- High-yield synthesis method of methyl 4-aminonicotinate
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The invention discloses a high-yield synthesis method of methyl 4-aminonicotinate, which comprises the following steps: by taking 3, 4-dipicolinic acid as a raw material, carrying out intramolecular dehydration substitution, ammonia ammonification, improved NBS Hofmann rearrangement and hydrolysis to obtain the methyl 4-aminonicotinate. The synthesis method disclosed by the invention is simpler to operate, mild in reaction condition and higher in total yield, and has an extremely high application value.
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Paragraph 0024-0027; 0033-0036; 0042-0045
(2021/09/08)
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- The synthesis of 7,8,9,10-Tetrafluoroellipticine
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We have synthesized a novel ellipticine analogue, 7,8,9,10-Tetrafluoroellipticine, in nine steps from hexafluorobenzene and ethyl cyanoacetate, via 1-(phenysulfonyl)-4,5,6,7-Tetrafluoroindole. The key step is lithiation of the indole and subsequent coupling with 3,4-pyridinedicarboxylic acid anhydride to afford a ketolactam. Reaction of the lactam with methyllithium followed by reduction with sodium borohydride yields 7,8,9,10-Tetrafluoroellipticine. formula presented.
- James Gruver,Onyango, Evans O.,Gribble, Gordon W.
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p. 144 - 152
(2018/07/05)
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- A cedar Joan maleic acid salt preparation method
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The invention provides a pixantrone maleate synthesis method which has the advantages of high yield, low impurity content, simple process and easiness in large-scale production. In the method, pyridine-3,4-dicarboxylic acid is used as a starting raw material which reacts with acetic anhydride to obtain pyridine-3,4-dicarboxylic anhydride; the pyridine-3,4-dicarboxylic anhydride conducts an Friedel-Crafts acylation reaction with 1,4-difluorobenzene, and the obtained mixture is subjected to catalytic cyclization to obtain a key intermediate; the intermediate reacts with amino-protected ethylenediamine to obtain protecting group-containing pixantrone; and after that, deprotection and salifying are performed to obtain the target product. In the Friedel-Crafts acylation reaction of the method, an n-hexane solution of sulfuric acid is used as a catalyst, thus the use is convenient, the aftertreatment is simple, and the potential risk in production is eliminated; the Cbz or Fmoc protected ethylenediamine reacts with substituted anthraquinone and then the protecting group is removed through catalytic hydrogenation to obtain pixantrone; the process effectively inhibits side reactions and reduces the impurity content; and meanwhile, the aftertreatment is simplified, and the yield increase is facilitated.
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Paragraph 0042; 0043; 0044
(2017/08/25)
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- ISOQUINOLINESULFONYL DERIVATIVE AS RHO KINASE INHIBITOR
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The present invention discloses a class of isoquinolinesulfonyl derivatives as RHO kinase inhibitors, and pharmaceutical compositions thereof, and relates to pharmaceutically acceptable uses thereof. Specifically, the present invention relates to a compound as represented by formula (I), or a pharmaceutically acceptable salt thereof.
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Paragraph 0132; 0133
(2017/06/12)
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- PYRIDAZINE DERIVATIVES AS HEDGEHOG PATHWAY INHIBITORS
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This invention relates to novel compounds. The compounds of the invention are hedgehog pathway agonists. Specifically, the compounds of the invention are useful as Smoothened (SMO) agonists. The invention also contemplates the use of the compounds for treating conditions treatable by the inhibition of the Hedgehog pathway and SMO, for example cancer.
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Paragraph 00183
(2015/01/16)
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- HETEROCYCLIC COMPOUNDS AS HEDGEHOG SIGNALING PATHWAY INHIBITORS
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This invention relates to novel compounds of formula (I). The compounds of the invention are hedgehog pathway antagonists. Specifically, the compounds of the invention are useful as Smoothened (SMO) inhibitors. The invention also contemplates the use of the compounds for treating conditions treatable by the inhibition of the Hedgehog pathway and SMO, for example cancer.
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Paragraph 00234
(2014/12/12)
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- Design and synthesis of 6-fluoro-2-naphthyl derivatives as novel CCR3 antagonists with reduced CYP2D6 inhibition
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In our previous study on discovering novel types of CCR3 antagonists, we found a fluoronaphthalene derivative (1) that exhibited potent CCR3 inhibitory activity with an IC50 value of 20 nM. However, compound 1 also inhibited human cytochrome P450 2D6 (CYP2D6) with an IC50 value of 400 nM. In order to reduce its CYP2D6 inhibitory activity, we performed further systematic structural modifications on 1. In particular, we focused on reducing the number of lipophilic moieties in the biphenyl part of 1, using C log D7.4 values as the reference index of lipophilicity. This research led to the identification of N-{(3-exo)-8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl}-3-(piperidin-1-ylcarbonyl)isonicotinamide 1-oxide (30) which showed comparable CCR3 inhibitory activity (IC50 = 23 nM) with much reduced CYP2D6 inhibitory activity (IC50 = 29,000 nM) compared with 1.
- Sato, Ippei,Morihira, Koichiro,Inami, Hiroshi,Kubota, Hirokazu,Morokata, Tatsuaki,Suzuki, Keiko,Iura, Yosuke,Nitta, Aiko,Imaoka, Takayuki,Takahashi, Toshiya,Takeuchi, Makoto,Ohta, Mitsuaki,Tsukamoto, Shin-ichi
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p. 8607 - 8618
(2008/12/23)
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- Hetero-annulated indazoles
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This invention is directed to heteroannulated indazoles namely to 2,5-disubstituted quinolino-, isoquinolino-, phthalazino-, and quinoxalino- annulated indazole-6(2H)-ones and related mono N-oxides. These compounds have been shown to have antitumor activity.
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- 2-aminoalkyl-5-aminoalkylamino substituted-isoquinoindazole-6(2H)-ones
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This invention is directed to 2-aminoalkyl-5-aminoalkylamino substituted isoquino [8,7,6-cd]indazole-6-(2H)-ones and to 2-aminoalkyl-5-aminoalkylamino substituted-isoquino [5,6,7-cd] indazole-6(2H)-ones. These compounds have been shown to have antitumor activity.
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- 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione and its dimaleate salt
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In the search for novel heteroanalogs of anthracendiones, 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione dimaleate salt (BBR 2778), was selected as the most promising compound. New methods of synthesis produce the compound in purity greater than 99%.
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- 6,9-Bisbenzoisoquinoline-5,10-diones. A Novel Class of Chromophore-Modified Antitumor Anthracene-9,10-diones: Synthesis and Antitumor Evaluations
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Synthetic procedures have been developed which lead to the 2-aza congeners 3 and several related N-oxides 4.The analoques 3 exhibited a wide range of in vitro cytotoxicity against L1210 leukemia, the human colon adenocarcinoma cell line LoVo, and the doxorubicin resistant LoVo/DX cell line.Selected analogues of 3 showed significant P388 antileukemic activity in mice with 3c exhibiting high activity.This activity was also retained in the related N-oxide 4a.These heterocyclic bioisosteric models are representative of the first anthracene-9,10-diones which display antileukemic activity comparable to mitoxantrone.
- Krapcho, A. Paul,Petry, Mary E.,Getahun, Zelleka,Landi, John J.,Stallman, John,et al.
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p. 828 - 837
(2007/10/02)
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- Toward a Broad Specrum Decontaminant for Reactive TOxic Phosphats/Phosphonates: N-Alkyl-3-Iodosopyridinium-4-Carboxylates
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N-n-hexadecyl-3-iodosopyridinium-4-carboxylate has pKa 5.0, and in comicellar aqueous cetyltrimethylammonium chloride, rapidly cleaves p-nitrophenyldiphenyl phosphate in acidic solution.e
- Moss, Robert A.,Zhang, Hongmei
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p. 6225 - 6228
(2007/10/02)
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- A Versatile and Efficient Construction of the 6H-Pyridocarbazole Ring System. Syntheses of the Antitumor Alkaloids Ellipticine, 9-Methoxyellipticine, and Olivacine and Their Analogues
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A general and efficient synthesis of the 6H-pyridocarbazole ring system is described, in which the key steps are (1) regioselective acylation of a 2-lithio-1-(phenylsulfonyl)indole (14) with 3,4-pyridinedicarboxylic acid anhydride (10), (2) cyclization of the deprotected keto acid 17 to keto lactam 19 with acetic anhydride, and (3) the addition of methyllithium to give, after reduction of the intermediate diol 23 with sodium borohydride, the target ring system.In this fashion, ellipticine (1a), 9-methoxyellipticine (1b), and 9-hydroxyellipticine (1c) were synthesized in excellent overall yields from indole.The use of Superhydride, in place of 1 equiv of methyllithium, provided a synthesis of olivacine (2), and the use of phthalic anhydride in the sequence allowed for the preparation of 6,11-dimethylbenzocarbazole (48).The overall yields of ellipticine (1a) (54percent) and 9-methoxyellipticine (1b) (47percent) in six steps from their respective indoles represent one of the most efficient syntheses of these antitumor alkaloids.
- Gribble, Gordon W.,Saulnier, Mark G.,Obaza-Nutaitis, Judy A.,Ketcha, Daniel M.
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p. 5891 - 5899
(2007/10/02)
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- 6,9 Bis(substituted-amino)benzo-[g]isoquinoline-5,10-diones
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A compound according to formula (I): wherein R is, C1-C10 alkyl; phenyl or C7-C10 aralkyl;, C2-C10 aklyl substituted with one or two substituents selected from the group consisting of OR1 and -NR2R3;, C2-C10 alkyl interrupted by one or two oxygen atoms or by a member selected from the group consisting of -NR4-, cis-CH=CH, trans-CH=CH- and -C=C-, and optionally substituted with one or two hydroxy (OH) or -NR2R3 groups; and wherein, R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl, C7-C10 aralkyl, -CHO, -COR5-, -COOR5, -S(O2)R5 and C2-C6 alkyl optionally substituted with -NR2R3;, R2 and R3 are the same or different and are selected from the group consisting of hydrogen, C1-C10 alkyl, C7-C10 aralkyl, phenyl, C2-C10 alkyl substituted with one or two hydroxy (OH) groups, -CHO, -COR5, -COOR5, and -S(O2)R5, R2 and R3 taken together with the nitrogen atom to which they are bound form an ethyleneimine ring or a 5- or 6-membered aromatic or non-aromatic heterocyclic ring optionally containing another heteroatom selected from the group consisting of sulfur, oxygen and nitrogen, R2 is H and R3 is -C(=NH)NH2 or R2 is -C(=NH)NH2 and R3 is H;, R4 is selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C10 hydroxyalkyl, C2-C10 alkyl substituted with -NR2R3, C7-C10 aralkyl, phenyl, -COR5, -COOR5 and -S(O2)R5;, R5 is selected from the group consisting of C1-C10 alkyl, C7-C10 aralkyl, α-, β-, or γ-naphthyl, phenyl, o-, m-, or p-tolyl as free bases and their salts with pharmaceutically acceptable acids, have been found to have cytostatic and anti-tumor activity.
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- Synthesis of 11-Amino-substituted-9-methoxy-5-methyl-6H-pyridocarbazoles
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A route to 11-amino-substituted-6H-pyridocarbazoles has been studied.Thus, condensation of 2-(4-lithiopyridine-3-yl)-4,4-dimethyloxazoline with 2-acetyl-5-methoxy-1-phenylsulphonylindole led to a low yield of the expected alcohol, which upon hydrolysis gave a complex mixture.A better starting building block was 4-acetyl-N,N-diisopropylnicotinamide obtained either from N,N-diisopropyl-4-lithionicotinamide (low yield) or from pyridine-3,4-dicarboxylic anhydride, using a 4-step sequence.This compound was treated with 2-lithio-5-methoxy-1-phenylsulphonylindole, affording N,N-diisopropyl-4-nicotinamide.Hydrolysis and then reduction led to 4-nicotinic acid whose amides were cyclized by phosphorus trichlorideoxide.Finally, the title compounds were obtained by Raney-nickel reduction-elimination of the 6-phenylsulphonyl protecting group.
- Praly-Deprez, Isabelle,Rivalle, Christian,Huel, Christiane,Belehradek, Jean,Paoletti, Claude,Bisagni, Emile
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p. 3165 - 3171
(2007/10/02)
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- PYRIDAZINES CONDENSED WITH A HETERO RING, II. PYRIDO AMINOPYRIDAZINES, I. SEPARATION AND STRUCTURE DETERMINATION OF THE ISOMERIC MONOCHLORO COMPOUNDS OBTAINED BY HYDROLYSIS OF 1,4-DICHLOROPYRIDOPYRIDAZINE
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The separation of the mixture of isomers 2 and 3, obtained by hydrolysis of 1,4-dichloropyrido pyridazine, was accomplished and the structures of the isomers (2: 1-Cl; 3:4-Cl) were verified by synthesis.Aminolysis of 2 and 3 yielded the hydroxy-ethylamino derivatives 4 and 5; a mixture of these compounds can also be synthesized from 2-tosyloxyethylcinchomeronic imide (20 -> 4, 5) in a good yield (84percent).
- Koermendy, K.,Kovacs, T.,Ruff, F.,Koevesdi, I.
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p. 487 - 500
(2007/10/02)
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- Benzocyclobutenes. Part 4. Synthesis of Benzocyclobutene-1,2-diones by Pyrolytic Methods
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Oxidation of the cyclic hydrazides prepared from phthalic anhydrides in the presence of anthracene gives the corresponding Diels-Alder adducts which, on flash vacuum pyrolysis, give benzocyclobutene-1,2-dione (BBD) and its 4-chloro, 3,6- and 4,5-dichloro, 4,5-dibromo, and 4,5-dimethyl derivatives in 75-98percent yield.Cyclobuta- and cyclobuta-naphthalene-1,2-dione as well as cyclobuta- and cyclobuta-pyridine-1,2-dione have been prepared similarly; the last three of these diones are very unstable.Cyclobutanaphthalene-1,2-dione has also been made by pyrolysis of benzindene-1,2,3-trione.Attempts to make thiophen and furan analogues of BBD from appropriate anthracene adducts failed as did attempts to make tetrachloro- and tetrabromo-derivatives of BBD by the pyrolysis of tetrahalogenophthalimidosulphoximides.
- Gould, Ken J.,Hacker, Nigel P.,McOmie, John F. W.,Perry, David H.
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p. 1834 - 1840
(2007/10/02)
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