| PATENT ASSIGNEE'S COUNTRY | USA |
| UPDATE | 09.01 |
| PATENT GRANT DATE | 04.09.01 |
| PATENT TITLE |
Selective inhibitors of prostaglandin endoperoxide synthase-2 |
| PATENT INVENTORS | Marnett; Lawrence J. (Nashville, TN); Kalgutkar; Amit S. (Nashville, TN) |
| PATENT ASSIGNEE | Vanderbilt University |
| PATENT FILE DATE | 06.04.99 |
| PATENT CLAIMS |
2. The compound of claim 1, which is 2-acetoxyphenyl-6-bromohexyl sulfide, or a pharmaceutically acceptable salt or hydrate thereof. 3. A pharmaceutical composition, comprising a compound of of claim 1 and a pharmaceutically acceptable carrier. 4. The pharmaceutical composition of claim 3, wherein said compound is selected from the group consisting of 2-(trifluoromethylacetoxy)thioanisole, 2-(.alpha.-bromoacetoxy)thioanisole, 2-acetoxyphenylbenzyl sulfide, 2-acetoxyphenyl-2-phenylethyl sulfide, 2-acetoxyphenylethyl sulfide, 2-acetoxyphenylpropyl sulfide, 2-acetoxyphenylbutyl sulfide, 2-acetoxyphenylpentyl sulfide, 2-acetoxyphenylhexyl sulfide, 2-acetoxyphenylheptyl sulfide, 2-acetoxyphenyl-2-butoxyethyl sulfide, 2-acetoxyphenyl-2-transheptenyl sulfide, 2-acetoxyphenylhept-2-ynyl sulfide, 2-acetoxyphenylhex-2-ynyl sulfide, 2-acetoxyphenylpent-2-ynyl sulfide, 2-acetoxyphenylbut-2-ynyl sulfide, 2-acetoxyphenylprop-2-ynyl sulfide, 2-acetoxyphenyloct-2-ynyl sulfide, 2-acetoxyphenylnon-2-ynyl sulfide, 2-acetoxyphenyldec-2-ynyl sulfide, 2-acetoxyphenylhept-3-ynyl sulfide, 2-[(.+-.-2-acetoxyphenylmercapto]oct-3-yne, 2-acetoxyphenyl-(6-iodohexyl) sulfide, 2-acetoxyphenyl-6-bromohexyl sulfide, 2-acetoxyphenylheptyl selenide, and 2-acetoxyphenylhept-2-ynyl ether or pharmaceutically acceptable salts or hydrates thereof. |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates generally to the fields of molecular pharmacology and the biochemistry of inflammation. More specifically, the present invention relates to a selective 2-acyloxyphenylalkyl, -alkenyl, -alkynyl, and 2-acyloxyphenylaryl sulfide inhibitors of prostaglandin endoperoxide synthase-2. 2. Description of the Related Art Prostaglandins, particularly prostaglandin E.sub.2 (PGE.sub.2), are involved in many diverse physiological and pathophysiological functions. These eicosanoids are produced by the action of prostaglandin endoperoxide synthase (PGHS, EC 1.14.99.1) on arachidonic acid. Prostaglandin endoperoxide synthase activity originates from two distinct and independently regulated isozymes, termed as prostaglandin endoperoxide synthase-1 and prostaglandin endoperoxide synthase-2 and are encoded by two different genes (1,2). Prostaglandin endoperoxide synthase-1 is expressed constitutively and is thought to play a physiological role, particularly in platelet aggregation, cytoprotection in the stomach, and regulation of normal kidney function (FIG. 1). Prostaglandin endoperoxide synthase-2 is the inducible isozyme and expression of prostaglandin endoperoxide synthase-2 is induced by a variety of agents which include endotoxin, cytokines, and mitogens (2,3). Importantly, prostaglandin endoperoxide synthase-2 is induced in vivo to significant levels upon pro-inflammatory stimuli (4). These discoveries led to the proposal that prostaglandin endoperoxide synthase-1 and prostaglandin endoperoxide synthase-2 serve different physiological and pathophysiological functions. For example, the disruption of beneficial prostaglandin production by all of the currently used non-steroidal antiinflammatory drugs (NSAIDs) results in a mechanism-based toxicity mainly in the gastrointestinal tract and kidney and thus limits their therapeutic usefulness especially when long-term treatment is involved (5-7). As a result of this critical finding, a major discovery effort has been excecuted in the pharmaceutical industry to identify selective and orally active prostaglandin endoperoxide synthase-2 inhibitors because they may provide the desired anti-inflammatory and analgesic properties without the deleterious and sometimes life threatening side effects commonly associated with the existing non-steroidal antiinflammatory drugs. The prior art is deficient in the lack of selective and orally active prostaglandin endoperoxide synthase-2 inhibitors. The present invention fulfills this longstanding need and desire in the art. In another embodiment of the present invention, there is provided a pharmaceutical composition, comprising the novel compounds of the present invention and a pharmaceutically acceptable carrier. In yet another embodiment of the present invention, there is provided a method of inhibiting the synthesis of prostaglandin endoperoxide syntase-2 (PGHS-2) in a mammal in need of such treatment, comprising the step of administering to said mammal an effective amount of a compound of Formula (I). Other and further aspects, features, and advantages of the present invention will be apparent from the following description of the presently preferred embodiments of the invention given for the purpose of disclosure. BRIEF DESCRIPTION OF THE DRAWINGS So that the matter in which the above-recited features, advantages and objects of the invention, as well as others which will become clear, are attained and can be understood in detail, more particular descriptions of the invention briefly summarized above may be had by reference to certain embodiments thereof which are illustrated in the appended drawings. These drawings form a part of the specification. It is to be noted, however, that the appended drawings illustrate preferred embodiments of the invention and therefore are not to be considered limiting in their scope. FIG. 1 shows a schematic of the physiological stimuli which lead to inflammation. FIG. 2A shows the structures of flosulide, NS-398, SC 8076, aspirin and DuP 697. FIG. 2B shows the synthetic scheme for the synthesis of compounds 2, 3, 4 and 6-14. FIG. 2C shows the synthetic scheme for the synthesis of compounds 15, 16, 17, 18 and 19. FIG. 2D shows the synthetic scheme for the synthesis of compounds 21, 22, 23, and 24. FIG. 2E shows the synthetic scheme for the synthesis of compounds 26, 27, 28, 29, 30 and 31. FIG. 2F shows the synthetic scheme for the synthesis of compounds 33-48 and 49-63. FIG. 2G shows the synthetic scheme for the synthesis of compounds 65, 66, 67, 69, 70 and 71. FIG. 2H shows the synthetic scheme for the synthesis of compounds 73, 74 and 75. FIG. 2I shows the synthetic scheme for the synthesis of compounds 79-91. FIG. 2J shows the synthetic scheme for the synthesis of compounds 36, 92, and 93. FIG. 2K shows the synthetic scheme for the synthesis of compounds 95, 96 and 97. FIG. 2L synthetic scheme for the synthesis of compounds 106, 107, 108, 109, 110, 111, 114, and 115. FIG. 2M shows synthetic scheme for the synthesis of compounds 118, 119, and 120. FIG. 2N shows the synthetic scheme for the synthesis of compounds 121, 122, 123, and 124. FIG. 2Q shows the synthetic scheme for the synthesis of compounds 126 and 127. FIG. 2P shows the synthetic scheme for the synthesis of compounds 128, 130 and 131. FIG. 2Q shows the synthetic scheme for the synthesis of compounds 132, 133, 134, 135, 136, 137, 138, 139, 140, and 141. FIG. 3 shows the time- and concentration-dependent inhibition of human PGHS-2 and ovine PGHS-1 by 2-acetoxythioanisole (2). HoloPGHS-1 (22 nM) or holoPGHS-2 (88 nM) was incubated with the indicated concentrations of 2 for 3 hours at room temperature. Cyclooxygenase reaction was initiated by the addition of 50 .mu.M [1-.sup.14 C]-arachidonic acid for 30 sec at 37.degree. C. Closed squares, PGHS-2+2; open squares, PGHS-1+2. 2-Acetoxythioanisole (mM) % Remaining Enzyme Activity FIG. 4 shows the time-dependent inhibition of the cyclooxygenase activity of Apo and HoloPGHS-2 by 2-Acetoxythioanisole (2). ApoPGHS-2 (5 .mu.M) or holoPGHS-2 (5 .mu.M) was incubated with a 1000-fold excess of 2. Periodic 0.16 .mu.M enzyme aliquots (final inhibitor concentration .about.160 .mu.M) were analyzed for remaining cyclooxygenase or peroxidase activity as described above. Closed squares, cyclooxygenase activity of holoPGHS-2; open squares, cyclooxygenase activity of apoPGHS-2; closed circles, peroxidase activity of holoPGHS-2; open circles, peroxidase activity of apoPGHS-2. FIG. 5 shows the time- and concentration-dependent inhibition of human PGHS-2 and ovine PGHS-1 by aspirin. HoloPGHS-1 (22 nM) or holoPGHS-2 (88 nM) was incubated with the indicated concentrations of aspirin for 1 hour at room temperature. Cyclooxygenase activity was initiated by the addition of [1-.sup.14 C]-arachidonic acid (50 .mu.M) for 30 sec at 37.degree. C. Open squares, PGHS-1+aspirin; closed squares, PGHS-2+aspirin. FIG. 6 shows the inactivation of the cyclooxygenase activities of holo and apoPGHS-2 by 2-acetoxythioanisole (2). Apo or HoloPGHS-2 (5 mM) was inactivated with a 1000-fold excess of 2-acetoxythioanisole (2) at 22.5.degree. C. in 100 mM Tris-HCl buffer, pH 8 containing 500 mM phenol for the indicated time period, and then hydroxylamine (80 mM) in 10 mM Tris-HCl buffer, pH 7.5 was added as indicated by the arrow. Periodic 0.16 .mu.M aliquots of holoPGHS-2 (open circles), holoPGHS-2+2-acetoxythioanisole (open squares), apoPGHS-2 (closed circles), apoPGHS-2+2-acetoxythioanisole (closed squares) were analyzed for remaining cyclooxygenase activity. FIG. 7 shows the effect of pH on the inhibition of the cyclooxygenase activity of human PGHS-2 by 2-acetoxythioanisole (2). ApoPGHS-2 (5 .mu.M, 1.62 .mu.g/.mu.L) in 100 mM sodium phosphate buffer of pH 6, 7, 8, and 9 was reconstituted with 2 equivalents of hematin. Compound 2 (1000-fold excess) in DMSO was added to the reaction mixture. Periodically, 0.16 .mu.M enzyme aliquots (final inhibitor concentration .about.178 .mu.M) were analyzed for remaining cyclooxygenase activity. Open circles, cyclooxygenase activity of holoPGHS-2 treated with 2 at pH 6; closed circles, cyclooxygenase activity of holoPGHS-2+2 at pH 7; open squares, cyclooxygenase activity of holoPGHS-2+2 at pH 8; closed squares, cyclooxygenase activity of holoPGHS-2+2 at pH 9. Control experiments in the absence of inhibitor remained linear throughout the assay period. FIG. 8 shows the time- and concentration-dependent inhibition of human PGHS-2 and ovine PGHS-1 by 2-(Trifluoromethylacetoxy)thioanisole (6). HoloPGHS-1 (22 nM) or holoPGHS-2 (88 nM) was incubated with the indicated concentrations of 6 for 3 hours at room temperature. Cyclooxygenase reaction was initiated by the addition of [1-.sup.14 C]-arachidonic acid (50 .mu.M) for 30 sec at 37.degree. C. Open squares, PGHS-1+6; closed squares, PGHS-2+6. FIG. 9 shows the time- and concentration-dependent inhibition of human PGHS-2 and ovine PGHS-1 by 2-acetoxyphenyl heptyl sulfide (54) and a comparison with 2-Hydroxyphenylheptyl sulfide (38). HoloPGHS-1 (22 nM) or holoPGHS-2 (88 nM) was incubated with the indicated concentrations of 54 and 38 for 3 hours at room temperature. Cyclooxygenase reaction was initiated by the addition of [1-.sup.14 C]-arachidonic acid (50 .mu.M) for 30 seconds at 37.degree. C. Closed squares, cyclooxygenase activity of holoPGHS-2 treated with 54; open squares, cyclooxygenase activity of holoPGHS-1 treated with 54; closed circles, cyclooxygenase activity of holoPGHS-2 treated with 38; open circles, cyclooxygenase activity of holoPGHS-1 treated with 38. FIG. 10 shows the effect of pH on the inhibition of the cyclooxygenase activity of human PGHS-2 by 2-Acetoxyphenylheptyl sulfide (54). ApoPGHS-2 (5 .mu.M, 1.62 .mu.g/.mu.L) in 100 mM sodium phosphate buffer of pH 6, 7, 8, and 9 was reconstituted with 2 equivalents of hematin. Compound 54 (181 .mu.M) in DMSO was added to the reaction mixture. Periodically, 0.16 .mu.M enzyme aliquots (final inhibitor concentration .about.6 .mu.M) were analyzed for remaining cyclooxygenase activity. Open circles, cyclooxygenase activity of holoPGHS-2 treated with 54 at pH 6; closed circles, cyclooxygenase activity of holoPGHS-2+54 at pH 7; open squares, cyclooxygenase activity of holo PGHS-2+54 at pH 8; closed squares, cyclooxygenase activity of holoPGHS-2+54 at pH 9. Control experiments in the absence of inhibitor remained linear throughout the assay period. FIG. 11 shows the time-dependency and concentration-dependent inhibition of human PGHS-2 and ovine PGHS-1 by 2-Acetoxyphenyl-2-butoxyethyl sulfide (67) and 2-acetoxyphenyl-3-propionoxypropyl sulfide (71). HoloPGHS-2 (22 nM) or holoPGHS-1 (88 nM) was incubated with the indicated concentrations of 67 or 71 for 3 hours at room temperature. Cyclooxygenase reaction was initiated by the addition of [1-.sup.14 C]-arachidonic acid (50 .mu.M) for 30 sec at 37.degree. C. Closed squares, cyclooxygenase activity of holoPGHS-2 treated with 67; open squares, cyclooxygenase activity of holoPGHS-1 treated with 67; open circles, cyclooxygenase activity of holoPGHS-1 treated with 71; closed circles, cyclooxygenase activity of holoPGHS-2 treated with 71. FIG. 12 shows the time- and concentration-dependent inhibition of human PGHS-2 and ovine PGHS-1 by 2-Acetoxyphenyl-hept-2-ynl sulfide (87). HoloPGHS-1 (22 nM) or holoPGHS-2 (88 nM) was incubated with the indicated concentrations of 87 for 3 hours at room temperature. Cyclooxygenase activity was initiated by the addition of 50 .mu.M [1-14C]-arachidonic acid for 30 sec at 37.degree. C. Closed squares, cyclooxygenase activity of PGHS-2; open squares, cyclooxygenase activity of PGHS-1; closed triangles, cyclooxygenase activity of holoPGHS-2 treated with the corresponding 2-hydroxyphenyl-hept-2-ynyl sulfide (82). FIG. 13 shows the time- and concentration-dependent inhibition of human PGHS-2 and ovine PGHS-1 by 2-Acetoxyphenyl-hex-2-ynyl sulfide (88). HoloPGHS-1 (22 nM) or holoPGHS-2 (88 nM) was incubated with the indicated concentrations of (88) for 3 hours at room temperature. Cyclooxygenase activity was initiated by the addition of 50 .mu.M [1-14C]-arachidonic acid for 30 sec at 37.degree. C. Closed squares, cyclooxygenase activity of PGHS-2; open squares, cyclooxygenase activity of PGHS-1. FIG. 14 compares the inhibition of PGHS-2 in activated macrophages by 2-Acetoxythioanisole (2) with aspirin. RAW 264.7 cells were activated for 7 hours at 37.degree. C. in serum free DMEM with LPS (500 ng/mL) and .gamma.-interferon (10 U/mL). Vehicle (DMSO) or compound 2 (100 .mu.M) or aspirin (100 .mu.M) in DMSO were added for 30 min at 37.degree. C. the cyclooxygenase reaction was initiated by adding [1-.sup.14 C]-arachidonic acid (20 .mu.M) for 15 min at 37.degree. C. FIG. 15 compares the inhibition of PGHS-2 in activated macrophages by 2-(Acetoxyphenyl)heptyl sulfide (54) with aspirin. RAW 264.7 cells were activated for 7 hours at 37.degree. C. in serum free DMEM with LPS (500 ng/mL) and .gamma.-interferon (10 U/mL). Vehicle (DMSO) or compound 54 or aspirin (100 .mu.M) in DMSO were added for 30 min at 37.degree. C. The cyclooxygenase reaction was initiated by adding [1-.sup.14 C]-arachidonic acid (20 .mu.M) for 15 min at 37.degree. C. FIG. 16 shows the inhibition of PGHS-2 in activated macrophages by 2-(Acetoxyphenyl) hept-2-ynyl Sulfide (87) and 2-(Acetoxyphenyl)heptyl Sulfide (54). RAW 264.7 cells were activated for 7 hours at 37.degree. C. in serum free DMEM with LPS (500 ng/mL) and .gamma.-interferon (10 U/mL). Vehicle (DMSO) or compounds 87 and 54 in DMSO were added for 30 min at 37.degree. C. The cyclooxygenase reaction was initiated by adding [1-.sup.14 C]-arachidonic acid (20 .mu.M) for 15 min at 37.degree. C. DETAILED DESCRIPTION OF THE INVENTION Two general structural classes of prostaglandin endoperoxide synthase-2 selective inhibitors are commonly reported in the literature. In addition to selective prostaglandin endoperoxide synthase-2 inhibition in vitro, many of these compounds possess potent anti-inflammatory activity in the rat adjuvant-induced arthritis model along with exceptional safety profiles in comparison with the existing antiinflammatory agents. The structural classes include the tricyclic non-acidic arylmethyl sulfones (8-11) (exemplified by DuP 697 and SC 8092) and the acidic sulfonamides (12-15) (exemplified by Flosulide and NS-398) (FIG. 2). The arylmethyl sulfonyl moiety in the tricyclic non-acidic compounds such as SC 8092 may play a key role in the selective prostaglandin endoperoxide synthase-2 inhibition by these compounds as reduction of the sulfone group in SC 8092 to the corresponding sulfide functionality generates SC 8076, a prostaglandin endoperoxide synthase-l selective inhibitor (11) (FIG. 2). In the present invention, a variety of substituted acyloxybenzene derivatives were synthesized and examined as selective prostaglandin endoperoxide synthase-2 inhibitors. Introduction of a 2-methylthio functionality leads to the corresponding 2-acetoxythioanisole 2 derivative which displays selective inhibition of the cyclooxygenase activity of prostaglandin endoperoxide synthase-2 (IC.sub.50 (PGHS-2) .about.264 .mu.M; IC.sub.50 (PGHS-1)>5 mM). Attempts to improve the potency of 2 as a prostaglandin endoperoxide synthase-2 selective inhibitor has led to the discovery of novel 2-acetoxyphenyl alkyl and aryl sulfides some of which are .about.300 times more potent than 2 as prostaglandin endoperoxide synthase-2 selective inhibitors. Thus, the present invention provides the discovery of a new structural class of selective prostaglandin endoperoxide synthase inhibitors. Subsequent inhibition studies with .sup.14 C-radiolabled inhibitors have established that selective prostaglandin endoperoxide synthase-2 inhibition arises from acetylation of an active site amino acid residue. The present invention is the first documentation of a selective covalent modification of prostaglandin endoperoxide synthase-2 by a selective prostaglandin endoperoxide synthase-2 inhibitor. In addition to the in vitro inhibition studies with purified human prostaglandin endoperoxide synthase-2 and ovine prostaglandin endoperoxide synthase-1, the ability of these new compounds in inhibiting prostaglandin endoperoxide synthase-2 activity in murine macrophages was also examined. Most of the inhibitors displayed potent inhibition of the prostaglandin endoperoxide synthase-2 activity in murine macrophages activated with LPS and IFN-.gamma. indicating that these compounds are active in vivo as well. The present invention is directed to a compound of the formula ##STR3## . Preferably, the representative examples of compounds of the present invention are selected from the group consisting of 2-(trifluoromethylacetoxy)thioanisole, 2-(.alpha.-bromoacetoxy)thioanisole, 2-acetoxyphenylbenzyl sulfide, 2-acetoxyphenyl-2-phenylethyl sulfide, 2-acetoxyphenylpropyl sulfide, 2-acetoxyphenylbutyl sulfide, 2-acetoxyphenylpentyl sulfide, 2-acetoxyphenylhexyl sulfide, 2-acetoxyphenylheptyl sulfide, 2-acetoxyphenyl-2-butoxyethyl sulfide, 2-acetoxyphenyl-2-transheptenyl sulfide, 2-acetoxyphenylhept-2-ynyl sulfide, 2-acetoxyphenylhex-2-ynyl sulfide, 2-acetoxyphenylpent-2-ynyl sulfide, 2-acetoxyphenylbut-2-ynyl sulfide and 2-acetoxyphenylprop-2-ynyl sulfide, acetoxyphenyloct-2-ynyl sulfide, acetoxyphenylnon-2-ynyl sulfide acetoxyphenyldec-2-ynyl sulfide, 2-acetoxyphenylhept-3-ynyl sulfide, 2-[(.+-.-2-acetoxyphenylmercapto]oct-3-yne, 2-acetoxyphenyl-(6-iodohexyl) sulfide, 2-acetoxyphenyl-6-bromohexyl sulfide, 2-acetoxyphenylheptyl selenide, and 2-acetoxyphenylhept-2-ynyl ether or pharmaceutically acceptable salts or hydrates thereof. Compounds of Formula (I) are capable of inhibiting inducible proinflammatory proteins, such as cyclooxygenase-2 and are therefore useful in therapy. These proinflammatory lipid mediators of the cyclooxygenase (CO) pathway are produced by the inducible cyclooxygenase-2 enzyme. Regulation, therefore, of cyclooxygenase-2 which is responsible for these products derived from arachidonic acid, such as the prostaglandins affect a wide variety of cells and tissue states and conditions. Expression of cyclooxygenase-1 is not affected by the compounds of Formula (I). This selective inhibition of cyclooxygenase-2 may alleviate or spare ulcerogenic liability associated with inhibition of cyclooxygenase-1 thereby inhibiting prostaglandins essential for cytoprotective effects. Thus, inhibition of the proinflammatory mediators is of benefit in controlling, reducing and alleviating many of these disease states. Most notably, prostaglandins have been implicated in pain (such as in the sensitization of pain receptors) or edema. This aspect of pain management includes treatment of neuromuscular pain, headache, cancer pain and arthritis pain. Compounds of Formula (I) or a pharmaceutically acceptable salt thereof, are of use in the prophylaxis or therapy in a human, or other mammal, by inhibition of the synthesis of the cyclooxygenase-2 enzyme. Accordingly, the present invention is also directed to a method of inhibiting the synthesis of prostaglandins by inhibition of prostaglandin endoperoxide syntase-2 (PGHS-2) in a mammal in need of such treatment, comprising the step of administering to said mammal an effective amount of a compound of Formula (I). Generally, this method is useful in the prophylaxis or therapeutic treatment of edema, fever, algesia, neuromuscular pain, headache, cancer pain or arthritic pain. Representative compounds useful in this method include 2-acetoxythioanisole, 2-(trifluoromethylacetoxy)thioanisole, 2-(.alpha.-chloroacetoxy)thioanisole, 2-(.alpha.-bromoacetoxy)thioanisole, 2-acetoxyphenylbenzyl sulfide, 2-acetoxyphenyl-2-phenylethyl sulfide, 2-acetoxyphenylethyl sulfide, 2-acetoxyphenylpropyl sulfide, 2-acetoxyphenylbutyl sulfide, 2-acetoxyphenylpentyl sulfide, 2-acetoxyphenylhexyl sulfide, 2-acetoxyphenylheptyl sulfide, 2-acetoxyphenyl-2-butoxyethyl sulfide, 2-acetoxyphenyl-2-trans-heptenyl sulfide, 2-acetoxyphenylhept-2-ynyl sulfide, 2-acetoxyphenylhex-2-ynyl sulfide, 2-acetoxyphenylpent-2-ynyl sulfide, 2-acetoxyphenylbut-2-ynyl sulfide and 2-acetoxyphenylprop-2-ynyl sulfide, acetoxyphenyloct-2-ynyl sulfide, acetoxyphenylnon-2-ynyl sulfide, acetoxyphenyldec-2-ynyl sulfide, 2-acetoxyphenylhept-3-ynyl sulfide, 2-[(.+-.-2-acetoxyphenylmercapto]oct-3-yne, 2-acetoxyphenyl-(6-iodohexyl) sulfide, 2-acetoxyphenyl-6-bromohexyl sulfide, 2-acetoxyphenylheptyl selenide, and 2-acetoxyphenylhept-2-ynyl ether or pharmaceutically acceptable salts or hydrates thereof. The present invention is also directed to a pharmaceutical composition, comprising a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent. In order to a use a compound of Formula (I) or a pharmaceutically acceptable salt thereof in therapy, it will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. This invention, therefore, also relates to a pharmaceutical composition comprising an effective, non-toxic amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent. Compounds of Formula (I), pharmaceutically acceptable salt thereof and pharmaceutical compositions incorporating such, may be conveniently administered by any of the routes conventionally used for drug administration, e.g., orally, topically, parenterally, or by inhalation. The compounds of Formula (I) may b e administered in conventional dosage forms prepared by combining a compound of Formula (I) with standard pharmaceutical carriers according to conventional procedures. The compounds of the present invention may also be administered in conventional dosages in combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. It will be appreciated that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well known variable. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The pharmaceutical carrier employed may be, for example, either a solid or a liquid. Representative solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium sterate, stearic acid and the like. Representative liquid carriers include syrup, peanut oil, olive oil, water and the like. Similarly, the carrier may include time delay material well known in the art such as glyceryl monosterate or glyceryl disterarate alone or with a wax. A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1 gram. When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension. Compounds of Formula (I) may be administered topically (non-systemically). This includes the application of a compound externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the bloodstream. Formulation suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments, pastes and drops suitable for administration to the ear, eye and nose. The active ingredient may comprise, for topical administration from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the Formulation. It may however, comprise as much as 10% w/w but preferably will comprise less than 5% w/w, more preferably from 0.1% to 1% w/w of the Formulation. Lotions according to the present invention include those suitable for application to the skin and eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisterizer such as glycerol or an oil such as castor oil or arachis oil. Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap, a mucilage, an oil of natural origin such as almond, corn, archis, castor, or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel. The formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin may also be included. Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenymercuric nitrate or acetate (.about.0.002%), benzalkonium chloride (.about.0.01%) and chlorhexidine acetate (.about.0.01%). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol. Compounds of formula (I) may be administered parenterally, i.e., by intravenous, intramuscular, subcutaneous, intranasal, intrarectal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. Appropriate dosage forms for such administration may be prepared by conventional techniques. Compounds may also be administered by inhalation, e.g., intranasal and oral inhalation administration. Appropriate dosage forms for such administration, such as aerosol formulation or a metered dose inhaler may be prepared by conventional techniques well known to those having ordinary skill in this art. For all methods of use disclosed herein for the compounds of the present invention, the daily oral dosage regiment will preferably be from about 0.1 to about 100 mg/kg of total body weight. The daily parenteral dosage regiment will preferably be from about 0.1 to about 100 mg/kg of total body weight. The daily topical dosage regimen will preferably be from about 0.1 to about 15 mg, administered one to four, preferably two to three times daily. It will also be recognized by one of skill in this art that the optimal quantity and spacing of individual dosages of a compound of the present invention, or a pharmaceutically acceptable salt thereof, will be determined by the nature and extent of the condition being treated and that such optimums can be determined by conventional techniques. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phophoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety. Suitable pharmaceutically acceptable cations are well known in the art and include alkaline, alkaline earth ammonium and quaternary ammonium cations. The following examples are given for the purpose of illustrating various embodiments of the invention and are not meant to limit the present invention in any fashion. |
| PATENT EXAMPLES |
EXAMPLE 1 Chemistry Melting points were determined using a Gallenkamp melting point apparatus and are uncorrected. Tetrahydrofuran (THF) was distilled from sodium benzophenone ketyl. Acetonitrile was distilled over calcium hydride. Unless stated otherwise, synthetic reactions were carried out under a argon atmosphere. All chemicals (Aldrich, Milwaukee, Wis. or Lancaster, Pa.) were reagent grade or better. .sup.1 H NMR spectra were recorded on a Bruker WP-360 or AM 400 spectrometers; chemical shifts are expressed in parts per million relative to internal tetramethylsilane (TMS) standard and spin multiplicities are given as s (singlet), bs (broad singlet), d (doublet), dd (doublet of doublet), t (triplet), q (quartet), and m (multiplet). Fast atom bombardment mass spectra (FAB-MS) were recorded on a Kratos Concept II HH four sector mass spectrometer. Column chromatography was performed using silica gel (60-100 mesh) from Fisher. EXAMPLE 2 Synthesis of 2-Hydroxy-1-methylphenylsulfone (3) To a reaction mixture containing 2-hydroxy-1-methylphenylmercaptan (1, 1 g, 7.13 mmol) in 20 mL of glacial acetic acid was added 30% H.sub.2 O.sub.2 (14 mL) dropwise at 0.degree. C. After the addition was complete, the reaction was warmed to 100.degree. C. and allowed to stir overnight. The mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (EtOAc:pet ether; 90:10) and then recrystallized from EtOH/ H.sub.2 O to afford 3 as a white crystalline solid in 52% yield: mp 95-97.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.8.85 (s, 1 H, OH), 7.67-7.71 (dd, 1 H, ArH), 7.51-7.56 (t, 1 H, ArH), 7.02-7.06 (m, 2 H, ArH), 3.13 (s, SO.sub.2 CH.sub.3). FAB-MS 173 (MH.sup.+, 55), 157 (55), 93 (30), 79 (100) (FIG. 2B). 2-Hydroxyphenylheptyl sulfone (92) was prepared in a similar manner as a colorless oil (137 mg, 62%). .sup.1 H NMR (CDCl.sub.3) .delta.7.62-7.64 (dd, 1 H, ArH), 7.51-7.55 (t, 1 H, ArH), 7.01-7.05 (m, 2 H, ArH), 3.11-3.15 (t, 2 H, CH.sub.2), 1.70-1.78 (m, 2 H, CH.sub.2), 1.24-1.36 (m, 8 H, CH.sub.2), 0.84-0.87 (t, 3 H, CH.sub.3) (FIG. 2J). EXAMPLE 3 Acetylation of the Phenol Derivatives: Method A A reaction mixture containing appropriate arenol (14.26 mmol) in 5 mL of acetic anhydride and 5 drops of H.sub.3 PO.sub.4 was heated on a water bath for 15 min. Water (10 mL) was added dropwise to the hot reaction mixture which was then cooled in an ice-bath. The aqueous solution was extracted with CHCl.sub.3 (3.times.30 mL). The combined organic extracts were washed with water, dried (MgSO.sub.4), filtered, and the solvent was removed under vacuo to afford the crude product which was purified on silica gel with EtOAc:petroleum ether (10:90) to afford the desired product in near quantitative yields. 2-Acetoxy-1-methylphenylsulfone (4) White crystalline solid from EtOH/H.sub.2 O in 91% yield: mp 107-109.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.8.01-8.04 (dd, 1 H, ArH), 7.65-7.68 (t, 1 H, ArH), 7.41-7.46 (t, 1 H, ArH), 7.25-7.28 (d, 1 H, ArH), 3.12 (s, 3 H, SO.sub.2 CH.sub.3), 2.3 (s, 3 H, COCH.sub.3) (FIG. 2B). 2-Acetoxyanisole (5) Colorless oil in 78% yield. .sup.1 H NMR (CDCl.sub.3) .delta.7.02-7.05 (t, 1H, ArH), 6.94-6.98 (m, 3 H, ArH), 3.83 (s, 3 H, CH.sub.3), 2.31 (s, 3 H, CH.sub.3); FAB-MS MH.sup.+ 167 (100), 124 (60), 79 (80). EXAMPLE 4 Acetylation of the Phenol Derivatives: Method B A reaction mixture containing 2-mercaptomethylphenol (1, 0.3 g, 2.14 mmol) in 5 mL of CH.sub.2 Cl.sub.2 was treated with dry pyridine (0.169 g, 2.2 mmol) and appropriate acid anhydride (2.14 mmol). The reaction mixture was stirred overnight and then diluted with water. The aqueous solution was extracted with Et.sub.2 O (3.times.10 mL). The combined organic solution was washed with water, dried (MgSO.sub.4), filtered, and the solvent was removed under vacuo. The crude product was chromatographed on silica gel and eluted with EtOAc:petroleum ether (2:98) to afford the desired product. Thus, 2-acyloxythioanisole analogs 6-14 were synthesized (FIG. 2B). 2-Acetoxyphenylheptyl sulfone (93) colorless oil in 56% yield. .sup.1 H NMR (CDCl.sub.3) .delta.7.98-8.0 (dd, 1 H, ArH), 7.65-7.69 (t, 1 H, ArH), 7.41-7.45 (t, 1 H, ArH), 7.24-7.26 (d, 1 H, ArH), 3.21-3.25 (t, 2 H, CH.sub.2), 2.37 (s, 3 H, COCH.sub.3), 1.62-1.72 (m, 2 H, CH.sub.2), 1.24-1.38 (m, 8 H, CH.sub.2), 0.84-0.87 (t, 3 H, CH.sub.3); FAB-MS 299 (MH.sup.+, 40), 257 (100), 79 (24) (FIG. 2J). EXAMPLE 5 Synthesis of 2-(Methoxymethyleneoxy)thioanisole (15) (Method A) To a reaction mixture containing 2-hydroxythioanisole (1, 1 g, 7.14 mmol) in dry pyridine (0.3 g, 3.9 mmol) was added powdered KOH (0.4 g, 7.09 mmol) (FIG. 2C). The resulting solution was treated with methoxymethylchloride (0.72 g, 9.0 mmol), heated to reflux for 3.5 hours, cooled and partitioned between 1 M NaOH and diethyl ether. The organic solution was washed with 1 M HCl (2.times.30 mL), brine (50 mL), and then dried (MgSO.sub.4). The solvent was removed under vacuo and the crude product was chromatographed on silica gel and eluted with petroleum ether:EtOAc (95:5) to afford the desired product as an colorless oil (1 g, 83%). .sup.1 H NMR (CDCl.sub.3) .delta.7.01-7.17 (m, 4 H, ArH), 5.25 (s, 2 H, CH.sub.2), 3.52 (s, 3 H, OCH.sub.3), 2.43 (s, 3 H, SCH.sub.3); FAB-MS 184 (MH.sup.+ -1, 20), 167 (25), 149 (100). EXAMPLE 6 Synthesis of 2-(Methoxymethyleneoxy)thioanisole (15) (Method B) To a reaction mixture containing 2-hydroxythioanisole (1, 1 g, 7.14 mmol) in dry acetonitrile (30 mL) was added potassium fluoride activated alumina powder (8 g) and methoxymethylchloride (0.72 g, 9.0 mmol) (FIG. 2C). The mixture was stirred overnight at room temperature. The reaction mixture was filtered over celite and the solvent was evaporated under vacuo. The residue was partitioned between water and diethyl ether. The organic solution was washed with water and then dried (MgSO.sub.4). The solvent was removed under vacuo and the crude product was chromatographed on silica gel and eluted with petroleum ether:EtOAc (95:5) to afford the desired product as an colorless oil (1.1 g, 85%). |
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