodimerized compound 15a was characterized as a highly potent and efficient CRBN degrader with only minimal effects on IKZF1 and IKZF3. The cellular selectivity of 15a for CRBN degradation was confirmed at the proteome level by quantitative mass spectrometry. Inactivation by compound 15a did not affect proliferation of different cell lines, prevented pomalidomide-induced degradation of IKZF1 and IKZF3, and antagonized the effects of pomalidomide on multiple myeloma cells. Homobifunctional CRBN degraders will be useful tools for future biomedical investigations of CRBN-related signaling and may help to further elucidate the molecular mechanism of thalidomide analogues.
Steinebach, Christian,Lindner, Stefanie,Udeshi, Namrata D.,Mani, Deepak C.,Kehm, Hannes,K?pff, Simon,Carr, Steven A.,Gütschow, Michael,Kr?nke, Jan
p. 2771 - 2782
(2018/09/25)

Synthesis and biological evaluation of thalidomide derivatives as potential anti-psoriasis agents
Several thalidomide derivatives were synthesized and evaluated for their anti-inflammatory activity. Introduction of the benzyl group to the parent thalidomide is unfavorable in which 2-(1-benzyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (4a) was inactivated. However, the inhibitory activities on TNF-α and IL-6 expression in HaCaT cells were improved by the substitution of a chloro-or methoxy-group at the phenyl position of 4a. The IL-6 inhibitory activity decreased in an order of 5c (69.44%) > 4c (48.73%) > 6c (3.19%) indicating the 3-substituted derivative is more active than the 4-substituted counterpart, which in turn is more active than the 2-substituted counterpart. Among them, 2-[1-(3-chlorobenzyl)-2,6-dioxopiperidin-3-yl]isoindoline-1,3-dione (5c) was found to inhibit TNF-α and IL-6 expression in HaCaT cells with a higher potency than thalidomide and no significant cell cytotoxicity was detected at 10 μM. In psoriasis, Compound 5c reduced IL-6, IL-8, IL-1β and IL-24 in imiquimod-stimulated models. Our results indicated that compound 5c is a potential lead of novel anti-psoriasis agents. Structural optimization of compound 5c and its in vivo assay are ongoing.
Tang, Kai-Wei,Tseng, Chih-Hua,Lin, Zih-Chan,Fang, Jia-You,Chen, Yeh-Long,Tzeng, Cherng-Chyi
(2018/12/02)

REGULATING CHIMERIC ANTIGEN RECEPTORS
This invention is in the area of compositions and methods for regulating chimeric antigen receptor immune effector cell, for example T-cell (CAR-T), therapy to modulate associated adverse inflammatory responses, for example, cytokine release syndrome and tumor lysis syndrome, using targeted protein degradation.
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Page/Page column 297; 298; 299

(2018/09/08)

TUNABLE ENDOGENOUS PROTEIN DEGRADATION WITH HETEROBIFUNCTIONAL COMPOUNDS
The present invention provides a means to modulate gene expression in vivo in a manner that avoids problems associated with CRISPR endogenous protein knock-out or knock-in strategies and strategies that provide for correction, or alteration, of single nucleotides. The invention includes inserting into the genome a nucleotide encoding a heterobifunctional compound targeting protein (dTAG) in-frame with the nucleotide sequence of a gene encoding an endogenously expressed protein of interest which, upon expression, produces an endogenous protein-dTAG hybrid protein. This allows for targeted protein degradation of the dTAG and the fused endogenous protein using a heterobifunctional compound.
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Page/Page column 278-279; 280

(2018/09/08)

A Novel Green Synthesis of Thalidomide and Analogs
Thalidomide and its derivatives are currently under investigation for their antiangiogenic, immunomodulative, and anticancer properties. Current methods used to synthesize these compounds involve multiple steps and extensive workup procedures. Described herein is an efficient microwave irradiation green synthesis method that allows preparation of thalidomide and its analogs in a one-pot multicomponent synthesis system. The multicomponent synthesis system developed involves an array of cyclic anhydrides, glutamic acid, and ammonium chloride in the presence of catalytic amounts of 4-N,N-dimethylaminopyridine (DMAP) to produce thalidomide and structurally related compounds within minutes in good isolated yields.
Benjamin, Ellis,Hijji, Yousef M.
(2017/09/19)

AN IMPROVED PROCESS FOR THE PREPARATION OF THALIDOMIDE
The present invention relates to an improved process for the preparation of thalidomide with high purity and high yield. The present invention also related to preparation thalidomide polymorphic α-form by direct crystallization.
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Page/Page column 7;8;9;10

(2017/07/01)

Thalidomide analogues: Tumor necrosis factor-alpha inhibitors and their evaluation as anti-inflammatory agents
A series of related thalidomide derivatives (2-9) were synthesized by microwave irradiation and evaluated for anti-inflammatory activity. Such activity was assessed in vivo and ex vivo. Compounds 2, 8 and 9 showed the highest levels of inhibition of TNF-α production. On rat paw edema and hyperalgesia assays, compound 9, (1,4-phthalazinedione) demonstrated the highest in vivo anti-inflammatory activity. Thus, compound 9 can be considered as a promising compound to be subjected to further modification to obtain new agents for the treatment of inflammatory diseases.
Casal, Juan José,Bollini, Mariela,Lombardo, María Elisa,Bruno, Ana María
p. 114 - 119
(2016/01/09)

IMPROVED PROCESS FOR THE PREPARATION OF POMALIDOMIDE AND ITS PURIFICATION
Methods of synthesizing pomalidomide are disclosed. Further, methods of purifying pomalidomide from a reaction mixture are also disclosed.
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Page/Page column 8; 9

(2015/06/08)

Efficient palladium-catalyzed double carbonylation of o-dibromobenzenes: Synthesis of thalidomide
We describe here a convenient and mild procedure for double carbonylation of o-dibromobenzenes with various 2-amino pyridines and naturally occurring amines, thus providing in good to excellent yields N-substituted phthalimides by using this palladium-catalyzed carbonylation procedure. Furthermore, for the first time we have applied the developed synthetic protocol for the synthesis of biologically active molecule thalidomide via a single step carbonylative cyclization reaction in excellent yield. the Partner Organisations 2014.
Chen, Jianbin,Natte, Kishore,Spannenberg, Anke,Neumann, Helfried,Beller, Matthias,Wu, Xiao-Feng
supporting information
p. 5578 - 5581
(2014/07/22)

THERAPEUTIC FOR HEPATIC CANCER
A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.
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(2011/02/18)

Radiosynthesis of 13N-labeled thalidomide using no-carrier-added [13N]NH3
Recent studies revealed that thalidomide (1) has unique and broad pharmacological effects on multi-targets although the application of 1 in therapy is still controversial. In this study, we synthesized nitrogen-13-labeled thalidomide ([13N]1) as a potential positron emission tomography (PET) probe using no-carrier-added [13N]NH 3 as a labeling agent. By use of an automated system, [ 13N]1 was prepared by reacting N-phthaloylglutamic anhydride (2) with [13N]NH3, following by cyclization with carbonyldiimidazole in a radiochemical yield of 56±12% (based on [ 11N]NH3, corrected for decay) and specific activity of 49±24GBq/μmol at the end of synthesis (EOS). At EOS, 570-780MBq (n=7) of [13N]1 was obtained at a beam current of 15 μA after 15 min proton bombardment with a synthesis time of 14 min from the end of bombardment. Using a small animal PET scanner, preliminary biodistribution of [ 13N]1 in mice was examined. Copyright
Kumata, Katsushi,Takei, Makoto,Ogawa, Masanao,Yui, Joji,Hatori, Akiko,Suzuki, Kazutoshi,Zhang, Ming-Rong
experimental part
p. 53 - 57
(2010/09/14)

Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same
Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.
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(2010/05/13)

Thalidomide metabolites and methods of use
The present invention concerns certain hydrolytic thalidomide metabolites, combinations thereof with other anti-neoplastic compounds and their use in the treatment of solid tumours.
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Page/Page column 3-5; sheet 8

(2008/12/06)

Method for the preparation of dicarboxylic imides
The present invention relates to a method for the preparation of a carboxylic imide having the general formula [in-line-formulae]R1—(CO)—(NR3)—(CO)—R2 , ??(I)[/in-line-formulae] wherein a carboxylic anhydride having the general formula [in-line-formulae]R1—(CO)—O—(CO)—R2 ??(II)[/in-line-formulae] is reacted with urea or a urea derivative of the form (R3HN)—(CO)—(NR3H) in a solvent. In particular, the method can be used for the preparation of thalidomide.
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Page/Page column 3

(2008/06/13)

Synthesis and TNF expression inhibitory properties of new thalidomide analogues derived via Heck cross coupling
A library of new thalidomide analogues containing an olefin functionality were synthesised using a Heck cross coupling reaction from their aryl halogenated precursor. All analogues were tested for their ability to inhibit the synthesis of the proinflammatory cytokine Tumour Necrosis Factor (TNF). Compounds 22, 29, 33 and 37 were the most effective in this assay inhibiting TNF expression 50%, 69%, 52% and 50%, respectively. Crown Copyright
Stewart, Scott G.,Spagnolo, Daniel,Polomska, Marta E.,Sin, Melvin,Karimi, Mahdad,Abraham, Lawrence J.
p. 5819 - 5824
(2008/03/13)

Process for the synthesis of thalidomide
The invention relates to a process for the preparation of thalidomide (I) ???comprising the reaction between glutamine (II) ???and a phthaloylating agent, preferably phthalic anhydride, to give N-phthaloyl-glutamine, which is directly transformed in thalidomide.
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Page/Page column 5/7

(2008/06/13)

Process for the synthesis of thalidomide
The invention relates to a process for the preparation of thalidomide (I) comprising the reaction between glutamine (II) and a phthaloylating agent, preferably phthalic anhydride, to give N-phthaloyl-glutamine, which is directly transformed in thalidomide.
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Page/Page column 3

(2008/06/13)

THALIDOMIDE ANALOGS
Thalidomide analogs that modulate tumor necrosis factor alpha (TNF-α) activity and angiogenesis are disclosed. In particularly disclosed embodiments, the thalidomide analogs are isosteric sulfur-containing analogs. Also disclosed are methods of treating a subject with the analogs.
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Page/Page column 31; 54

(2008/06/13)

A synthesis of racemic thalidomide
A synthesis of racemic thalidomide is described using formal [3+3] cycloaddition strategy as the key step. The total yield of thalidomide was 30% in three steps from ester 2.
Chang, Meng-Yang,Chen, Shui-Tein,Chang, Nein-Chen
p. 1375 - 1382
(2007/10/03)

Solid phase synthesis of 3-toluenesulfonylglutarimides
A novel route for the synthesis of 3-toluenesulfonylglutarimides on a solid support is described. The cyclization step involves stepwise [3+3] strategy of Rink Amide resin bound onto an α-toluenesulfonyl group with various α,β-unsaturated esters.
Chang, Meng-Yang,Lin, Kuo-Ging,Chen, Shui-Tein,Chang, Nein-Chen
p. 795 - 797
(2007/10/03)

A synthesis of thalidomide
A synthesis of racemic thalidomide (1) was described and the important formal [3+3] cycloaddition strategy was a key step. The total yield of thalidomide (1) was 18% in five steps from known 3.
Chang, Meng-Yang,Chang, Chung-Ho,Chen, Shui-Tein,Chang, Nein-Chen
p. 383 - 385
(2007/10/03)

Physicochemical characterization and solubility analysis of thalidomide and its N-alkyl analogs
Purpose. The present study was primarily aimed at exploring the feasibility of improving percutaneous delivery via chemical manipulation of the thalidomide molecule to form analogs with improved physicochemical properties. N-Alkyl analogs were synthesized with the belief that these would be suitably hydrophobic and far less crystalline than the reference compound. This article presents their physicochemical properties. Methods. Thalidomide and three of its N-alkyl analogs were synthesized. Identification and levels of purity (>96%) were assured through element analysis, fast atom-bombardment mass spectrometry, nuclear magnetic resonance spectroscopy, and high-performance liquid chromatography. N-Octanol/water partition cohigh efficients were determined at pH 6.4. Solubilities in water and a series of n-alkanols were obtained. Best-fit solubility parameters were determined from the solubilities of the respective compounds in London solvents and were also calculated from respective hexane solubilities, melting points and heats of fusion. Results. Methylation of the thalidomide molecule at its acidic nitrogen led to an aqueous solubility about 6-fold higher than thalidomide but, because the alkyl chain length was further extended from methyl to pentyl, aqueous solubilities decreased essentially exponentially. The destabilization of the crystalline structure with increasing alkyl chain length led to an increased solubility in nonpolar media. The log partition coefficient increased linearly with increasing alkyl chain length and the solubility parameters declined systematically through this series. By adding a methyl group to the thalidomide structure, the melting point dropped by more than 100°C. Adding to the alkyl chain length led to further, more modest decreases. Heats of fusion decreased dramatically upon thalidomide's alkylation as well. Conclusion. Alkylation of the thalidomide molecule resulted in compounds with physicochemical properties that appear to be markedly better suited for percutaneous delivery.
Goosen,Laing,Plessis,Goosen,Flynn
p. 13 - 19
(2007/10/03)

Chemical stabilities and biological activities of thalidomide and its N-aikyl analogs
Purpose. To determine whether the N-alkyl analogs of the thalidomide are active and stable, their stabilities in buffer and their abilities to inhibit tumor necrosis factor alpha (TNF-α) in vitro in human peripheral blood mononuclear cell cultures were investigated. Methods. TNF-α concentrations were determined with the aid of ELISA kits. Chemical stabilities of the compounds were determined in three phosphate buffer solutions (pH 6, 6.4, and 7.4) at 25 and 32°C by high-pressure liquid chromatography, and half-lives were calculated. Results. The addition of N-alkyl groups to the glutarimide ring of the thalidomide molecule had little effect on the ability such compounds have to inhibit TNF-α production. There was no statistical difference between the activity of thalidomide and its N-alkyl analogs at a 95% confidence level. Like thalidomide, the N-alkyl analogs in this series inhibit an average of 60% of the TNF-α synthesis in lipopolysaccharide-stimulated peripheral blood mononuclear cell cultures. Thalidomide and its N-alkyl analogs are hydrolyzed at very similar rates, with half-lives ranging from 25 to 35 h at 32°C at pH 6.4 and an average rate constant of 2.35 × 10-2/h. Conclusions. Alkylating thalidomide had little effect on its ability to inhibit the production of TNF-α in these cell cultures. All of the compounds tested seem to have some, perhaps comparable, therapeutic potential.
Goosen, Colleen,Laing, Timothy J.,Du Plessis, Jeanetta,Goosen, Theunis C.,Rao, Tharaknath B.,Flynn, Gordon L.
p. 1232 - 1235
(2007/10/03)

Microwave Promoted Synthesis of a Rehabilitated Drug: Thalidomide
A new direct synthesis of thalidomide in high yield by microwave irradiation of N-phthaloyl-L-glutamic in the presence of thiourea is described. Thalidomide was also obtained in good yield from L-glutamic acid, phthalic anhydride and thiourea in a one-pot procedure.
Seijas, Julio A.,Vazquez-Tato, M. Pilar,Gonzales-Bande, Cristobal,Martinez, M. Montserrat,Pacios-Lopez, Beatriz
p. 999 - 1000
(2007/10/03)

Synthesis and immunological activity of water-soluble thalidomide prodrugs
A series of new water-soluble thalidomide prodrugs was prepared. All compounds were derivatized on the nitrogen of the glutarimide ring. Esters of natural amino acids and succinic acid derivatives have been introduced by reaction with the hydroxymethyl thalidomide 2. Nicotinic acid derivatives were prepared from halomethyl derivatives. Additionally, a methoxymethyl derivative and a carboxymethyl derivative were prepared directly from thalidomide. Most compounds showed a very large increase in water solubility compared to thalidomide itself (0.012 mg/mL). The amorphous hydrochlorides of the N-methylalanine ester 8, valine ester 9, and glycylglycine ester 10, respectively, were the most soluble compounds showing solubility greater than 300 mg/mL, which equals an increase greater than 15,000-fold. The lipophilicity of the prodrugs has been determined by their HPLC capacity factors k′. The stability of selected compounds was determined. The hydrolysis rates follow pseudo-first order kinetics. In order to assess the immunological activity, the prodrugs were tested using tumor necrosis factor-α and interleukin-2 inhibition assays. Selected compounds were additionally investigated on their abililty to inhibit the local Shwartzman reaction, an assay to determine the vascular permeability. The prodrugs retained high effectiveness in the inhibition of TNF-α release. Our results indicated that the more stable prodrugs exhibited higher activity in the immunological assays. Some compounds showed higher activity than thalidomide itself, suggesting a high affine binding to the pharmacophore. In conclusion, the prodrugs exhibited high water solubility and high activity and might therefore be used in therapeutic applications.
Hess, Sonja,Akermann, Michaela A.,Wnendt, Stephan,Zwingenberger, Kai,Eger, Kurt
p. 1279 - 1291
(2007/10/03)

A concise two-step synthesis of thalidomide
A two-step synthesis of thalidomide is presented. The sequence requires no purifications. Treatment of L-glutamine with N-carbethoxyphthalimide produces N-phthaloyl-L-glutamine. Cyclization of N-phthaloyl-L-glutamine to afford thalidomide is accomplished by treatment with CDI in the presence of a catalytic amount of DMAP.
Muller, George W.,Konnecke, William E.,Smith, Alison M.,Khetani, Vikram D.
p. 139 - 140
(2013/09/08)

Imides
Cyclic imides are inhibitors of tumor necrosis factor α and can be used to combat cachexia, endotoxic shock, and retrovirus replication. A typical embodiment is 2-(2,6-dioxo-3-piperidinyl)-4-azaisoindoline-1,3-dione.
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(2008/06/13)

Cyclic amides
Cyclic amides are inhibitors of tumor necrosis factor and can be used to combat cachexia, endotoxic shock, and retrovirus replication. A typical embodiment is 3-phenyl-3-(1-oxoisoindolin-2-yl)propionamide.
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(2008/06/13)

Method of treating abnormal concentrations of TNF α
Compounds of the structure STR1 wherein R is selected from the group consisting of hydrogen, alkyl radicals of 1-6 carbon atoms, the phenyl radical, and the benzyl radical; and wherein R' is selected from the group consisting of the phthalimido radical and the succinimido radical and of the structure STR2 wherein X is CH2 or C=O; R" is H, --CH2 CH3, --C6 H5, --CH2 C6 H5, --CH2 CH=CH2, or STR3 and hydrolysis products of said compounds wherein R" is H and the piperidino ring or both the piperidino and the imido ring are hydrolyzed are useful for the control of abnormal concentrations of TNF α manifested in septic shock, cachexia and HIV infection without substantially effecting the concentration of other cytokines.
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(2008/06/13)

Ring closure of N-phthaloylglutamines
Cyclic imides are inhibitors of tumor necrosis factor α and can be used to combat cachexia, endotoxic shock, and retrovirus replication. A typical embodiment is 2-(2,6-dioxo-3-piperidinyl)-4-azaisoindoline-1,3-dione.
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(2008/06/13)

Comparative teratological investigation of compounds structurally and pharmacologically related to thalidomide
Compounds differing from thalidomide in either the phthalimide or the 2,6-dioxopiperidine moiety of the molecule were synthetized and tested for teratogenic potency in White New Zealand rabbits. Both the 2,6-dioxopiperidine and 2-oxopiperidine derivatives of phthalimide and phthalimidine were found to be highly teratogenic. A somewhat higher teratogenic potential appeared to be associated with the 2,6-dioxopiperidine derivatives. The most potent teratogen investigated was clearly 3-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-dioxopiperidine (EM 12). Compounds in which the phthalimide ring was replaced by 2,3-dihydro-1,1-dioxido-3-oxo-1,2-benzisothiazol, did not induce any embryopathic effect differing from control data. No consistent correlation between teratogenic activity and sedative properties of the compounds was detected. The results are discussed in respect to current views of the molecular mechanism leading to thalidomide embryopathy.
Helm,Frankus,Friderichs,Graudums,Flohe
p. 941 - 949
(2007/10/02)