WO2003070194A2

WO2003070194A2 - Amino acid and peptide-modified forms of glucocorticoids

Info

Publication number: WO2003070194A2
Application number: PCT/US2003/005204
Authority: WO
Inventors: Mark G. Currie; Paul Grover; Steve Jones; Chris H. Senanayake; Xiaoyi Nie
Original assignee: Sepracor Inc.
Priority date: 2002-02-20
Filing date: 2003-02-20
Publication date: 2003-08-28
Also published as: WO2003070194A3; AU2003217623A1; AU2003217623A8

Abstract

Amino acid corticosteroid esters which may function as pro-drugs, and formulations of the amino acid corticosteroid esters with a second active ingredient such as formoterol are disclosed. Composition of the invention include amino acid corticosteroid esters of Formula (I) that are used to make solution-stable pharmaceutical compositions or stable co-dispersions of pharmaceutical compositions in an aerosol formulation, or in a manual pump spray formulation containing one or more active ingredients. The compounds are useful for treating rhinitis and asthma, particularly by inhalation, and for treating inflammation, particularly by local or topical administration.

Description

AMINO ACID AND PEPTIDE-MODIFIED FORMS OF GLUCOCORTICOIDS

RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application No. 60/358,115, filed on February 20, 2002, the teachings of which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

[0002] The invention relates to antiasthmatic amino acid-modified forms of glucocorticoids, and to mixtures of formoterol and the amino acid-modified forms of glucocorticoids.

BACKGROUND OF THE INVENTION

[0003] Glucocorticoids, in topical, oral and inhaled formulations, are useful for their anti-inflammatory and immunosuppressive activities. Although many formulations are effective, significant side-effects exhibited by glucocorticoids that prevent realization of their maximum pharmacologic value remain a common clinical problem. These side-effects stem, in part, from the difficulty of effectively delivering the glucocorticoid drug to a target tissue without increasing systemic concentrations of the drug.

[0004] Inhaled glucocorticoids are an effective therapy for the control of asthma, and improvement with steroids is one of the hallmarks of asthma (Barnes, PJ (1998) in Asthma: Basic Mechanisms and Clinical Management (3^r ed)). The inhaled glucocorticoids work to reduce the inflammation in either lungs, e.g. for asthma, or nose, e.g. for nasal allergies. Inhaled glucocorticoids are most often administered using a metered dose inhaler (MDI). In the best of circumstances, in controlled clinical settings, only around 30% of the administered dose gets into the lungs. In the general patient population probably only 10% or so of the dose gets into the lungs due to improper use of the inhaler. The rest of the administered drug is deposited in the throat and upper airways, or is swallowed. The drug that is deposited in the throat is responsible for some side effects seen with inhaled glucocorticoids (cough, oropharyngeal candidiasis and dysphonia). For early generation inhaled glucocorticoids, the swallowed drug leads to the same side effects seen with oral glucocorticoids. In light of the tremendous efficacy of inhaled glucocorticoids in asthma, much effort has gone into reducing the side effects from their use. Although newer glucocorticoids (e.g. budesonide, ciclesonide, triamcinolone and fluticasone) exhibit reduced systemic side effects from swallowed drug - being either poorly absorbed in the gut or subject to extensive inactivation in the liver - they nonetheless display systemic side effects as a result of absorption from the lung into the systemic circulation. The side effects include decreased bone density (Israel, E et al, (2001), New England Journal of Medicine 345:941-947 and Wong, CA βt al, (2000) Lancet 355:1399-1403), which has been correlated with increased risk of fracture. Thus the need still exists for inhaled glucocorticoids with reduced systemic effects.

[0005] Another problem frequently encountered with delivery of glucocorticoids to the lung by way of inhalation is the instability of an aerosol formulation containing one or more active ingredients. The active substances are sometimes formulated in the necessary concentrations as solutions or suspensions, wherein the degree of concentration of the individual substances which can be obtained, or even the chemical stability of the individual substances can be problematic.

[0006] If an aerosol formulation lacks stability, then the pressurized dose of the formulation delivered from a metered dose valve is not reproducible. Rapid settling or flocculation, causing degradation of the formulation, are common sources of dose irreproducibility in suspension formulations. Whether or not a surfactant is used in a formulation, such dose irreproducibility can be a problem in the case of either a single active ingredient or two active ingredients. [0007] In order to reduce systemic effects, one approach takes advantage of inactive prodrugs that are activated in the lung tissues. For example, Dietzel et al. (Prog. Respir Res. 31, 91-93 (2001)) have described an isopropyl group esterified at the 21 position of the glucocorticoid core structure. Another approach that has been suggested is the formulation of a glucocorticoid as a liposome. Axelsson et al in a series of US patents (4,693,999; 5,614,514 and 5,888,995) describe selected glucocorticoids modified for formulation into liposomes by esterification at the 21 position with saturated and mono-unsaturated fatty acids with chain lengths up to 20 carbons.

SUMMARY OF THE INVENTION

[0008] The present invention relates to novel amino acid corticosteroid esters, and to aerosol formulations of the amino acid corticosteroid esters. It has now been discovered that amino acid-modified glucocorticoids of Formula I:

21

(I) or pharmaceutically acceptable salts thereof, are compounds having an unexpected utility, that of making solution-stable prodrugs or stable co-dispersions of prodrugs in an aerosol formulation, or in a manual pump spray formulation containing one or more active ingredients.

[0009] A further advantage of the compositions according to an embodiment of the invention is the reduction of side effects of the glucocorticoid. [0010] In the compounds of Formula I according to the invention, R¹ and R², independently for each occurrence, represent a hydrogen, lower alkyl or lower

1 9 acyl, or taken together R and R form a substituted or unsubstituted ketal;

R³ is an ester residue of an α- amino acid, or an ester residue of an N-protected α- amino acid;

1 1 9

R is methyl or -OR ; and

X and Y are independently hydrogen or halogen, with the proviso that, when together R¹ and R² form an acetonide, R³ is not valine.

[0011] The invention inter alia also includes the following embodiments: a compound of Formula I having the structure:

a compound of Formula I having the structure:

a compound of Formula I having the structure:

a compound of Formula I having the structure:

a compound of Formula I having the structure:

and

a compound of Formula I having the structure:

[0012] Another embodiment of the invention is a pharmaceutical formulation for inhalation including at least one compound according Formula I, the compound present in an amount sufficient to provide a plurality of therapeutically effective doses; optionally, a second active ingredient in the form of a non- steroidal bronchodilator or inhibitor of bronchospasm, in an amount sufficient to provide a plurality of therapeutically effective doses; and a pharmaceutically acceptable fluid for suspension or solution, and, optionally, a propellant.

[0013] The second active ingredient may be either the (S,R) isomer of formoterol, or the (R,R) isomer of formoterol. The teachings of U.S. patent numbers 6,299,863 and 6,303,145 with respect to formoterol are incorporated herein by reference in their entireties.

[0014] Yet another embodiment of the invention is a pharmaceutical formulation for topical administration including at least one compound according to Claim 1, the compound present in an amount sufficient to provide a plurality of therapeutically effective doses, and a pharmaceutically acceptable fluid for suspension or solution.

[0015] In another aspect, the invention relates to methods for treating rhinitis, asthma, chronic obstructive pulmonary disease, and inflammatory diseases and conditions, and the symptoms thereof, and methods for preventing the onset of rhinitis, asthma, chronic obstructive pulmonary disease, and inflammatory diseases and conditions, comprising administering the compounds of Formula 1 alone, or with the second active ingredient. In another aspect, the invention includes a method of treating bronchospasm by administering the compounds of Formula 1 alone, or with the second active ingredient. The invention further includes a method of inducing bronchodilation by administering the compounds of Formula 1 alone, or with the second active ingredient. [0016] Another embodiment of the invention is a metered dose inhaler containing a medicinal formulation including at least one compound of Formula I, and the second active ingredient, wherein both the compound of Formula I, and the second active ingredient are present in an amount sufficient to provide a plurality of therapeutically effective doses of each, respectively; a pharmaceutically acceptable fluid for suspension or solution; and a propellant in an amount sufficient to propel a plurality of the therapeutically effective doses from the metered dose inhaler.

[0017] Yet another embodiment of the invention is a kit for treating asthma or rhinitis, or inhibiting the onset of symptoms of asthma or rhinitis in a patient in need thereof, the kit including a metered dose inhaler; a pharmaceutical composition including at least one compound according to Structure I; optionally, a second pharmaceutical composition comprising an amount of the second active ingredient. In one embodiment, the second active ingredient is (R,R)-formoterol. Optionally, the kit also includes instructions for using the metered dose inhaler to administer the first composition, or a mixture of the first and second compositions to a patient in need thereof.

[0018] The present invention has many advantages. In a composition according to the invention, lipophilicity and hydrophilicity are modulated or balanced, leading to the chemical and physical stability of the formulation. By chemical and physical stability is meant that the formulation does not tend to break down, degrade over time, or separate by settling or flocculation. As a result, compared to prior art compositions, it is easier to obtain a desired degree of concentration of the individual substances in a formulation of the invention. [0019] For inhalation therapy, an aerosol formulation with more than one pharmaceutically active substance is often desired. To make such a composition, the substances are usually dissolved or suspended. Problems arise if both substances cannot be readily suspended or dissolved in the same medium. An alpha amino-acid modified glucocorticoid according to an embodiment of the invention, however, is more readily suspendable with micronized formoterol than are glucocorticoids that have not been amino-acid modified.

[0020] Further, the greater stability of an aerosol formulation of the invention, compared to that of prior art formulations, provides the advantage that, a pressurized dose of the formulation according to an embodiment of the invention, delivered from a metered dose valve, is reproducible.

[0021] Another advantage of the alpha amino-acid glucocorticoid compounds according to an embodiment of the invention is that they may function as prodrugs that provide a reduction in side effects from the glucocorticoid. Alpha amino-acid modified glucocorticoid esters are cleaved to the glucocorticoid and the amino acid by the catalytic activity of leukocyte-elastase, a serine-protease. High elastase activities are observed in vivo in the case of inflammatory diseases of the lungs, in the case of rhinitis, in synovial fluid, in the case of rheumatoid arthritis, and on the skin surface in the case of different forms of eczema. (See, eg., Davies, P., (1991) Annals of the New York Academy of Sciences, ed. Weinbaum Giles and Krell, vol 624, pp 219-229). Thus, the active glucocorticoid can be released selectively at the inflammation site, resulting in an increase of the concentration of the active glucocorticoid at the site. The concentrations of the active glucocorticoid in non- inflamed areas are thus minimized, reducing the potential local and systemic side- effects. DETAILED DESCRIPTION OF THE INVENTION

[0022] A description of preferred embodiments of the invention follows. It will be understood that the particular embodiments of the invention are shown by way of illustration and not as limitations of the invention. At the outset, the invention is described in its broadest overall aspects, with a more detailed description following. The features and other details of the compositions and methods of the invention will be further pointed out in the claims.

[0023] The present invention is directed to compositions, methods of preparation thereof, and methods of use thereof, the compositions including at least one compound of Formula I:

in which the substituents are as defined above. One embodiment is a compound of

1 9

Formula I, wherein R is H or lower alkyl; and R is propyl or cyclohexyl. Examples of steroids having the foregoing structure include budesonide, ciclesonide, fluticasone, and triamcinolone.

[0024] The group R is defined as "an ester residue of an α-amino acid or an ester residue of an N-protected α-amino acid." By this is intended that the carboxylate of the α-amino acid may be conceptually dehydratively condensed with the 21 -alcohol of the steroid. Thus R³ has the formula:

resulting in compounds having the structure:

in which R⁴ is a side chain appropriate to an α-amino acid and R is hydrogen in the case of an amino acid and a protecting group, such as acetyl, in the case of a "protected" amino acid. Exemplary R⁴'s would be methyl for alanine, isobutyl for leucine, benzyl for phenylalanine, etc. When the α-amino acid is proline, the compounds have a structure which doesn't quite fit the representation above:

[0025] The amine of the α-amino acid may be protected with any of the well- known protecting groups R⁵ for amines. [See Greene and Wuts Protective Groups in Organic Synthesis Second Edition John Wiley & Sons, New York 1991, pages 309-370 which are incorporated herein by reference.]. Exemplary R⁵'s include 9- fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl, t-butoxycarbonyl (Boc), acetyl, benzyl, and benzoyl.

[0026] In a preferred embodiment the steroid is amino-acid-modified budesonide having the absolute stereochemistry shown:

In another preferred embodiment the steroid is amino-acid-modified ciclesonide having the absolute stereochemistry shown:

In another preferred embodiment the steroid is amino-acid-modified fluticasone having the absolute stereochemistry shown:

In yet another preferred embodiment the steroid is amino-acid-modified triamcinalone having the absolute stereo chemistry shown:

[0027] The compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present invention is meant to include all such possible isomers, as well as, their racemic and optically pure forms. Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Mael r Chem. Ed. 62, 114-120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration. [0028] An alpha amino acid suitable for bonding to a glucocorticoid to produce a compound according to the invention may be chosen from alpha amino acids that are neutral and hydrophobic; acid and hydrophobic; neutral and hydrophilic; acid and hydrophilic; and basic and hydrophilic. As such, suitable amino acids for use in preparing a compound of the invention include valine, leucine, isoleucine, alanine, phenylalanine, glycine, and sarcosine.

[0029] Suitable amino acids may further be chosen from proline and hydroxyproline. Yet additional suitable amino acids may be chosen from tlireonine, serine, asparagine, glutamine, citrulline, homoserine, methionine sulfoxide, and methionine sulfone.

[0030] Additional suitable alpha amino acids include glutamic acid and aspartic acid. A suitable amino acid may be chosen from arginine, histidine, lysine, hydroxylysine, and ornithine. Betaine may also be used to make a composition of the invention.

[0031] It is well-understood by those of skill in the art of peptide synthesis that any of the amino acids used in making a composition of the invention, such as, for example, a compound according to Formula I, may be an N-protected amino acid. For example, an amino group may be protected by an amino protective group chosen from the group consisting of 9-fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl, t-butoxycarbonyl (Boc), acetyl, benzyl, and benzoyl.

[0032] It is also well understood by those of skill in the art that an amino acid, such as, for example, serine or threonine, used to make a compound, for example, according to Formula I, may have a hydroxy group protected by a hydroxy protecting group. Examples of hydroxy protective groups include benzyl, benzoyl (Bz), 2,2,2-trifluoro-l-benzyloxycarbonylaminoethyl (Ztf), tert-butyl (tBu), 4- toluenesulfonyl (Tos), and 2,4-dinitrophenyl (Dnp). [0033] In general, the compounds of the present invention may be prepared by methods well known in the art, or by modifications thereof, using readily available materials, reagents and conventional synthesis procedures. For example, the synthesis of the amino-acid-modified glucocorticoids according to the invention is done according to the processes that are familiar to one skilled in the art, as they are used in general in the case of peptide syntheses (See, eg., Beyermann, Michael, et al, "Rapid Continuous Peptide Synthesis via FMOC Amino Acid Chloride Coupling and 4-(Aminomethyl)piperidine Deblocking," J.Org.Chem. 55: 721-728 (1990)), the teachings of which are incorporated herein by reference.

[0034] Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. Lower alkyl is an alkyl of one to six carbons, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, pentyl, hexyl, and the like.

[0035] A comprehensive list of abbreviations utilized by organic chemists (i.e. persons of ordinary skill in the art) appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled "Standard List of Abbreviations" is incorporated herein by reference.

[0036] Compositions according to an embodiment of the invention are useful in treating asthma, rhinitis, rheumatoid arthritis, and other inflammatory or allergic conditions. For example, they are useful for intra-articular injection for alleviating the joint pain, swelling and stiffness associated with rheumatoid arthritis and osteoarthritis with an inflammatory component; also for bursitis, epicondylitis and tenosynovitis. They may be used topically, transdermally and intradermally (intra- lesional) in lichen simplex chronicus, granuloma annulare, lichen planus, keloids, alopeica areata, discoid lupus erythematosus, localised neurodermatitis, cystic acne, granuloma annulare, nummular and dyshydrotic eczema, and hypertrophic scars (keloids). The treatment of macular degeneration with compounds of the invention is analogous to that described in Billson, US patent 5,770,589, which is incorporated herein by reference. [0037] The terms "treating" and "methods of treating" when used in comiection with the present invention are used interchangeably, and mean amelioration, prevention or relief from the symptoms and/or effects associated with conditions such as, for example, asthma, rhinitis, and other inflammatory and allergic conditions. The person of ordinary skill in the medical art recognizes that "prevention" of the symptoms and/or effects associated with asthma and rhinitis is not an absolute term. In the medical art it is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or seriousness of the condition, or to inhibit the onset of symptoms of the condition.

[0038] As the terms are used herein, "drug", "pharmaceutical", "therapeutically effective substance", and "therapeutic substance" have the same meaning; are used interchangeably; and include:

(i) Compounds and compositions recognized in the official United

States Pharmacopoeia, the official Homeopathic Pharmacopoeia of the United States, or the official National Formulary, or any supplement of any of them;

(ii) Compounds and compositions intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and

(iii) Compounds and compositions (other than food) intended to affect the structure or any function of the body of man or other animals.

[0039] Examples of therapeutically effective substances include, but are not limited to formoterol, and alpha amino acid-modified glucocorticoids of the invention.

[0040] Any of the compositions of the present invention described herein may be administered with a suitable pharmaceutical carrier, the choice of which depends on, for example, the route of administration. The terms "suitable pharmaceutical carrier," "pharmaceutically acceptable," and grammatical variations thereof, as they refer to compositions, carriers, diluents and reagents, are used herein interchangeably. As the terms are used herein, "suitable pharmaceutical carrier" and "pharmaceutically acceptable" refer to non-toxic materials that do not interfere with the effectiveness of the biological activity of active ingredients, and represent that the materials are capable of administration to or upon a vertebrate with a minimum of undesirable physiological effects such as nausea, dizziness, gastric upset and the like. The characteristics of the carrier will depend on the route of administration.

[0041] The preparation of a pharmacological composition that contains active ingredients dissolved or dispersed therein is well understood in the art and need not be limited based on formulation. Liquid preparations include solutions, suspensions, colloids, hydrogels, and emulsions, for example, water or water- propylene glycol mixtures. Such compositions may be prepared as injectables, either as liquid solutions or suspensions. Solid forms suitable for dissolving in a hydrogel or a liquid solution, or for suspending in liquid prior to use, can also be prepared. The preparation can also be emulsified. The active ingredient can be mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient and in amounts suitable for use in the therapeutic methods described herein. Suitable excipients include, for example, water, saline, dextrose, glycerol, ethanol or the like and combinations thereof. In addition, if desired, the composition can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like which enhance the effectiveness of the active ingredient. Details on techniques for formulation and administration may be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.). [0042] To achieve the improvements described herein, the present invention provides for a route of administration of the compositions of the invention that is either an administration by inhalation, a topical or transdermal administration, an oral administration, an administration by injection, or that is a combination of two or more of these administration routes.

[0043] For administration by inhalation, at least one amino acid-modified glucocorticoid according to an embodiment of the invention, or a mixture of the amino acid-modified glucocorticoid and micronized formoterol is suitably inhaled from a nebulizer, from a pressurized metered dose inhaler or as a dry powder from a dry powder inhaler (e.g. sold as TURBUHALER®) or from a dry powder inhaler utilizing gelatin, plastic or other capsules, cartridges or blister packs.

[0044] Dry powder inhalers include devices that meter the pharmaceutical composition or drug from a chamber within the device or those that deliver pre- metered doses utilizing gelatin, plastic or other capsules, cartridges, or blister packs and/or strips.

[0045] Formulations and devices for dry powder inhalers are well known to those skilled in the art. For use in a dry powder inhaler, the particle size of the active ingredients may be reduced by micronization, crystallization, spray drying or other known techniques.

[0046] For drugs such as formoterol to be absorbed by the alveoli of the lungs, the particle size of the drug is normally reduced to less than about 10 micrometers, preferably between about 0.5 micrometers and about 5 micrometers. [0047] Formulations and devices for nebulizers and metered dose inhalers are also well known to those skilled in the art. In formulations where the active ingredient is in a suspension it is important that the particles are below 20 μm in size and preferably below 5 μm in size. This may be achieved by micronization, crystallization, spray drying or other known techniques. Techniques of micronization, and formulations and devices for nebulizers and metered dose inhalers are described in U.S.Patent Numbers 3,994,974; 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 6,299,863; and 6,303,145, the teachings of which are hereby incorporated by reference.

[0048] The solvent or suspension agent utilized for nebulization may be any pharmacologically suitable fluid such as water, aqueous saline, alcohols or glycols, e.g., ethanol, isopropylalcohol, glycerol, propylene glycol, polyethylene glycol, etc. or mixtures thereof. Saline solutions utilize salts which display little or no pharmacological activity after administration. Both inorganic salts, such as alkali metal or ammonium halogen salts e.g. sodium chloride, potassium chloride or organic salts, such as potassium, sodium and ammonium salts of organic acids, e.g., ascorbic acid, citric acid, acetic acid, tartaric acid, etc. may be used for this purpose.

[0049] Other excipients and additives may be added to the formulation. The active ingredient may be stabilized by the addition of an inorganic acid, e.g., hydrochloric acid, nitric acid, sulphuric acid and/or phosphoric acid; an organic acid, e.g., ascorbic acid, citric acid, acetic acid, and tartaric acid etc.; a complexing agent such as EDTA or citric acid and salts thereof; or an antioxidant such as vitamin E or ascorbic acid. These may be used alone or together to stabilize the active ingredient. Preservatives can also be added such as benzalkonium chloride or benzoic acid and salts thereof. Surfactant may be added particularly to improve the physical stability of suspensions. These include lecithins, disodium dioctylsulphosuccinate, oleic acid and sorbitan esters. [0050] The active ingredient may also be suspended or dissolved in a liquefied propellant, sealed in a container with a metering valve and fitted into an actuator. Such metered dose inhalers are well known in the art. The metering valve may meter 10 to 500 μL and preferably 25 to 150 μL.

[0051] An aerosol formulation according to an embodiment of the invention includes a liquefied gas propellant chosen from carbon dioxide (CO₂), nitrous oxide (N₂O), sulfur hexafluoride (SF₆), and mixtures of the foregoing. Although the foregoing propellants are more environmentally sound, alternatively, the propellants used may be halocarbons, hydrocarbons or other liquefied gasses. The most frequently used are trichlorofluoromethane, dichlorfluoromethane, dichlortetrafluoroethane, tetrafluoroethane (HFA-134a), 1,1-difluoroethane (HFA- 152a), difluoromethane (HFA-32), pentafluoroethane (HFA-125), heptafluoropropane (HFA-227ea), perfluoropropane, perfluorobutane, perfluorpentane, butane, isobutane, and pentane. In particular, tetrafluoroethane (HFA-134a) and heptafluoropropane (HFA-227ea) and mixtures thereof may be used.

[0052] As well as propellant, formulations may contain other excipients. Surfactants may be added particularly to improve the physical stability of suspensions and valve performance. These include lecithins, disodium dioctylsulphosuccinate, oleic acid and sorbitan esters. Cosolvents may also be added to improve solubility of surfactant in propellant or modify the pharmacological performance. These include alcohols and glycols, e.g., ethanol, isopropylalcohol, glycerol, propylene glycol, polyethylene glycol, etc., or mixtures thereof. Further excipients may be added to improve performance or taste, e.g., fatty acids and salts thereof such as magnesium stearate, menthol oil etc. [0053] For topical application, there are employed as non-sprayable forms, viscous to semi-solid or solid forms comprising a carrier compatible with topical application and having a dynamic viscosity preferably greater than water. Suitable formulations include but are not limited to solutions, suspensions, emulsions, creams, ointments, powders, liniments, salves, aerosols, etc., which are, if desired, sterilized or mixed with auxiliary agents, e.g., preservatives, stabilizers, wetting agents, buffers or salts for influencing osmotic pressure, etc. For topical application, also suitable are sprayable aerosol preparations wherein the active ingredient, preferably in combination with a solid or liquid inert carrier material, is packaged in a squeeze bottle or in admixture with a pressurized volatile, normally gaseous propellant, e.g., a freon.

[0054] The topical pharmaceutical carrier may include any substance capable of dispersing and maintaining contact between the active ingredients and the skin. The vehicle may be glycerin, alcohol or water based. Examples of such vehicles include aloe vera, which is a gel base, together with ethanol, isopropyl alcohol, water, propylene glycol and a non-ionic surfactant such as laureth-4. Other water- based alcohol/ glycerin vehicles and carriers are within the scope of the present invention. A typical water-based lotion will contain from 45 to 50 parts of glycerin, one to three parts Tween 80TM, from 45 to 50 parts of water and from 1 to 50 parts of the compound of the invention.

[0055] Also included in the scope of the invention are ointments, emulsions or dispersions in which water, if present, is a minor constituent. Typical ointment formulation comprises from 90 to 98 parts of a mixture of petrolatum, mineral oil, mineral wax and wool wax alcohol, from 0.5 to 3 parts of a mixture of polyoxyethylene and sorbitan monooleate (Tween 80TM), from 1 to 5 parts of water, and from 1 to 50 parts of the compound of the invention. Another suitable non-aqueous ointment can be prepared from 95 parts of liquid petrolatum USP, 5 parts polyethylene and from 1 to 50 parts of the compound of the invention. The resulting ointment spreads easily and has an even consistency over wide temperature extremes. It is, in addition, non-irritating and non-sensitizing. [0056] Formulations of the compounds of the invention may also be prepared containing from 0 to 25% by weight of urea. In general, in such urea containing ointments, the water content will vary from 5 to 50%> by weight of the composition. Any suitable ointment carrier may be used such as lanolin, ethylene glycol polymers and the like. In the case of formulations containing urea, it is known in the art that borate salts may often be added to stabilize the pharmaceutical composition (see U.S. patent 2,917,433, the disclosure of which is incorporated herein by reference).

[0057] Water based compositions may also be employed, in which case the compound of the invention will commonly be in solution, and the aqueous solution may, if desired, be thickened with a suitable gel to provide a less mobile composition. Such compositions are well known in the art.

[0058] For oral administration, a diluent or carrier, generally non-toxic and chemically inert to the medicament, e.g. lactose, dextran, mannitoi or glucose or any additives that will give the medicament a desired taste, can be added to the powdered medicament.

EQUIVALENTS

[0059] While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

1. A compound of Formula I :

(I) or a pharmaceutically acceptable salt thereof,

1 9 wherein R and R , independently for each occurrence, represent a hydrogen, lower alkyl or lower acyl, or taken together R¹ and R² form a substituted or unsubstituted ketal;

R is chosen from an ester residue of an α- amino acid, and an ester residue of an

N-protected α- amino acid;

R is methyl or -OR ; and

A compound according to Claim 1 of Formula I, wherein R¹ is H or lower alkyl; and R is propyl or cyclohexyl.

A compound according to Claim 1 of Formula II:

(II)

A compound according to Claim 1 of Formula III:

(III)

A compound according to Claim 1, of formula:

6. A compound according to Claim 1 , of formula:

A compound according to Claim 3 of formula:

A compound according to Claim 4 of formula:

9. A compound according to Claim 1, wherein R is an ester residue of an amino acid or an N-protected amino acid chosen from valine, leucine, isoleucine, alanine, phenylalanine, glycine, and sarcosine.

10. A compound according to Claim 1, wherein R³ is an ester residue chosen from proline, hydroxyproline, N-protected proline, and N-protected hydroxyproline.

11. A compound according to Claim 1, wherein R³ is an ester residue of an amino acid or an N-protected amino acid chosen from tlireonine, serine, asparagine, glutamine, citrulline, homoserine, methionine sulfoxide, and methionine sulfone.

12. A compound according to Claim 1, wherein R³ is an ester residue of an amino acid or an N-protected amino acid chosen from glutamic acid and aspartic acid.

13. A compound according to Claim 1 , wherein R³ is an ester residue of an amino acid or an N-protected amino acid chosen from arginine, histidine, lysine, hydroxylysine, and ornithine.

14. A compound according to Claim 1, wherein R³ is an ester residue of betaine.

15. A compound according to Claim 1, wherein at least one amino group is protected by an amino protective group chosen from the group consisting of 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl, acetyl, benzyl, and benzoyl.

16. A compound according to Claim 11, wherein a serine or threonine hydroxy group is protected by a hydroxy protective group.

17. The compound according to Claim 16, wherein said protecting group is chosen from benzyl, benzoyl, 2,2,2-trifluoro-l- benzyloxycarbonylaminoethyl, tert-butyl, 4-toluenesulfonyl, and 2,4- dinitrophenyl.

18. A method of treating inflammatory conditions comprising administering a compound of Claim 1.

19. The method of Claim 18, wherein the condition is asthma or chronic obstructive pulmonary disease.

20. A method for treating rhinitis comprising administering a compound of Claim 1.

21. A method for treating bronchospasm comprising administering a compound of Claim 1.

22. A method for inducing bronchodilation comprising administering a compound of Claim 1.

23. A method according to Claim 18 wherein said compound is administered by inhalation.

24. A method according to Claim 20 wherein said compound is administered by inhalation.

25. A method according to Claim 21 wherein said compound is administered by inhalation.

26. A method according to Claim 22 wherein said compound is administered by inhalation.

27. A method for treating a disorder chosen from osteoarthritis, bursitis, epicondylitis, tenosynovitis, lichen simplex chronicus, granuloma annulare, lichen planus, keloids, alopeica areata, discoid lupus erythematosus, localised neurodermatitis, cystic acne, granuloma annulare, nummular and dyshydrotic eczema, hypertrophic scars and macular degeneration comprising administering the compound of Claim 1.

28. A pharmaceutical formulation for topical administration comprising at least one compound according to Claim 1, the compound present in an amount sufficient to provide a plurality of therapeutically effective doses, and a pharmaceutically acceptable fluid for suspension or solution.

29. A pharmaceutical formulation for inhalation comprising at least one compound according to Claim 1, the compound present in an amount sufficient to provide a plurality of therapeutically effective doses, and a pharmaceutically acceptable fluid for suspension or solution.

30. A pharmaceutical formulation for inhalation comprising: a) at least one compound according to Claim 1, the compound present in an amount sufficient to provide a plurality of therapeutically effective doses;

b) a second active ingredient in an amount sufficient to provide a plurality of therapeutically effective doses; and

c) a pharmaceutically acceptable fluid for suspension or solution.

31. The pharmaceutical formulation for inhalation according to Claim 30, wherein the second active ingredient is formoterol, or a pharmaceutically acceptable salt thereof.

32. The pharmaceutical formulation for inhalation according to Claim 30 additionally comprising a propellant in an amount sufficient to propel a plurality of said therapeutically effective doses from an aerosol canister.

33. The pharmaceutical formulation of Claim 32 wherein the propellant is a compressed or liquefied gas selected from the group consisting of carbon dioxide, nitrous oxide, and sulfur hexafluoride, or a mixture of the foregoing.

34. A metered dose inhaler containing a medicinal formulation comprising: a) at least one compound according to Claim 1, the compound present in an amount sufficient to provide a plurality of therapeutically effective doses of the compound; b) a second active ingredient in an amount sufficient to provide a plurality of therapeutically effective doses of the second active ingredient;

c) a pharmaceutically acceptable fluid for suspension or solution; and

d) a propellant in an amount sufficient to propel a plurality of said therapeutically effective doses of the compound and a plurality of said therapeutically effective doses of the second active ingredient from the metered dose inhaler.

35. The metered dose inhaler of Claim 34, wherein the second active ingredient is formoterol, or a pharmaceutically acceptable salt thereof.

36. A kit for treating asthma or rhinitis, or inhibiting the onset of symptoms of asthma or rhinitis in a patient in need thereof, said kit comprising:

(a) a metered dose inhaler;

(b) a first pharmaceutical composition comprising at least one compound according to Claim 1 ;

(c) a second pharmaceutical composition comprising a second active ingredient; and

(d) optionally, instructions for using the metered dose inhaler to administer the first composition, the second composition, or a mixture of the first and second compositions to a patient in need thereof.