- Synthesis and pharmacological investigation of azaphthalazinone human histamine H1 receptor antagonists
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5-Aza, 6-aza, 7-aza and 8-aza-phthalazinone, and 5,8-diazaphthalazinone templates were synthesised by stereoselective routes starting from the appropriate pyridine/pyrazine dicarboxylic acids by activation with CDI, reaction with 4-chlorophenyl acetate ester enolate to give a β-ketoester, which was hydrolysed, and decarboxylated. The resulting ketone was condensed with hydrazine to form the azaphthalazinone core. The azaphthalazinone cores were alkylated with N-Boc-D-prolinol at N-2 by Mitsunobu reaction, de-protected, and then alkylated at the pyrrolidine nitrogen to provide the target H 1 receptor antagonists. All four mono-azaphthalazinone series had higher affinity (pKi) for the human H1 receptor than azelastine, but were not as potent as the parent non-aza phthalazinone. The 5,8-diazaphthalazinone was equipotent with azelastine. The least potent series were the 7-azaphthalazinones, whereas the 5-azaphthalazinones were the most lipophilic. The more hydrophilic series were the 8-aza series. Replacement of the N-methyl substituent on the pyrrolidine with the n-butyl group caused an increase in potency (pA2) and a corresponding increase in lipophilicity. Introduction of a β-ether oxygen in the n-butyl analogues (2-methoxyethyl group) decreased the H1 pA2 slightly, and increased the selectivity against hERG. The duration of action in vitro was longer in the 6-azaphthalazinone series. The more potent and selective 6-azaphthalazinone core was used to append an H3 receptor antagonist fragment, and to convert the series into the long acting single-ligand, dual H1 H3 receptor antagonist 44. The pharmacological profile of 44 was very similar to our intranasal clinical candidate 1.
- Procopiou, Panayiotis A.,Browning, Christopher,Gore, Paul M.,Lynn, Sean M.,Richards, Stephen A.,Slack, Robert J.,Sollis, Steven L.
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p. 6097 - 6108
(2012/11/07)
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- PHTHALAZINE AND PYRIDO [3,4-D] PYRIDAZ INE COMPOUNDS AS H1 RECEPTOR ANTAGONISTS
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The present invention relates to compounds of formula (I), and salts thereof, processes for their preparation, to compositions containing them and to their use in the treatment of various diseases, such as allergic rhinitis.
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Page/Page column 55
(2009/05/30)
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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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- 2-SUBSTITUTED 4-BENZYLPHTHALAZINONE DERIVATIVES AS HISTAMINE H1 AND H3 ANTAGONISTS
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The present invention relates to compounds of formula (I), and salts thereof, processes for their preparation, to compositions containing them and to their use in the treatment of various disorders, such as allergic rhinitis.
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Page/Page column 90-91
(2008/06/13)
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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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- A Convenient Synthesis of 3-Acylindoles via Friedel-Crafts Acylation of 1-(Phenylsulfonyl)indole. A New Route to Pyridocarbazole-5,11-quinones and Ellipticine
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A Friedel-Crafts acylation of 1-(phenylsulfonyl)indoles (1) with carboxylic acid anhydrides and acid chlorides in the presence of aluminum chloride gives 3-acyl-1-(phenylsulfonyl)indoles (2) in 81-99percent yields.Base hydrolysis converts 2 to 3-acylindoles (3) in 79-96percent yields.The reaction of 1-(phenylsulfonyl)indole (1a) with oxalyl chloride gives acid chloride 2h, which is converted to 3-cyanoindole (7) in three steps (75percent yield).Although a similar Friedel-Crafts alkylation of 1 was unsuccessful, in some cases the 3-acyl-1-(phenylsulfonyl)indoles 2a,e,f could be reduced to 3-alkyl-1-(phenylsulfonyl)indoles 8a,b,c in nearly quantitative yield with sodium borohydride in trifluoroacetic acid.The acid chloride derived from keto acid 9 did not cyclize to the desired pyridocarbazole-5,11-quinone 24 but rather to chloro keto lactam 10.However, acylation of 1a with acid chloride 22 followed by strong-base-mediated cyclization gives 24.Since quinone 24 has been previously converted to the alkaloid ellipticine 26, this route to 24 represents a new synthesis of ellipticine.Related synthetic schemes give rise to quinones 16 and 20.
- Ketcha, Daniel M.,Gribble, Gordon W.
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p. 5451 - 5457
(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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- Synthesis of the Pyridine Analogues of Phthalide
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Routes for the preparation of the four isomeric pyridine analogues of phthalide are described starting from the readily available pyridine 2,3- and 3,4-diacids, or derivatives, and making use of the differential reactivity of substituents at pyridine 2- versus 3- and 3- versus 4-positions.
- Ashcroft, William R.,Beal, Michael G.,Joule, John A.
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p. 3012 - 3015
(2007/10/02)
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