5.09 Pyrans and their Benzo Derivatives: Applications GRAHAM R. GEEN, JOHN M. EVANS and ANTONIO K. VONG SmithKline Beecham Pharmaceuticals, Harlow, UK 5.09.1 PHARMACEUTICALS 470 5.09.1.1 Antibiotics and Antiinfectives 470 5.09.1.1.1 Macrolide antibiotics 470 5.09.1.1.2 Aminoglycosides 472 5.09.1.1.3 Anthracycline antibiotics 473 5.09.1.1.4 Miscellaneous antibiotics 473 5.09.1.2 Cardiovascular Agents 474 5.09.1.3 Neurological Modulators 477 5.09.1.4 Antiallergic and Antiasthmatic Agents 477 5.09.1.5 Antiinftammatory Agents 478 5.09.1.6 Reproduction and Genitourinary Agents 479 5.09.1.7 Growth Promoters 479 5.09.1.8 Antidiabetic Agents 480 5.09.1.9 Miscellaneous 481 5.09.1.10 Healthcare 481 5.09.2 VETERINARY PRODUCTS 482 5.09.2.1 Antibiotics and Antiinfectives 483 5.09.2.2 Antiinflammatory Agents 483 5.09.3 AGROCHEMICALS 485 5.09.4 TOXINS 485 5.09.4.1 Marine Toxins 486 5.09.4.2 Terrestrial Toxins 487 5.09.5 POLYMERS AND ADDITIVES 488 5.09.5.1 Polymers 488 5.09.5.1.1 Natural polymers 488 5.09.5.1.2 Hydrogels 489 5.09.5.1.3 Glycopolymers 489 5.09.5.1.4 Photoactive polymers 490 5.09.5.1.5 Photosensitizers andphotoinitiators 490 5.09.5.2 Surfactants 491 5.09.6 FOOD PRODUCTS 492 5.09.7 DYES AND PIGMENTS 493 5.09.7.1 Fluorescent Dyes and Brighteners 493 5.09.7.2 Laser Dyes 494 5.09.7.3 Color Formers 494 5.09.7.4 Photochromism 495 5.09.7.5 Infrared Absorbing Dyes 496 5.09.7.6 Natural Dyes 496 5.09.8 USE IN CHEMICAL SYNTHESIS 496 469 470 Pyrans and their Benzo Derivatives: Applications 5.09.9 CYCLODEXTRINS 498 5.09.9.1 Pharmaceuticals 499 5.09.9.2 Agrochemicals 499 5.09.9.3 Flavors and Fragrances 499 5.09.9.4 Reprographics and Phototechnological Applications 500 5.09.1 PHARMACEUTICALS A large number of pharmaceutical agents containing the pyran unit that have been encountered in a survey of the literature, including patent applications and granted patents. A selection is thus required of the more pertinent for inclusion in this part of the chapter. Compounds that have reached the healthcare market in at least one country form the major part of this section and are joined by those compounds that await registration, or that have been registered, as they are likely to be launched in the near future. The inclusion of compounds that are currently in clinical trials has been restricted to those that are in the final phase. Such trials include administration to patients suffering from the disease targeted for the compound. Having passed to this stage of what is becoming an ever more rigorous process, compounds in this class are highly likely to be launched. However, no distinction is made between the different classes considered, as apart from post-launch, their status is not entirely clear. The pharmaceutical agents that contain the pyran ring are arranged by therapeutic area (disease state), and in each area they are grouped by structure and phar- macological mechanism of action. 5.09.1.1 Antibiotics and Antiinfectives 5.09.1.1.1 Macrolide antibiotics The macrolide antibiotics are part of a large and diverse class of natural products isolated from the culture broths of certain soil microorganisms. The fermentation-derived macrolides are classified by the ring size of the aglycone, the basic lactone ring system, to which are appended either or both amino and neutral sugar residues. The predominant subclasses are based on a 14- or 16-membered aglycone. Reviews have covered the 14-membered- <B-93MI 509-0l> and 16-membered aglycones <B- 94MI 509-01). The archetypal 14-membered aglycone antibiotic, erythromicin (1), isolated from Sac- charopolyspora erythraea, is the most widely used member of the macrolide class <57JA6070), being prescribed for the treatment of respiratory tract, skin and soft tissue infections, particularly in cases of penicillin allergy. However, erythromycin can cause intestinal discomfort, and its instability in the acidic environment of the stomach leads to unsatisfactory pharmacokinetics. Certain intramolecular reactions involving degradation of the aglycone occur in this environment that lead to inactive products, and in an effort to counter this tendency and to improve the palatability, a number of semisynthetic analogues has been developed. Roxithromycin (2) <81FRP2473525>, azithromycin (3) <84EUP101186>, clarithromycin (4) <84JAN187>, flurithromycin (5) <83JAN1439>, dirithromycin (6) <90JANl27l>, and erythromycin carbonate (7) <89EUP307l77> were designed to foil undesired trans- formation of the aglycone nucleus, while erythromycin acistrate (8) is a prodrug formulated as the stearate addition salt <88MI 509-01). Other salt derivatives of erythromycin are in development. The 16-membered macrolides comprise two main families, the tylosins and the leucomycins, that are based on the substitution patterns of their aglycone units. While the former class has not as yet produced any compounds for human use, the latter has provided several drugs. Thus, josamycin (9) has been isolated from Streptomyces narbonensis <67JAN174>, and midecamycin (10) from Strep- tomyces mycarofaciens <71JAN319>. Miokamycin, diacetylated midecamycin (11) <76JAN536>, and rokitamycin (12) <81JAN1OO1> are two semisynthetic analogues that have been prepared to improve absorption and palatability. Although studies into the mechanism of action of the macrolides have concentrated on erythro- mycin, it is considered that they all possess the ability to penetrate the cell, bind to the 50S ribosomal subunit and disrupt protein synthesis. Amphotericin B (13), first approved for use in 1958, remains the primary systemically administered fungicidal compound used today. Toxicity is a major side effect, and many complexes and for- mulations have been evaluated in an effort to reduce it while retaining the antifungal potency. One Pyrans and their Benzo Derivatives: Applications 471 NMe2 o OH (1) A = C=0, R1 = H, R2 = OH 1 2 (2) A = C=NOCH2O(CH2)2OMe, R = H, R = OH 1 2 (3) A = N(Me)CH2, R = H, R = OH (4) A = C=O, R1 = H, R2 = OMe (5) A = C=0, R1 = H, R2 = F (8) A = C=0, R1 = Ac, R2 = H; stearate salt OR4 CHO (9) R1 = COBu\ R2 = R4 = H, R3 = Ac (10) R1 = R3 = COEt, R2 = R4 = H (11) R1 = R3 = COEt, R2 = R4 = Ac (12) R1 = COPrn, R2 = COEt, R3 = R4 = H formulation that is reported to offer this advantageous profile is the 1:1 complex of amphotericin B with cholesteryl sulfate <91MI 509-01 >. The compound exerts its pharmacological effect by binding to ergosterol, which is commonly found in fungal cell membranes, thus leading to membrane instability and breakdown. CO2H 472 Pyrans and their Benzo Derivatives: Applications Extraction of the mycelia oi Streptomyces tsukubaensis <87JAN1249> produces the novel macrolide immunosuppressant agent tacrolimus (14). It is particularly useful in combination with cortico- steroids following liver or kidney transplantations, and is beneficial in countering graft rejection. MeO. MeO,, o (14) 5.09.1.1.2 Aminoglycosides Another important class of antibiotic agents is the aminocyclitol aminoglycosides exemplified by the gentamicin C complex (15) <63USP3O91572>, a Gram-negative bactericide. Like the macrolide antibiotics they are thought to act directly on the ribosome (but at the 30S unit) and thus to inhibit protein synthesis. Other closely related compounds isolated from natural sources are sisomicin (16; R = H) from Micromonospora inyoesis <70JAN551>, micronomicin (17) from Micronospora sagamiensis <74JAN793>, astromicin (18) from Micromonospora olivoasterospora <77JAN552>, and the furanose ribostamycin (19) from Streptomyces ribosidificus <7OJAN173>. Semisynthetic analogues, designed to improve the spectrum of antibiotic activity, are netilimicin (16; R = Et) <76CC206> derived from sisomicin, dibekacin (20) <71JAN485>, isepamicin (21) <75GEP(O)2437159>, and arbekacin (22) <80BEP879925>. NHMe HO NH2 H,N NHR MeO (18) R'HN NHR5 NHR4 (17) R1 = Ac, R2-R5 = H, R6 = Me (20) R!-R« = H 4 2 3 5 6 (21) R>-R = H R = R = OH, R = (S)-COCH(OH)CH2NH2, R = Me 4 6 5 (22) R'-R , R = H, R = (S)-COCH(OH)(CH2)2NH2 Pyrans and their Benzo Derivatives: Applications 473 5.09.1.1.3 Anthracycline antibiotics The members of the class of naturally occurring anthracycline antibiotics derived from anthra- quinone that are reviewed here have been isolated from culture broths of Streptomyces species. They have a particular application as antitumor agents and exert their pharmacological activity by blocking the synthesis of RNA copies of DNA at the cellular level by binding to DNA. Daunorubicin (23) <64NAT706> and doxorubicin (24) <69MI 509-0l>, are both produced by culturing Streptomyces peucitus. The latter is active against a whole range of cancers and has been one of the most widely used chemotherapeutic agents for human tumors. However two of the drawbacks of these agents are their level of cardiotoxicity and incidence of alopecia (hair loss). In order to improve the therapeutic ratio further natural analogues have been sought and aclarubicin (25), isolated from Streptomyces galileus <75JAN830>, is particularly useful against some forms of lung cancer, with a lower incidence of side effects. Beside the search for natural analogues with improved side effect profile, several semisynthetic analogues such as zorubicin (26) <74GEP(O)23272ll>, pirarubicin (27) <79JAN1O82>, and idarubicin (28) <76Mi 509-01 > have been prepared. An interesting synthetic analogue is epirubicin (29) where the stereochemistry of the 4'-hydroxyl group in the sugar residue is inverted <75JMC703>. The mode of antitumor action and efficacy of the compound class are retained in this compound while the cardiotoxicity is reduced. CO,Me "OH "OH NH2 (23) R1 = OMe, R2 = Ac, R3 = OH 1 2 3 (24) R = OMe, R = COCH2OH, R = OH (26) R'= OMe, R2 = C(Me)=NHCOPh, R3 = OH 2 3 (27) R'= OMe, R = COCH2OH, R = OTHP (28) R1 = H, R2 = Ac, R3 = OH 1 2 3 (29) R = OMe, R = COCH2OH, R = epi-OU Undue levels of toxicity precluded the progression of the natural anthracycline nogalamycin (30), but a semisynthetic derivative menogaril (31) was used to overcome this problem <77JAN628>.