Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
  • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
  • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
  • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/02—Nasal agents, e.g. decongestants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/04—Antipruritics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents

Definitions

• the present invention is directed to the treatment of asthma, allergic rhinitis, and skin disorders.
• the present invention is directed toward the use of 5,6,7-trihydroxyheptanoic acid and its analogs to treat these conditions.
• Lipoxin A 4 is an anti-inflammatory eicosanoid biosynthesized from arachidonic acid, and is produced locally at inflammation sites via the interaction of neutrophils with platelets or of other leukocytes with epithelial cells. Lipoxin A 4 is believed to act endogenously to resolve inflammation by inhibiting neutrophil influx into inflamed tissue and by inducing macrophage phagocytosis/clearance of activated neutrophils. Lipoxin A 4 binds to at least two receptors with nM affinity. The first is the lipoxin A 4 cognate receptor, called ALXR. This is the same as the formyl peptide receptor FPRL-1.
• the second receptor is cysLT-i, the high affinity receptor for the cysteinyl leukotriene LTD 4 .
• Lipoxins are thought to function as ALXR agonists and cysLTi receptor antagonists [Fronert et al., Am. J. Pathol. 2001 , 758(1), 3-8].
• lipoxin A 4 structural analogs inhibit allergen-induced eosinophil infiltration, decrease production of pro-inflammatory allergic mediators like cysteinyl leukotrienes, IL-5, and eotaxin, and reduce tissue edema in several animal models, i including: a mouse model of allergic asthma [Levy et al., Nat. Med. 2002, 8(9), 1018-1023]; allergen-induced skin inflammation in mice and guinea pigs [Schottelieus et al., J. Immun. 2002, 769(12), 1029-1036]; and allergen- induced pleurisy in rats [Bandeira-Melo et al., J. Immun. 2000, 764(5), 2267- 2271].
• the present invention is directed to methods for the treatment of asthma, allergic rhinitis, and skin disorders.
• a 5,6,7-trihydroxyheptanoic acid or analog is administered to a patient via oral or inhalation delivery for the treatment of asthma.
• a 5,6,7-trihydroxyheptanoic acid or analog is administered to a patient via oral or topical nasal delivery for the treatment of allergic rhinitis.
• a 5,6,7-trihydroxyheptanoic acid or analog is administered to a patient via topical delivery for the treatment of skin disorders, such as allergic dermatitis, psoriasis, and rosacea.
• composition comprising a compound of formula I is administered to a mammal in need thereof:
• R 1 is C 2 H 5 , CO 2 R, CONR 2 R 3 , CH 2 OR 4 , 1 ,3,4-oxadiazole-2-yl, or
• R is H, Ci- 6 straight chain or branched alkyl, C 3-6 cycloalkyl, or phenyl, or R 1 is a carboxylate salt of formula CO 2 R + , where R + is Li + , Na + , K + , or an ammonium moiety of formula + NR 10 R 11 R 12 R 13 ;
• R 2 , R 3 are independently H, C 1-6 alkyl, C 3-6 cycloalkyl, benzyl, phenyl,
• R 4 is H, C(O)R 14 , C 1-6 alkyl, C 3-6 cycloalkyl, benzyl, or phenyl;
• R 5 , R 6 are independently H, C(O)R 14 , C 1-6 alkyl, C 3-6 cycloalkyl, benzyl, phenyl, OH, OCH 3 , or OC 2 H 5 , provided that at most only one of R 2 , R 3 is OH, OCH 3 , or OC 2 H 5 ;
• R 10 -R 13 are independently H or Ci -6 alkyl, each alkyl group optionally bearing an OH or OCH 3 substituent;
• R 14 is H, C 1-6 alkyl, C 3-6 cycloalkyl, benzyl, or phenyl;
• R 15 is C 1-6 alkyl, C 3-6 cycloalkyl, benzyl, or phenyl;
• Preferred compounds of formula I are those wherein:
• R 1 is C 2 H 5 , CO 2 R, CH 2 OR 4 , 1 ,3,4-oxadiazole-2-yl, or a carboxylate salt of formula CO 2 ' R + ;
• R + is Li + , Na + , K + , or NH 4 + ;
• R is H 1 CH 3 , C 2 H 5 , H-C 3 H 7 , or /-C 3 H 7 ;
• R 4 is H, COCH 3 , or CH 3 ;
• Compound 1 is commercially available from Biomol Research Laboratories, Plymouth Meeting, PA, and compound 2 can be prepared as detailed in Lee et. al, Biochemical and Biophysical Research Communications 1991 , 780(3), 1416-21.
• Compounds 3-6 can be prepared as described in examples 1-4 below.
• a solution of methyl ester 1 in aqueous MeOH is heated to reflux in the presence of 3 equivalents of lithium hydroxide. After 6 h the reaction is cooled to room temperature and the pH of the solution is adjusted to 6 by the addition of 70-9 mesh sulfonic acid resin MP (commercially available from Novabiochem/EMD Biosciences, 10394 Pacific Center Court, San Diego, CA 92121). The solution is filtered through a 0.2 ⁇ M poly-terfluoroethylene syringe filter and concentrated to afford the lithium carboxylate 4 as a white solid.
• 2-deoxy-D-ribose is converted to the acetonide-protected lactol 10 by treatment with 2-methoxypropene and catalytic pyridinium p-toluenesulfonate (PPTS) in ethyl acetate.
• PPTS catalytic pyridinium p-toluenesulfonate
• Deprotection of 12 using 0.1 N HCI in ethanol for 5 minutes, followed by quenching with aqueous NaHCO 3 affords 8 after silica gel chromatographic purification.
• compositions are formulated in accordance with methods known in the art.
• compositions may contain a second drug, other than a compound of formula I.
• compositions of the present invention contain a pharmaceutically effective amount of a compound of formula I.
• a pharmaceutically effective amount means an amount sufficient to reduce or eliminate asthma, allergic rhinitis, or skin disorder symptoms.
• the compositions of the present invention will contain from 0.001 to 5% of a compound of formula I.
• the compositions of the present invention will contain from 0.1 to 5% of a compound of formula I.
• compositions administered according to the present invention may also include various other ingredients, including but not limited to surfactants, tonicity agents, buffers, preservatives, co-solvents and viscosity building agents.
• tonicity agents may be employed to adjust the tonicity of the composition.
• sodium chloride, potassium chloride, magnesium chloride, calcium chloride, dextrose and/or mannitol may be added to the composition to approximate physiological tonicity.
• Such an amount of tonicity agent will vary, depending on the particular agent to be added. In general, however, the compositions will have a tonicity agent in an amount sufficient to cause the final composition to have an acceptable osmolality (generally about 150 - 450 mOsm, preferably 250 - 350 mOsm).
• An appropriate buffer system e.g., sodium phosphate, sodium acetate, sodium citrate, sodium borate or boric acid
• the particular concentration will vary, depending on the agent employed.
• the buffer will be chosen to maintain a target pH within the range of PH 5.5 - 8.
• Topical products are typically packaged in multidose form.
• Preservatives are typically required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, polyquaternium-1 , or other agents known to those skilled in the art.
• Such preservatives are typically employed at a level of from 0.001 to 1.0% w/v.
• Unit dose compositions of the present invention will be sterile, but typically will not contain a preservative and will be unpreserved.
• compositions of the present invention can be formulated for various desired dosage forms, depending upon the disorder to be treated.
• the compositions may be formulated as a composition to be delivered via inhalation using for example a nebulizer, in order to treat asthma.
• the compositions may be formulated as a topical nasal spray to treat allergic rhinitis.
• the compositions may be formulated as a lotion, cream, or ointment to treat skin disorders, such as allergic dermatitis, contact hypersensitivity, urticaria (hives), rosacea, or psoriasis.
• a representative pharmaceutical formulation in nebulized form containing a compound of the invention, useful for the treatment of asthma according to the methods of the present invention, is exemplified below.
• a formulation for oral administration containing a compound of the invention, useful for the treatment of asthma according to the methods of the present invention, is exemplified below.
• a topically administerable nasal solution for the treatment of allergic rhinitis according to the methods of the invention is exemplified below.
• a topically administerable ointment for the treatment of skin disorders such as allergic dermatitis, contact hypersensitivity, urticaria (hives), rosacea, or psoriasis according to the methods of the invention, is exemplified below.
• a preferred container for a nasal product is a high-density polyethylene container equipped with a nasal spray pump.

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• Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pulmonology (AREA)
• Dermatology (AREA)
• Emergency Medicine (AREA)
• Otolaryngology (AREA)
• Immunology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pyrane Compounds (AREA)

Priority Applications (6)

Applications Claiming Priority (2)

Publications (2)

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• 2007
  • 2007-11-06 MX MX2009004962A patent/MX2009004962A/es not_active Application Discontinuation
  • 2007-11-06 KR KR1020097011453A patent/KR20090086573A/ko not_active Ceased
  • 2007-11-06 WO PCT/US2007/083695 patent/WO2008058098A2/en not_active Ceased
  • 2007-11-06 US US11/935,457 patent/US20080108695A1/en not_active Abandoned
  • 2007-11-06 AU AU2007316482A patent/AU2007316482A1/en not_active Abandoned
  • 2007-11-06 JP JP2009535499A patent/JP2010509240A/ja active Pending
  • 2007-11-06 BR BRPI0718540-5A patent/BRPI0718540A2/pt not_active IP Right Cessation
  • 2007-11-06 TW TW096141830A patent/TW200829232A/zh unknown
  • 2007-11-06 CN CNA2007800410362A patent/CN101534806A/zh active Pending
  • 2007-11-06 CA CA002668645A patent/CA2668645A1/en not_active Abandoned
  • 2007-11-06 ZA ZA200902909A patent/ZA200902909B/xx unknown
  • 2007-11-06 EP EP07863926A patent/EP2079459A2/en not_active Withdrawn
• 2009
  • 2009-02-19 US US12/388,579 patent/US20090156667A1/en not_active Abandoned

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