Sorbinil

Less activated substrates such as uorohaloben2enes also undergo nucleophilic displacement and thereby permit entry to other useful compounds. Bromine is preferentially displaced in -bromofluoroben2ene [460-00-4] by hydroxyl ion under the following conditions calcium hydroxide, water, cuprous oxide catalyst, 250°C, 3.46 MPa (500 psi), to give -fluorophenol [371-41-5] in 79% yield (162,163). This product is a key precursor to sorbinil, an en2yme inhibitor (aldose reductase). 

Intramolecular Alkylations. Intramolecular spiroalkylation of the suitably functionalized 5(477)-oxazolone 188 produced 189 in good to excellent yield. Acid hydrolysis of 189 then gave the cyclic amino acid 190 required in the synthesis of the aldose reductase inhibitor sorbinil (Scheme 7.57). ... 

Another complication of diabetes is blindness, which is due to blood vessel damage at the back of the eye (proliferative retinopathy), this accounts for about 12% of all blindness. In hyperglycemia, fructose is only slowly metabolized, and sorbitol accumulates in tissues. Because aldose reductase is found in kidneys, optic nerve, and peripheral neurons, retinopathy and painful neuropathies develop in poorly controlled or long-standing diabetes as a result of sugar alcohol (sorbitol) accumulation. Aldose reductase inhibitors, such as tokestat (5.129) or sorbinil (5.130), have been evaluated as agents to ameliorate these additional symptoms of diabetes. 

Aldose reductase inhibitors (SEDA-19, 397 SEDA-20, 399 SEDA-21, 447 SEDA-22, 477) have been developed for the treatment of secondary complications in diabetes (1,2). They include alrestatin, benurestat, epalrestat, fidarestat, imirestat, lidorestat, minalrestat, ponalrestat, ranirestat, risarestat, sorbinil, tolrestat, zenarestat, and zopolrestat (all rINNs). 

The aldose reductase inhibitors inhibit or reduce secondary complications induced by diabetes, specifically in tissues in which glucose uptake is not insulin-dependent (probably neural tissue, the lens, and glomeruli). Many of them (including alrestatin, imirestat, ponalrestat, and sorbinil) have been used in clinical trials, but have been withdrawn because of adverse effects or lack of effect (2). Their main adverse effects include fever, nausea, diarrhea, increases in liver enzymes, skin rashes, including toxic epidermal necrolysis and Stevens-Johnson syndrome, marked thrombocytopenia, lymphadenopathy, splenomegaly, and adult respiratory distress syndrome. 

Tolrestat was withdrawn because of deaths from fatal hepatic necrosis (3) and poor efficacy in clinical trials. Sorbinil was withdrawn because of hypersensitivity reactions in more than 10% of patients. 

Sorbinil (= (S)-6-Fluoro- Synthetic chromane AR (human lens) (0.2)... 

ALDOSE REDUCTASE INHIBITORS (ARI) act at the enzyme aldose reductase, which is the first enzyme in the sorbitol (or polyol) pathway which converts glucose to sorbitol. It is thought that in hyperglycaemic states there may be an accumulation of sorbitol, leading to hyperosmotic pathology. ARI agents are under trial for use in the treatment of peripheral diabetic neuropathies, retinopathy and nephropathies. (These include tolrestat. also alrestatin, sorbinil, zenarestat and zopolrestat)... 

Most aldose reductase inhibitors (e.g. sorbinil, alrestatin, tolrestat and ponalrestat) inhibit the enzyme in a non-competitive or uncompetitive way - they compete neither with the substrate nor with the cofactor (NADPH). Therefore, an inhibitory binding site in the enzyme is postulated (Sarges, 1989). 

The absence of side effects in a 1-year clinical trial with ponalrestat was reported by Ziegler et al. (1991), but in this study no therapeutic efficacy was seen A 6-month study with ponalrestat to elucidate the effects on kidney function was also free from side effects (Pedersen et al., 1991). Dizziness, possibly based on a blood pressure-lowering effect, was reported for tolrestat. In addition, hepatocyte lesion accompanied by changes in hepatic parameters within the first 3-6 months of treatment was seen (Ryder et al., 1987). For sorbinil, significant hypersensitivity reactions have been reported (Sarges, 1989). 

A lack of effect on the course of minimal diabetic retinopathy of ponalrestat was reported by Tromp et al. (1991). For sorbinil, there was no preventive... 

Sorbinil Retinopathy Trial Research Group (1990). Arch. Ophthalmol. 108, 1234-1244. 

Fluorophenol is widely used intermediate in the industrial production of pharmaceuticals (Cisapride and Sabeluzole from Janssen, Sorbinil from Pfizer, Progabide from Synthelabo (Fig. 1) and more recently an agrochemical specialities (Fig. 2). 

The effects of sorbinil, its enantiomer, and the racemic form on calf lens AR in vitro, and in vivo on sorbitol accumulation in the sciatic nerve of diabetic rats, are shown in Table 8.5. At 1 x 10 6 M, ( - )-sorbinil was only marginally active (23%), while (+ )-sorbinil caused 98% inhibition. A limited number of sorbinil analogues with different substitution patterns have been disclosed they are shown in Table 8.5 together with their activities in vitro and in vivo. The racemic 6,7-dichloro, 6,8-dichloro and 6-chloro analogues (Nos. 5,6 and 7) are more potent in vitro than racemic sorbinil (No. 1) this is also the case in vivo for the 6,8-dichloro and the 6-chloro analogues, which inhibit sorbitol accumulation by 82 and 64%, compared with 45% for (+ )-sorbinil, at a dose of 0.75 mg/kg p.o. in the streptozotocin-induced diabetic rat. An account of the development of sorbinil, and additional structure-activity relationships in that series, has recently appeared [60]. 

The 2,3-dihydro[AH ] -1 -benzopyran nucleus of sorbinil has been replaced... 

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