Potent anti-inflammatory soft corticosteroid compounds and uses thereof

Abstract

To provide a method for treating a disease.SOLUTION: Provided are potent soft corticosteroids, a pharmaceutical composition comprising the same, and a method for using the same as an anti-inflammatory agent. Also provided is a method for softening fluticasone propionate and similar corticosteroid and attaining a potent but safer alternative. Compounds which are equally as potent as fluticasone but safer than fluticasone, in particular S-fluoromethyl 17α-dichloroacetoxy-6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-dien-17β-carbothioate is provided. Another compound of particular interest is 2-hydroxyethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 518,922, filed June 13, 2017, U.S. Provisional Patent Application No. 62 / 559,201, filed September 15, 2017, and U.S. Provisional Patent Application No. 62 / 562,099, filed September 22, 2017, all of which are incorporated by reference in their entirety and relied upon herein.

[0002] Field Potent soft corticosteroids, pharmaceutical compositions containing them, and methods for their use as anti-inflammatory agents, as well as methods for softening fluticasone propionate and similar corticosteroids to arrive at potent but safer alternatives. [Background technology]

[0003] Background technology Topical or other local applications of potent glucocorticoids can produce severe toxic effects such as Cushingoid facies, pituitary-adrenal suppression, skin atrophy, immunosuppression, and impaired wound healing. Other types of toxic reactions, including allergies and cataracts, can result from long-term use of this type of drug.

[0004] Ocular application of glucocorticosteroids poses additional problems. Due to the ocular defense mechanisms, only a small fraction of the dose applied to the eye reaches its target site, with over 90 percent of the total dose typically reaching the systemic circulation. This, in turn, results in the serious systemic side effects described above. Furthermore, the use of these drugs in the eye can result in a more serious and specific side effect: elevated intraocular pressure (IOP). Indeed, corticosteroid-induced chronic or acute glaucoma has been reported since the early 1960s. Generally, corticosteroids are only needed topically to manage inflammation. However, absorbed steroids are associated with the serious side effects described above. The effects of corticosteroids on glycosaminoglycans (GAGs) in the aqueous humor outflow tract and adjacent tissues are thought to be important in the development of glucocorticoid-induced ocular hypertension.

[0005] Therefore, there is a great need for potent topical anti-inflammatory steroids that lack systemic effects and consequently do not produce the serious systemic side effects associated with this class of drugs.

[0006] "Soft" steroids are compounds that have potent anti-inflammatory activity comparable to conventional steroids but have minimal systemic effects. These compounds include Δ 4 and Δ 1,4 These include 17α-alkoxy-11β-hydroxy-3-oxoandrostenes, as well as related 11-substituted compounds that are esters or thioesters of 17β-carboxylic acids. These 17α-ethers are described in U.S. Patent No. 4,710,495 to Bodor. Preferred compounds are taught to be haloalkyl esters of 17α-alkoxy-11β-hydroxyandrost-4-en-3-one-17β-carboxylic acids.

[0007] Another series of "soft" steroids described as having potent anti-inflammatory activity but minimal systemic effects are the 17α-carbonates of Bodor, U.S. Patent No. 4,996,335. These compounds include, in preferred embodiments, haloalkyl 17α-alkoxycarbonyloxy-11β-hydroxyandrost-4-en-3-one- 17β-carboxylates and the corresponding Δ 1,4 One of these compounds is chloromethyl 17α-ethoxycarbonyloxy-11β-hydroxyandrosta-1,4-dien-3-one-17β-carboxylate, also known as loteprednol etabonate (LE), which was approved by the FDA in 1998 and is sold worldwide in five or more products.

[0008] Throughout the design and development of the first generation of "soft" corticosteroids, over 120 compounds were synthesized and studied, combining the soft pharmacophore core of 17α-carbonate-17β-chloromethyl ester with conventional modifications of the corticosteroid structure (e.g., fluorination at 6α and / or 9α, methylation at 16α and 16β positions, and altering the 17β-ester and 17α-carbonate functional groups). QSAR studies suggested that known potency-enhancing groups are also highly effective in this type of soft steroid. Relative receptor binding activity (RRBA) values ​​correlated closely with the presence or absence of fluoro substituents, molecular volume (calculated by semiempirical quantum chemical methods), and calculated partition coefficients. Some substituted LE derivatives were extremely potent; for example, the 6α,9α-difluoro-16α-methylloteprednol derivative exhibited the highest RRBA (2100, compared with 100 for dexamethasone) of any known corticosteroid. However, it was discovered that in this class, the more potent the new steroids, the less "soft" they were. In other words, they were closer to currently known potent corticosteroids, which are not readily hydrolyzed / inactivated but are susceptible to oxidative metabolism. Thus, compounds substituted at positions 6, 9, and 16 ultimately proved not to be true "soft" drugs.

[0009] Etyprednol dichloroacetate (ED; ethyl 17α-dichloroacetoxy-11β-hydroxyandrosta-1,4-dien-3-one-17β-carboxylate) is an inactive metabolite of prednisolone. 1 EDTA is a second-generation soft corticosteroid designed using retrometabolic principles, starting with 1-cortienic acid (1), which is converted to 17α-dichloroacetate (2) and esterification to EDTA (3). See Scheme 1 below; see also U.S. Patent No. 5,981,517 to Bodor. [ka]

[0010] ED is a unique second-generation "soft" corticosteroid, the first to contain a halogen substituent at the 17α position, which in fact serves as an important pharmacophore. It has been shown that the dichloro functionality is required for activity (monochloro derivatives lack activity due to the unfavorable positioning of the chlorine atom due to steric hindrance). The dichloroacetyl functionality is also responsible for the "soft" nature of ED. The dichloro substituent increases the second-order rate constant, kcat / kM, of the enzymatic hydrolysis of the acetate ester by 20-fold compared to the unsubstituted ester, whereas the monochlorine substituent causes no change. In contrast to the first generation of "soft" corticosteroids based on corticosteroids, represented by loteprednol etabonate (LE; 4), which are hydrolytically inactivated by ester cleavage of the 17β-chloromethyl ester, in ED, hydrolysis does not cleave at the 17β-ester but primarily at the 17α-dichloroacetyl functionality. Nevertheless, the corresponding 17α-OH-metabolite is inactive, thus fulfilling the requirements of a soft drug. [ka]

[0011] However, there is still a great need in the art for new anti-inflammatory steroids that have potent, localized anti-inflammatory activity but minimal or no systemic effects. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] U.S. Patent No. 4,710,495 [Patent Document 2] U.S. Patent No. 4,996,335 [Patent Document 3] U.S. Patent No. 5,981,517 Summary of the Invention [Means for solving the problem]

[0013] overview As mentioned above, Δ 1 Second-generation soft steroids based on α-corticoic acid (etiprednol dichloroacetate) appear to be hydrolyzed primarily to the 17α-dichloroacetate rather than the 17β-ester. In some animal species, both ester functional groups can be hydrolyzed, which has a strong influence on the "soft" nature of these compounds. Conversely, the ED is somewhat more potent than LE (RRBA of approximately 200 vs. 160). Surprisingly, potency-enhancing conventional F or Cl substitutions in the 6α and 9α and 16α-methyl or β-methyl groups can result in even more potent yet softer corticosteroids, unlike the situation with first-generation LE family compounds. Therefore, we undertook the synthesis of this new and select class of steroids and report on their properties here.

[0014] In a first principal exemplary embodiment of the present application, a soft corticosteroid is provided that has enhanced topical or localized anti-inflammatory activity and an improved therapeutic index compared to fluticasone propionate, the compound having formula (I): [ka] wherein each X is independently F or Cl and Y is O or S.

[0015] In another exemplary embodiment, the soft corticosteroid of formula (I) is S-fluoromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate (fluticasone dichloroacetate); S-chloromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta androsta-1,4-diene-17β-carbothioate; fluoromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate; or chloromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate. Among the compounds of formula (I), the most similar analogs of fluticasone propionate, i.e., the just-named S-fluoromethyl compounds, possess significant activity while possessing the desired hydrolysis susceptibility, making them potent yet safer alternatives to fluticasone propionate.

[0016] In another exemplary embodiment, an anti-inflammatory effective amount of a compound having Formula (I): [ka] wherein each X is independently selected from the group consisting of F and Cl; and Y is O or S. A pharmaceutical composition is provided comprising a compound selected from the group consisting of benzodiazepines, ... In more specific embodiments, the compound of formula (I) is S-fluoromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate; S-chloromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate; fluoromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate; or chloromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate.

[0017] In yet a further embodiment, there is provided an ophthalmic composition comprising an anti-inflammatory effective amount of a compound of formula (I) above and an ophthalmologically acceptable, non-toxic carrier for said compound. In a more specific embodiment, the compound of formula (I) is one of the four specific compounds named above.

[0018] Another embodiment herein provides a method for reducing inflammation in or on a warm-blooded animal exhibiting a localized inflammatory response. The method comprises the step of topically administering to said animal an anti-inflammatory effective amount of a compound of formula (I), particularly when the compound is one of the four specific compounds named above, or an anti-inflammatory effective amount of a pharmaceutical composition as defined above, particularly when the compound of formula (I) is one of the four specific compounds named above.

[0019] Another embodiment herein is a method for reducing inflammation in or on a warm-blooded animal exhibiting a local inflammatory response, the method comprising the step of locally administering to said animal an anti-inflammatory effective amount of a compound of formula (I), particularly when the compound is one of the four specific compounds named above, or an anti-inflammatory effective amount of a pharmaceutical composition as defined above, particularly when the compound of formula (I) is one of the four specific compounds named above.

[0020] Another embodiment herein is a method for reducing inflammation in the eye(s) of a warm-blooded animal exhibiting an ocular inflammatory response, the method comprising administering to the eye(s) of said animal an anti-inflammatory effective amount of a compound of formula (I), particularly when the compound is one of the four specific compounds named above, or an anti-inflammatory effective amount of an ophthalmic composition as defined above, particularly when the compound of formula (I) is one of the four specific compounds named above.

[0021] Another embodiment is a method for reducing inflammation of the nasal mucosa in a warm-blooded animal exhibiting a nasal inflammatory response, the method comprising the step of intranasally administering to said animal an anti-inflammatory effective amount of a compound of formula (I), particularly when the compound of formula (I) as defined above is one of the four specific compounds named above, or an anti-inflammatory effective amount of a pharmaceutical composition as defined above, particularly when the compound of formula (I) is one of the four specific compounds named above.

[0022] Yet another embodiment is a method for alleviating asthma or COPD in the lungs or bronchi of a warm-blooded animal exhibiting an inflammatory response in the lungs or bronchi, which method comprises administering to a subject a compound of formula (I) as defined above in an anti-inflammatory effective amount, particularly when that compound is one of the four specific compounds named above, or in particular a compound of formula (I) is one of the four specific compounds named above, comprising administering to said animal by oral inhalation an anti-inflammatory effective amount of a pharmaceutical composition as defined above.

[0023] Yet another embodiment is a method for reducing inflammation of the upper or lower intestinal tract in a warm-blooded animal exhibiting an intestinal inflammatory response, the method comprising the step of rectally administering to said animal an anti-inflammatory effective amount of a compound of formula (I) as defined above, particularly when the compound is one of the four specific compounds named above, or an anti-inflammatory effective amount of a pharmaceutical composition as defined above, particularly when the compound of formula (I) is one of the four specific compounds named above.

[0024] Another embodiment is a method for reducing inflammation of the upper or lower intestinal tract in a warm-blooded animal exhibiting an intestinal inflammatory response, the method comprising orally administering to said animal an anti-inflammatory effective amount of a compound of formula (I) as defined above, particularly when the compound is one of the four specific compounds named above, or an anti-inflammatory effective amount of a pharmaceutical composition as defined above, particularly when the compound of formula (I) is one of the four specific compounds named above.

[0025] Yet another embodiment is a method for reducing inflammation in the ear(s) of a warm-blooded animal exhibiting an ear inflammatory response, the method comprising the step of administering to the ear(s) of said animal an anti-inflammatory effective amount of a compound of formula (I), particularly when the compound of formula (I) as defined above is one of the four specific compounds named above, or an anti-inflammatory effective amount of a pharmaceutical composition as defined above, particularly when the compound of formula (I) is one of the four specific compounds named above.

[0026] Another embodiment is a method for reducing inflammation in a joint or joints of a warm-blooded animal exhibiting an arthritic inflammatory response, the method comprising the step of injecting into said joint or joints an anti-inflammatory effective amount of a compound of formula (I) as defined above, particularly when the compound is one of the four specific compounds named above, or an anti-inflammatory effective amount of a pharmaceutical composition as defined above, particularly when the compound of formula (I) is one of the four specific compounds named above.

[0027] A still further embodiment is a method for reducing inflammation of the skin of a warm-blooded animal exhibiting an inflammatory skin response, the method comprising transdermally administering to said animal an anti-inflammatory effective amount of a compound of formula (I) as defined above, particularly when the compound is one of the four specific compounds named above, or an anti-inflammatory effective amount of a pharmaceutical composition as defined above, particularly when the compound of formula (I) is one of the four specific compounds named above.

[0028] Yet another embodiment herein is a method for reducing inflammation of the mouth, gums or throat of a warm-blooded animal exhibiting an inflammatory reaction of the mouth, gums or throat, the method comprising orally administering to said animal an anti-inflammatory effective amount of a compound of formula (I) as defined above, particularly when the compound is one of the four specific compounds named above, or an anti-inflammatory effective amount of a pharmaceutical composition as defined above, particularly when the compound of formula (I) is one of the four specific compounds named above.

[0029] In yet a further embodiment, there is provided a process for softening a 17α-alkylcarbonyloxy-substituted corticosteroid compound of formula (II): [ka] wherein each X is independently F or Cl, Y is O or S, and R is C1-C3 alkyl, and the compound of formula (II) has topical or localized corticosteroid activity as well as systemic corticosteroid activity, and the process comprises the step of synthesizing a corresponding corticosteroid compound in which the 17α-OCOR group in formula (II) is replaced with a 17α-dichloroacetoxy (17α-OCOCHCl2) group to obtain the resulting soft corticosteroid compound of formula (I), [ka] wherein X and Y are as defined above in formula (II), and the compound of formula (I) has substantially equivalent topical or localized corticosteroid activity compared to the corresponding compound of formula (II), but has substantially reduced systemic corticosteroid activity compared to the corresponding compound of formula (II). In a specific embodiment of this process, the resulting soft corticosteroid compound of formula (I) is S-fluoromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate; S-chloromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta androsta-1,4-diene-17β-carbothioate; fluoromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate; or chloromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate.

[0030] In a second principal exemplary embodiment of the present application, there is provided a soft corticosteroid having enhanced topical or localized anti-inflammatory activity and an improved therapeutic index compared to the corresponding 17α-alkoxycarbonyl (—OCOR) ester, the compound being represented by formula (III): [ka] wherein each X' is independently H, F, or Cl, provided that at least one X' is F or Cl, Y is O or S, and the wavy line indicates the α or β configuration.

[0031] In another exemplary embodiment, the soft corticosteroid of Formula (III) is 2-hydroxyethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate or 2-hydroxyethyl 17α-dichloroacetoxy-9α-fluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate. The compounds of Formula (III) possess significant activity while possessing desirable hydrolytic susceptibility, making them potent yet safer alternatives to the corresponding 17α-alkoxycarbonyl (-OCOR) esters.

[0032] In another exemplary embodiment, an anti-inflammatory effective amount of a compound having Formula (III): [ka] wherein each X' is independently selected from the group consisting of H, F, and Cl, provided that at least one X' is F or Cl, Y is O or S, and the wavy line represents an α or In a more specific embodiment, the compound of formula (III) is 2-hydroxyethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate or 2-hydroxyethyl 17α-dichloroacetoxy-9α-fluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate.

[0033] In yet a further embodiment, there is provided an ophthalmic composition comprising an anti-inflammatory effective amount of a compound of formula (III) above and an ophthalmologically acceptable non-toxic carrier for said compound. In a more specific embodiment, the compound of formula (III) is one of the two specific compounds named above.

[0034] Another embodiment herein is a method for reducing inflammation in or on a warm-blooded animal exhibiting a localized inflammatory response, the method comprising the step of topically administering to said animal an anti-inflammatory effective amount of a compound of formula (III) as defined above, particularly when the compound is one of the two specific compounds of formula (III) named above, or an anti-inflammatory effective amount of a pharmaceutical composition as defined above, particularly when the compound of formula (III) is one of the two specific compounds named above.

[0035] Another embodiment herein is a method for reducing inflammation in or on a warm-blooded animal exhibiting a local inflammatory response, the method comprising the step of locally administering to said animal an anti-inflammatory effective amount of a compound of formula (III) as defined above, particularly when the compound is one of the two specific compounds of formula (III) named above, or an anti-inflammatory effective amount of a pharmaceutical composition as defined above, particularly when the compound of formula (III) is one of the two specific compounds named above.

[0036] Another embodiment herein is a method for reducing inflammation in the eye(s) of a warm-blooded animal exhibiting an ocular inflammatory response, the method comprising the step of administering to the eye(s) of said animal an anti-inflammatory effective amount of a compound of formula (III), particularly when the compound of formula (III) as defined above is one of the two specific compounds of formula (III) named above, or an anti-inflammatory effective amount of an ophthalmic composition as defined above, particularly when the compound of formula (III) is one of the two specific compounds named above.

[0037] Another embodiment is a method for reducing inflammation of the nasal mucosa in a warm-blooded animal exhibiting a nasal inflammatory response, the method comprising the step of intranasally administering to said animal an anti-inflammatory effective amount of a compound of formula (III), particularly when the compound of formula (III) as defined above is one of the two specific compounds named above, or an anti-inflammatory effective amount of a pharmaceutical composition as defined above, particularly when the compound of formula (III) is one of the two specific compounds named above.

[0038] Yet another embodiment is a method for alleviating asthma or COPD in the lungs or bronchi of a warm-blooded animal exhibiting an inflammatory response in the lungs or bronchi, the method comprising administering to said animal by oral inhalation an anti-inflammatory effective amount of a compound of formula (III), particularly when the compound of formula (III) as defined above is one of the two specific compounds of formula (III) named above, or an anti-inflammatory effective amount of a pharmaceutical composition as defined above, particularly when the compound of formula (III) is one of the two specific compounds named above.

[0039] Yet another embodiment is a method for reducing inflammation of the upper or lower intestinal tract in a warm-blooded animal exhibiting an intestinal inflammatory response, the method comprising the step of rectally administering to said animal an anti-inflammatory effective amount of a compound of formula (III), particularly when the compound of formula (III) as defined above is one of the two specific compounds named above, or an anti-inflammatory effective amount of a pharmaceutical composition as defined above, particularly when the compound of formula (III) is one of the two specific compounds named above.

[0040] Another embodiment is a method for reducing inflammation of the upper or lower intestinal tract in a warm-blooded animal exhibiting an intestinal inflammatory response, the method comprising orally administering to said animal an anti-inflammatory effective amount of a compound of formula (III), particularly when the compound of formula (III) as defined above is one of the two specific compounds named above, or an anti-inflammatory effective amount of a pharmaceutical composition as defined above, particularly when the compound of formula (III) is one of the two specific compounds named above.

[0041] Yet another embodiment is a method for reducing inflammation in the ear(s) of a warm-blooded animal exhibiting an ear inflammatory response, the method comprising the step of administering to the ear(s) of said animal an anti-inflammatory effective amount of a compound of formula (III), particularly when the compound of formula (III) as defined above is one of the two specific compounds named above, or an anti-inflammatory effective amount of a pharmaceutical composition as defined above, particularly when the compound of formula (III) is one of the two specific compounds named above.

[0042] Another embodiment is a method for reducing inflammation in a joint or joints of a warm-blooded animal exhibiting an arthritic inflammatory response, the method comprising the step of injecting into said joint or joints an anti-inflammatory effective amount of a compound of formula (III), particularly when the compound of formula (III) as defined above is one of the two specific compounds named above, or an anti-inflammatory effective amount of a pharmaceutical composition as defined above, particularly when the compound of formula (III) is one of the two specific compounds named above.

[0043] A still further embodiment is a method for reducing inflammation of the skin of a warm-blooded animal exhibiting an inflammatory skin response, the method comprising the step of transdermally administering to said animal an anti-inflammatory effective amount of a compound of formula (III), particularly when the compound of formula (III) as defined above is one of the two specific compounds named above, or an anti-inflammatory effective amount of a pharmaceutical composition as defined above, particularly when the compound of formula (III) is one of the two specific compounds named above.

[0044] Yet another embodiment herein is a method for reducing inflammation of the mouth, gums or throat of a warm-blooded animal exhibiting an inflammatory reaction of the mouth, gums or throat, the method comprising orally administering to said animal an anti-inflammatory effective amount of a compound of formula (III), particularly when the compound of formula (III) as defined above is one of the two specific compounds named above, or an anti-inflammatory effective amount of a pharmaceutical composition as defined above, particularly when the compound of formula (III) is one of the two specific compounds named above.

[0045] In yet a further embodiment, there is provided a process for softening a 17α-alkylcarbonyloxy-substituted corticosteroid compound of formula (IV), comprising: [ka] wherein each X' is independently H, F or Cl, provided that at least one X' is F or Cl, Y is O or S, R is C1-C3 alkyl, and the wavy line indicates the α or β configuration; wherein the compound of formula (IV) has topical or localized corticosteroid activity as well as systemic corticosteroid activity; and the process comprises the step of synthesizing a corresponding corticosteroid compound in which the 17α-OCOR group in formula (IV) is replaced with a 17α-dichloroacetoxy (17α-OCOCHCl2) group to obtain the resulting soft corticosteroid compound of formula (III); [ka] wherein X', Y, and the wavy line are as defined above in formula (IV), and the compound of formula (III) has substantially equivalent topical or localized corticosteroid activity compared to the corresponding compound of formula (IV), but has substantially reduced systemic corticosteroid activity compared to the corresponding compound of formula (IV). In a specific embodiment of this process, the resulting soft corticosteroid compound of formula (III) is 2-hydroxyethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate; or 2-hydroxyethyl 17α-dichloroacetoxy-9α-fluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate.

[0046] In yet a further embodiment, a pharmaceutical composition suitable for topical or other local application There is provided the use of a compound having formula (I) in the preparation of [ka] wherein each X is independently F or Cl and Y is O or S, and the pharmaceutical composition comprises an anti-inflammatory effective amount of the compound and a pharmaceutically acceptable, non-toxic carrier for the compound.

[0047] In yet another exemplary embodiment, there is provided a use of a compound having formula (I) in the preparation of an ophthalmic composition: [ka] wherein each X is independently F or Cl and Y is O or S, and the ophthalmic composition comprises an anti-inflammatory effective amount of the compound and an ophthalmologically acceptable, non-toxic carrier for the compound.

[0048] In a further exemplary embodiment, a pharmaceutical composition suitable for topical or other local application is provided for use in reducing inflammation in or on a warm-blooded animal exhibiting an inflammatory response, the pharmaceutical composition comprising an anti-inflammatory effective amount of a compound having formula (I): [ka] wherein each X is independently F or Cl and Y is O or S, and a pharmaceutically acceptable, non-toxic carrier for the compound, wherein the inflammatory response is localized or regional. In another exemplary embodiment, an anti-inflammatory effective amount of a compound having formula (I): [ka] wherein each X is independently F or Cl and Y is O or S; and an ophthalmologically acceptable, non-toxic carrier for the compound.

[0049] In yet another exemplary embodiment, formula (IV) [ka] wherein each X' is independently H, F, or Cl, with the proviso that at least one X' is F or Cl, Y is O or S, R is C1-C3 alkyl, and the wavy line indicates the α or β configuration, by replacing the 17α-OCOR group with a 17α-dichloroacetoxy (17α-OCOCHCl2) group to provide a soft corticosteroid compound of formula (III): [ka] wherein each of X' and Y is as defined in formula (IV) above, wherein the compound of formula (IV) has topical or localized corticosteroid activity as well as systemic corticosteroid activity, and the compound of formula (III) has substantially equivalent topical or localized corticosteroid activity as compared to the corresponding compound of formula (IV), but has substantially reduced systemic corticosteroid activity as compared to the corresponding compound of formula (IV).

[0050] In another exemplary embodiment, there is provided a use of a compound having formula (III) in the preparation of a pharmaceutical composition suitable for topical or other local application: [ka] wherein each X' is independently H, F, or Cl, provided that at least one X' is F or Cl, Y is O or S, and the wavy line indicates the α or β configuration; and the pharmaceutical composition comprises an anti-inflammatory effective amount of the compound and a pharmaceutically acceptable, non-toxic carrier for the compound.

[0051] In yet another exemplary embodiment, there is provided a use of a compound having formula (III) in the preparation of an ophthalmic composition: [ka] wherein each X' is independently H, F, or Cl, provided that at least one X' is F or Cl, Y is O or S, and the wavy line indicates the α or β configuration; and the ophthalmic composition comprises an anti-inflammatory effective amount of the compound and an ophthalmically acceptable, non-toxic carrier for the compound.

[0052] In another exemplary embodiment, there is provided a pharmaceutical composition suitable for topical or other local application for use in reducing inflammation in or on a warm-blooded animal exhibiting an inflammatory response, the pharmaceutical composition comprising an anti-inflammatory effective amount of a compound having formula (III): [ka] wherein each X' is independently H, F, or Cl, with the proviso that at least one X' is F or Cl, Y is O or S, and the wavy line indicates the α or β configuration, and a pharmaceutically acceptable, non-toxic carrier for the compound, wherein the inflammatory response is localized or regional.

[0053] In yet another exemplary embodiment, an anti-inflammatory effective amount of a compound having formula (III): [ka] wherein each X' is independently H, F, or Cl, with the proviso that at least one X' is F or Cl, Y is O or S, and the wavy line indicates the α or β configuration; and an ophthalmologically acceptable, non-toxic carrier for the compound. DETAILED DESCRIPTION OF THE INVENTION

[0054] Detailed Description As used herein, the term "softening" refers to reducing the systemic corticosteroid activity / toxicity (or side effects) of an anti-inflammatory corticosteroid by replacing oxidatively metabolizable groups in the corticosteroid compound (e.g., as in (II)) with readily hydrolyzable groups, while maintaining high local / regional corticosteroid activity. In particular, the term "softening" refers to reducing the systemic corticosteroid activity / toxicity (or side effects) of an anti-inflammatory corticosteroid by replacing oxidatively metabolizable groups in the corticosteroid compound (e.g., as in (II)) with readily hydrolyzable groups. This means synthesizing a corticosteroid compound [(I) or (III) above] in which the 17α-OCOR group is replaced with a 17α-dichloroacetoxy (17α-OCOCHCl2) group, while retaining potency-enhancing substitutions at the 6α, 9α, and 16α positions of compound (II) or (IV), respectively, to yield the corresponding (I) or (III).

[0055] The synthesis of ED(3) is illustrated above in Scheme 1. Using a process similar to that shown for compounds of formula 3, but 1 ED analogs represented by general formula 5 were synthesized by replacing -cortienic acid with fluorinated analogs 6 and 7 shown below. [ka]

[0056] Cortienic acids 6 and 7 were converted to the corresponding 17α-dichloroacetyl esters, which were the starting materials for various 17β-esters 8-15, listed in Table 1 below and included in the use examples hereinafter.

[0057] Finally, commercially available 6α,9α-difluoro-16α-methylprednisolone (18), a precursor of fluticasone propionate (FLU), one of the most used and highly potent corticosteroids, was oxidized to the corresponding coltienic acid derivative 19, which was then converted, if necessary, to thiocoltienic acid 23. As illustrated in Scheme 2 below, dichloroacetylation of 19 and 23 to 20 and 24, respectively, followed by esterification of the 17β-carboxy function, led to the target halo (Cl or F) 16α-methyl esters 21, 22, 25, and 26. [ka]

[0058] Compound 25 is a soft analog of fluticasone propionate in which the 17α-propionyl functionality is replaced with a more hydrolytically unstable dichloroacetyl functionality. Compound 25 and some of its other structural analogs are surprisingly superior to fluticasone in terms of being highly active yet having improved safety and therefore improved therapeutic indices. [ka]

[0059] Etiprednol dichloroacetate and its analogs significantly inhibited IL-1β release from the human monocytic cell line THP-1. The in vitro anti-inflammatory effects of Etiprednol dichloroacetate and its analogs were evaluated using LPS-induced TNFα release under various conditions (diluted or undiluted human whole blood, preincubation with serum) to measure the intrinsic anti-inflammatory activity and systemic biological stability of the various compounds. The results are shown in Table 1.

[0060] Two representative analogs of ED were selected for in vivo studies in the widely used ovalbumin-sensitized and challenged Brown Norway rat model. Allergic challenge in this animal leads to widespread inflammation in the lungs, characterized by increased numbers of eosinophils and mucus-producing goblet cells, and perivascular edema exudates. Furthermore, airway hyperresponsiveness, a major feature of asthma, also develops. ED was then compared with the selected 9α-fluoro-16β-methyl analog (11) in this model. Finally, fluticasone analog 25 was compared with fluticasone. The results are summarized in Table 2.

[0061] Table 1: In vitro anti-inflammatory activity (IC in nM) of selected 17α-dichloroacetoxyetiprednol analogs represented by structure (5). 50 value): [Table 1] * Inhibition of TNFα production in blood cells stimulated with LPS. Variability reflects differences in the blood of different individuals (3-6 individuals donated blood). (a) Diluted blood 1:5 (b) Undiluted ** Inhibition of mitogen-induced PBMC proliferation *** Inhibition of TNF-α production in LPS-stimulated whole blood cells (IC in nM) 50 ) (c) No preincubation in human plasma (d) Overnight preincubation

[0062] Table 2: Effects of etiprednol dichloroacetate (ED), analog 11, fluticasone (FLU) and its analog 25 administered intratracheally (2 hours before challenge) on airway changes in ovalbumin-sensitized and challenged Brown Norway rats (N=10). [Table 2] * ED50 = 50% effective dose (Prisma); MSED = minimum statistically significant effective dose (Mann-Whitney U test) ** Airway hyperresponsiveness measured as the relative response to maximal acetylcholine doses *** Bronchoalveolar lavage fluid ND = Not Measured

[0063] The present inventors and collaborators previously reported the pronounced anti-inflammatory activity of ED (3) against TNF-α production in LPS-stimulated human blood. We also noted a difference in the activity of 3 in diluted (1:5) versus undiluted blood. The efficacy of ED decreased with increasing amounts of serum protein present, and this decline in activity was demonstrated by LC / MS / MS to coincide with the rate of elimination of the parent compound and the appearance of proposed major metabolites. At the time, the putative degrading enzyme for ED was unknown and was thought to be a carboxylesterase. Surprisingly, the major metabolite identified was the 17α-hydroxy derivative, a dichloroacetyl functional group that is more readily cleaved than the highly constrained 17β-ester.

[0064] Recently, the present inventors and collaborators have identified the hydrolytic enzyme as paraoxonase 1, which is associated with HDL in human blood. This finding not only explains the dilution effect but also raises the possibility of identifying highly potent corticosteroids with multiple substitutions but improved therapeutic indices. As previously mentioned, substituted loteprednol derivatives (6α, 9α, 16α, β) do not readily hydrolyze and are therefore not acceptably "soft." Furthermore, fluticasone, a supposedly "soft" steroid, does not undergo hydrolysis of its 17β-fluoromethylthioester and instead relies on relatively slow metabolism catalyzed by P-450. This application describes the study of ED-substituted analogs, including the dichloroacetyl analog of fluticasone (25).

[0065] Table 1 shows the results of in vitro activity in various conditions. The effect of dilution of the 50 is up to 10-fold lower than that of undiluted blood. Another important property studied was the effect of preincubation before assessing TNF-α production. This is an indication of the unexpectedly excellent stability of these compounds in the general circulatory system. Previous studies have shown that ED(3) loses its activity during incubation (5-fold over 2 days and 100-fold over 5 days). Under the same conditions, the equally effective dexamethasone and budesonide maintain full activity.

[0066] Two of these compounds were selected for further in vivo studies. The 9α-fluoro-16-β-methyl analog of ED (11) and the fluticasone analog (25) were studied in an ovalbumin-sensitized Brown Norway rat model. Various parameters measured, including allergen-induced airway hyperresponsiveness (AHR), allergen-induced cellular infiltration (eosinophils in bronchoalveolar lavage fluid (BALF) and lung tissue), goblet cell hyperplasia, increased mucus secretion, and allergen-induced perivascular edema formation, are shown in Table 2.

[0067] The results clearly demonstrate that substitution with 9α- and 6α,9α-difluoro and 16-methyl groups enhances etiprednol's activity. However, the most attractive feature is its enhanced softness, as reflected by the effect of serum / blood incubation time on efficacy. Clearly, current paraoxonase hydrolyzes the 17α-dichloroacetyl functional group with little slowing down due to the above-mentioned substituents, unlike the LE series. Interestingly, the 9α-F-16β-methyl analog of ED (3) (11) shows no significant improvement over ED, except for mucus production. On the other hand, the fluticasone analog 25 is overall superior to FLU, primarily in reducing eosinophilia and edema formation.

[0068] As illustrated by the results contained in Tables 1 and 2, selected substituted analogs of second-generation soft steroids, ED, unexpectedly / surprisingly possess both overall higher local / regional anti-inflammatory activity and significantly improved therapeutic indices compared to hard and 17α-carbonate soft analogs. In particular, the fluticasone analog, compound 25, is expected to be superior to fluticasone, the most potent but also the most toxic corticosteroid with the steepest side effect curve.

[0069] For the following exemplary embodiments, unless otherwise indicated, chemicals were purchased from SIGMA (St. Louis, MO, USA). Etiprednol dichloroacetate (ethyl 17α-dichloroacetoxy-11β-hydroxyandrosta-1,4-dien-3-one-17β-carboxylate, BNP-166) was synthesized at the Department of Chemistry, Institute for Drug Research, Budapest, Hungary. Urethane, Primazin (2% xylazine), Ketalar (10% ketamine), and Unopette kit were purchased from Realal (Budapest, Hungary), Alfasan International BV (AB Woerden, The Netherlands), Parke Davis (London, UK), and BD Biosciences (Franklin Lakes, NJ, USA), respectively. [Example]

[0070] Example 1: 11β,17α-dihydroxyandrosta-1,4-dien-3-one-17β-carboxylic acid (1) To a solution of prednisolone (70 g, 0.194 mol) in a mixture of tetrahydrofuran (600 ml) and methanol (220 ml) at 30°C was added warm (50°C) water (550 ml). A solution of sodium metaperiodate (120 g, 0.561 mol) in HCl (1H 2 O) was added over 25 minutes. The reaction mixture was stirred at room temperature for 2 hours. The organic solvent was removed in vacuo. The precipitate was collected by filtration, washed twice with water, and, without drying, dissolved in 0.25 N aqueous sodium hydroxide (880 ml). Insoluble impurities were removed by filtration, and the clear solution was washed twice with methylene chloride and acidified with 0.5 N hydrochloric acid (550 ml) until pH = 1. The precipitate was collected by filtration, washed three times with water, and dried at 40 °C to constant weight. Yield: 63.7 g (95%), white crystalline powder. Mp 230 °C (decomp.).

[0071] 1 H NMR (250 M H z , DMSO-d6): δ 0.92 (3 H, s, CH3-18), 1.40 (3 H, s, CH3-19), 4.36 (1 H, ms, H α -11), 5.91 (1 H, d, J = 10 Hz, H-2). Example 2: 17α-Dichloroacetoxy-11β-hydroxyandrosta-1,4-dien-3-one-17β-carboxylic acid (2)

[0072] Dichloroacetyl chloride (62.5 mL, 95.8 g; 0.65 mol) in methylene chloride (1500 mL) was added slowly over 2 hours to a stirred solution of potassium bicarbonate (139.5 g, 1.39 mol) and 1 (45.0 g, 0.13 mol) in water (2000 mL). The resulting reaction mixture was acidified with 5 N hydrochloric acid (135 mL) until pH = 1-2. The layers were separated, and the aqueous layer was extracted with methylene chloride (2 x 210 mL). The combined organic layers were washed with saturated ammonium chloride solution (2 x 360 mL). The organic layer was stirred with a solution of potassium bicarbonate (17.1 g, 172 mmol) in water (1000 mL) for 30 minutes. The process was repeated using a solution of potassium bicarbonate (8.6 g, 86.0 mmol) in water (600 mL). The combined aqueous solution was washed with methylene chloride (135 ml) and then slowly acidified with 2N hydrochloric acid with stirring to pH = 1-2. The solution was warmed to 45-50°C, and the precipitated white solid was collected by filtration and washed with water. The resulting white powder was dried in vacuo at 45°C to constant weight. Yield: 55.4 g (93%), white crystalline powder. Mp 210-214°C.

[0073] [ka] Example 3: Ethyl 17α-dichloroacetoxy-11β-hydroxyandrosta-1,4-dien-3-one-17β-carboxylate (3) (ED-Ethyprednol Dichloroacetate)

[0074] Method A: Esterification of 2 with ethyl iodide

[0075] To a stirred suspension of 2 (50 g, 0.109 mol) and anhydrous potassium carbonate (16.58 g, 0.120 mol) in anhydrous dimethylformamide (500 mL) was added ethyl iodide (13.1 mL, 25.5 g; 0.164 mol) at room temperature. After stirring for 1.5 h, the reaction mixture was diluted with saturated aqueous sodium chloride solution (1000 mL) and stirred for 1 h. The resulting precipitate was collected by filtration and washed with water (3 × 180 mL). The crude product (53.2 g) was recrystallized from ethyl acetate (400 mL). Yield: 31.9 g (61%), white crystalline powder. Mp 201-202.5 °C.

[0076] [ka]

[0077] Method B: Esterification of 2 with diethyl sulfate

[0078] The procedure described above (Method A) was followed, except that diethyl sulfate (21.5 ml, 25.3 g, 0.164 mol) was used instead of ethyl iodide. Yield: 70%. Example 4: 9α-Fluoro-11β,17α-dihydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic acid (6)

[0079] Prepared as described above for 1 starting from 9α-fluoroprednisolone. Yield: 89%, white crystalline powder. Mp 258-259°C.

[0080] [ka] Example 5: 6α,9α-difluoro-11β,17α-dihydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic acid (7)

[0081] Prepared as described above for 1 starting from 6α,9α-difluoro-prednisolone. Yield: 97%, white crystalline powder. Mp 265-267°C.

[0082] 1 H NMR (CD3OD): δ 1.17 (3H, s, CH3-18), 1.24 (3H, d, CH3-16), 1.59 (3H, s, CH3-19), 2.60 (1H, m, H-8), 4.25 (1H, ddd, H α -11), 5.54 (1H, dddd, H β -6), 6.29 (1H, m, H-4), 6.32 (1H, dd, H-2), 7.34 (1H, dd, H-1). Example 6: 17-α-Dichloroacetoxy-9α-fluoro-16β-methyl-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylic acid (8)

[0083] Dichloroacetyl chloride (3.1 mL, 4.76 g; 32.3 mmol) in dichloromethane (75 mL) was added slowly over 2 hours to a stirred solution of potassium bicarbonate (6.94 g, 69.3 mmol) and 6 (1.75 g, 4.62 mmol) in water (100 mL). The resulting reaction mixture was diluted with 5N hydrochloric acid (4.8 mL) until the pH reached 1.2. The solution was acidified with 2N hydrochloric acid. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 10 ml). The combined organic layers were washed with saturated ammonium chloride solution (2 x 13 ml). The organic layer was stirred with a solution of potassium bicarbonate (0.608 g, 6.07 mmol) in water (35 ml) for 30 minutes. The process was repeated with a solution of potassium bicarbonate (0.306 g, 3.05 mmol) in water (22 ml). The combined aqueous solution was washed with dichloromethane (10 ml) and then slowly acidified with 2N hydrochloric acid with stirring to pH = 1-2. The solution was warmed to 45-50 °C, and the precipitated white solid was collected by filtration and washed with water. The resulting white powder was dried in vacuo at 45 °C to constant weight. Yield: 1.95 g (86%), white crystalline powder. Mp 193-194 °C.

[0084] 1 H NMR (MeOH-d4): δ 1.13 (3H, s, CH3-19), 1.43 (3H, d, CH3-16), 4.29 (1H, m, H α -11), 6.10 (1H, m, H-4), 6.30 (1H, dd, H-2), 7.40 (1H, d, H-10). Example 7: 17α-Dichloroacetoxy-6α,9α-difluoro(difloro)-16β-methyl-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylic acid (9)

[0085] Prepared as described above for 8 starting from 7. Yield: 78%, white crystalline powder. Mp 186°C.

[0086] 1 H NMR (CDI3 + 3 drops of methanol-d4): δ 1.07 (3H, s, H-18), 1.40 (3H, d, CH3-16), 1.51 (3H, s, H-19), 2.17 (1H, m, H α -16), 2.45 (1H, m, H-8), 4.29 (1H, m, H α -11), 5.37 (1H, dddd, Hβ -6), 5.91 (1H, s, CHCI2), 6.32 (1H, dd, H-2), 6.38 (1H, m, h-4), 7.16 (1H, dd, H-1). 13 C NMR (CDCI3 + 3 drops methanol-d4): δ 16.7 (18), 20.0 (CH3-16), 22.9 (19), 32.6 (8), 33.9 (7), 34.8 (15), 36.1 (12), 43.0 (14), 45.1 (16), 47.3 (13), 48.2 (10), 64.3 (CHCI2), 71.2 (11), 82.6 (6), 92.7 (17), 99.1 (9), 120.7 (4), 129.7 (2), 151.5 (1), 162.3 (5), 163.4 (OC=O), 169.6 (20), 186.1 (3). Example 8: Methyl 17α-dichloroacetoxy-9α-fluoro-16β-methyl-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate (10)

[0087] To a stirred suspension of 8 (0.35 g, 0.8 mmol) and anhydrous potassium carbonate (0.122 g, 0.88 mmol) in anhydrous dimethylformamide (3.5 ml) was added methyl iodide (0.17 g, 1.2 mmol) at room temperature. After stirring for 1.5 h, the reaction mixture was diluted with saturated aqueous sodium chloride (8 ml) and stirred for 90 min. The resulting precipitate was collected by filtration and washed with water (3 × 5 ml). The crude product (0.32 g) was purified by column chromatography on silica gel eluting with dichloromethane-methanol 95:5, followed by recrystallization from ethyl acetate / n-hexane. Yield: 90%, off-white crystalline powder. Mp 213-215°C.

[0088] 1 H NMR (CDCI3): δ 1.08 (3H, s, CH3-18), 1.57 (3H, s, CH3-19), 1.46 (3H, d, CH3-16), 2.22 (1H, m, Hα -16), 4.44 (1H, m, H α -11), 6.14 (1H, m, H-4), 6.35 (1H, dd, H-2), 7.20 (1H, d, H-1), 3.71 (3H, s, CHO), 5.91 (1H, s, CHCI2). 13 C NMR (CDCI3): 151.6 (C-1), 130.0 (C-2), 186.3 (C-3), 125.3 (C-4), 166.5 (C-5), 30.9 (C-6), 27.5 (C-7), 33.9 (C-8), 100.0 (C-9), 48.1 (C-10), 72.0 (C-11), 37.3 (C-12), 47.7 (C-13), 43.3 (C-14), 35.0 (C-15), 45.6 (C-16), 20.0 (CH3-16), 92.8 (C-17), 17.3 (C-18), 23.0 (C-19), 167.8 (C-20), 51.9 (CHO), 163.4 (OC=O), 64.3 (CHCI2). Example 9: Ethyl 17α-dichloroacetoxy-9α-fluoro-16β-methyl-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate (11)

[0089] Prepared as described above for 10 starting from 8 and using diethyl sulfate instead of methyl iodide. Yield: approx. 100%, white crystalline powder. Mp 194-195°C.

[0090] [ka] Example 10: Chloromethyl 17α-dichloroacetoxy-9α-fluoro-16β-methyl-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate (12)

[0091] Prepared as described above for 11, starting from 8 and using a 4 molar excess of chloroiodomethane instead of methyl iodide. After stirring for 8.5 h, the reaction mixture was diluted with saturated aqueous sodium chloride. The crude product was isolated by extraction with diethyl ether and purified by column chromatography on silica gel eluting with ethyl acetate-n-hexane 1:1. The product was then recrystallized from ethyl acetate / n-hexane. Yield: 48%, white crystalline powder. Mp 177-180°C.

[0092] 1 H NMR (CDCI3): δ 1.13 (3H, s, CH3-18), 1.57 (3H, s, CH3-19), 1.48 (3H, d, CH3-16), 2.23 (1H, m, H α -16), 4.46 (1H, m, H α -11), 6.15 (1H, m, H-4), 6.36 (1H, dd, H-2), 7.18 (1H, d, H-1), 3.50 / 5.94 (2H, d, CH2O), 5.92 (1H, s, CHCI2). 13 C NMR (CDCI3): 151.3 (C-1), 130.1 (C-2), 186.2 (C-3), 125.4 (C-4), 166.3 (C-5), 30.9 (C-6), 27.5 (C-7), 33.9 (C-8), 99.7 (C-9), 48.0 (C-10), 71.9 (C-11), 37.3 (C-12), 48.0 (C-13), 43.5 (C-14), 34.9 (C-15), 45.8 (C-16), 19.9 (CH3-16), 91.9 (C-17), 16.9 (C-18), 23.0 (C-19), 165.3 (C-20), 68.9 (CH2O), 163.4 OC=O), 64.1 (CHCI2). Example 11: 2-Hydroxyethyl 17α-dichloroacetoxy-9α-fluoro-16β-methyl-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate (13)

[0093] Starting from 8, 11 was prepared as described above, using a 6 molar excess of 2-bromoethanol and a catalytic amount of potassium iodide instead of methyl iodide. The reaction mixture was stirred for 24 h, and after diluting it with water, the crude product was isolated by extraction with diethyl ether and purified by column chromatography on silica gel eluting with dichloromethane-methanol 95:5. The product was then triturated with n-hexane. Crystallization was carried out by ethanol. Yield: 50%, white crystalline powder. Mp 193°C.

[0094] 1 H NMR (CDCI3): δ 1.11 (3H, s, CH3-18), 1.57 (3H, s, CH3-19), 1.46 (3H, d, CH3-16), 2.23 (1H, m, H α -16), 4.41 (1H, m, H α -11), 6.15 (1H, m, H-4), 6.35 (1H, dd, H-2), 7.21 (1H, d, H-1), 4.28 (2H, m, CH2O), 3.82 (2H, m, CH2OH), 5.93 (1H, s, CHCI2). 13 C NMR (CDCI3): 151.9 (C-1), 129.9 (C-2), 186.5 (C-3), 125.2 (C-4), 166.9 (C-5), 30.9 (C-6), 27.6 (C-7), 33.9 (C-8), 100.0 (C-9), 48.1 (C-10), 72.0 (C-11), 37.0 (C-12), 47.8 (C-13), 43.4 (C-14), 35.0 (C-15), 45.7 (C-16), 20.0 (CH3-16), 92.8 (C-17), 17.2 (C-18), 22.9 (C-19), 167.2 (C-20), 66.5 (CH2O), 60.9 (CH2OH), 163.7 (OC=O), 64.3 (CHCI2). Example 12: Methyl 6α,9α-difluoro-17α-dichloroacetoxy-16β-methyl-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate (14)

[0095] Prepared as described above for 10 starting from 9. Yield: 51%, white crystalline powder. Mp 216-217°C.

[0096] 1 H NMR (CDCI3): δ 1.08 (3H, s, H-18), 1.46 (3H, d, CH3-16), 1.55 (3H, s, H-19), 2.50 (1H, m, H-8), 3.72 (3H, s, CH3O), 4.44 (1H, m, H α -11), 5.38 (1H, dddd, H β -6), 5.92 (1H, s, CHCI2), 6.38 (1H, dd, H-2), 6.45 (1H, m, H-4), 7.12 (1H, dd, H-1). 13 C NMR (CDCI): δ 17.2 (18), 20.0 (CH3-16), 23.1 (19), 32.6 (8), 33.9 (7), 34.9 (15), 37.1 (12), 43.0 (14), 45.5 (16), 47.7 (13), 47.9 (10), 51.9 (CH3O), 64.3 (CHCI2), 71.8 (11), 86.3 (6), 92.5 (17), 98.6 (9), 121.3 (4), 130.4 (2), 150.2 (1), 161.0 (5), 163.3 (OC=O), 171.7 (20), 185.4 (3). Example 13: Ethyl 6α,9α-difluoro-17α-dichloroacetoxy-16β-methyl-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate (15)

[0097] Prepared as described above for 11 starting from 9. The crude product was recrystallized from ethyl acetate / n-hexane. Yield: 57%, white crystalline powder. Mp 155-156°C.

[0098] [ka] Example 14: Chloromethyl 6α,9α-difluoro-17α-dichloroacetoxy-16β-methyl-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate (16)

[0099] Starting from 9, 12 was prepared as described above, using a 4 molar excess of chloroiodomethane instead of methyl iodide. The reaction mixture was stirred for 26.5 h and then diluted with water. The crude product was isolated by extraction with diethyl ether and purified by column chromatography on silica gel eluting with dichloromethane-methanol 95:5. The resulting product was recrystallized from ethyl acetate / n-hexane. Yield: 28%, white crystalline powder. Mp 142-144°C.

[0100] 1 H NMR (CDCI3): δ 1.13 (3H, s, H-18), 1.49 (3H, d, CH3- 16), 1.55 (3H, s, H -19), 2.51 (1H, m, H-8), 4.46 (1H, m, H α-11), 5.41 (1H, dddd, H β -6), 5.50 / 5.97 (1H + 1H, d, CH2CI), 5.93 (1H, s, CHCI2), 6.39 (1H, dd, H-2), 6.45 (1H, m, H-4), 7.11 (1H, dd, H-1). Example 15: 2-Hydroxyethyl 6α,9α-difluoro-17α-dichloroacetoxy-16β-methyl-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate (17)

[0101] Starting from 9, 13 was prepared as described above, using a 6 molar excess of 2-bromoethanol and a catalytic amount of potassium iodide instead of methyl iodide. The reaction mixture was stirred for 5.5 h and diluted with water. After that, the crude product was isolated by extraction with diethyl ether and purified by column chromatography on silica gel eluting with dichloromethane-methanol 95:5. The product was then recrystallized from ethyl acetate / n-hexane. Yield: 45%, white crystalline powder. Mp 205-207°C.

[0102] [ka] Example 16: Fluoromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate (21)

[0103] Step 1: Preparation of 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic acid (20)

[0104] 11β,17α-Dihydroxy-6α,9α-difluoro-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic acid 19 (2.55 g, 6.5 mmol) was added continuously to a solution of KHCO (7.0 g) in water (100 ml). To this stirred solution, dichloroacetyl chloride (3.12 ml, 32.48 mmol) dissolved in dichloromethane (75 ml) was added dropwise at room temperature over 2 hours. Stirring was continued for another hour. The reaction mixture was then acidified with 1N HCl, and the phases were separated. The organic phase was washed with water, dried, and evaporated to give a portion of the title product (1.06 g). The aqueous phase was extracted with ethyl acetate, and this extract, after drying and evaporation, yielded a further fraction (1.73 g) of the title product. The combined product was recrystallized from methanol (25 ml) to give pure product 20 (2.21 g, 67%). Mp: 206 °C (dec), [α] D :+8.9°(c=0.5,EtOH).

[0105] [ka]

[0106] C 23 H 26 Analysis calculated for Cl2F2O6 (507.35): C 54.44; H 5.17; Found: C 53.72; H 5.02.

[0107] Step 2: The carboxylic acid derivative 20 (0.51 g, 1.0 mmol) from Step 1 above was dissolved in DMF (7 ml), KHCO3 (0.15 g, 1.5 mmol) was added, and the mixture was stirred at 0 °C for 0.5 h. Bromofluoromethane gas was then introduced via a capillary tube for 1 min. The amount of gas absorbed was approximately 1.7 g. After stirring at 0 °C for 2 h, the mixture was allowed to stand overnight. Then, to achieve complete conversion, an additional amount of gas (approximately 0.5 g) was absorbed, and stirring was continued for another 4 h. The reaction mixture was poured into ice water, and the separated product (0.5 g) was isolated by filtration. The crude title product was recrystallized from methanol (50 ml) using charcoal, and the solution was concentrated to a volume of approximately 10 ml. Yield: 0.34 g of 21, mp: 241 °C; [α] D :+7.3° (c=0.5, ethyl acetate).

[0108] [ka] Example 17: Chloromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate (22)

[0109] 17α-Dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic acid 20 (1.0 g, 2.0 mmol, Example 5, Step 1) was dissolved in DMF (15.0 mL) and KHCO (0.30 g, 3.0 mmol) was added with stirring. After stirring for 0.5 h, chloroiodomethane (0.58 mL, 8.0 mmol) was added and stirring at rt continued overnight. The mixture was then poured into ice water, and the crude product was isolated by filtration. Recrystallization from ethanol using charcoal for decolorization gave 0.42 g of the title product 22. mp: 226 °C, [α] D :+15.1 o (c=0.5, ethyl acetate).

[0110] 1H NMR (500 MHz, DMSO): δ 0.91 (3H, d, CH3-16), 1.05 (3H, s, H-18), 1.49 (3H, s, H -19), 3.29 (1H, m, H β -16), 4.19 (1H, m, H α -11), 5.63 (1H, dddd, H β -6), 5.63 (1H, dddd, H β -6), 5.63 (1H, d, HOCH α -11), 5.87 / 5.96 (1H+1H, d, OCH2F), 6.11 (1H, d, H-4), 6.29 (1H, dd, H-2), 7.06 (1H, s, CHCI2), 7.24 (1H, d, H-1). Ei-MS:[M] + : 554 / 556 / 558(3 / 3 / 1);m / z:140(100),139(94),134(77);Ci-MS:[M+H] + :555 / 557 / 559(96 / 100 / 36). Example 18: S-Fluoromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate (25)

[0111] Step 1: Preparation of 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid (24)

[0112] 11β,17α-Dihydroxy-6α,9α-difluoro-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid 23 (7.6 g, 18.4 mmol) was converted to the 17α-dichloroacetate derivative according to the procedure described for Step 1 of 20. However, the oily residue produced by evaporation of the final ethyl acetate solution was triturated with diisopropyl ether to give the title compound 24 as a solid (9.40 g, 97%). The crude material was purified by recrystallization from chloroform. Yield: 6.67 g (69%), mp: 170°C (dec).

[0113] C 23 H 26 Analytical calculated value for Cl2F2O5S (523.42): S6.13; Found: S6.19.

[0114] Step 2: The carbothioic acid derivative (1.05 g, 2.0 mmol) from Step 1 above was dissolved in ethyl acetate (12 mL), water (3.5 mL), and triethylamine (0.31 mL, 2.2 mmol). Benzyltributylammonium chloride (90 mg) was added. The heterogeneous stirred mixture was cooled to 0°C, and then bromofluoromethane gas was introduced via a capillary tube for approximately 1 minute. The amount absorbed was approximately 1.5 g. Stirring was continued, and the temperature was allowed to warm to room temperature over a period of 2 hours. TLC examination (silica gel, eluent: hexane-ethyl acetate-acetic acid (5:4:1)) indicated complete conversion. The mixture was diluted with ethyl acetate (10 mL), the phases were separated, and the organic phase was washed successively with 0.5 N HCl, saturated NaHCO3 solution, and brine. The solution was then filtered through a neutral alumina pad and evaporated to give a solid. Column chromatography on silica gel using n-hexane-ethyl acetate (1:1) as eluent gave the title compound 25 (0.80 g, 72%). The sample was recrystallized from ethanol. mp: 267 °C, [α] D :+40.0°(c=0.3,ethanol).

[0115] 1H NMR (500 MHz, pyridine-d5): δ 1.16 (3H, d, CH3-16), 1.44 (3H, s, H-18), 1.73 (3H, s, H-19), 3.61 (1H, m, H β -16), 4.68 (1H, m, H α -11), 5.68 (1H, dddd, H β Ei-MS:[M] + :554 / 556(2 / 1);m / z:139(100),333(89),140(73);Ci-MS:[M+H] + :555 / 557(100 / 69). C 24 H 27 Analysis calculated for Cl2F3O5S (555.44): S 5.77; Found: S 5.75. Example 19: S-Chloromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate (26)

[0116] 17α-Dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid 24 (1.04 g, 2.0 mmol, Step 1) was dissolved in DMF (12 mL), and the solution was cooled to 0°C. NaHCO3 (0.26 g, 3.0 mmol) was added and stirred for 10 min, followed by dropwise addition of chloroiodomethane (0.22 mL, 3.0 mmol). The temperature was raised to rt over 1 h, and stirring was continued for 3 h. The mixture was then poured into water (240 mL), and the product was extracted with ethyl acetate. The extract was washed with brine, dried, and evaporated to dryness. The partially solid residue was purified by column chromatography on silica gel using chloroform-ethyl acetate (4:1) as eluent. The main fraction (0.81 g) was triturated with hot methanol and after cooling pure title compound 26 (0.35 g) was recovered. Mp: 272 °C, [α] D :+59.8°(c=0.5,ethanol).

[0117] [ka] Pharmacological studies

[0118] animal

[0119] Male Brown Norway rats weighing 140-170 g at the start of the experiment were purchased from Charles River Hungary LTD (Budapest, Hungary). Upon arrival, the animals were examined for obvious signs of illness and then quarantined for one week before use. The animals were maintained in standard animal cages (5 per cage) on a constant 12-hour light / dark cycle. The animals had free access to tap water and standard chow purchased from Charles River. Animals were treated in accordance with the European Communities Council Directive (86 / 609 / EEC), and all experimental procedures were approved by the Institutional Animal Care Committee (Institute for Drug Research, Budapest, Hungary).

[0120] Animal sensitization, treatment and challenge

[0121] The animals were randomly assigned to the various treatment groups (4-5 animals per group), weighed, and numbered. On days 0, 14, and 21, the animals were sensitized by subcutaneous administration of alum-precipitated ovalbumin (25 μg ovalbumin + 20 mg Al(OH)3 in 0.5 ml saline per animal) on the back. At the same time, in each case, 0.25 ml (10 9 The animals were injected intraperitoneally with heat-inactivated Bordatella pertussis vaccine at 100 μg / ml (100 μg / ml). On day 28, various test doses of glucocorticoids (0.1, 1.0, 10.0, and 100 μg / kg) were administered intratracheally 2 hours before challenge. Intratracheal drug application was performed under short-term general anesthesia plus muscle relaxation induced by intramuscularly administered xylazine (10 mg / kg) and ketamine (10 mg / kg). The animals were placed on their backs. The animals were maintained in a supine position, and a special cannula (Vasocan Braunule) was passed through the larynx and advanced to the middle of the trachea. Powdered solid material (10 mg) [vehicle (lactose monohydrate) and active drug] was delivered to the lungs via a 5 ml syringe. Control animals were treated with vehicle only. Antigen challenge was performed by exposing the animals to vaporized 1% aqueous ovalbumin solution (saline) administered via a "Nose Only Exposure System for Rodents; Technical and Scientific Equipment GmbH, Bad Homburg, Germany" for 1 hour.

[0122] Bronchoalveolar lavage

[0123] Forty-eight hours after challenge, the animals were sacrificed by urethane overdose, and bronchoalveolar lavage fluid (BALF) was then obtained. After tracheotomy, a polyethylene catheter was inserted and advanced to the tracheal bifurcation. The airway was then lavaged with 3 ml of Hank's balanced salt solution preheated to 37°C. Lavage with the same volume of buffer was repeated three times, and the lavage fluid was collected in a centrifuge tube containing sodium citrate. After phloxine B staining (Unopette kit), the total number of eosinophils in the collected BALF was counted.

[0124] Measurement of airway hyperresponsiveness ex vivo

[0125] Tracheas were removed from the animals and carefully stripped free of adhesive tissue, after which they were cut into single rings. The prepared rings were suspended in an organ bath chamber containing Krebs buffer and maintained at 37°C with continuous aeration. For recording of isometric tension changes, rings were placed under 1.0 g tension, and after a 30-minute equilibration period, the cumulative concentration-response to acetylcholine was measured. The maximal response of control (sensitized, unchallenged, and untreated) tracheal rings was measured at 10 -3The magnitude of this response was defined as 100%. All other contractions were expressed as percentages and related to the control response. The concentration of acetylcholine required to produce a contraction equal to 50% of the control contraction was determined for each preparation using linear regression. Two to three rings were examined from each animal.

[0126] histochemistry

[0127] Whole-lobular lung specimens from each animal were collected after bronchoalveolar lavage. Samples were fixed in phosphate-buffered 8% formalin for 2 weeks and then routinely processed for histochemistry. Thick sections (5 μm) were cut and mounted on surface-treated slides. Perivascular and peribronchial eosinophilia was revealed in sections stained with modified May-Grünwald-Giemsa stain by counting the total eosinophils within the field in all peribronchial and perivascular lung tissue at 630x magnification. Areas of perivascular edema were revealed in periodic acid-Schiff (PAS)-stained specimens counterstained with hematoxylin. Fifty randomly selected microvessels from each experimental group were digitally exposed at 400x magnification (Zeiss Axiocam; Axiovert 200 system). Measurement of perivascular edema area was performed using Zeiss Axiovision 3.1 software (Carl Zeiss Vision GmbH, Jena, Germany). The extent of perivascular edema was expressed as a percentage of the area of ​​each microvascular area. Mucus production and goblet cell hyperplasia in similarly prepared (PAS + hematoxylin) lung tissue sections were measured at 400x magnification by counting the total epithelial cells of each airway segment in the entire preparation. The change in the number of mucus-producing cells was expressed as the ratio of PAS-positive goblet cells to the total epithelial cells counted in all lobules of the tissue section.

[0128] Cytokine assays

[0129] Commercially available human cytokine ELISA sets were used. TNF-α and GM-CSF sets were purchased from BD Pharmingen (San Diego, CA, USA), and IL-1β sets were obtained from R&D Systems (Minneapolis, MN, USA). ELISAs were performed according to the manufacturer's protocol. Cell-free supernatants were tested in duplicate. The detection limits were 7.8 pg / ml for TNF-α, 4.7 pg / ml for GM-CSF, and 3.9 pg / ml for IL-1β. Results were expressed as mean percent inhibition. IC for test compounds 50 Values ​​were calculated by linear regression.

[0130] IL-1β production in stimulated THP.1 cells

[0131] THP.1 cells (human monocytic cell line: American Type Culture Collection, Rockville, MD, USA) were cultured in 10% FCS at 5 × 10 -5 Cells were maintained in RPMI-1640 medium supplemented with M 2-mercapto-ethanol, 2 mM glutamine, and antibiotics and split every 3 days. To examine the effects of test compounds, 2 × 10 cells were used for IL-1β production, as previously described (Nemeth et al., 1995). 6 Cells / well (1 ml / well volume in a 24-well plate) were stimulated with 1 μg / ml LPS and 25 μg / ml silica. Test compounds were dissolved in RPMI-1640 medium or medium containing 0.01% DMSO. Two equivalent cell cultures per treatment group were performed in three independent experiments. IL-1β levels in cell-free supernatants were measured by ELISA.

[0132] Lipopolysaccharide-stimulated TNF-α production in human blood

[0133] Peripheral blood from healthy donors was collected aseptically into heparinized (Vacutainer™) sterile tubes. Whole blood samples from each individual were used in parallel in all experiments, both undiluted and diluted 5-fold with RPMI-1640 medium. Blood samples were distributed into 24-well plates and incubated with graded concentrations of test compound and 1 μg / ml lipopolysaccharide for 24 hours at 37°C in a CO2 incubator. Controls were treated with lipopolysaccharide and vehicle (PBS or 0.01% dimethyl sulfoxide in PBS). After incubation, cell-free supernatants were separated by centrifugation (1000g for 10 minutes) and stored at -20°C until the amount of TNF-α was measured. Test compounds were examined in blood samples from five different individuals. Two equivalent cultures per treatment were performed.

[0134] Preincubation of experimental compounds with serum and measurement of their effects on TNF-α production by lipopolysaccharide-stimulated human peripheral blood mononuclear cells

[0135] Mononuclear cells from peripheral blood of healthy donors were isolated on a Ficoll gradient. One million cells in 0.9 ml of RPMI 1640 medium were distributed into a 24-well plate, and graded concentrations of test compounds prepared immediately or 18 hours prior to treatment in fresh human serum were added (0.05 ml) along with lipopolysaccharide (0.05 ml; 1 μg / ml final concentration). Preincubation of the compounds with serum was carried out at 37°C. The cultures were treated as described above.

[0136] ED 50 Calculation and statistical evaluation of

[0137] ED 50 Values ​​were calculated using GraphPad Prism software (GraphPad Software, Inc., San Diego CA, USA). Statistical analysis was performed using the Mann-Whitney U test or Student's t test to determine differences between treatments (e.g., etiprednol dichloroacetate). The differences between the serotonin receptor agonist (vs. budesonide) were analyzed by two-way analysis of variance. All calculations were performed using Statistica for Windows® software version 5.1 (Stat Soft Inc., Tulsa, OK, USA).

[0138] Lectin-stimulated proliferation of peripheral mononuclear cells

[0139] Mononuclear cells from heparinized peripheral blood of healthy donors were isolated on a suitable gradient (Optiprep solution, 1.077 g / ml). Serial dilutions (2 × 10 -5 ~2×10 -8 Cells (range of 10 M) were prepared in 100 μl of medium per well of a sterile round-bottom 96-well microtiter plate. Control wells contained culture medium alone. 100 μl of cell suspension (10 μg / ml) containing concanavalin A (2 μg / ml) was added. 6 A total of 100 cells / ml were added to each well. Growth background control cell suspensions contained no lectin. All cultures were performed in triplicate. Microtiter plates were incubated at 37°C in a humidified atmosphere containing 5% CO2 for 72 hours. For the final 18 hours of incubation, cell cultures were treated with [ 3 [H]thymidine was added to a final concentration of 0.1 μCi / well. At the end of the incubation, cells were harvested onto glass microfiber filters (Whatman G / F) and associated radioactivity was measured by liquid scintillation.

[0140] Stability of etiprednol dichloroacetate in the presence of human plasma

[0141] Etiprednol dichloroacetate (BNP-166) was added to freshly prepared human plasma from healthy donors at a concentration of 5 ng / ml and incubated at 37°C for various intervals. After incubation, the amounts of the parent compound (ethyl-17α-dichloroacetoxy-11β-hydroxyandostra-1,4-dien-3-one-17β-carboxylate) and one of its major metabolites, M-OH (17α,11β-dihydroxyandostra-1,4-dien-3-one-17β-carboxylate), were measured using HPLC / MS / MS. Briefly, fluocinolone acetonide served as the internal standard (20 ng / ml), and samples were extracted by liquid-liquid extraction on an Extrelut® column and separated on a Purospher STAR 30 x 2 mm (3 μm) reversed-phase column at a flow rate of 0.3 ml / min using a linear gradient with a mobile phase system containing acetonitrile, water, and acetic acid. Measurements were performed on a triple quadrupole mass spectrometer (Perkin-Elmer SCIEX API 2000) equipped with an electrospray interface operating in positive ionization mode. Multiple ion monitoring, i.e., parent ion → daughter ion transitions of 485.2 → 265.2, 375.2 → 265.2, and 495.2 → 337.2, were used for quantification of etiprednol dichloroacetate, its M-OH metabolite, and the internal standard, respectively. Results are expressed as peak areas normalized to the internal standard. The stability of selected ED analogs (10, 11, 13, 17, 21, 25) was measured as described above for ED (3). Compounds 13, 17, 21, and 25 were particularly stable. It is also noteworthy that compounds 13 and 17 are more potent but also softer than the corresponding 17β-C(O)CH2CH3 compounds 11 and 15, respectively. See Table 1 above.

[0142] The compounds of formula (I) or (III) can be combined with a suitable pharmaceutically acceptable, non-toxic carrier to provide a pharmaceutical composition for use in treating localized or other localized inflammation. Of course, taking into account the lack of systemic activity, Thus, the compounds of formula (I) and (III) are not intended for the treatment of conditions in which the need for systemic adrenocortical therapy is indicated, such as adrenocortical insufficiency. Examples of inflammatory conditions that may be treated with pharmaceutical compositions comprising at least one compound of Formula (I) or (III) and one or more pharmaceutical carriers include skin disorders (e.g., atopic dermatitis, acne, psoriasis, or contact dermatitis); allergic conditions such as bronchial asthma; respiratory diseases such as COPD; eye and visual diseases involving acute and chronic allergic and inflammatory reactions (e.g., ocular inflammatory conditions such as blepharitis, conjunctivitis, episcleritis, scleritis, keratitis, anterior uveitis, and sympathetic ophthalmitis); inflammation of the mouth, gums, and / or throat (e.g., gingivitis or oral aphthae); inflammation of the nasal mucosa (e.g., inflammation caused by allergies); inflammation of the upper and lower intestinal tract (e.g., ulcerative colitis); inflammation associated with arthritis; and anorectal inflammation, pruritus, and pain associated with hemorrhoids, proctitis, crypt inflammation, fissures, postoperative pain, and pruritus ani. Such compositions may also be applied topically as a preventative measure against the inflammation and tissue rejection that occurs in connection with transplantation.

[0143] Naturally, the choice of carrier and dosage form will vary depending on the particular condition and route of administration for which the composition is to be administered.

[0144] Examples of various types of preparations suitable for local / topical administration include ointments, lotions, creams, powders, drops (e.g., eye drops, ear drops, or nose drops), sprays (e.g., for nose or throat), suppositories, retention enemas, chewable or suction-able tablets or pellets (e.g., for treating aphthous ulcers), and aerosols. Ointments and creams can be formulated, for example, using an aqueous or oily base, adding suitable thickeners and / or gelling agents and / or glycols. Thus, such bases can include, for example, water and / or oil (e.g., liquid paraffin or vegetable oil (e.g., peanut oil or castor oil)) or glycol solvents (e.g., propylene glycol or 1,3-butanediol). Thickeners that may be used according to the nature of the base include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycols, wool fat, hydrogenated lanolin and beeswax and / or glyceryl monostearate and / or non-ionic emulsifiers.

[0145] The solubility of steroids in ointments or creams can be enhanced by the incorporation of aromatic alcohols such as benzyl alcohol, phenylethyl alcohol, or phenoxyethyl alcohol.

[0146] Lotions can be formulated using an aqueous or oily base and generally contain one or more of the following: emulsifiers, dispersants, suspending agents, thickeners, solvents, colorants, and fragrances. Powders can be formed using any suitable powder base, such as talc, lactose, or starch. Drops can be formulated using an aqueous base, also containing one or more dispersants, suspending agents, or solubilizing agents. Spray compositions can be formulated as aerosols, for example, using a suitable propellant, such as dichlorodifluoromethane or trichlorofluoromethane.

[0147] Spray or powder formulations may be prepared for oral inhalation in the treatment of asthma, COPD, etc., as is well known in the art. Solutions and suspensions may be prepared for oral or rectal administration, for example, for use in the treatment of intestinal inflammation, as described in more detail in the Examples hereinafter. Parenteral / injectable formulations may be prepared for direct injection into a joint(s) in the treatment of arthritis, consistent with methods well known to those skilled in the art of parenteral formulations.

[0148] The percentage of active ingredient in a composition may vary depending on the exact compound used, the type of formulation prepared, and the The dosage will vary depending on the specific condition for which the composition is administered and the dosage of the compound of Formula (I) or (III). Formulations generally contain from about 0.0001 to about 5.0% by weight of a compound of Formula (I) or (III). Topical preparations generally contain from 0.0001 to 2.5%, preferably from 0.01 to 0.5%, and are administered once daily or as needed. Additionally, the compounds of Formula (I) or (III) can generally be incorporated into topical and other topical compositions formulated substantially similar to currently available compositions containing known glucocorticosteroids at dosage levels similar to (or, in the case of the most potent compounds of the present invention, correspondingly lower) than known highly active agents (e.g., methylprednisolone acetate and beclomethasone dipropionate), or at dosage levels significantly lower than known less active agents such as hydrocortisone.

[0149] Thus, for example, inhalation formulations suitable for use in the treatment of asthma can be prepared as metered-dose aerosol units containing representative species (e.g., S-fluoromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate or 2-hydroxyethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate) according to procedures well known to those skilled in the art of pharmaceutical formulation. Such aerosol units can contain a microcrystalline suspension of one of the above-mentioned compounds in a suitable propellant (e.g., trichlorofluoromethane and dichlorodifluoromethane) with oleic acid or other suitable dispersing agent. Each unit typically contains 1 to 10 milligrams of the aforementioned active ingredient, of which approximately 5 to 50 micrograms is released per actuation.

[0150] Another example of a pharmaceutical composition is a foam to be applied to the anus or perianal area, suitable for treating a wide variety of anorectal inflammatory disorders, comprising 0.05% to 0.1% of a compound of formula (I) or (III) (e.g., the S-fluoromethyl or 2-hydroxyethyl compound described above) and 1% of a local anesthetic (e.g., pramoxine hydrochloride) in a mucoadhesive foam base such as propylene glycol, ethoxylated stearyl alcohol, polyoxyethylene-10-stearyl ether, cetyl alcohol, methylparaben, propylparaben, triethanolamine, and water, together with an inert propellant.

[0151] Yet another pharmaceutical formulation is a solution or suspension suitable for use as a retention enema, where a single dose typically contains 20 to 40 milligrams of a compound of Formula (I) or (III) (e.g., the S-fluoromethyl or 2-hydroxyethyl compound described above) along with sodium chloride, polysorbate 80, and 1 to 6 ounces of water (the water is added immediately before use). The suspension can be administered as a retention enema or by continuous infusion several times a week in the treatment of ulcerative colitis.

[0152] Other pharmaceutical formulations according to the present application are illustrated in the examples below. [Table 3]

[0153] Another example of a nasal spray suitable for treating seasonal or perennial allergic and non-allergic rhinitis is formulated similarly to FLONASE® Nasal Spray, 50 mcg, in which the active ingredient of FLONASE® Nasal Spray, fluticasone propionate, is replaced with a representative compound of formula (I) or (III) herein, preferably S-fluoromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate or 2-hydroxyethyl 17α-dichloroacetoxy(dichlororacetoxy)-6α,9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate. The nasal spray delivers 50 mcg of ultrafine compound of Formula (I) or (III) using a metered atomizing spray pump. The composition also contains microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, benzalkonium chloride (0.02% w / w), polysorbate 80, phenylethyl alcohol (0.25% w / w), and has a pH of 5-7. An exemplary dosage is 200 mcg daily (in one nostril once daily). Two 50mcg sprays or one 50mcg spray in each nostril twice daily).

[0154] For oral inhalation to treat asthma, for example, the fluticasone propionate present in FLOVENT® HFA 44 mcg oral inhalation aerosol, FLOVENT® HFA 110 mcg oral inhalation aerosol, or FLOVENT® HFA 220 mcg oral inhalation aerosol can be replaced with an equivalent amount of a compound of Formula (I) or (III) herein, preferably S-fluoromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate or 2-hydroxyethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carboxylate. In addition to the micronized corticosteroid, each inhaler contains the propellant HFA-134a (1,1,1,2-tetrafluoroethane). For S-fluoromethyl compounds, each actuation of the propellant delivers the equivalent of 44, 110, or 220 mcg of the corticosteroid fluticasone propionate.

[0155] All US patents and all literature articles identified herein above and below are incorporated by reference and relied upon in their entirety.

[0156] References Bodor N. Androstene derivatives, US Patent 5,981,517; 1999. Pat. WO 97 / 42,214. Kurucz I, Nemeth K, Meszaros S, Torok, K, Nagy Z, Zubovics Z, Horvath K, Bodor N. Anti-inflammatory effect and soft properties of etiprednol dicloacetate (BNP-166), a new, anti-asthmatic steroid. Pharmazie. 2004;5:412-416. Kurucz I, Toth S, Nemeth K, Torok K, Csillik-Perczel V, Pataki A, Salamon C, Nagy Z, Szekely J, Horvath K, Bodor N. Potency and specificity of the pharmacological action of a new, anti-asthmatic, topically administered soft steroid, etiprednol dicloacetate (BNP-166). J. Pharm. & Exp. Ther. 2003;307(1):83-92. Also published online July 31, 2003 as DOI:10.1124 / jpet.103.053652. Csanadi A, Horvath Gy, Szekeres T, Hasko T, Ila L, Ivanics J, Patthy M, Salat J, Seres G, Pallagi I, Toth G, Szederkenyi F, Konya A, Tegdes A, Bodor N, Zubovics Z. Etiprednol dicloacetate, a new soft glucocorticoid drug candidate. Development of chemistry. Pharmazie. 2004;5:349-359. Bodor N, Buchwald P. Retrometabolic Drug Design and Targeting. 2012;ISBN 978-0-470- 94945-0. Buchwald P, Bodor N. Soft glucocorticoid design: structural elements and physicochemical parameters determining receptor-binding affinity. Pharmazie. 2004;5:396-404. Barton P, Laws AP, Page MI. Structure-activity relationships in the esterase-catalyzed hydrolysis and transferification of esters and lactones. J Chem Soc Perkin Trans. 1994;2:2021-2029. Bodor N. Soft steroids having anti-inflammatory activity. US Patent 4,996,335; 1991. Belgium Patent BE 889,563;C1.C073; 1981. Bodor N. Designing safer drugs based on the soft drug approach. Trends Pharmacol. 1982;3:53-56. Bodor N. Soft drugs: principles and methods for the design of safer drugs. Med Res Rev.1984;3:449-469. Bodor N. Soft Drugs. In Encyclopedia of Human Biology, Dulbecco R ed. 1991;7(76):1-27. Bodor N, Buchwald P. Molecular size based approach to estimate partition properties for organic solutes. J Phys Chem B. 1997;101:3404-3412. Buchwald P, Bodor N. Octanol-water partition: searching for predictive models. Curr Med Chem. 1998;5:353-380. Zhou J, Jin C, Weike S. Improved Synthesis of Fluticasone Propionate. Org Process Res Dev. 2014;18:928-933; and references cited therein. Huang TJ, Eynott P, Salmon M, Nicklin PL, Chung KF. Effect of topical immunomodulators on acute allergic inflammation and bronchial hyperresponsiveness in sensitised rats. Eur J Pharmacol. 2002;437:187-194. Schneider T, van Velzen D, Moqbel R, Issekutz AC. Kinetics and quantitation of eosinophil and neutrophil recruitment to allergic lung inflammation in a brown Norway rat model. Am J Respir Cell Mol Biol. 1997;17:702-712. Taylor BM, Kolbasa KP, Chin JE, Richards IM, Fleming WE, Griffin RL, Fidler SF, Sun FF. Roles of adhesion molecules ICAM-1 and α4 integrin in antigen-induced changes in microvascular permeability associated with lung inflammation in sensitized brown Norway rats. Am J Respir Cell Mol Biol. 1997; 17:757-766. Samir A, Bodor N, Imai T. Identification of esterase involved in the metabolism of two corticosteroid soft drugs. Biochemical Pharmacology. 2017; 127:82-89 .

[0157] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) Compounds having formula (I):

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Claims

1. Compounds having formula (I): 【Chemistry 32】 wherein each X is independently F or Cl and Y is S.

2. 2. The compound of claim 1, wherein the compound is selected from the group consisting of S-fluoromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate and S-chloromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate.

3. 3. The compound of claim 1 or claim 2, wherein each X is F and Y is S.

4. A pharmaceutical composition comprising an anti-inflammatory effective amount of a compound according to any one of claims 1 to 3 and a pharmaceutically acceptable, non-toxic carrier for said compound suitable for topical or other local application.

5. An ophthalmic composition comprising an anti-inflammatory effective amount of a compound according to any one of claims 1 to 3 and an ophthalmologically acceptable, non-toxic carrier for said compound.

6. 1. A pharmaceutical composition suitable for topical or other local application for use in reducing inflammation in or on a surface of a warm-blooded animal exhibiting an inflammatory response, said pharmaceutical composition comprising an anti-inflammatory effective amount of a compound having formula (I): 【Transformation 38】 wherein each X is independently F or Cl and Y is S, and a pharmaceutically acceptable, non-toxic carrier for said compound, wherein said inflammatory response is localized or regional.

7. 7. The pharmaceutical composition of claim 6, wherein each X is F and Y is S.

8. The inflammatory response ocular inflammatory reactions; nasal inflammatory reaction; Inflammatory reactions in the lungs or bronchi; Intestinal inflammatory response; Inflammatory reactions in the ears; Arthritis inflammatory response; inflammatory reactions of the skin; and Inflammatory reactions in the mouth, gums, or throat 8. The pharmaceutical composition of claim 6 or 7, wherein the pharmaceutical composition is selected from the group consisting of:

9. 17α-Alkylcarbonyloxy-substituted corticosteroid compounds of formula (II): 【Transformation 33】 wherein each X is independently F or Cl, Y is S, and R is C １ -C ３ wherein the compound of formula (II) has topical or localized corticosteroid activity as well as systemic corticosteroid activity, and the process comprises converting the 17α-OCOR group in formula (II) to 17α-dichloroacetoxy (17α-OCOCHCl ２ ) group to produce the resulting soft corticosteroid compound of formula (I): 【Transformation 34】 wherein X and Y are each as defined in formula (II) above, wherein said compound of formula (I) has equivalent topical or localized corticosteroid activity compared to the corresponding compound of formula (II), but has reduced systemic corticosteroid activity compared to the corresponding compound of formula (II).

10. 10. The process of claim 9, wherein the resulting soft corticosteroid compound of formula (I) is selected from the group consisting of S-fluoromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate and S-chloromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate.

11. 11. The process of claim 9 or 10, wherein in formula (I) and formula (II), each X is F and Y is S.

12. 12. The process of any one of claims 9 to 11, wherein the compound of formula (I) has equivalent topical or localized corticosteroid activity compared to the corresponding compound of formula (II), but has reduced systemic corticosteroid activity compared to the corresponding compound of formula (II).

13. The process of any one of claims 9 to 12, wherein the compound of formula (I) has an improved therapeutic index compared to the corresponding compound of formula (II).

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