N

COC6H4-4-Cl

Indomethacin (13) is quite photostable in the solid state (7.5% decomposition after 72 h irradiation)32 but reacts in solution.18 In methanol the usual decarboxylation is the main process33- 34 when mercury lamps are used, while daylight irradiation leads to products conserving the carboxyl group which have been rationalised as arising via the acyl radical (Scheme 6).35

Scheme 7

Scheme 7

Scheme 8

In the case of the related drug 2-(2,6-dichlorophenylamino)phenylacetic acid (diclofenac, 14), on the other hand, dechlorination - as stated above, one of the general photochemical reaction of aromatics - is the dominant process. Sequential loss of both chlorine atoms is followed by ring closure, reasonably via radical addition, to yield the carbazole-1-acetic acids (15) and (16) as the main products (Scheme 7).36 It may be noticed that 2-(2,6-dichloro-3-methylphenylamino)benzoic acid, also an anti-inflammatory agent (meclofenamic acid, 17), likewise undergoes photochemical dechlorination and ring closure to the carbazoles (18) and (19) (Scheme 8).37

Photoreactivity has been reported also for some anti-inflammatory and analgesic drugs different from arylacetic acids. Thus, benzydamine (20) (irradiation of the hydrochloride in methanol leads to hydroxylation in position 5 as well as well as to Fries type 0-N(2) chain migration, to yield products (21) and (22) respectively, see Scheme 9).38 Benorylate (23) likewise undergoes a Fries rearrangement to give (24) which then further rearranges thermally to product (25) (see Scheme 10).39 The photo-Fries rearrangement is a general reaction with aromatic esters and amides, and occurs via a radical mechanism, rather than via the ionic mechanism of the thermal reaction. 5-Aminosalicylic acid (26), used for the treatment of chronic inflammatory bowel diseases, undergoes light-accelerated oxidation and polymerisation (Scheme ll).40

CH2Ph hv

^ MeOH H0 0(CH2)3NMe2

0(CH2)3NMe2

Scheme 9

CH2Ph

NHAc

NHAc

Scheme 10

The narcotic analgesic methadone hydrochloride (27) reacts when irradiated by UV light both in aqueous solution41 and in the solid state.42 The processes observed (fragmentation and cyclisation, see Scheme 12) are a typical manifestation of the radical-like character of the nit* state of ketones (a- and ji-cleavage, see Scheme 1, a). However, this drug is photostable in an isotonic solution when exposed to ambient light.43

EtCOCPh2CH2CHCH3 NMe2

EtCHO + Ph2C=CHCHCH3 +

NMe2 CH3C

Scheme 12

The enkefalinase inhibitor thiorfan (28), a new generation analgesic, is quite sensitive to oxidation and is converted to the disulphide; this reaction is accelerated by light.44

PhCH2CH(SH)CONHCH2COOH (28)

2.1.2 Pyrazolone Analgesic and Antipyretic Drugs. The largely used drugs of this structure are photoreactive, and cleavage of the pyrazole ring occurs in most cases.45ยป 46 Typical reactions are shown below for the case of aminopyrine (29) (Scheme 13) and for that of phenylbutazone (30) (Scheme 14).

hv h20

Me NMe2

Me OH

0 0

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