Ординатура / Офтальмология / Английские материалы / Carbonic Anhydrase Its Inhibitors and Activators_Supuran, Scozzafava, Conway_2004

TABLE 4.15

IC50 and pKa Data for Sulfonamides 4.102

aFor the SO2NH2 protons in 30% EtOH/water.

bFor CO2 hydration against hCA II.

Source: From Hartman, G.D. et al. (1992) Journal of Medicinal Chemistry 35, 3027–3033. With permission.

derivatives bearing 5-secondary/tertiary-amino groups, of type 4.125 (Table 4.18). Such compounds also possessed strong CA inhibitory properties. In contrast to the sulfonamides, compound 4.125 showed a strong binding to the ocular pigment and a moderate reactivity toward glutathione.

In addition to the Merck group, topically active CAIs were reported also by other researchers (Pierce et al. 1993; Sharir et al. 1994), this time incorporating the classical acetazolamideor methazolamide-like ring systems in derivatives of types

4.126 to 4.131.

By treating amine 4.43 with cyclic unsaturated anhydrides (e.g., maleic anhydride), the imide 4.126 was obtained, which on oxidation with t-BuOOH/OsO4 led to the trans-diol 4.127. This compound was reported to act as a topically active CAI in rabbits (Pierce et al. 1993). The same group condensed 4.43 with 3-oxoadipic

Copyright © 2004 CRC Press, LLC

SCHEME 4.14

acid, obtaining a Schiff base, which on reduction with NaBH3CN led to the secondary amine 4.128, reported to act as a strong CAI (Sharir et al. 1994). Compounds of type 4.129 that possessed 5-ω-carboxypolymethylenecarboxamido moieties were reported by Antonaroli et al. (1992) to have IC50 values of the order of 10–7 M and some topical activity in lowering IOP in rabbits, but detailed studies have not been performed with these derivatives.

The culmination of the ring approach was reached with the report of Ponticello et al. (1987) that thieno-thiopyran-2-sulfonamides of types 4.130 and 4.131 are water soluble, and this ring system led to the first clinically used topically acting sulfonamide dorzolamide (Maren 1995; Supuran et al. 2003).

Two types of sulfonamides were prepared: the thieno[2,3-b]thiopyran- 4.130 and the thieno[3,2-b]thiopyran-2-sulfonamides 4.131. Scheme 4.16 presents syntheses

Copyright © 2004 CRC Press, LLC

SCHEME 4.15

of derivatives from the first class, starting from the key intermediate ketone 4.132 reported earlier (Ponticello et al. 1987; Baldwin et al. 1989).

Treatment of 4.132 with sulfuric acid–acetic anhydride in methylene chloride provided in high yield the 2-sulfonic acid, which was converted to the sulfonyl chloride with PCl5. Subsequent amidation let to sulfonamide 4.133 (Scheme 4.16). Its reduction with sodium borohydride afforded the alcohol 4.134, which could be oxidized at the thiopyran moiety by different agents to the corresponding sulfone 4.135 and sulfoxide 4.136, respectively. This last compound was then used to prepare the unsaturated derivative 4.137, as well as the parent (unsubstituted) sulfonamide of the series 4.138. By Ritter’s reaction with nitriles in the presence of sulfuric acid, 4.136 was used for obtaining amides 4.139, which were reduced by borane-dimethyl sulfide to amines 4.140. Some compounds of these types showed a good water solubility (1 to 2%, which is excellent for a sulfonamide) and very good CA inhibitory activities (Table 4.19).

From the data from Table 4.19, it can be seen that generally compounds of type 4.141 are very strong CAIs, with important differences of activity seen for diverse groups substituted at position 4 as well as for different oxidation states of the sulfur moiety. The sulfones (4.141, n = 2) were the most active: very good activities were found for the ketone 4.141e, the unsubstituted derivative 4.141f, the primary amine 4.141g and its alkyl derivatives 4.141h–n. Compound 4.141m (MK-927), originally

Copyright © 2004 CRC Press, LLC

H2NO2S

S

4.124

R1

S N R2

H2NO2S

O

4.125

selected for clinical trials (Ponticello et al. 1987; Baldwin et al. 1989), needs special mention. Its racemate is a highly active inhibitor (IC50 = 0.55 ∞ 10–8 M), but by resolving the compound into its pure enantiomers, the (R)-optical antipode 4.141n was found to be >10 times more active than its antipode. Moreover, x-ray crystallographic studies on enzyme inhibitor complexes by using 4.141n and 4.141o revealed differences in the relative orientation of these inhibitors within the active site of human CA II, as well as conformational change in the protein on binding, involving a side-chain movement of His 64 (Smith et al. 1994). In conclusion, binding of the (R)-enantiomer is favored over the (S)-enantiomer, which explains the differences in IC50 values shown in Table 4.19.

Shinkai (1992) also reported the enantioselective synthesis of the isomer (R)- MK-927, renamed MK-417 (4.141n). Scheme 4.17 outlines the most important steps of this synthesis developed for the industrial scale. Oxidation of ketone 4.132 with H2O2 in the presence of sodium wolframate afforded sulfone 4.133, which was enantioselectively reduced to the key compound, alcohol 4.136. Different reductions were tried: in the presence of (–)-B-chlorodiisopinocamphenylborane (when the (R):(S) ratio was 11:89), (S)-B-methyl-1,3,2-oxazaborolidine (R):(S) ratio of 9:1) or yeast. For large-scale applications, the second catalyst proved most suitable, being easily accessible from L-proline and affording good yields of the desired enantiomer (Shinkai 1992). Compound 4.136 was converted to the tosylate 4.142 possessing

Copyright © 2004 CRC Press, LLC

TABLE 4.16

Inhibition and pKa Data for Thieno [2,3-b]-Thiophene-2-

Sulfonamide Derivatives 4.114

the same configuration (by treatment with TsCl and NaC CH), which by an SN2 reaction with iso-butylamine (with inversion of configuration at C-4) led to 4.143. The sulfonamido group was introduced by treatment with sulfonyl chloride and amidation, these reactions not affecting the chiral center at C-4, leading to MK-417 (compound 4.141n). For reasons little understood Merck, Sharp & Dome chose for launching into the market a structurally related inhibitor, i.e., MK-507 (4.144), named dorzolamide.

The structure and the pharmacology of these CAIs are extremely similar to those of other thienothiopyransulfonamides discussed previously, but MK-507 contains two chiral centers because of the presence of a 6-methyl group. Its enantioselective synthesis has been reported and optimized for large-scale production (Scheme 4.18; Blacklock et al. 1993).

Starting from methyl-(R)-3-hydroxybutyrate tosylate 4.145, which was treated with 2-lithiomercapto-thiophene 4.146 and in an SN2 reaction (with inversion of

Copyright © 2004 CRC Press, LLC

TABLE 4.17

Inhibition and pKa Data for Thieno [3,2-b]- Thiophene-2-Sulfonamide Derivatives 4.124

TABLE 4.18

Inhibition and pKa Data for Thieno[2,3-b]Furan-2- Sulfonamide Derivatives 4.125

Copyright © 2004 CRC Press, LLC

configuration), the alkylation product with the desired stereochemistry, 4.147, was obtained. Cyclization of 4.147 (after hydrolysis of the ester moiety) was achieved in the presence of trifluoroacetic anhydride in toluene, when ketone 4.148 was obtained in good yields. Its reduction with LiAlH4 in 95% yield gave the cis-alcohol 4.149a, which was epimerized to 4.149b in the presence of cold 1 N H2SO4. A mixture of 76:24 trans/cis epimeric alcohols resulted, which was oxidized with H2O2/Na2WO4 to the sulfone 4.150. By a Ritter reaction with acetonitrile, 4.150 was transformed into the acetamido derivative 4.151. An interesting discovery in these syntheses was that the Ritter reaction occured with retention of configuration for the trans alcohol and with considerable inversion for the cis alcohol. However, finally the desired compound 4.151 was formed preferentially. This was converted to the corresponding sulfonyl chloride 4.152 and sulfonamide 4.153, followed by reduction of the acetamide to the ethylamino moiety with borane-dimethylsulfide, to obtain 4.144. The hydrochloride salt of 4.144 is dorzolamide (MK-507).

The second clinically used topical CAI brinzolamide (4.154) was developed by Alcon Laboratories, probably by using dorzolamide (4.144) as lead (Dean et al. 1993). The two compounds are structurally very similar, with brinzolamide possessing a slightly modified ring, i.e., the 2-substituted-2H-thieno[3,2-e]-1,2-thiazine-6- sulfonamide class. The main difference between the Merck and Alcon work was that Alcon researchers did not generally publish their research in scientific journals but only patented these compounds (Dean et al. 1993). Only recently have some brinzolamide congeners been described in some detail in a published paper (Chen et al. 2000).

Copyright © 2004 CRC Press, LLC

Similar to the thienothiopyran sulfonamides developed by Merck, the 2-substi- tuted-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamides to which brinzolamide (4.154) belongs act as a low nanomolar inhibitor for hCA II, being slightly less effective as hCA IV inhibitors. However, the brinzolamide type compounds are less water soluble as compared to dorzolamide, and thus are formulated as suspensions for topical administration. Another important characteristic is that they are more effective than dorzolamide and produce less eye stinging and burning. A defect is that they provoke much more blurred vision after administration, obviously because of the suspension nature of the formulation (Supuran et al. 2003).

Copyright © 2004 CRC Press, LLC

TABLE 4.19

Inhibition Data for Thieno-Thiopyran-2-

Sulfonamide Derivatives 4.141

Source: From Ponticello, G.S. et al. (1987) Journal of Medicinal Chemistry 30, 591–597. With permission.

A common problem of both dorzolamide and brinzolamide is that they contain chiral centers, and the preparation of the pure enantiomer (4S,6S) in the case of dorzolamide and (4R) in the case of brinzolamide is rather expensive. Thus, the Alcon group has recently reported some brinzolamide-like compounds of type 4.155 (Chen et al. 2000) that do not contain chiral centers. These derivatives principally differ from brinzolamide by the absence of the 4-substituent (that induced the chirality) and a rather large number of substituents in position 2 of the heterocyclic ring (the R group of formula 4.155), as well as by the presence of an additional double bond in the six-membered heterocycle annulated to the thiophene nucleus, which represents an innovative feature over the previously topically active sulfonamides prepared by the ring approach. These compounds were effective nanomolar inhibitors against hCA II and hCA IV, and showed good IOP lowering (20 to 30%) properties in naturally hypertensive Dutch-belted rabbits after administration as

Copyright © 2004 CRC Press, LLC