Isoquinoline sulfonamides

In another synthesis, neamine was linked by a spacer to a known isoquinoline sulfonamide protein kinase inhibitor to make the conjunct molecule (compound 87). A molecule such as 87 should bind the active site of these enzymes with great affinity [58]. 

Y-27632 (25) is a synthetic pyridine derivative that inhibits Rho kinase (ROCK)-I and ROCK-II. As expected, Y27632 (25) inhibits the formation of stress fibers in cultured cells and motility in a number of systems [36]. In addition, two isoquinoline sulfonamides, HA1077 (26) and H-1152 (27), were developed as ROCK inhibitors [37,38]. 

A series of indeno[l,2-c]isoquinolines have been described [27] and INO-lOOl has been investigated in the clinic. Although the structure of INO-lOOl has not been reported, sulfonamide 28 is a representative structure (IC50 = lnM, EC5O = 10nM). CEP-9722 is in Phase I clinical trials, while its exact structure has not been disclosed, it is a prodrug of CEP-8983 (29) and patent applications highlight 30. Preclinical efficacy in combination with TMZ and camptothecin have been... 

Palladiun-catalyzed two component cascade cyclization of 1-iodo-vinylbenzenes 489 and sulfonamide 490 gave 6-substituted 2-tosyl-ll-methylene-2,3,4,6,11,1 la-hexahydro-lH-pyrazino[l,2-b]isoquinolines 491 (07T6152). 

In a study on the activation of macrocyclic enediynes by transannular cyclization it was found that the deprotection of the sulfonamide group of ketone 91 triggered the formation of aminol 92 which readily provided the isoquinoline derivative 93 via a Bergman cyclization reaction <04AG(E)132>. 

It has recently been demonstrated that bromo-tns-pyrrolidino-phosphonium hexafluorophosphate (PyBroP) can be functiOTiing as a mild activator of azine N-oxide providing regioselective addition of Ai-nucleophiles (amines, sulfonamides, and NH-heterocycUc compounds) to pyridine, quinoline, and isoquinoline N-oxides (Scheme 53) [112,113]. A strong regiochemical preference for the orf/io-substitution pattern in aU these cases is likely caused by specific electrostatic attraction of nucleophilic species and the intermediate phosphonium salt 76. This synthetic procedure was successfully extended for other types of nucleophilic reagents (phenols, thiols, malonates). 

The Bobbitt variation of the Pomeranz-Fritsch cyclization to obtain 4-hydroxytetrahydroisoquinolines continues to be a useful approach. " Jackson and co-workers have worked out a superior method for the preparation of substituted isoquinolines which involves cyclization, under mildly acidic conditions, of acetal sulfonamides. ... 

Ichikawa J, Sakoda K, Moriyama H, Wada Y (2006) Syntheses of ring-fluorinated isoquinolines and quinolines via intramolecular substitution cyclization of 1,1-difluoro-l-alkenes bearing a sulfonamide moiety. Synthesis 10 1590-1598... 

Sulfonamides are sufficiently reactive to serve as nucleophiles in the reaction with difluorostyrenes under basic conditions (Scheme 27) [100]. Imines and oximes have also been utilized as nucleophiles to provide 3-fluoroisoquinolines and their V-oxides, respectively (Scheme 28) [101]. When the isoquinoline V-oxide was treated with an isocyanate, the oxygen atom on the nitrogen was consequently eliminated after the 1,3-dipolar addition to afford a l-amino-3-fluoroisoquinoline (Scheme 28). 

---