US20020013294A1 - Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives - Google Patents

Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives Download PDF

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US20020013294A1
US20020013294A1 US09774558 US77455801A US2002013294A1 US 20020013294 A1 US20020013294 A1 US 20020013294A1 US 09774558 US09774558 US 09774558 US 77455801 A US77455801 A US 77455801A US 2002013294 A1 US2002013294 A1 US 2002013294A1
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Mitchell DeLong
John McIver
Robert Youngquist
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Duke University
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Procter and Gamble Co
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K8/00Cosmetics or similar toilet preparations
    • A61K8/18Cosmetics or similar toilet preparations characterised by the composition
    • A61K8/30Cosmetics or similar toilet preparations characterised by the composition containing organic compounds
    • A61K8/55Phosphorus compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/66Phosphorus compounds
    • A61K31/662Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K8/00Cosmetics or similar toilet preparations
    • A61K8/18Cosmetics or similar toilet preparations characterised by the composition
    • A61K8/30Cosmetics or similar toilet preparations characterised by the composition containing organic compounds
    • A61K8/64Proteins; Peptides; Derivatives or degradation products thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILET PREPARATIONS
    • A61Q1/00Make-up preparations; Body powders; Preparations for removing make-up
    • A61Q1/02Preparations containing skin colorants, e.g. pigments
    • A61Q1/10Preparations containing skin colorants, e.g. pigments for eyes, e.g. eyeliner, mascara
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILET PREPARATIONS
    • A61Q5/00Preparations for care of the hair
    • A61Q5/02Preparations for cleaning the hair
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILET PREPARATIONS
    • A61Q5/00Preparations for care of the hair
    • A61Q5/06Preparations for styling the hair, e.g. by temporary shaping or colouring
    • A61Q5/065Preparations for temporary colouring the hair, e.g. direct dyes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILET PREPARATIONS
    • A61Q7/00Preparations for affecting hair growth
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02Phosphorus compounds
    • C07F9/28Phosphorus compounds with one or more P—C bonds
    • C07F9/30Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
    • C07F9/302Acyclic unsaturated acids
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02Phosphorus compounds
    • C07F9/28Phosphorus compounds with one or more P—C bonds
    • C07F9/30Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, Se)
    • C07F9/304Aromatic acids (P-C aromatic linkage)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K2800/00Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/59Mixtures
    • A61K2800/596Mixtures of surface active compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K2800/00Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74Biological properties of particular ingredients

Abstract

A method for treating hair loss in mammals uses compositions containing 2-decarboxy-2-phosphinico prostaglandin derivatives. The compositions can be applied topically to the skin. The compositions can arrest hair loss, reverse hair loss, and promote hair growth. Compositions containing 2-decarboxy-2-phosphinico prostaglandin derivatives can also be used to lower intraocular pressure and treat bone disorders.

Description

    FIELD OF THE INVENTION
  • This invention relates to compositions and methods for using 2-decarboxy-2-phosphinico derivatives of prostaglandins. More particularly, this invention relates to the use of 2-decarboxy-2-phosphinico derivatives of prostaglandins for treating hair loss in mammals. This invention further relates to the use of 2-decarboxy-2-phosphinico derivatives of prostaglandins for lowering intraocular pressure and treating bone disorders in mammals. [0001]
  • BACKGROUND OF THE INVENTION Hair Loss—Cosmetic Treatment
  • Hair loss is a common problem which is, for example, naturally occurring or chemically promoted through the use of certain therapeutic drugs designed to alleviate conditions such as cancer. Often such hair loss is accompanied by lack of hair re-growth which causes partial or full baldness. [0002]
  • Hair growth on the scalp does not occur continuously, but rather occurs by a cycle of activity involving alternating periods of growth and rest. This cycle is divided into three main stages; anagen, catagen, and telogen. Anagen is the growth phase of the cycle and is characterized by penetration of the hair follicle deep into the dermis with rapid proliferation of cells which are differentiating to form hair. The next phase is catagen, which is a transitional stage marked by the cessation of cell division, and during which the hair follicle regresses through the dermis and hair growth ceases. The next phase, telogen, is characterized as the resting stage during which the regressed follicle contains a germ with tightly packed dermal papilla cells. At telogen, the initiation of a new anagen phase is caused by rapid cell proliferation in the germ, expansion of the dermal papilla, and elaboration of basement membrane components. When hair growth ceases, most of the hair follicles reside in telogen and anagen is not engaged, thus causing the onset of full or partial baldness. [0003]
  • Attempts to invoke the re-growth of hair have been made by, for example, the promotion or prolongation of anagen. Currently, there are two drugs approved by the United States Food and Drug Administration for the treatment of male pattern baldness: topical minoxidil (marketed as ROGAIN® by Pharmacia & Upjohn), and oral finasteride (marketed as PROPECIA® by Merck & Co., Inc.). However, the search for efficacious hair growth inducers is ongoing due to factors including safety concerns and limited efficacy. [0004]
  • The thyroid hormone thyroxine (“T4”) converts to thyronine (“T3”) in human skin by deiodinase I, a selenoprotein. Selenium deficiency causes a decrease in T3 levels due to a decrease in deiodinase I activity; this reduction in T3 levels is strongly associated with hair loss. Consistent with this observation, hair growth is a reported side effect of administration of T4. See, e.g., Berman, “Peripheral Effects of L-Thyroxine on Hair Growth and Coloration in Cattle”, [0005] Journal of Endocrinology, Vol. 20, pp. 282-292, (1960); and Gunaratnam, “The Effects of Thyroxine on Hair Growth in the Dog”, J. Small Anim. Pract., Vol. 27, pp. 17-29 (1986). Furthermore, T3 and T4 have been the subject of several patent publications relating to treatment of hair loss. See, e.g., Fischer et al., DE 1,617,477, published Jan. 8, 1970; Mortimer, GB 2,138,286, published Oct. 24, 1984; and Lindenbaum, WO 96/25943, assigned to Life Medical Sciences, Inc., published Aug. 29, 1996.
  • Unfortunately, however, administration of T3 or T4, or both, to treat hair loss is often not practicable because these thyroid hormones can induce significant cardiotoxicity. See, e.g., Walker et al., U.S. Pat. No. 5,284,971, assigned to Syntex, issued Feb. 8, 1994 and Emmett et al., U.S. Pat. No. 5,061,798, assigned to Smith Kline & French Laboratories, issued Oct. 29, 1991. [0006]
  • In an alternative approach, prostaglandins have been proposed to promote hair growth because prostaglandins may have a similar benefit to thyroid hormones, i.e., increasing hair length and changing pigmentation. Naturally occurring prostaglandins (e.g., PGA[0007] 2, PGB2, PGE1, PGF, and PGI2) are C-20 unsaturated fatty acids. PGF, the naturally occurring Prostaglandin F analog in humans, is characterized by hydroxyl groups at the C9 and C11 positions on the alicyclic ring, a cis-double bond between C5 and C6, and a trans-double bond between C13 and C14. PGF has the formula:
    Figure US20020013294A1-20020131-C00001
  • Analogs of naturally occurring Prostaglandin F are known in the art. For example, see U.S. Pat. No. 4,024,179 issued to Bindra and Johnson on May 17, 1977; German Patent No. DT-002,460,990 issued to Beck, Lerch, Seeger, and Teufel published on Jul. 1, 1976; U.S. Pat. No. 4,128,720 issued to Hayashi, Kori, and Miyake on Dec. 5, 1978; U.S. Pat. No. 4,011,262 issued to Hess, Johnson, Bindra, and Schaaf on Mar. 8, 1977; U.S. Pat. No. 3,776,938 issued to Bergstrom and Sjovall on Dec. 4, 1973; P. W. Collins and S. W. Djuric, “Synthesis of Therapeutically Useful Prostaglandin and Prostacyclin Analogs”, [0008] Chem. Rev., Vol. 93,, pp. 1533-1564 (1993); G. L. Bundy and F. H. Lincoln, “Synthesis of 17-Phenyl-18,19,20-Trinorprostaglandins: I. The PG1 Series”, Prostaglandin, Vol. 9, No. 1, pp. 1-4 (1975); W. Bartman, G. Beck, U. Lerch, H. Teufel, and B. Scholkens, “Luteolytic Prostaglandin: Synthesis and Biological Activity”, Prostaglandin, Vol. 17, No. 2, pp. 301-311 (1979).
  • Prostaglandins in general have a wide range of biological activities. For example, PGE[0009] 2 has the following properties: a) regulator of cell proliferation, b) regulator of cytokine synthesis, c) regulator of immune responses and d) inducer of vasodilatation. Vasodilatation is thought to be one of the mechanisms of how minoxidil provides a hair growth benefit. In vitro results in the literature also indicate some anti-inflammatory properties of the prostaglandins. c.f.; Tanaka, H., Br J. Pharm., 116, 2298, (1995).
  • However, previous attempts at using prostaglandins to promote hair growth have been unsuccessful. Different prostaglandins can bind to multiple receptors at various concentrations with a biphasic effect. Therefore, it is an object of this invention to provide methods for using prostaglandins to grow hair and to provide compositions that promote hair growth. It is a further object of this invention to provide a selection of appropriate prostaglandins that will promote hair growth in humans and lower animals. [0010]
  • Bone Disorders—Pharmaceutical Treatment
  • In addition to the biological activities discussed above, prostaglandins are also known to affect bone. Therefore, it is a further object of this invention to provide compositions and methods for using prostaglandins to treat bone disorders. [0011]
  • Accelerated bone loss may result from drug administration, such as corticosteroids, prolonged bed rest, disuse of a limb, and microgravity. In osteoporotics, an imbalance in the bone remodeling process develops in which bone is resorbed at a rate faster than it is being made. Although this imbalance occurs to some extent in most individuals, male and female, as they age, it is more severe and occurs at a younger age in osteoporotics, particularly those who develop the post menopausal form of the condition. Bone loss due to the above conditions can result in complete removal of trabeculae and a deterioration of bone architecture such that the strength of the remaining bone decreases disproportionately. [0012]
  • To completely return the bone to normal strength, new trabeculae should be formed to restore architecture and increase bone mass. When restoration of normal architecture is associated with an increase in strength and return to normal stiffness and shock absorbing capability, the bone is less likely to fracture. Subjects suffering from other bone disorders, such as osteoarthritis, Paget's disease, periodontal disease, and fractures may also benefit from treatments that restore normal architecture and bone mass. [0013]
  • Various agents have been tried in attempts to treat bone disorders by slowing bone loss or increasing bone mass. Agents for slowing bone loss and reestablishing bone density are exemplified by antiresorptive agents such as bisphosphonates. [0014]
  • Prostaglandin E analogs are potent stimulators of bone resorption and formation. Anabolic agents such as some prostaglandin E analogs may be detrimental to one suffering from bone disorders such as osteoporosis because increased resorption may cause perforation and loss of trabeculae or may weaken the exsting trabecular structure. Increased resorption may also occur in cortical bone, which may increase the incidence of fracture at some sites. [0015]
  • Anabolic agents such as fluoride and other prostaglandin E analogs have been used to increase bone mass. However, such agents have failed to build bone that is structurally and architecturally similar to the type of bone lost. [0016]
  • Naturally occurring PGF[0017] , shown above, is also known to affect bone resorption. However, naturally occurring prostaglandins have several drawbacks that limit their desirability for systemic administration. Naturally occurring prostaglandins are characterized by their activity at a certain prostagladin receptor, however, their activity is not limited to any one receptor. Therefore, systemic administration of naturally occurring prostaglandins can cause side effects such as inflammation, surface irritation, smooth muscle contraction, pain, and bronchoconstriction.
  • Therefore, it is an object of this invention to provide compositions and methods using prostaglandins to treat bone disorders without significant undesirable side effects. It is a further object of this invention to provide a selection of appropriate prostaglandins that will promote bone growth in humans and lower animals. [0018]
  • Intraocular Pressure—Pharmaceutical Treatment
  • In addition to the pharmacological properties discussed above, naturally occurring prostaglandins are also known to reduce intraocular pressure. Reduction of intraocular pressure is effective to treat disorders such as glaucoma. See C. Iiljebris, G. Selen, B. Resul, J. Sternschantz, and U. Hacksell, “Derivatives of 17-Phenyl-18, 19,20-trinorprostaglandin F[0019] 2α. Isopropyl Ester: Potential Antiglaucoma Agents”, Journal of Medicinal Chemistry, Vol. 38, No. 2, pp. 289-304 (1995). However, as discussed above, the naturally occurring prostaglandins generally are not specific for any one prostaglandin receptor, and thus are known to cause side effects.
  • Therefore, it is an object of this invention to provide compositions and methods using prostaglandins to lower intraocular pressure without significant undesirable side effects. It is a further object of this invention to provide a selection of appropriate prostaglandins that will lower intraocular pressure in humans and lower animals. [0020]
  • SUMMARY OF THE INVENTION
  • This invention relates to compositions and methods for treating hair loss. The methods comprise administering the compositions comprising specific prostaglandins that interact strongly with hair-selective receptors, such as the FP receptor. The choice of prostaglandin is important because the prostaglandin must selectively activate the FP receptor and not activate any other receptors that would negate the effect of activating the FP receptor or that would cause significant undesirable side effects. The prostaglandins used in this invention are [0021] 2-decarboxy-2-phosphinico derivatives of prostaglandins. This invention further relates to the use of 2-decarboxy-2-phosphinico derivatives of prostaglandins to prepare compositions for treating hair loss. The compositions comprise: component A) the 2-decarboxy-2-phosphinico derivative of a prostaglandin, component B) a carrier, and optionally component C) an activity enhancer.
  • This invention further relates to compositions and methods for treating bone disorders. The methods comprise administering, to subjects suffering from bone disorders such as osteoporosis, compositions comprising 2-decarboxy-2-phosphinico derivatives of prostaglandins. This invention further relates to the use of 2-decarboxy-2-phosphinico derivatives of prostaglandins to prepare compositions for treating bone disorders. [0022]
  • This invention further relates to compositions and methods for lowering intraocular pressure. The methods comprise administering, to subjects suffering from conditions such as glaucoma, compositions comprising 2-decarboxy-2-phosphinico derivatives of prostaglandins. This invention further relates to the use of 2-decarboxy-2-phosphinico derivatives of prostaglandins to prepare compositions for lowering intraocular pressure. [0023]
  • DETAILED DESCRIPTION OF THE INVENTION
  • In one aspect, this invention relates to compositions for treating hair loss in mammals. “Treating hair loss” includes arresting hair loss or reversing hair loss, or both, and promoting hair growth. [0024]
  • Publications and patents are referred to throughout this disclosure. All U.S. Patents cited herein are hereby incorporated by reference. [0025]
  • All percentages, ratios, and proportions used herein are by weight unless otherwise specified. [0026]
  • Definition and Usage of Terms
  • The following is a list of definitions for terms, as used herein: [0027]
  • “Activate” means binding and signal transduction of a receptor. [0028]
  • “Acyl group” means a monovalent group suitable for acylating a nitrogen atom to form an amide or carbamate, an alcohol to form a carbonate, or an oxygen atom to form an ester group. Preferred acyl groups include benzoyl, acetyl, tert-butyl acetyl, para-phenyl benzoyl, and trifluoroacetyl. More preferred acyl groups include acetyl and benzoyl. The most preferred acyl group is acetyl. [0029]
  • “Aromatic group” means a monovalent group having a monocyclic ring structure or fused bicyclic ring structure. Monocyclic aromatic groups contain 5 to 10 carbon atoms, preferably 5 to 7 carbon atoms, and more preferably 5 to 6 carbon atoms in the ring. Bicyclic aromatic groups contain 8 to 12 carbon atoms, preferably 9 or 10 carbon atoms in the ring. Aromatic groups are unsubstituted. The most preferred aromatic group is phenyl. [0030]
  • “Carbocyclic group” means a monovalent saturated or unsaturated hydrocarbon ring. Carbocyclic groups are monocyclic, or are fused, spiro, or bridged bicyclic ring systems. Monocyclic carbocyclic groups contain 4 to 10 carbon atoms, preferably 4 to 7 carbon atoms, and more preferably 5 to 6 carbon atoms in the ring. Bicyclic carbocyclic groups contain 8 to 12 carbon atoms, preferably 9 to 10 carbon atoms in the ring. Carbocyclic groups are unsubstituted. Preferred carbocyclic groups include cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. More preferred carbocyclic groups include cyclohexyl, cycloheptyl, and cyclooctyl. The most preferred carbocyclic group is cycloheptyl. Carbocyclic groups are not aromatic. [0031]
  • “Cyano group” means a group containing a nitrile functionality. [0032]
  • “FP agonist” means a compound that activates the FP receptor. [0033]
  • “FP receptor” means known human FP receptors, their splice variants, and undescribed receptors that have similar binding and activation profiles as the known human FP receptors. “FP” means the receptor is of the class which has the highest affinity for PGF[0034] of all the naturally occurring prostaglandins. FP refers to a known protein.
  • “Halogen atom” means F, Cl, Br, or I. Preferably, the halogen atom is F, Cl, or Br; more preferably Cl or F; and most preferably F. [0035]
  • “Halogenated heterogenous group” means a substituted heterogenous group or a substituted heterocyclic group, wherein at least one substituent is a halogen atom. Halogenated heterogenous groups can have a straight, branched, or cyclic structure. Preferred halogenated heterogenous groups have 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms. Preferred halogen atom substituents are Cl and F. [0036]
  • “Halogenated hydrocarbon group” means a substituted monovalent hydrocarbon group or a substituted carbocyclic group, wherein at least one substituent is a halogen atom. Halogenated hydrocarbon groups can have a straight, branched, or cyclic structure. Preferred halogenated hydrocarbon groups have 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms. Preferred halogen atom substituents are Cl and F. The most preferred halogenated hydrocarbon group is trifluoromethyl. [0037]
  • “Heteroaromatic group” means an aromatic ring containing carbon and 1 to 4 heteroatoms in the ring. Heteroaromatic groups are monocyclic or fused bicyclic rings. Monocyclic heteroaromatic groups contain 5 to 10 member atoms (i.e., carbon and heteroatoms), preferably 5 to 7, and more preferably 5 to 6 in the ring. Bicyclic heteroaromatic rings contain 8 to 12 member atoms, preferably 9 or 10 in the ring. Heteroaromatic groups are unsubstituted. Preferred heteroaromatic groups include thienyl, thiazolyl, purinyl, pyrimidyl, pyridyl, and furanyl. More preferred heteroaromatic groups include thienyl, furanyl, and pyridyl. The most preferred heteroaromatic group is thienyl. [0038]
  • “Heteroatom” means an atom other than carbon in the ring of a heterocyclic group or the chain of a heterogeneous group. Preferably, heteroatoms are selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Groups containing more than one heteroatom may contain different heteroatoms. “Heterocyclic group” means a saturated or unsaturated ring structure containing carbon and 1 to 4 heteroatoms in the ring. No two heteroatoms are adjacent in the ring. Heterocyclic groups are not aromatic. Heterocyclic groups are monocyclic, or are fused or bridged bicyclic ring systems. Monocyclic heterocyclic groups contain 4 to 10 member atoms (i.e., including both carbon atoms and at least 1 heteroatom), preferably 4 to 7, and more preferably 5 to 6 in the ring. Bicyclic heterocyclic groups contain 8 to 12 member atoms, preferably 9 or 10 in the ring. Heterocyclic groups are unsubstituted. Preferred heterocyclic groups include piperzyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and piperdyl. [0039]
  • “Heterogeneous group” means a saturated or unsaturated chain containing 1 to 18 member atoms (i.e., including both carbon and at least one heteroatom). No two heteroatoms are adjacent. Preferably, the chain contains 1 to 12 member atoms, more preferably 1 to 6, and most preferably 1 to 4. The chain may be straight or branched. Preferred branched heterogeneous groups have one or two branches, preferably one branch. Preferred heterogeneous groups are saturated. Unsaturated heterogeneous groups have one or more double bonds, one or more triple bonds, or both. Preferred unsaturated heterogeneous groups have one or two double bonds or one triple bond. More preferably, the unsaturated heterogeneous group has one double bond. Heterogeneous groups are unsubstituted. [0040]
  • “Monovalent hydrocarbon group” means a chain of 1 to 18 carbon atoms, preferably 1 to 12 carbon atoms. “Lower monovalent hydrocarbon group” means a monovalent hydrocarbon group having 1 to 6, preferably 1 to 4 carbon atoms. Monovalent hydrocarbon groups may have a straight chain or branched chain structure. Preferred monovalent hydrocarbon groups have one or two branches, preferably 1 branch. Preferred monovalent hydrocarbon groups are saturated. Unsaturated monovalent hydrocarbon groups have one or more double bonds, one or more triple bonds, or combinations thereof. Preferred unsaturated monovalent hydrocarbon groups have one or two double bonds or one triple bond; more preferred unsaturated monovalent hydrocarbon groups have one double bond. [0041]
  • “Pharmaceutically acceptable” means suitable for use in a human or other mammal. [0042]
  • “Prostaglandin” means a fatty acid derivative which has a variety of potent biological activities of a hormonal or regulatory nature. [0043]
  • “Protecting group” is a group that replaces the active hydrogen of a hydroxyl moiety thus preventing undesired side reaction at the hydroxyl moiety. Use of protecting groups in organic synthesis is well known in the art. Examples of protecting groups are found in Chapter 2 [0044] Protecting Groups in Organic Synthesis by Greene, T. W. and Wuts, P. G. M., 2nd ed., Wiley & Sons, Inc., 1991. Preferred protecting groups include silyl ethers, alkoxymethyl ethers, tetrahydropyranyl, tetrahydrofuranyl, esters, and substituted or unsubstituted benzyl ethers.
  • “Safe and effective amount” means a quantity of a prostaglandin high enough to provide a significant positive modification of the subject's condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio). [0045]
  • “Selective” means having a binding or activation preference for a specific receptor over other receptors which can be quantitated based upon receptor binding or activation assays. [0046]
  • “Subject” means a living vertebrate animal such as a mammal (preferably human) in need of treatment. [0047]
  • “Substituted aromatic group” means an aromatic group wherein 1 to 4 of the hydrogen atoms bonded to carbon atoms in the ring have been replaced with other substituents. Preferred substituents include: halogen atoms, cyano groups, monovalent hydrocarbon groups, substituted monovalent hydrocarbon groups, heterogeneous groups, aromatic groups, substituted aromatic groups, or any combination thereof. More preferred substituents include halogen atoms, monovalent hydrocarbon groups, and substituted monovalent hydrocarbon groups. Preferred substituted aromatic groups include naphthyl. The substituents may be substituted at the ortho, meta, or para position on the ring, or any combination thereof. The preferred substitution pattern on the ring is ortho or meta. The most preferred substitution pattern is ortho. [0048]
  • “Substituted carbocyclic group” means a carbocyclic group wherein 1 to 4 hydrogen atoms bonded to carbon atoms in the ring have been replaced with other substituents. Preferred substituents include: halogen atoms, cyano groups, monovalent hydrocarbon groups, monovalent heterogeneous groups, substituted monovalent hydrocarbon groups, aromatic groups, substituted aromatic groups, or any combination thereof. More preferred substituents include halogen atoms and substituted monovalent hydrocarbon groups. Carbocyclic group does not include aromatic rings. [0049]
  • “Substituted heteroaromatic group” means a heteroaromatic group wherein 1 to 4 hydrogen atoms bonded to carbon atoms in the ring have been replaced with other substituents. Preferred substituents include: halogen atoms, cyano groups, monovalent hydrocarbon groups, substituted monovalent hydrocarbon groups, heterogeneous groups, substituted heterogeneous groups, phenyl groups, phenoxy groups, or any combination thereof. More preferred substituents include halogen atoms, halogenated hydrocarbon groups, halogenated heterogenous groups, monovalent hydrocarbon groups, and phenyl groups. [0050]
  • “Substituted heterocyclic group” means a heterocyclic group wherein 1 to 4 hydrogen atoms bonded to carbon atoms in the ring have been replaced with other substituents. Preferred substituents include: halogen atoms, cyano groups, monovalent hydrocarbon groups, substituted monovalent hydrocarbon groups, heterogeneous groups, substituted heterogeneous groups, halogenated hydrocarbon groups, halogenated heterogenous groups, phenyl groups, phenoxy groups, or any combination thereof. More preferred substituents include halogen atoms and halogenated hydrocarbon groups. Substituted heterocyclic groups are not aromatic. [0051]
  • “Substituted heterogeneous group” means a heterogeneous group, wherein 1 to 4 of the hydrogen atoms bonded to carbon atoms in the chain have been replaced with other substituents. Preferred substituents include halogen atoms, hydroxy groups, alkoxy groups (e.g., methoxy, ethoxy, propoxy, butoxy, and pentoxy), aryloxy groups (e.g., phenoxy, chlorophenoxy, tolyloxy, methoxyphenoxy, benzyloxy, alkyloxycarbonylphenoxy, and acyloxyphenoxy), acyloxy groups (e.g., propionyloxy, benzoyloxy, and acetoxy), carbamoyloxy groups, carboxy groups, mercapto groups, alkylthio groups, acylthio groups, arylthio groups (e.g., phenylthio, chlorophenylthio, alkylphenylthio, alkoxyphenylthio, benzylthio, and alkyloxycarbonylphenylthio), aromatic groups (e.g., phenyl and tolyl), substituted aromatic groups (e.g., alkoxphenyl, alkoxycarbonylphenyl, and halophenyl), heterocyclic groups, heteroaromatic groups, and amino groups (e.g., amino, mono- and di-alkylamino having 1 to 3 carbon atoms, methylphenylamino, methylbenzylamino, alkanylamido groups of 1 to 3 carbon atoms, carbamamido, ureido, and guanidino). [0052]
  • “Substituted monovalent hydrocarbon group” means a monovalent hydrocarbon group wherein 1 to 4 of the hydrogen atoms bonded to carbon atoms in the chain have been replaced with other substituents. Preferred substituents include halogen atoms; halogenated hydrocarbon groups; halogenated heterogenous groups; alkyl groups (e.g., methyl, ethyl, propyl, and butyl); hydroxy groups; alkoxy groups (e.g., methoxy, ethoxy, propoxy, butoxy, and pentoxy); aryloxy groups (e.g., phenoxy, chlorophenoxy, tolyloxy, methoxyphenoxy, benzyloxy, alkyloxycarbonylphenoxy, and acyloxyphenoxy); acyloxy groups (e.g., propionyloxy, benzoyloxy, and acetoxy); carbamoyloxy groups; carboxy groups; mercapto groups; alkylthio groups; acylthio groups; arylthio groups (e.g., phenylthio, chlorophenylthio, alkylphenylthio, alkoxyphenylthio, benzylthio, and alkyloxycarbonylphenylthio); aryl groups (e.g., phenyl, tolyl, alkoxyphenyl, alkoxycarbonylphenyl, and halophenyl); heterocyclyl groups; heteroaryl groups; and amino groups (e.g., amino, mono- and di-alkanylamino groups of 1 to 3 carbon atoms, methylphenylamino, methylbenzylamino, alkanylamido groups of 1 to 3 carbon atoms, carbamamido, ureido, and guanidino). [0053]
  • Prostaglandins Used in the Invention
  • The prostaglandins suitable for use in this invention are selected from the group consisting of 2-decarboxy-2-phosphinico derivatives of prostaglandins; optical isomers, diastereomers, and enantiomers of the 2-decarboxy-2-phosphinico derivatives; pharmaceutically-acceptable salts of the 2-decarboxy-2-phosphinico derivatives; and biohydrolyzable amides, esters, and imides of the 2-decarboxy-2-phosphinico derivatives. [0054]
  • Suitable 2-decarboxy-2-phosphinico derivatives can have a formula selected from the group consisting of: [0055]
    Figure US20020013294A1-20020131-C00002
  • R[0056] 1 is selected from the group consisting of a hydrogen atom, lower monovalent hydrocarbon groups, lower substituted monovalent hydrocarbon groups, and lower heterogeneous groups. R1 is preferably selected from the group consisting of a hydrogen atom; an alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and t-butyl; a halogenated hydrocarbon group such as trifluoromethyl or CH2CH2CF3; CH2CH2OH, and CH2CH2CH2OH. More preferably, R1 is a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, trifluoromethyl, CH2CH2CF3, CH2CH2OH, or CH2CH2CH2OH. Most preferably, R1 is a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, or CH2CH20H.
  • R2 is selected from the group consisting of a hydrogen atom, a monovalent hydrocarbon group, a substituted monovalent hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group. Preferably R[0057] 2 is H, CH2CO2H, CH2C(O)NHOH, methyl, CF3, ethyl, n-propyl, isopropyl, CH2CH2OH, CH2CH(OH)CH2OH, benzyl, or t-butyl. More preferably, R2 is H, methyl, CF3, ethyl, n-propyl, isopropyl, CH2CH2OH, CH2C(O)NHOH, and benzyl. Most preferably, R2 is H, methyl, CF3, ethyl, n-propyl, isopropyl, or CH2CH2OH.
  • R[0058] 3is selected from the group consisting of an oxygen atom, a sulfur atom, and NH. Preferably, R3 is an oxygen atom or NH; more preferably, R3is an oxygen atom.
  • R[0059] 4 is selected from the group consisting of an oxygen atom and a sulfur atom. Preferably, R4 is an oxygen atom.
  • R[0060] 5is a divalent group. R5 is selected from the group consisting of a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, and a substituted heterogeneous group. R5 may be saturated or unsaturated, i.e., R5 may contain one or more single bond, double bond, triple bond, or combinations thereof. When R5 is a heterogeneous group, R5 has only one heteroatom, which is selected from the group consisting of oxygen, sulfur, and nitrogen. The preferred heteroatom is oxygen. R5 preferably has 1 to 5 member atoms, more preferably 3 to 5 member atoms.
  • Bond a is selected from the group consisting of a single bond, a trans double bond, and a triple bond. [0061]
  • R[0062] 6 is a divalent group selected from the group consisting of —C(O)— and —C(R9)(OR9)—.
  • R[0063] 7 is selected from the group consisting of a divalent group having the formula —(CR9(R9))p—X—(CR9(R9))q, wherein p is an integer from 0 to 3 and q is an integer from 0 to 3, and wherein X is selected from the group consisting of an oxygen atom, a divalent hydrocarbon group, a sulfur atom, SO, SO2, and NR9. Preferably, X is selected from the group consisting of a single bond, a trans double bond, a triple bond, an oxygen atom, a sulfur atom, and NR9.
  • R[0064] 8 is selected from the group consisting of a methyl group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, aromatic group, a substituted aromatic group, a heteroaromatic group, a substituted heteroaromatic group. When R8 is a monocyclic group, it has 5 to 10 member atoms. When R8 is a bicyclic group, it has 8 to 12 member atoms. Preferably, R8 is selected from the group consisting of a monocyclic carbocyclic group, a substituted monocyclic carbocyclic group, a monocyclic heterocyclic group, a substituted monocyclic heterocyclic group, aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group.
  • R[0065] 9 is a hydrogen atom or a lower monovalent hydrocarbon group. Preferably, R9 is a hydrogen atom.
  • R[0066] 10 is a hydrogen atom or a lower monovalent hydrocarbon group. Preferably, R10 is a hydrogen atom.
  • Component A) may also be any optical isomer, diastereomer, and enantiomer of any of the above structures; or any pharmaceutically-acceptable salts of any of the above structures; or any biohydrolyzable amides, esters, and imides of any of the above structures; or combinations thereof. [0067]
  • The prostaglandin used in this invention preferably has the formula: [0068]
    Figure US20020013294A1-20020131-C00003
  • wherein, R[0069] 1, R2, R3, R4, R5, R6, R7, R8, R9, and bond a are as described above. More preferably, R9 is a hydrogen atom.
  • Suitable prostaglandins for component A) can be prepared by conventional organic syntheses. Examples of suitable prostaglandins for component A) can be prepared by the following reaction scheme. [0070]
    Figure US20020013294A1-20020131-C00004
  • In the reaction scheme above, R[0071] 1, R2, R5, R6, R7, R8, R9, and bond a are as described above, X is a halogen atom, and Q and Q2 are protecting groups. The Corey Lactone (S1a) starting material is commercially available (from Aldrich Chemical Company or Cayman Chemical Company). Known Wadsworth-Horner-Emmons chemistry is used to attach the bottom chain of the desired prostaglandin to the Corey Lactone, creating compounds of the type S1b. There follows standard prostaglandin omega chain manipulation and functional group protection, including optional alkene reduction, which creates compounds of type S1c. At this point, the standard course of prostaglandin synthesis is altered; the omega-functionalized Wittig reagent depicted is used to create 2-decarboxy prostaglandin derivatives of the type S1d. When the carboxycyclic acid containing prostaglandin is available, compounds of the type S1d are also obtained by a one-carbon degradation using a modification of the Hunsdiecker reaction.
  • Compounds depicted by S1e are available from compounds of the type S1d via a phosphinite coupling reaction with an alkyl diethyloxyphosphinite, which is obtained, as shown, from the chlorodiethyloxyphosphine reagent, which is commercially available. Compounds depicted by Formula III are available from compounds of the type S1e via optional removal of the alkene and subsequent removal of the protecting groups Q and Q[0072] 2 of S1e.
  • Alternatively, compounds of the type S1f can be prepared from intermediate S1e, where the protecting groups Q and Q[0073] 2 are judiciously selected from a variety available to those skilled in the art (see, for example: Protecting Groups in Organic Synthesis by Greene, T. W. and Wuts, P. G. M., 2nd ed., Wiley & Sons, Inc., 1991). Subsequent removal of Q at C11, followed by oxidation would give the ketone precursor to S1f. Compounds of the type S1f can then be obtained by final deprotection.
  • Compounds of Formula I can be prepared from compounds of formula S1f by condensation with hydroxyl amine. Compounds of Formula II can be reduced to prepare compounds of Formula I by treatment with sodium cyanoborohydride in THF:acetic acid (1:1) and thereafter quenching with HCl. Using conventional organic synthesis techniques, one skilled in the art could prepare prostaglandins suitable for use in this invention. [0074]
  • Examples of suitable prostaglandins of Formula I include Formula 1A. Formula 1A is [0075]
    TABLE 1A
    Substituents in Formula 1A
    Figure US20020013294A1-20020131-C00005
    R9 R1 R7 R8
    H CH3 CH2S
    Figure US20020013294A1-20020131-C00006
    H CH2CH3 CH2S
    Figure US20020013294A1-20020131-C00007
    H CH3 CH2O
    Figure US20020013294A1-20020131-C00008
    H CH3 CH2CH2CH2CH2 CH3
    H CH3 CH2CH2CH2CH2CH2 CH3
    H CH3 CH2O
    Figure US20020013294A1-20020131-C00009
    H CH3 CH2NH
    Figure US20020013294A1-20020131-C00010
    CH3 CH3 CH2CH2CH2CH2 CH3
    H CH2CH3 CH2S
    Figure US20020013294A1-20020131-C00011
    H CH2CH2CH2CH3
    Figure US20020013294A1-20020131-C00012
    Figure US20020013294A1-20020131-C00013
  • Examples of suitable prostaglandins of Formula II include Formula 2A. Formula 2A is [0076]
    TABLE 2A
    Substituents in Formula 2A
    Figure US20020013294A1-20020131-C00014
    b a R1 R7-R8
    cis trans CH3
    Figure US20020013294A1-20020131-C00015
    single single CH3
    Figure US20020013294A1-20020131-C00016
    single single CH2CH3
    Figure US20020013294A1-20020131-C00017
    single single CH2CH3
    Figure US20020013294A1-20020131-C00018
    cis trans CH2CH3
    Figure US20020013294A1-20020131-C00019
    single single CH(CH3)2
    Figure US20020013294A1-20020131-C00020
  • Examples of suitable prostaglandins of Formula III include Formulae 3A and 3B. Formula 3A is [0077]
    TABLE 3A
    Substituents in Formula 3A
    Figure US20020013294A1-20020131-C00021
    R1 R7 R8
    CH3 CH2CH2
    Figure US20020013294A1-20020131-C00022
    CH3 CH2S
    Figure US20020013294A1-20020131-C00023
    CH3 CH2O
    Figure US20020013294A1-20020131-C00024
    CH2CH3 CH2O
    Figure US20020013294A1-20020131-C00025
    CH2CH3 CH2O
    Figure US20020013294A1-20020131-C00026
    CH2CH2CH3 CH2CH2
    Figure US20020013294A1-20020131-C00027
    CH3 CH2NH
    Figure US20020013294A1-20020131-C00028
    CH3 CH2NH
    Figure US20020013294A1-20020131-C00029
    CH3 CH2CH2CH2CH2 CH3
    CH2CH3 CH2
    Figure US20020013294A1-20020131-C00030
    CH3 CH2O
    Figure US20020013294A1-20020131-C00031
    CH3 CH2CH═CHCH2 CH3
    CH3 CH2O
    Figure US20020013294A1-20020131-C00032
    CH2CH2CH3 CH2CH2
    Figure US20020013294A1-20020131-C00033
    CH3 CH2
    Figure US20020013294A1-20020131-C00034
    CH2CH3 CH2O
    Figure US20020013294A1-20020131-C00035
  • [0078]
    TABLE 3B
    Substituents in Formula 3B
    Figure US20020013294A1-20020131-C00036
    R1 R7 R8
    CH3 CH2S
    Figure US20020013294A1-20020131-C00037
    CH2CH3 CH═CH
    Figure US20020013294A1-20020131-C00038
    CH3
    Figure US20020013294A1-20020131-C00039
    Figure US20020013294A1-20020131-C00040
    CH3 —CH═C═CH—
    Figure US20020013294A1-20020131-C00041
    CH3 CH2S
    Figure US20020013294A1-20020131-C00042
    CH3 CH2O
    Figure US20020013294A1-20020131-C00043
    CH2CH3 CH2O
    Figure US20020013294A1-20020131-C00044
    CH3 CH2NH
    Figure US20020013294A1-20020131-C00045
    CH3 CH2NH
    Figure US20020013294A1-20020131-C00046
    H CH2CH2
    Figure US20020013294A1-20020131-C00047
  • Compositions of the Invention Hair Loss
  • This invention further relates to a composition for treating hair loss. “Treating hair loss” means arresting hair loss, reversing hair loss, or both, and promoting hair growth. The composition comprises A) the PGF described above and B) a carrier. The composition may further comprise C) one or more optional activity enhancers. [0079]
  • The composition can be a pharmaceutical or cosmetic composition, administered for treatment or prophylaxis of hair loss. Standard pharmaceutical formulation techniques are used, such as those disclosed in [0080] Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. (1990).
  • The composition further comprises component B) a carrier. “Carrier” means one or more compatible substances that are suitable for administration to a mammal. Carrier includes solid or liquid diluents, hydrotopes, surface-active agents, and encapsulating substances. “Compatible” means that the components of the composition are capable of being commingled with the prostaglandins, and with each other, in a manner such that there is no interaction which would substantially reduce the efficacy of the composition under ordinary use situations. Carriers must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the mammal being treated. The carrier can be inert, or it can possess pharmaceutical benefits, cosmetic benefits, or both, depending on the intended use as described herein. [0081]
  • The choice of carrier for component B) depends on the route by which A) the prostaglandin will be administered and the form of the composition. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, or parenteral) or topical administration (e.g., local application on the skin, ocular, liposome delivery systems, or iontophoresis). Topical administration directly to the locus of desired hair growth is preferred. [0082]
  • Carriers for systemic administration typically comprise one or more ingredients selected from the group consisting of a) diluents, b) lubricants, c) binders, d) disintegrants, e) colorants, f) flavors, g) sweeteners, h) antioxidants, j) preservatives, k) glidants, m) solvents, n) suspending agents, o) surfactants, combinations thereof, and others. [0083]
  • Ingredient a) is a diluent. Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; polyols such as propylene glycol; calcium carbonate; sodium carbonate; glycerin; mannitol; sorbitol; and maltodextrin. [0084]
  • Ingredient b) is a lubricant. Suitable lubricants are exemplified by solid lubricants including silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma. [0085]
  • Ingredient c) is a binder. Suitable binders include polyvinylpyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, methylcellulose, microcrystalline cellulose, and hydroxypropylmethylcellulose; carbomer; providone; acacia; guar gum; and xanthan gum. [0086]
  • Ingredient d) is a disintegrant. Suitable disintegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmelose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. [0087]
  • Ingredient e) is a colorant such as an FD&C dye. [0088]
  • Ingredient f) is a flavor such as menthol, peppermint, and fruit flavors. [0089]
  • Ingredient g) is a sweetener such as saccharin and aspartame. [0090]
  • Ingredient h) is an antioxidant such as butylated hydroxyanisole, butylated hydroxytoluene, and vitamin E. [0091]
  • Ingredient j) is a preservative such as phenol, alkyl esters of parahydroxybenzoic acid, benzoic acid and the salts thereof, boric acid and the salts thereof, sorbic acid and the salts thereof, chorbutanol, benzyl alcohol, thimerosal, phenylmercuric acetate and nitrate, nitromersol, benzalkonium chloride, cetylpyridinium chloride, methyl paraben, and propyl paraben. Particularly preferred are the salts of benzoic acid, cetylpyridinium chloride, methyl paraben and propyl paraben, and sodium benzoate. [0092]
  • Ingredient k) is a glidant such as silicon dioxide. [0093]
  • Ingredient m) is a solvent, such as water, isotonic saline, ethyl oleate, alcohols such as ethanol, glycerin, glycols (e.g., polypropylene glycol and polyethylene glycol), and buffer solutions (e.g., phosphate, potassium acetate, boric carbonic, phosphoric, succinic, malic, tartaric, citric, acetic, benzoic, lactic, glyceric, gluconic, glutaric, and glutamic). [0094]
  • Ingredient n) is a suspending agent. Suitable suspending agents include AVICEL® RC-591 from FMC Corporation of Philadelphia, Pennsylvania and sodium alginate. [0095]
  • Ingredient o) is a surfactant such as lecithin, polysorbate 80, sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene monoalkyl ethers, sucrose monoesters, lanolin esters, and lanolin ethers. Suitable surfactants are known in the art and commercially available, e.g., the TWEENS® from Atlas Powder Company of Wilmington, Del. [0096]
  • Compositions for parenteral administration typically comprise A) 0.1 to 10% of a prostaglandin and B) 90 to 99.9% of a carrier comprising a) a diluent and m) a solvent. Preferably, component a) is propylene glycol and m) is ethanol or ethyl oleate. [0097]
  • Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms comprise a safe and effective amount, usually at least 5%, and preferably from 25% to 50%, of A) the prostaglandin. The oral dosage compositions further comprise B) 50 to 95% of a carrier, preferably 50 to 75%. [0098]
  • Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed. Tablets typically comprise A) the prostaglandin, and B) a carrier comprising ingredients selected from the group consisting of a) diluents, b) lubricants, c) binders, d) disintegrants, e) colorants, f) flavors, g) sweeteners, k) glidants, and combinations thereof. Preferred diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and sucrose. Preferred binders include starch, and gelatin. Preferred disintegrants include alginic acid, and croscarmelose. Preferred lubricants include magnesium stearate, stearic acid, and talc. Preferred colorants are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain g) sweeteners such as aspartame and saccharin, or f) flavors such as menthol, peppermint, and fruit flavors. [0099]
  • Capsules (including time release and sustained release formulations) typically comprise A) the prostaglandin, and B) a carrier comprising one or more a) diluents disclosed above in a capsule comprising gelatin. Granules typically comprise A) the prostaglandin, and preferably further comprise k) glidants such as silicon dioxide to improve flow characteristics. [0100]
  • The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this invention. One skilled in the art can optimize appropriate ingredients without undue experimentation. [0101]
  • The solid compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that A) the prostaglandin is released in the gastrointestinal tract at various times to extend the desired action. The coatings typically comprise one or more components selected from the group consisting of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, acrylic resins such as EUDRAGIT® coatings (available from Rohm & Haas G.M.B.H. of Darmstadt, Germany), waxes, shellac, polyvinylpyrrolidone, and other commercially available film-coating preparations such as Dri-Klear, manufactured by Crompton & Knowles Corp., Mahwah, N.J. or OPADRY® manufactured by Colorcon, Inc., of West Point, Pa. [0102]
  • Compositions for oral administration can also have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically comprise A) the prostaglandin and B) a carrier comprising ingredients selected from the group consisting of a) diluents, e) colorants, and f) flavors, g) sweeteners, j) preservatives, m) solvents, n) suspending agents, and o) surfactants. Peroral liquid compositions preferably comprise one or more ingredients selected from the group consisting of e) colorants, f) flavors, and g) sweeteners. [0103]
  • Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as a) diluents including sucrose, sorbitol and mannitol; and c) binders such as acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose. Such compositions may further comprise b) lubricants, e) colorants, f) flavors, g) sweeteners, h) antioxidants, and k) glidants. [0104]
  • The compositions for treating hair loss may further comprise component C) an optional activity enhancer. Component C) is preferably selected from the group consisting of i) hair growth stimulants (other than the prostaglandin) and ii) penetration enhancers. [0105]
  • Component i) is an optional hair growth stimulant. Component i) is exemplified by vasodilators, antiandrogens, cyclosporins, cyclosporin analogs, antimicrobials, antiinflammatories, thyroid hormones, thyroid hormone derivatives, and thyroid hormone analogs, non-selective prostaglandin agonists or antagonists, retinoids, triterpenes, combinations thereof, and others. “Non-selective prostaglandin” agonists and antagonists differ from component A) in that they do not selectively activate the FP receptor, and they may activate other receptors. [0106]
  • Vasodilators such as potassium channel agonists including minoxidil and minoxidil derivatives such as aminexil and those described in U.S. Pat. Nos. 3,382,247, 5,756,092, 5,772,990, 5,760,043, 5,466,694, 5,438,058, 4,973,474, and cromakalin and diazoxide can be used as optional hair growth stimulants in the composition. [0107]
  • Examples of suitable antiandrogens include 5-α-reductase inhibitors such as finasteride and those described in U.S. Pat. No. 5,516,779, and in Nane et al., [0108] Cancer Research 58, “Effects of Some Novel Inhibitors of C17,20-Lyase and 5α-Reductase in vitro and in vivo and Their Potential Role in the Treatment of Prostate Cancer,” as well as cyproterone acetate, azelaic acid and its derivatives and those compounds described in U.S. Pat. No. 5,480,913, flutamide, and those compounds described in U.S. Pat. Nos. 5,411,981, 5,565,467, and 4,910,226.
  • Antimicrobials include selenium sulfide, ketoconazole, triclocarbon, triclosan, zinc pyrithione, itraconazole, asiatic acid, hinokitiol, mipirocin and those described in EPA 0,680,745, clinacycin hydrochloride, benzoyl peroxide, benzyl peroxide and minocyclin. [0109]
  • Examples of suitable anti-inflammatories include glucocorticoids such as hydrocortisone, mometasone furoate and prednisolone, nonsteroidal anti-inflammatories including cyclooxygenase or lipoxygenase inhibitors such as those described in U.S. Pat. No. 5,756,092, and benzydamine, salicylic acid, and those compounds described in EPA 0,770,399, published May 2, 1997, WO 94/06434, published Mar. 31, 1994, and FR 2,268,523, published Nov. 21, 1975. [0110]
  • 3,5,3′-Triiodothyronine is an example of a suitable thyroid hormone. [0111]
  • Examples of suitable non-selective prostaglandins agonists and antagonists include compounds such as those described in WO 98/33497, Johnstone, published Aug. 6, 1998, WO 95/11003, Stjemschantz, published Apr. 27, 1995, JP 97-100091, Ueno and JP 96-134242, Nakamura. [0112]
  • Suitable retinoids include isotretinoin, acitretin, and tazarotene. [0113]
  • Other optional hair growth stimulants for component i) include benzalkonium chloride, benzethonium chloride, phenol, estradiol, chlorpheniramine maleate, chlorophyllin derivatives, cholesterol, salicylic acid, cysteine, methionine, red pepper tincture, benzyl nicotinate, D,L-menthol, peppermint oil, calcium pantothenate, panthenol, castor oil, prednisolone, resorcinol, chemical activators of protein kinase C, glycosaminoglycan chain cellular uptake inhibitors, inhibitors of glycosidase activity, glycosaminoglycanase inhibitors, esters of pyroglutamic acid, hexosaccharic acids or acylated hexosaccharic acids, aryl-substituted ethylenes, N-acylated amino acids, flavinoids, ascomycin derivatives and analogs, histamine antagonists such as diphenhydramine hydrochloride, triterpenes such as oleanolic acid and ursolic acid and those described in U.S. Pat. Nos. 5,529,769, 5,468,888, 5,631,282, and 5,679,705, JP 10017431, WO 95/35103, JP 09067253, WO 92/09262, JP 62093215, and JP 08193094; saponins such as those described in EP 0,558,509 to Bonte et al., published Sep. 8, 1993 and WO 97/01346 to Bonte et al., published Jan. 16, 1997, proteoglycanase or glycosaminoglycanase inhibitors such as those described in U.S. Pat. Nos. 5,015,470, 5,300,284, and 5,185,325, estrogen agonists and antagonists, pseudoterins, cytokine and growth factor promoters, analogs or inhibitors such as interleukin1 inhibitors, interleukin-6 inhibitors, interleukin-10 promoters, and tumor necrosis factor inhibitors, vitamins such as vitamin D analogs and parathyroid hormone antagonists, Vitamin B12 analogs and panthenol, interferon agonists and antagonists, hydroxyacids such as those described in U.S. Pat. No. 5,550,158, benzophenones, and hydantoin anticonvulsants such as phenytoin, and combinations thereof. [0114]
  • Other additional hair growth stimulants are described in JP 09-157,139 to Tsuji et al., published Jun. 17, 1997; EP 0277455 A1 to Mirabeau, published Aug. 10, 1988; WO 97/05887 to Cabo Soler et al., published Feb. 20, 1997; WO 92/16186 to Bonte et al., published Mar. 13, 1992; JP 62-93215 to Okazaki et al., published Apr. 28, 1987; U.S. Pat. No. 4,987,150 to Kurono et al., issued Jan. 22, 1991; JP 290811 to Ohba et al., published Oct. 15, 1992; JP 05-286,835 to Tanaka et al., published Nov. 2, 1993, FR 2,723,313 to Greff, published Aug. 2, 1994, U.S. Pat. No. 5,015,470 to Gibson, issued May 14, 1991, U.S. Pat. No. 5,559,092, issued Sep. 24, 1996, U.S. Pat. No. 5,536,75 1, issued Jul. 16, 1996, U.S. Pat. No. 5,714,515, issued Feb. 3, 1998, EPA 0,319,991, published Jun. 14, 1989, EPA 0,357,630, published Oct. 6, 1988, EPA 0,573,253, published Dec. 8, 1993, JP 61-260010, published Nov. 18, 1986, U.S. Pat. No. 5,772,990, issued Jun. 30, 1998, U.S. Pat. No. 5,053, 410, issued Oct. 1, 1991, and U.S. Pat. No. 4,761,401, issued Aug. 2, 1988. [0115]
  • The most preferred activity enhancers are minoxidil and finasteride, most preferably minoxidil. Component ii) is a penetration enhancer that can be added to all of the compositions for systemic administration. The amount of component ii), when present in the composition, is typically 1 to 5 %. Examples of penetration enhancers include 2-methyl propan-2-ol, propan-2-ol, ethyl-2-hydroxypropanoate, hexan-2,5-diol, polyoxyethylene(2) ethyl ether, di(2-hydroxypropyl) ether, pentan-2,4-diol, acetone, polyoxyethylene(2) methyl ether, 2-hydroxypropionic acid, 2-hydroxyoctanoic acid, propan-1-ol, 1,4-dioxane, tetrahydrofuran, butan-1,4-diol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, polyoxyethylene ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate, di-isopropyl adipate, di-isopropyl sebacate, dibutyl sebacate, diethyl sebacate, dimethyl sebacate, dioctyl sebacate, dibutyl suberate, dioctyl azelate, dibenzyl sebacate, dibutyl phthalate, dibutyl azelate, ethyl myristate, dimethyl azelate, butyl myristate, dibutyl succinate, didecyl phthalate, decyl oleate, ethyl caproate, ethyl salicylate, isopropyl palmitate, ethyl laurate, 2-ethylhexyl pelargonate, isopropyl isostearate, butyl laurate, benzyl benzoate, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butyl stearate, benzyl salicylate, 2-hydroxypropanoic acid, 2-hydroxyoctanoic acid, dimethyl sulfoxide, N,N-dimethyl acetamide, N,N-dimethyl formamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, phosphine oxides, sugar esters, tetrahydrofurfural alcohol, urea, diethyl-m-toluamide, 1-dodecylazacyloheptan-2-one, omega three fatty acids and fish oils, and combinations thereof. [0116]
  • In a preferred embodiment of the invention, the prostaglandins are topically administered. Topical compositions that can be applied locally to the skin may be in any form including solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. Topical compositions comprise: component A) the prostaglandin described above and component B) a carrier. The carrier of the topical composition preferably aids penetration of the prostaglandins into the skin to reach the environment of the hair follicle. Topical compositions preferably further comprise C) one or more of the optional activity enhancers described above. [0117]
  • The exact amounts of each component in the topical composition for treating hair loss depend on various factors. The amount of component A) depends on the IC[0118] 50 of the prostaglandin selected. “IC50” means inhibitory concentration 50th percentile. The amount of component A) added to the topical composition is:
  • IC50×10−2≧% of component A) IC50×10−3,
  • where IC[0119] 50 is expressed in nanomolar units. For example, if the IC50 of the prostaglandin is 1 nM, the amount of component A) will be 0.001 to 0.01%. If the IC50 of the prostaglandin is 10 nM, the amount of component A) will be 0.01 to 0.1%. If the IC50 of the prostaglandin is 100 nM, the amount of component A) will be 0.1 to 1.0%. If the IC50 of the prostaglandin is 1000 nM, the amount of component A) will be 1.0 to 10%, preferably 1.0 to 5%. If the amount of component A) is outside the ranges specified above (i.e., either higher or lower), efficacy of the treatment may be reduced. IC50 can be calculated according to the method in Reference Example 1, below. One skilled in the art can calculate IC50 without undue experimentation.
  • The topical composition preferably further comprises 1 to 20% component C), and a sufficient amount of component B) such that the amounts of components A), B), and C), combined equal 100%. The amount of B) the carrier employed in conjunction with the prostaglandin is sufficient to provide a practical quantity of composition for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references: [0120] Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).
  • Component B) the carrier may comprise a single ingredient or a combination of two or more ingredients. In the topical compositions, component B) is a topical carrier. Preferred topical carriers comprise one or more ingredients selected from the group consisting of water, alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, polypropylene glycol-2 myristyl propionate, dimethyl isosorbide, combinations thereof, and the like. More preferred carriers include propylene glycol, dimethyl isosorbide, and water. [0121]
  • The topical carrier may comprise one or more ingredients selected from the group consisting of q) emollients, r) propellants, s) solvents, t) humectants, u) thickeners, v) powders, and w) fragrances in addition to, or instead of, the preferred topical carrier ingredients listed above. One skilled in the art would be able to optimize carrier ingredients for the topical compositions without undue experimentation. [0122]
  • Ingredient q) is an emollient. The amount of ingredient q) in the topical composition is typically 5 to 95%. Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1 ,2-diol, butane-1 ,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petrolatum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, polydimethylsiloxane, and combinations thereof. Preferred emollients include stearyl alcohol and polydimethylsiloxane. [0123]
  • Ingredient r) is a propellant. The amount of ingredient r) in the topical composition is typically 5 to 95%. Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. [0124]
  • Ingredient s) is a solvent. The amount of ingredient s) in the topical composition is typically 5 to 95 %. Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Preferred solvents include ethyl alcohol. [0125]
  • Ingredient t) is a humectant. The amount of ingredient t) in the topical composition is typically 5 to 95 %. Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Preferred humectants include glycerin. [0126]
  • Ingredient u) is a thickener. The amount of ingredient u) in the topical composition is typically 0 to 95%. [0127]
  • Ingredient v) is a powder. The amount of ingredient v) in the topical composition is typically 0 to 95 %. Suitable powders include chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. [0128]
  • Ingredient w) is a fragrance. The amount of ingredient w) in the topical composition is typically 0.001 to 0.5%, preferably 0.001 to 0.1%. [0129]
  • Component C) the optional activity enhancer is as described above. Any of the i) hair growth stimulants and ii) penetration enhancers may be added to the topical compositions. Preferably, the topical composition comprises 0.01 to 15% of component i) the optional hair growth stimulant. More preferably, the composition comprises 0.1 to 10%, and most preferably 0.5 to 5% of component i). Preferably, the topical composition comprises 1 to 5% of component ii). [0130]
  • In an alternative embodiment of the invention, the topical composition may be applied to growing hair and skin in the locus of the growing hair to darken to darken hair, reverse hair graying, and thicken the hair. For example, the topical composition may be applied to hair growing on the scalp or eyelashes. The topical composition can be, for example, a cosmetic composition prepared as described above. An example of a composition that may be applied to eyelashes is a mascara. The prostaglandin may be added to mascara compositions known in the art, such as the mascara described in U.S. Pat. No. 5,874,072, which is hereby incorporated by reference. The mascara comprises dd) a water-insoluble material, ee) a water-soluble, film-forming polymer, ff) a wax, o) a surfactant, gg) a pigment, and s) a solvent. [0131]
  • Ingredient dd) is a water-insoluble material selected from the group consisting of acrylate copolymers; styrene/acrylate/methacrylate copolymers; acrylic latex; styrene/acrylic ester copolymer latex; polyvinylacetate latex; vinyl acetate/ethylene copolymer latex; styrene/butadiene copolymer latex; polyurethane latex; butadiene/acrylonitrile copolymer latex; styrene/acrylate/acrylonitrile copolymer latex; and mixtures thereof, wherein the acrylate copolymers, and the styrene/acrylate/methacrylate copolymers additionally comprise ammonia, propylene glycol, a preservative and a surfactant. [0132]
  • Ingredient ee) is a water-soluble, film-forming polymer. Ingredient ee) is selected from the group consisting of vinyl alcohol/poly(alkyleneoxy)acrylate, vinyl alcohol/vinyl acetate/poly-(alkyleneoxy)acrylate, polyethylene oxide, polypropylene oxide, acrylates/octyl-acrylamide copolymers and mixtures thereof. [0133]
  • Ingredient ff) is a wax. “Wax” means a lower-melting organic mixture or compound of high molecular weight, solid at room temperature and generally similar in composition to fats and oils except that they contain no glycerides. Some are hydrocarbons, others are esters of fatty acids and alcohols. Waxes useful in this invention are selected from the group consisting of animal waxes, vegetable waxes, mineral waxes, various fractions of natural waxes, synthetic waxes, petroleum waxes, ethylenic polymers, hydrocarbon types such as Fischer-Tropsch waxes, silicone waxes, and mixtures thereof wherein the waxes have a melting point between 55 and 100° C. [0134]
  • Ingredient o) is surfactant, as described above. Ingredient o) in the mascara is preferably a surfactant having an HLB from 3 to 15. Suitable surfactants include those disclosed in the [0135] C.T.F.A. Cosmetic Ingredient Handbook, pp.587-592 (1992); Remington's Pharmaceutical Sciences, 15th Ed., pp. 335-337 (1975); and McCutcheon's Volume 1, Emulsifiers & Detergents, North American Edition, pp. 236-239 (1994).
  • Ingredient gg) is a pigment. Suitable pigments include inorganic pigments, organic lake pigments, pearlescent pigments, and mixtures thereof. Inorganic pigments useful in this invention include those selected from the group consisting of rutile or anatase titanium dioxide, coded in the Color Index under the reference CI 77,891; black, yellow, red and brown iron oxides, coded under references CI 77,499, 77,492 and, 77,491; manganese violet (CI 77,742); ultramarine blue (CI 77,007); chromium oxide (CI 77,288); chromium hydrate (CI 77,289); and ferric blue (CI 77,510) and mixtures thereof. [0136]
  • The organic pigments and lakes useful in this invention include those selected from the group consisting of D&C Red No. 19 (CI 45,170), D&C Red No. 9 (CI 15,585), D&C Red No. 21 (CI 45,380), D&C Orange No. 4 (CI 15,510), D&C Orange No. 5 (CI 45,370), D&C Red No. 27 (CI 45,410), D&C Red No. 13 (CI 15,630), D&C Red No. 7 (CI 15,850), D&C Red No. 6 (CI 15,850), D&C Yellow No. 5 (CI 19,140), D&C Red No. 36 (CI 12,085), D&C Orange No. 10 (CI 45,425), D&C Yellow No. 6 (CI 15,985), D&C Red No. 30 (CI 73,360), D&C Red No. 3 (CI 45,430), and the dye or lakes based on Cochineal Carmine (CI 75,570) and mixtures thereof. [0137]
  • The pearlescent pigments useful in this invention include those selected from the group consisting of the white pearlescent pigments such as mica coated with titanium oxide, bismuth oxychloride, colored pearlescent pigments such as titanium mica with iron oxides, titanium mica with ferric blue, chromium oxide and the like, titanium mica with an organic pigment of the above-mentioned type as well as those based on bismuth oxychloride and mixtures thereof. [0138]
  • Ingredient s) is a solvent described above, preferably water. [0139]
  • The amount of A) the prostaglandin added to the mascara is as described above for topical compositions. [0140]
  • The prostaglandins may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. A preferred formulation for topical delivery of the present compounds uses liposomes as described in Dowton et al., “Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclosporin A: I. An in vitro Study Using Hairless Mouse Skin”, [0141] S.T.P. Pharma Sciences, Vol. 3, pp. 404-407 (1993); Wallach and Philippot, “New Type of Lipid Vesicle: Novasome®”, Liposome Technology, Vol. 1, pp. 141-156 (1993); Wallach, U.S. Pat. No. 4,911,928, assigned to Micro-Pak, Inc., issued Mar. 27, 1990; and Weiner et al., U.S. Pat. No. 5,834,014, assigned to The University of Michigan and Micro-Pak, Inc., issued Nov. 10, 1998 (with respect to Weiner et al., with a compound as described herein administered in lieu of, or in addition to, minoxidil).
  • The prostaglandins may also be administered by iontophoresis. See, e.g., Internet site www.unipr.it/arpa/dipfarm/erasmus/erasm14.html; Banga et al., “Hydrogel-based lontotherapeutic Delivery Devices for Transdermal Delivery of Peptide/Protein Drugs”, [0142] Pharm. Res., Vol. 10 (5), pp. 697-702 (1993); Ferry, “Theoretical Model of Iontophoresis Utilized in Transdermal Drug Delivery”, Pharmaceutical Acta Helvetiae, Vol 70, pp. 279-287 (1995); Gangarosa et al., “Modern Iontophoresis for Local Drug Delivery”, Int. J. Pharm., Vol. 123, pp. 159-171 (1995); Green et al., “Iontophoretic Delivery of a Series of Tripeptides Across the Skin in vitro”, Pharm. Res., Vol 8, pp. 1121-1127 (1991); Jadoul et al., “Quantification and Localization of Fentanyl and TRH Delivered by Iontophoresis in the Skin”, Int. J. Pharm., Vol. 120, pp. 221-8 (1995); O'Brien et al., “An Updated Review of its Antiviral Activity, Pharmacokinetic Properties and Therapeutic Efficacy”, Drugs, Vol. 37, pp. 233-309 (1989); Parry et al., “Acyclovir Biovailability in Human Skin”, J. Invest. Dermatol., Vol. 98 (6), pp. 856-63 (1992); Santi et al., “Drug Reservoir Composition and Transport of Salmon Calcitonin in Transdermal Iontophoresis”, Pharm. Res., Vol 14 (1), pp. 63-66 (1997); Santi et al., “Reverse Iontophoresis—Parameters Determining Electroosmotic Flow: I. pH and Ionic Strength”, J. Control. Release, Vol. 38, pp. 159-165 (1996); Santi et al., “Reverse Iontophoresis—Parameters Determining Electroosmotic Flow: II. Electrode Chamber Formulation”, J. Control. Release, Vol. 42, pp. 29-36 (1996); Rao et al., “Reverse Iontophoresis: Noninvasive Glucose Monitoring in vivo in Humans”, Pharm. Res., Vol. 12 (12), pp. 1869-1873 (1995); Thysman et al., “Human Calcitonin Delivery in Rats by Iontophoresis”, J. Pharm. Pharmacol., Vol. 46, pp. 725-730 (1994); and Volpato et al., “Iontophoresis Enhances the Transport of Acyclovir through Nude Mouse Skin by Electrorepulsion and Electroosmosis”, Pharm. Res., Vol. 12 (11), pp. 1623-1627 (1995).
  • The prostaglandins may be included in kits comprising a prostaglandin, a systemic or topical composition described above, or both; and information, instructions, or both that use of the kit will provide treatment for hair loss in mammals (particularly humans). The information and instructions may be in the form of words, pictures, or both, and the like. In addition or in the alternative, the kit may comprise a prostaglandin, a composition, or both; and information, instructions, or both, regarding methods of application of the prostaglandin or composition, preferably with the benefit of treating hair loss in mammals. [0143]
  • Bone Disorders
  • In addition to benefits in treating hair loss, the prostaglandins of this invention may also be useful to treat bone disorders. Without wishing to be bound by theory, it is believed that the prostaglandins are useful in increasing bone volume and trabecular number through formation of new trabeculae, formation of bone mass while maintaining a normalized bone turnover rate, and formation at the endosteal surface without removing bone from the existing cortex. [0144]
  • This invention further relates to compositions for treating bone disorders. Compositions for treating bone disorders can be prepared by standard pharmaceutical formulation techniques, such as those disclosed in [0145] Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. (1990), using the ingredients described above. The preferred routes of administration for treating bone disorders are transdermal, intranasal, rectal, sublingual, and oral.
  • Suitable oral compositions for treating bone disorders typically comprise A) a prostaglandin described above and B) a carrier. A typical tablet composition comprises A) the prostaglandin and B) a carrier comprising ingredients selected from the group consisting of a) diluents, b) lubricants, c) binders, d) disintegrants, e) colorants, f) flavors, g) sweeteners, k) glidants, and combinations thereof. Preferred diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and sucrose. Preferred lubricants include magnesium stearate, stearic acid, and talc. Preferred binders include microcrystalline cellulose, starch, and gelatin. Preferred disintegrants include sodium starch glycolate, alginic acid, and croscarmelose. [0146]
  • Typical parenteral pharmaceutical compositions for treating bone disorders comprise A) the prostaglandin and B) a carrier comprising ingredients selected from the group consisting of j) preservatives and m) solvents. Preferred preservatives include methyl paraben and ethyl paraben. Preferred solvents include isotonic saline. One skilled in the art can optimize ingredients for the compositions to treat bone disorders without undue experimentation. [0147]
  • The prostaglandins can optionally be used in combination with other ingredients which have a beneficial effect on bone loss. Thus, other actives such as vitamin D analogs, hormones, calcium supplements, diphosphonate compounds such as those extensively described in the literature of the Procter & Gamble Company, combinations thereof, and the like may also be administered to patients in need of such treatment in conjunction with the prostaglandins. Dosage levels and means of administration include pulsed-dosing, and are as described in the literature. [0148]
  • Intraocular Pressure
  • The prostaglandins used in this invention are also useful in decreasing intraocular pressure. Thus, these prostaglandins are useful in the treatment of glaucoma. This invention further relates to compositions for lowering intraocular pressure. The preferred route of administration for lowering intraocular pressure is topical. Topical pharmaceutical compositions for ocular administration typically comprise A) a prostaglandin, B) a carrier, such as purified water, and one or more ingredients selected from the group consisting of y) sugars such as dextrans, particularly dextran 70, z) cellulose or a derivative thereof, aa) a salt, bb) disodium EDTA (Edetate disodium), and cc) a pH adjusting additive. [0149]
  • Examples of z) cellulose derivatives suitable for use in the topical pharmaceutical composition for ocular administration include sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, and hydroxypropylmethylcellulose. Hydroxypropylmethylcellulose is preferred. [0150]
  • Examples of aa) salts suitable for use in the for use in the topical pharmaceutical composition for ocular administration include sodium chloride, potassium chloride, and combinations thereof. [0151]
  • Examples of cc) pH adjusting additives include HCl or NaOH in amounts sufficient to adjust the pH of the topical pharmaceutical composition for ocular administration to 7.2-7.5. [0152]
  • Methods of the Invention Hair Loss
  • This invention further relates to a method for treating hair loss in mammals. The method comprises administering to a mammal (preferably a human) suffering from hair loss, a prostaglandin described above. For example, a mammal diagnosed with alopecia including male pattern baldness and female pattern baldness can be treated by the methods of this invention. Preferably, a systemic or topical composition comprising A) the prostaglandin and B) a carrier is administered to the mammal. More preferably, the composition is a topical composition comprising A) the prostaglandin, B) the carrier, and C) an optional activity enhancer. [0153]
  • The dosage of the prostaglandin administered to treat hair loss depends on the method of administration. For systemic administration, (e.g., oral, rectal, nasal, sublingual, buccal, or parenteral), typically, 0.5 mg to 300 mg, preferably 0.5 mg to 100 mg, more preferably 0.1 mg to 10 mg, of a prostaglandin described above is administered per day. These dosage ranges are merely exemplary, and daily administration can be adjusted depending on various factors. The specific dosage of the prostaglandin to be administered, as well as the duration of treatment, and whether the treatment is topical or systemic are interdependent. The dosage and treatment regimen will also depend upon such factors as the specific prostaglandin used, the treatment indication, the efficacy of the compound, the personal attributes of the subject (such as, for example, weight, age, sex, and medical condition of the subject), compliance with the treatment regimen, and the presence and severity of any side effects of the treatment. [0154]
  • For topical administration (e.g., local application on the skin, liposome delivery systems, or iontophoresis), the topical composition is typically administered once per day. The topical compositions are administered daily for a relatively short amount of time (i.e., on the order of weeks). Generally, 6 to 12 weeks is sufficient. The topical compositions are preferably leave-on compositions. In general, the topical composition should not be removed for at least several hours after administration. [0155]
  • In addition to the benefits in treating hair loss, the inventors have found that the prostaglandins in the compositions and methods of this invention also darken and thicken hair and may reverse hair graying. This invention further relates to a method for darkening hair, thickening hair, and reversing hair graying. The method comprises applying the topical composition for treating hair loss to hair, to skin in the locus of hair, or both. In a preferred embodiment of the invention, the topical composition, such as the mascara composition described above, is applied to eyelashes. [0156]
  • Bone Disorders
  • This invention further relates to methods for treating bone disorders sing the prostaglandins described above. The method comprises administering to a mammal (preferably a human) suffering from a bone disorder, a prostaglandin described above. For example, a mammal diagnosed with osteoporosis can be treated by the methods of this invention. Preferably, a systemic composition comprising A) the prostaglandin and B) a carrier is administered to the mammal. The preferred routes of administration for treating bone disorders are transdermal, intranasal, rectal, sublingual, and oral. [0157]
  • The dosage range of the prostaglandin for systemic administration to treat bone disorders is from about 0.01 to about 1000 μg/kg body weight, preferably from about 0.1 to about 100 μg per body weight, most preferably form about 1 to about 50 μg/kg body weight per day. The transdermal dosages will be designed to attain similar serum or plasma levels, based upon techniques known to those skilled in the art of pharmacokinetics and transdermal formulations. Plasma levels for systemic administration are expected to be in the range of 0.01 to 100 nanograms/ml, more preferably from 0.05 to 50 ng/ml, and most preferably from 0.1 to 10 ng/ml. While these dosages are based upon a daily administration rate, weekly or monthly accumulated dosages may also be used to calculate the clinical requirements. [0158]
  • Dosages may be varied based on the patient being treated, the condition being treated, the severity of the condition being treated, the route of administration, etc. to achieve the desired effect. [0159]
  • Intraocular Pressure
  • The prostaglandins of the present invention are also useful in decreasing intraocular pressure. Thus, these prostaglandins are useful in the treatment of glaucoma. This invention further relates to a method for lowering intraocular pressure in mammals. The method comprises administering to a mammal (preferably a human) a prostaglandin described above. For example, a mammal diagnosed with glaucoma can be treated by the methods of this invention. The preferred route of administration for treating glaucoma is topical. Preferably, a topical composition for ocular administration described above is administered to the mammal. The topical composition for ocular administration is typically administered once per day. The topical compositions are administered daily for a relatively short amount of time (i.e., on the order of weeks). Generally, 6 to 12 weeks is sufficient.[0160]
  • EXAMPLES
  • These examples are intended to illustrate the invention to those skilled in the art and should not be interpreted as limiting the scope of the invention set forth in the claims. [0161]
  • Reference Example 1 Radioligand Binding Assay
  • IC[0162] 50 of a prostaglandin can be determined relative to PGF using the Radioligand Binding Assay. As a control, the IC50 for PGF itself should be no lower than 1.0 nM and no higher than 5.0 nM.
  • In this assay, COS-7 cells are transiently transfected with the hFP recombinant plasmid using LipofectAMINE Reagent. Forty-eight hours later, the tranfected cells are washed with Hank's Balanced Salt Solution (HBSS, without CaCl[0163] 2, MgCl2, MgSO4, or phenol red). The cells are detached with versene, and HBSS is added. The mixture is centrifuged at 200 g for 10 minutes, at 4° C. to pellet the cells. The pellet is resuspended in Phosphate-Buffered Saline-EDTA buffer (PBS; 1 mM EDTA; pH 7.4; 4° C.). The cells are disrupted by nitrogen cavitation (Parr model 4639), at 800 psi, for 15 minutes at 4° C. The mixture is centrifuged at 1000 g for 10 minutes at 4° C. The supernatant is centrifuged at 100,000 g for 60 minutes at 4° C. The pellet is resuspended to 1 mg protein/mL TME buffer (50 mM Tris; 10 mM MgCl2; 1 mM EDTA; pH 6.0; 4° C.) based on protein levels measured using the Pierce BCA Protein Assay kit. The homogenate is mixed for 10 seconds using a Kinematica POLYTRON ® (available from KINEMATICA AG, Luzemerstrassel47A CH-6014 Littau, Switzerland). The membrane preparations are then stored at −80° C., until thawed for assay use.
  • The receptor competition binding assays are developed in a 96 well format. Each well contains 100 g of hFP membrane, 5 nM (3H) PGF2α, and the various competing compounds in a total volume of 200 L. The plates are incubated at 23° C. for 1 hour. The incubation is terminated by rapid filtration using the Packard Filtermate 196 harvester through Packard UNILTER® GF/B filters (available from Packard Instrument Co., Inc. of Downers Grove Illinois) pre-wetted with TME buffer. The filter is washed four times with TME buffer. Packard Microscint 20, a high efficiency liquid scintillation cocktail, is added to the filter plate wells and the plates remain at room temperature for three hours prior to counting. The plates are read on a Packard TOPCOUNT® Microplate Scintillation Counter (also available from Packard Instrument Co., Inc.) [0164]
  • Reference Example 2 Telogen Conversion Assay
  • Prostaglandins are tested for their potential to grow hair using the Telogen Conversion Assay. The Telogen Conversion Assay measures the potential of a prostaglandin to convert mice in the resting stage of the hair growth cycle (“telogen”), to the growth stage of the hair growth cycle (“anagen”). [0165]
  • Without intending to be limited by theory, there are three principal phases of the hair growth cycle: anagen, catagen, and telogen. It is believed that there is a longer telogen period in C3H mice (Harlan Sprague Dawley, Inc., Indianapolis, Ind.) from approximately 40 days of age until about 75 days of age, when hair growth is synchronized. It is believed that after 75 days of age, hair growth is no longer synchronized. Wherein about 40 day-old mice with dark fur (brown or black) are used in hair growth experiments, melanogenesis occurs along with hair (fur) growth wherein the topical application of hair growth inducers are evaluated. The Telogen Conversion Assay herein is used to screen prostaglandins for potential hair growth by measuring melanogenesis. [0166]
  • Three groups of 44 day-old C3H mice are used: a vehicle control group, a positive control group, and a test prostaglandin group, wherein the test prostaglandin group is administered a prostaglandin used in the method of this invention. The length of the assay is 24 days with 15 treatment days (wherein the treatment days occur Mondays through Fridays). Day 1 is the first day of treatment. A typical study design is shown in Table 4 below. Typical dosage concentrations are set forth in Table 3, however the skilled artisan will readily understand that such concentrations may be modified. [0167]
    TABLE 4
    Assay Parameters
    Group Animal Concen- Application Length
    # # Compound tration volume of Study
    1  1-10 Test 0.01% in 400 μL topical 26 days
    Compound vehicle**
    2 11-20 Positive 0.01% in 400 μL topical 26 days
    Control vehicle**
    (T3)*
    3 21-30 Vehicle** N/A 400 μL topical 26 days
  • (commercially available from Sigma Chemical Co., St. Louis, Mo.). [0168]
  • The mice are treated topically Monday through Friday on their lower back (base of tail to the lower rib). A pipettor and tip are used to deliver 400 μL to each mouse's back. The 400 μL application is applied slowly while moving hair on the mouse to allow the application to reach the skin. [0169]
  • While each treatment is being applied to the mouse topically, a visual grade of from 0 to 4 will be given to the skin color in the application area of each animal. As a mouse converts from telogen to anagen, its skin color will become more bluish-black. As indicated in Table 5, the grades 0 to 4 represent the following visual observations as the skin progresses from white to bluish-black. [0170]
    TABLE 5
    Evaluation Criteria
    Visual Observation Grade
    Whitish Skin Color 0
    Skin is light gray (indication of initiation of anagen) 1
    Appearance of Blue Spots 2
    Blue Spots are aggregating to form one large blue area 3
    Skin is dark blue (almost black) with color covering majority of 4
    treatment area (indication of mouse in full anagen)
  • Reference Example 3 Ovariectomized Rat Assay
  • Bone activity of the prostaglandins can be conveniently demonstrated using an assay designed to test the ability of the prostaglandins to increase bone volume, mass, or density. An example of such assays is the ovariectomized rat assay. [0171]
  • In the ovariectomized rat assay, six-month old rats are ovariectomized, aged 2 months, and then dosed once a day subcutaneously with a prostaglandin. Upon completion of the study, bone mass and/or density can be measured by dual energy x-ray absorptometry (DXA) or peripheral quantitative computed tomography (pQCT), or micro computed tomography (mCT). Alternatively, static and dynamic histomorphometry can be used to measure the increase in bone volume or formation. [0172]
  • Reference Example 4 Pharmacological Activity for Glaucoma Assay
  • Pharmacological activity for glaucoma can be demonstrated using assays designed to test the ability of the subject compounds to decrease intraocular pressure. Examples of such assays are described in the following reference, incorporated herein: C. Iiljebris, G. [0173]
  • Selen, B. Resul, J. Sternschantz, and U. Hacksell, “Derivatives of 17-Phenyl-18,19,20-trinorprostaglandin F[0174] 2α Isopropyl Ester: Potential Antiglaucoma Agents”, Journal of Medicinal Chemistry, Vol. 38 No. 2 (1995), pp. 289-304.
  • Example 1
  • Compositions for topical administration are made, comprising: [0175]
    Component 1-1 1-2
    Prostaglandin (wt %) 0.42 1.14
    IC50 the PGF (nM) 42 114
    Ethanol (wt %) 59.74 59.32
    Propylene Glycol (wt %) 19.92 19.77
    Dimethyl Isosorbide (wt %) 19.92 19.77
  • The prostaglandins in the topical compositions are as follows: [0176]
    Example Prostaglandin
    1-1
    Figure US20020013294A1-20020131-C00048
    1-2
    Figure US20020013294A1-20020131-C00049
  • A human male subject suffering from male pattern baldness is treated by a method of this invention. Specifically, for 6 weeks, one of the above compositions is daily administered topically to the subject to induce hair growth. [0177]
  • Example 2
  • A composition for topical administration is made according to the method of Dowton et al., “Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclosporin A: I. An in vitro Study Using Hairless Mouse Skin”, [0178] S.T.P. Pharma Sciences, Vol. 3, pp. 404-407 (1993), using a PGF in lieu of cyclosporin A and using the NOVASOME® 1 (available from Micro-Pak, Inc. of Wilmington, Del.) for the non-ionic liposomal formulation.
  • A human male subject suffering from male pattern baldness is treated each day with the above composition. Specifically, for 6 weeks, the above composition is administered topically to the subject. [0179]
  • Example 3
  • Shampoos are made, comprising: [0180]
    Component Ex. 3-1 Ex. 3-2 Ex. 3-3 Ex. 3-4
    Ammonium Lauryl Sulfate 11.5% 11.5% 9.5% 7.5%
    Ammonium Laureth Sulfate 4% 3% 2% 2%
    Cocamide MEA 2% 2% 2% 2%
    Ethylene Glycol Distearate 2% 2% 2% 2%
    Cetyl Alcohol 2% 2% 2% 2%
    Stearl Alcohol 1.2% 1.2% 1.2% 1.2%
    Glycerin 1% 1% 1% 1%
    Polyquaternium 10 0.5% 0.25%
    Polyquaternium 24 0.5% 0.25%
    Sodium Chloride 0.1% 0.1% 0.1% 0.1%
    Sucrose Polyesters of Cottonate 3% 3%
    Fatty Acid
    Sucrose Polyesters of Behenate 2% 3%
    Fatty Acid
    Polydimethyl Siloxane 3% 2%
    Cocaminopropyl Betaine 1% 3% 3%
    Lauryl Dimethyl Amine Oxide 1.5% 1.5% 1.5% 1.5%
    Decyl Polyglucose 1% 1%
    DMDM Hydantoin 0.15% 0.15% 0.15% 0.15%
    PGF having IC50 of 42 nM 0.42% 0.42%
    PGF having IC50 of 114 nM 0.11% 0.11%
    Minoxidil 3% 2%
    Phenoxyethanol 0.5% 0.5% 0.5% 0.5%
    Fragrance 0.5% 0.5% 0.5% 0.5%
    Water q.s. q.s. q.s. q.s.
  • The prostaglandins are the same as in Example 1. [0181]
  • A human subject suffering from male pattern baldness is treated by a method of this invention. Specifically, for 12 weeks, a shampoo described above is used daily by the subject. [0182]
  • Example 4
  • A mascara composition is prepared. The composition comprises: [0183]
    Component % W/W
    WATER, DEIONIZED, USP q.s.
    BLACK 1080 MICRONIZED TYPE 10.000 
    GLYCERYL MONOSTEARATE (2400 TYPE) 8.500
    C18-36 ACID TRIGLYCERIDE 5.500
    STEARIC ACID, TRIPLE PRESSED, LIQUID 4.000
    ETHYL ALCOHOL SD 40-B, 190 PROOF/SERIAL #: 4.000
    BEESWAX WHITE, FLAKES 3.250
    SHELLAC, NF 3.000
    LECITHIN, GRANULAR (TYPE 6450) 2.500
    TRIETHANOLAMINE 99% - TANK 2.470
    PARAFFIN WAX 2.250
    PARAFFIN WAX 118/125 2.250
    CARNAUBA WAX, NF 2.000
    POTASSIUM CETYL PHOSPHATE 1.000
    PHENOXYETHANOL 0.800
    OLEIC ACID NF 0.750
    DL-PANTHENOL 0.350
    PVP/VA COPOLYMER 0.250
    METHYLPARABEN, NF 0.200
    DIAZOLIDINYL UREA 0.200
    SIMETHICONE 0.200
    ETHYLPARABEN NF 0.150
    PENTAERYTHRITYL HYDROGENATED ROSINATE 0.150
    PROPYLPARABEN, NF 0.100
    TRISODIUM EDTA 0.100
    PROSTAGLANDIN having IC50 of 114 nM 0.114
  • The prostaglandin is the same as in Example 1-2. [0184]
  • A human female subject applies the composition each day. Specifically, for 6 weeks, the above composition is administered topically to the subject to darken and thicken eyelashes. [0185]
  • Example 5
  • A pharmaceutical composition in the form of a tablet is prepared by conventional methods, such as mixing and direct compaction, formulated as follows: [0186]
    Ingredient Quantity (mg per tablet)
    Prostaglandin 5
    Microcrystalline Cellulose 100 
    Sodium Starch Glycollate 30 
    Magnesium Stearate 3
  • The prostaglandin is the same as in Example 1-2. [0187]
  • When administered orally once daily, the above composition substantially increases bone volume in a patient suffering from osteoporosis. [0188]
  • Example 6
  • A pharmaceutical compositions in liquid form is prepared by conventional methods, formulated as follows: [0189]
    Ingredient Quantity
    Prostaglandin 1 mg
    Phosphate buffered physiological saline 10 ml
    Methyl Paraben 0.05 ml
  • The prostaglandin used is the same as in Example 1-2. [0190]
  • When 1.0 ml of the above composition is administered subcutaneously once daily, the above composition substantially increases bone volume in a patient suffering from osteoporosis. [0191]
  • Example 7
  • A topical pharmaceutical composition for lowering intraocular pressure are prepared by conventional methods and formulated as follows: [0192]
    Ingredient Amount (wt %)
    Prostaglandin 0.004
    Dextran 70 0.1
    Hydroxypropyl methylcellulose 0.3
    Sodium Chloride 0.77
    Potassium chloride 0.12
    Disodium EDTA (Edetate disodium) 0.05
    Benzalkonium chloride 0.01
    HCl and/or NaOH pH 7.2-7.5
    Purified water q.s. to 100%
  • The prostaglandin is the same as in Example 1-2. [0193]
  • When the above composition is administered once daily for 6 to 12 weeks, it lowers intraocular pressure in a patient suffering from glaucoma. [0194]
  • Effects of the Invention
  • The compositions and methods herein provide a cosmetic benefit with respect to hair growth and appearance in subjects desiring such treatment. The compositions and methods herein also provide pharmaceutical benefits with respect to treating bone disorders and lowering intraocular pressure in subjects needing such treatment. [0195]

Claims (30)

    What is claimed is:
  1. 1. A 2-decarboxy-2-phosphinico prostaglandin analog having the structure:
    Figure US20020013294A1-20020131-C00050
    R1 is selected from the group consisting of a hydrogen atom, lower monovalent hydrocarbon groups, and lower heterogeneous groups;
    R2 is selected from the group consisting of a hydrogen atom, a monovalent hydrocarbon group, a substituted monovalent hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group;
    R3 is selected from the group consisting of an oxygen atom, a sulfur atom, and NH;
    R4 is selected from the group consisting of an oxygen atom and a sulfur atom;
    R5 is a divalent group selected from the group consisting of a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, and a substituted heterogeneous group;
    bond a is selected from the group consisting of a single bond, a trans double bond, and a triple bond;
    R6 is a divalent group selected from the group consisting of —C(O)—and —C(R9)(0R9)—;
    R7 is selected from the group consisting of a divalent group having the formula —(CR9(R9))p—X—(CR9(R9))q, wherein p is an integer from 0 to 3 and q is an integer from 0 to 3, and wherein X is selected from the group consisting of an oxygen atom, a divalent hydrocarbon group, a sulfur atom, SO, SO2, and NR9;
    R8 is selected from the group consisting of a methyl group or a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, aromatic group, a substituted aromatic group, a heteroaromatic group, a substituted heteroaromatic group;
    R9 is selected from the group consisting of a hydrogen atom and a lower monovalent hydrocarbon group; and
    R10 is a lower monovalent hydrocarbon group.
  2. 2. A composition for treating hair loss comprising:
    A) an active ingredient selected from the group consisting of 2-decarboxy-2-phosphinico derivatives of prostaglandins; optical isomers, diastereomers, and enantiomers of the 2-decarboxy-2-phosphinico derivatives; pharmaceutically-acceptable salts of the 2-decarboxy-2-phosphinico derivatives; biohydrolyzable amides, esters, and imides of the 2-decarboxy-2-phosphinico derivatives; and combinations thereof; and
    B) a carrier.
  3. 3. The composition of claim 2, wherein the 2-decarboxy-2-phosphinico derivative has a structure selected from the group consisting of:
    Figure US20020013294A1-20020131-C00051
    wherein R1 is selected from the group consisting of a hydrogen atom, and lower monovalent hydrocarbon groups, and lower heterogeneous groups;
    R2 is selected from the group consisting of a hydrogen atom, a monovalent hydrocarbon group, a substituted monovalent hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group;
    R3 is selected from the group consisting of an oxygen atom, a sulfur atom, and NH;
    R4 is selected from the group consisting of an oxygen atom and a sulfur atom;
    R5 is a divalent group selected from the group consisting of a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, and a substituted heterogeneous group; with the proviso that when R5 is a heterogeneous group, R5 has only one heteroatom, which is selected from the group consisting of oxygen, sulfur, and nitrogen;
    bond a is selected from the group consisting of a single bond, a trans double bond, and a triple bond;
    R6 is a divalent group selected from the group consisting of —C(O)— and —C(R9)(OR9)—;
    R7 is selected from the group consisting of a divalent group having the formula —(CR9(R9))p—X—(CR9(R9))q, wherein p is an integer from 0 to 3 and q is an integer from 0 to 3, and wherein X is selected from the group consisting of an oxygen atom, a divalent hydrocarbon group, a sulfur atom, SO, SO2, and NR9;
    R8 is selected from the group consisting of a methyl group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, a substituted heteroaromatic group;
    R9 is selected from the group consisting of a hydrogen atom and a lower monovalent hydrocarbon group; and
    R10 is selected from the group consisting of a hydrogen atom and a lower monovalent hydrocarbon group.
  4. 4. The composition of claim 3, wherein R1 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated hydrocarbon group, CH2CH2OH, and CH2CH2CH2OH.
  5. 5. The composition of claim 3, wherein R is selected from the group consisting of H, CH2CO2H, CH2C(O)NHOH, methyl, CF3, ethyl, n-propyl, isopropyl, CH2CH2OH, CH2CH(OH)CH2OH, benzyl, and t-butyl.
  6. 6. The composition of claim 3, wherein R3 is selected from the group consisting of an oxygen atom and NH.
  7. 7. The composition of claim 3, wherein R4 is an oxygen atom.
  8. 8. The composition of claim 3, wherein R5 has 1 to 5 member atoms.
  9. 9. The composition of claim 3, wherein R6 is —C(H)(OH)—.
  10. 10. The composition of claim 3, wherein X is selected from the group consisting of a single bond, a trans double bond, a triple bond, an oxygen atom, a sulfur atom, and NR9.
  11. 11. The composition of claim 3, wherein R8 is selected from the group consisting of a monocyclic carbocyclic group, a substituted monocyclic carbocyclic group, a monocyclic heterocyclic group, a substituted monocyclic heterocyclic group, aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group.
  12. 12. The composition of claim 3, wherein R9 is a hydrogen atom.
  13. 13. The composition of claim 3, wherein R10 is a hydrogen atom.
  14. 14. The composition of claim 3, wherein the 2-decarboxy-2-phosphinico derivative has the structure:
    Figure US20020013294A1-20020131-C00052
    wherein, R1, R2, R3, R4, R5, R6, R7, R8, R9, and bond a are as described above.
  15. 15. The composition of claim 2, wherein component B) comprises an ingredient selected from the group consisting of: q) emollients, r) propellants, s) solvents, t) humectants, u) thickeners, v) powders, w) fragrances, water, alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, polypropylene glycol-2 myristyl propionate, dimethyl isosorbide, and combinations thereof.
  16. 16. The composition of claim 2, further comprising component C) an activity enhancer selected from the group consisting of i) a hair growth stimulant, ii) a penetration enhancer, and combinations thereof.
  17. 17. The composition of claim 16, wherein component A) is present in the composition in an amount of: IC50×10−2≧% of component A) ≧IC50×10−3, where IC50 is expressed in nanomolar units; component C) is present in an amount of 1 to 20% component C), and a sufficient amount of component B) is present such that the amounts of components A), B), and C), combined equal 100%.
  18. 18. The composition of claim 2, wherein component A) is present in the composition in an amount of: IC50×10−2≧% of component A) ≧IC50×10−3, where IC50 is expressed in nanomolar units.
  19. 19. A method for treating hair loss comprising administering to a mammal suffering from hair loss, a composition comprising:
    A) an active ingredient selected from the group consisting of 2-decarboxy-2-phosphinico derivatives of prostaglandins; optical isomers, diastereomers, and enantiomers of the 2-decarboxy-2-phosphinico derivatives; pharmaceutically-acceptable salts of the 2-decarboxy-2-phosphinico derivatives; biohydrolyzable amides, esters, and imides of the 2-decarboxy-2-phosphinico derivatives; and combinations thereof.
  20. 20. The method of claim 19, wherein the of 2-decarboxy-2-phosphinico derivative has a structure selected from the group consisting of:
    Figure US20020013294A1-20020131-C00053
    wherein R1 is selected from the group consisting of a hydrogen atom, and lower monovalent hydrocarbon groups, and lower heterogeneous groups;
    R2 is selected from the group consisting of a hydrogen atom, a monovalent hydrocarbon group, a substituted monovalent hydrocarbon group, a heterogeneous group, a substituted heterogeneous group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, an aromatic group, a substituted aromatic group, a heteroaromatic group, and a substituted heteroaromatic group;
    R3 is selected from the group consisting of an oxygen atom, a sulfur atom, and NH;
    R4 is selected from the group consisting of an oxygen atom and a sulfur atom;
    R5 is a divalent group selected from the group consisting of a hydrocarbon group, a substituted hydrocarbon group, a heterogeneous group, and a substituted heterogeneous group; with the proviso that when R5 is a heterogeneous group, R5 has only one heteroatom, which is selected from the group consisting of oxygen, sulfur, and nitrogen;
    bond a is selected from the group consisting of a single bond, a trans double bond, and a triple bond;
    R6 is a divalent group selected from the group consisting of —C(O)— and —C(R9)(OR9)—;
    R7 is selected from the group consisting of a divalent group having the formula —(CR9(R9))p—X—(CR9(R9))q, wherein p is an integer from 0 to 3 and q is an integer from 0 to 3, and wherein X is selected from the group consisting of an oxygen atom, a divalent hydrocarbon group, a sulfur atom, SO, SO2, and NR9;
    R8 is selected from the group consisting of a methyl group, a carbocyclic group, a substituted carbocyclic group, a heterocyclic group, a substituted heterocyclic group, aromatic group, a substituted aromatic group, a heteroaromatic group, a substituted heteroaromatic group;
    R9 is selected from the group consisting of a hydrogen atom and a lower monovalent hydrocarbon group; and
    R10 is selected from the group consisting of a hydrogen atom and a lower monovalent hydrocarbon group.
  21. 21. The method of claim 19, wherein the composition is administered by a route selected from the group consisting of systemic and topical routes.
  22. 22. The method of claim 21, wherein the composition is a topical composition in a form selected from the group consisting of solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, and skin patches.
  23. 23. The method of claim 22, wherein the composition is a topical composition further comprising B) a topical carrier, wherein the topical carrier comprises an ingredient selected from the group consisting of q) emollients, r) propellants, s) solvents, t) humectants, u) thickeners, v) powders, w) fragrances, water, alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, dimethyl isosorbide, polypropylene glycol-2 myristyl propionate, and combinations thereof.
  24. 24. The method of claim 19, wherein the composition further comprises C) an activity enhancer selected from the group consisting of i) a hair growth stimulant, ii) a penetration enhancer, and combinations thereof.
  25. 25. The method of claim 24, wherein component i) is selected from the group vasodilator, an antiandrogen, a cyclosporin, a cyclosporin analog, an antimicrobial, an anti-inflammatory, a thyroid hormone, a thyroid hormone derivative, and a thyroid hormone analog, a non-selective prostaglandin agonist, a non-selective prostaglandin antagonist, a retinoid, a triterpene, and combinations thereof.
  26. 26. The method of claim 24, wherein component ii) is selected from the group consisting of 2-methyl propan-2-ol, propan-2-ol, ethyl-2-hydroxypropanoate, hexan-2,5-diol, polyoxyethylene(2) ethyl ether, di(2-hydroxypropyl) ether, pentan-2,4-diol, acetone, polyoxyethylene(2) methyl ether, 2-hydroxypropionic acid, 2-hydroxyoctanoic acid, propan-l-ol, 1,4-dioxane, tetrahydrofuran, butan-1,4-diol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, polyoxyethylene ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate, di-isopropyl adipate, di-isopropyl sebacate, dibutyl sebacate, diethyl sebacate, dimethyl sebacate, dioctyl sebacate, dibutyl suberate, dioctyl azelate, dibenzyl sebacate, dibutyl phthalate, dibutyl azelate, ethyl myristate, dimethyl azelate, butyl myristate, dibutyl succinate, didecyl phthalate, decyl oleate, ethyl caproate, ethyl salicylate, isopropyl palmitate, ethyl laurate, 2-ethyl-hexyl pelargonate, isopropyl isostearate, butyl laurate, benzyl benzoate, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butyl stearate, benzyl salicylate, 2-hydroxypropanoic acid, 2-hydroxyoctanoic acid, dimethyl sulfoxide, N,N-dimethyl acetamide, N,N-dimethyl formamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, phosphine oxides, sugar esters, tetrahydrofurfural alcohol, urea, diethyl-m-toluamide, 1-dodecylazacyloheptan-2-one, and combinations thereof.
  27. 27. The method of claim 21, wherein the composition is a topical composition locally administered on the skin once per day.
  28. 28. The method of claim 27, wherein the composition is administered once per day for 6 to 12 weeks.
  29. 29. A mascara composition comprising:
    A) an active ingredient selected from the group consisting of 2-decarboxy-2-phosphinico derivatives of prostaglandins; optical isomers, diastereomers, and enantiomers of the 2-decarboxy-2-phosphinico derivatives; pharmaceutically-acceptable salts of the 2-decarboxy-2-phosphinico derivatives; biohydrolyzable amides, esters, and imides of the 2-decarboxy-2-phosphinico derivatives; and combinations thereof,
    dd) a water-insoluble material,
    ee) a water-soluble, film-forming polymer,
    ff) a wax;
    o) a surfactant;
    gg) pigment; and
    s) a solvent.
  30. 30. A method for darkening and thickening hair comprising applying to growing hair and skin, a composition comprising:
    A) an active ingredient selected from the group consisting of 2-decarboxy-2-phosphinico derivatives of prostaglandins; optical isomers, diastereomers, and enantiomers of the 2-decarboxy-2-phosphinico derivatives; pharmaceutically-acceptable salts of the 2-decarboxy-2-phosphinico derivatives; biohydrolyzable amides, esters, and imides of the 2-decarboxy-2-phosphinico derivatives; and combinations thereof; and
    B) a carrier.
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060121069A1 (en) * 2000-03-31 2006-06-08 Duke University Compositions and methods for treating hair loss using oximyl and hydroxylamino prostaglandins
US20060135609A1 (en) * 2004-10-21 2006-06-22 Duke University Ophthamological drugs
US20060247214A1 (en) * 2000-03-31 2006-11-02 Duke University Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
US20070254920A1 (en) * 2006-04-26 2007-11-01 Aerie Pharmaceuticals, Inc. Prodrug derivatives of acids using alcohols with homotopic hydroxy groups and methods for their preparation and use
US20070298134A1 (en) * 2004-12-29 2007-12-27 R-Tech Ueno, Ltd. Composition and Method for Scalp and Hair Treatment
US20090286769A1 (en) * 2000-03-31 2009-11-19 Duke University Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
US20100105775A1 (en) * 2008-10-29 2010-04-29 Delong Mitchell A Amino acid salts of prostaglandins
USRE43372E1 (en) 1999-03-05 2012-05-08 Duke University C16 unsaturated FP-selective prostaglandins analogs
US8524777B2 (en) 2005-03-16 2013-09-03 Allergan Inc. Enhanced bimatoprost ophthalmic solution
US8586630B2 (en) 2005-03-16 2013-11-19 Allergan, Inc. Enhanced bimatoprost ophthalmic solution
US8618086B2 (en) 2000-03-31 2013-12-31 Duke University Compositions and methods for treating hair loss using C16-C20 aromatic tetrahydro prostaglandins
US8722739B2 (en) 2008-10-29 2014-05-13 Novaer Holdings, Inc. Amino acid salts of prostaglandins
US9006291B2 (en) 2009-02-03 2015-04-14 Pharma Patent Holding Inc. Composition, method and kit for enhancing hair
US9522153B2 (en) 2009-12-22 2016-12-20 Allergan, Inc. Compositions and methods for lowering intraocular pressure

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6696466B1 (en) * 2000-09-07 2004-02-24 Leslie Joe Dunaway Methods of treating select neuronal inflammatory disorders using hydroxyalkylquinolines
US6765001B2 (en) * 2001-12-21 2004-07-20 Medicis Pharmaceutical Corporation Compositions and methods for enhancing corticosteroid delivery
JP2005519887A (en) 2001-12-21 2005-07-07 ポンスス ファルマ アーベー New composition
US8580851B2 (en) 2002-08-21 2013-11-12 Sucampo Ag Ophthalmic solution
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US7326717B2 (en) 2003-05-06 2008-02-05 L'oreal Pyrimidine n-oxide compounds for stimulating the growth of keratin fibers and/or reducing loss thereof
KR101091461B1 (en) * 2003-11-07 2011-12-07 센주 세이야꾸 가부시키가이샤 Pharmaceutical composition containing prostaglandin
US9394520B2 (en) 2006-12-08 2016-07-19 University Of Rochester Expansion of hematopoietic stem cells
US20090018204A1 (en) * 2007-07-13 2009-01-15 Brinkenhoff Michael C Composition and method for enhancing hair growth
FR2920309B1 (en) 2007-08-28 2010-05-28 Galderma Res & Dev Using travoprost to treat hair loss
WO2010064203A1 (en) 2008-12-02 2010-06-10 L'oreal Combination of reduced glutathione and amino acids for improving the quality of the hair in women
FR2949052B1 (en) 2009-08-13 2015-03-27 Oreal Process for cosmetic treatment of the scalp.
EP3278808A1 (en) 2010-08-12 2018-02-07 Fate Therapeutics, Inc. Improved hematopoietic stem and progenitor cell therapy
ES2632444T3 (en) 2011-09-30 2017-09-13 Bluebird Bio, Inc. Compounds that enhance viral transduction
EP2785834A4 (en) 2011-12-02 2015-04-29 Fate Therapeutics Inc Enhanced stem cell composition
EP3295940A1 (en) 2012-04-16 2018-03-21 Case Western Reserve University Compositions and methods of modulating 15-pgdh activity
US9943545B2 (en) 2013-03-15 2018-04-17 Fate Therapeutics, Inc. Stem cell culture media and methods of enhancing cell survival
KR20150025984A (en) * 2013-08-30 2015-03-11 (주)아모레퍼시픽 Composition for promoting hair growth or restoration containing 21-o-angeloyltheasapogenol e3

Citations (71)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3435053A (en) * 1966-06-06 1969-03-25 Upjohn Co Cyclopenta(b)pyrans
US3524867A (en) * 1966-06-06 1970-08-18 Upjohn Co Process for producing cyclopenta (b)pyrans
US3598858A (en) * 1958-05-28 1971-08-10 Sune Bergstrom Pge2 and pge3
US3776938A (en) * 1958-05-28 1973-12-04 S Bergstrom Dihydro-pge1
US3776939A (en) * 1958-05-28 1973-12-04 S Bergstrom Dihydro-pgf1a
US3839409A (en) * 1958-05-28 1974-10-01 Kemiska Inst Karolinska I Pge3 esters and alkanoates
US3882241A (en) * 1969-12-01 1975-05-06 Upjohn Co Use of prostaglandins E and F for prevention of pregnancy in humans
US3882245A (en) * 1972-11-01 1975-05-06 Upjohn Co Use of prostaglandins in combating shock
US3896156A (en) * 1970-06-30 1975-07-22 Upjohn Co Dihydroprostaglandin e, analogs
US3928588A (en) * 1974-02-22 1975-12-23 Upjohn Co Method of reducing the undesirable gastrointestinal effects of prostaglandin synthetase inhibitors
US3966792A (en) * 1973-02-28 1976-06-29 Ono Pharmaceutical Co., Ltd. Prostaglandin compounds
US3984455A (en) * 1973-07-16 1976-10-05 The Upjohn Company Prostaglandin E1 analogs
US4004020A (en) * 1973-12-21 1977-01-18 Schering Aktiengesellschaft Novel prostanoic acid derivatives and process for the preparation thereof
US4011262A (en) * 1972-07-13 1977-03-08 Pfizer Inc. 13,14-Dihydro-15-substituted-ω-pentanorprostaglandins of the two series
US4024179A (en) * 1972-11-08 1977-05-17 Pfizer Inc. Substituted ω-pentanorprostaglandins
US4061671A (en) * 1974-04-03 1977-12-06 Hoechst Aktiengesellschaft Analogues of prostaglandins
US4073934A (en) * 1975-04-18 1978-02-14 Schering Aktiengesellschaft Novel acetylenic prostaglandin analogs
US4089885A (en) * 1976-11-05 1978-05-16 American Home Products Corporation Prostaglandin derivatives
US4123441A (en) * 1976-09-22 1978-10-31 The Upjohn Company Enlarged-hetero-ring prostacyclin analogs
US4128720A (en) * 1975-02-14 1978-12-05 Ono Pharmaceutical Company Prostaglandin analogues
US4158667A (en) * 1976-02-04 1979-06-19 The Upjohn Company 6-Keto PGF analogs
US4217360A (en) * 1975-02-27 1980-08-12 Schering Aktiengesellschaft Novel 1,3-benzodioxaneprostanoic acid derivatives and process for the preparation thereof
US4225508A (en) * 1979-07-05 1980-09-30 The Upjohn Company 19-Hydroxy-PGI2 compounds
US4225507A (en) * 1979-07-05 1980-09-30 The Upjohn Company 19-Hydroxy-19-methyl-PGI2 compounds
US4284646A (en) * 1976-08-06 1981-08-18 Schering Aktiengesellschaft Prostanoic acid derivatives and their preparation
US4499293A (en) * 1976-09-22 1985-02-12 The Upjohn Company PGI2 Salts
US4621100A (en) * 1981-09-25 1986-11-04 The Upjohn Company Treatment of osteoporosis with prostaglandins
US4704386A (en) * 1985-08-29 1987-11-03 G. D. Searle & Co. 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[(phenylsulfinyl-, and phenylsulfonyl)alkanoyl]hydrazides
US4889845A (en) * 1986-06-09 1989-12-26 American Cyanamid Company Vehicle for topical application of pharmaceuticals
US5063057A (en) * 1990-09-26 1991-11-05 Elizabeth Arden Co., Division Of Conopco, Inc. Cosmetic capsules
US5219885A (en) * 1987-02-16 1993-06-15 Froelich Juergen Prostaglandin E1 derivatives as pharmaceutically active agents, and pharmaceutical compositions containing these compounds, especially for transcutaneous administration
US5340813A (en) * 1992-11-09 1994-08-23 Cell Therapeutics, Inc. Substituted aminoalkyl xanthine compounds
US5422371A (en) * 1992-05-27 1995-06-06 Arch Development Corp. Methods and compositions for inhibiting 5α-reductase activity
US5500230A (en) * 1987-01-23 1996-03-19 The General Hospital Corporation Method for treatment of glaucoma with nitrogen containing guanylate cyclase activators
US5508303A (en) * 1992-05-29 1996-04-16 Toray Industries, Inc. Hair-growing composition
US5516652A (en) * 1993-10-06 1996-05-14 Merck Frosst Canada Inc. DNA encoding prostaglandin receptor IP
US5567079A (en) * 1992-11-17 1996-10-22 Felder; Anton Method for the hydraulic branching of an open stream and hydraulically working channel branch
US5576315A (en) * 1991-05-03 1996-11-19 G.D. Searle & Co. Substituted dibenzoxazepine compounds and methods for treating osteoporosis and ischemia
US5578618A (en) * 1988-09-06 1996-11-26 Pharmacia Aktiebolag Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension
US5578643A (en) * 1992-05-20 1996-11-26 Loyola University Of Chicago Protective prostaglandins for use in conjunction with chemotherapeutic agents
US5587391A (en) * 1993-12-28 1996-12-24 Allergan Cyclopentane(ene) heptenoic or heptanoic acids and derivatives thereof useful as therapeutic agents
US5605814A (en) * 1993-08-31 1997-02-25 Merck Frosst Canada Inc. DNA encoding human prostaglandin receptor EP2
US5658897A (en) * 1996-04-08 1997-08-19 Allergan Cyclopentane(ene) heptanoic or cyclopentane(ene) heptenoic acid, 2-hydrocarbyl phosphinyloxyalkyl or phosphonamidoalkyl as therapeutic agents
US5663203A (en) * 1986-09-11 1997-09-02 Schering Aktiengesellschaft Agents containing prostacyclin derivatives for topical application
US5670506A (en) * 1993-04-05 1997-09-23 Cell Therapeutics, Inc. Halogen, isothiocyanate or azide substituted xanthines
US5703108A (en) * 1996-02-28 1997-12-30 Pfizer Inc. Bone deposition by certain prostaglandin agonists
US5719140A (en) * 1993-04-30 1998-02-17 G.D. Searle & Co. 2, 3-, 4-, 5-, 6-, 7-, 8-, 9- and /or 10-substituted dibenzoxazepine compounds, pharmaceutical compositions and methods of use
US5770759A (en) * 1987-04-30 1998-06-23 R-Tech Ueno, Ltd. Prostaglandins of the F series
US5792851A (en) * 1996-09-03 1998-08-11 Albert Einstin College Of Medicine Of Yeshiva University, A Division Of Yeshiva University Human prostaglandin transporter
US5834498A (en) * 1992-09-21 1998-11-10 Allergan Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents
US5840847A (en) * 1993-06-25 1998-11-24 Merck Frosst Canada, Inc. Purified prostaglandin receptor FP
US5877211A (en) * 1997-11-21 1999-03-02 Allergan EP2 receptor agonists as neuroprotective agents for the eye
US5885974A (en) * 1994-12-06 1999-03-23 Michael M. Danielov Therapeutic methods utilizing naturally derived bio-active complexes and delivery systems therefor
US5885766A (en) * 1995-02-17 1999-03-23 Societe L'oreal S.A. Method of screening of substances for their effect on the expression of mediators of inflammation in a hair follicle
US5889052A (en) * 1993-08-03 1999-03-30 Alcon Laboraties, Inc. Use of cloprostenol and fluprostenol analogues to treat glaucoma and ocular hypertension
US5892099A (en) * 1997-01-27 1999-04-06 Ono Pharmaceutical Co., Ltd. 3,7-dithiaprostanoic acid derivative
US5958723A (en) * 1995-01-26 1999-09-28 Merck Frosst Canada & Co. DNA encoding prostaglandin receptor DP
US5972965A (en) * 1995-07-21 1999-10-26 Fujisawa Pharmaceutical Co., Ltd. 4,5-diaryl oxazole derivatives
US5977173A (en) * 1997-09-09 1999-11-02 Wos; John August Aromatic C16 -C20 -substituted tetrahydro prostaglandins useful as FP agonists
US5985597A (en) * 1993-05-26 1999-11-16 Merck Frosst Canada, Inc. DNA encoding prostaglandin receptor EP1
US5990346A (en) * 1995-06-26 1999-11-23 Teijin Limited Prostaglandins and processes for production thereof
US5994397A (en) * 1995-12-22 1999-11-30 Alcon Laboratories, Inc. Substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives
US6013823A (en) * 1992-06-08 2000-01-11 New Pharma International Corp. Trans-pentavalent 2-15-deoxy-16-hydroxy-16-methyl-PGE1 methyl ester (B-407)
US6025375A (en) * 1993-12-20 2000-02-15 Fujisawa Pharmaceutical Co., Ltd. 4,5-diaryloxazole derivatives
US6030959A (en) * 1997-04-04 2000-02-29 Monsanto Company Gastro-specific prodrugs
US6031001A (en) * 1994-09-21 2000-02-29 Synphra Ab Use of prostaglandins
US6037364A (en) * 1992-09-21 2000-03-14 Allergan Sales, Inc. Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents
US6037368A (en) * 1997-05-09 2000-03-14 Mount Sinai School Of Medicine 8-iso- prostaglandins for glaucoma therapy
US6043264A (en) * 1995-01-06 2000-03-28 Toray Industries, Inc. Benzene-condensed heterocyclic derivatives and their uses
US6048895A (en) * 1997-09-09 2000-04-11 The Procter & Gamble Company Aromatic C16-C20 substituted tetrahydro prostaglandins useful as FP agonists
US6372730B1 (en) * 1999-08-04 2002-04-16 The Procter & Gamble Company 2-decarboxy-2-phosphinico Prostaglandin F analogs

Family Cites Families (258)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US37914A (en) * 1863-03-17 Improved automatic nose-bag
US146439A (en) * 1874-01-13 Improvement in pruning-shears
US37913A (en) * 1863-03-17 Improvement in sewing-machines
DE1617477U (en) 1950-09-27 1950-12-14 Heinrich Dressel Wheel holder for raeder, such as for strollers and small vehicles.
US3382247A (en) * 1965-11-01 1968-05-07 Upjohn Co 6-amino-1, 2-dihydro-1-hydroxy-2-imino-4-phenoxypyrimidines
US3538120A (en) 1967-05-22 1970-11-03 Ciba Geigy Corp Cyclopentyl-alkanoic acids
DE1617477A1 (en) 1967-06-22 1970-01-08 Fischer Hans W Organic Hair Growth Tonic with warranty
US3636120A (en) 1967-10-09 1972-01-18 Upjohn Co Prostaglandin e primary alcohols
GB1285372A (en) 1968-08-29 1972-08-16 Upjohn Co Improvements in or relating to prostaglandins and the preparation thereof
GB1251750A (en) 1968-11-12 1971-10-27
DE1910561A1 (en) 1969-03-01 1970-09-10 Herten Dr Med Kurt Means of preventing hair loss
BE755555A (en) * 1969-09-02 1971-03-01 Richardson Merrell Inc Quinoxaline derivatives
FR2108027B1 (en) 1970-09-28 1974-03-29 Curt Georgi Imes Spa
GB1324737A (en) 1970-11-02 1973-07-25 Upjohn Co Prostaglandins and the preparation thereof
JPS5212919Y2 (en) 1971-06-14 1977-03-23
BE791369A (en) 1971-11-16 1973-05-14 American Cyanamid Co Cyanurates tris (meta-hydroxybenzyl) subject to a steric impediment and useful as antioxidants
JPS525744Y2 (en) 1972-03-18 1977-02-05
US3798275A (en) 1972-04-05 1974-03-19 Ciba Geigy Corp Etherified mercapto-methoxyamines
GB1386146A (en) 1972-05-03 1975-03-05 Ici Ltd Cyclopentane derivatives
US4304907A (en) 1972-05-10 1981-12-08 The Upjohn Company Bicyclo lactone intermediates for prostaglandin analogs
US3974213A (en) 1972-07-13 1976-08-10 Pfizer Inc. 13,14-Dihydro-15-substituted-ω-pentanorprostaglandins
GB1428137A (en) 1972-09-27 1976-03-17 Ici Ltd Prostanoic acid derivatives
JPS4969636U (en) 1972-09-29 1974-06-18
JPS5220141Y2 (en) 1972-10-13 1977-05-10
JPS4969636A (en) 1972-11-07 1974-07-05
ES420325A1 (en) 1972-11-08 1976-04-16 Pfizer A process for preparing a prostaglandin.
NL7315307A (en) 1972-11-08 1974-05-10
US4152527A (en) * 1972-11-08 1979-05-01 Pfizer Inc. 15-Substituted-ω-pentanorprostaglandins
US3984424A (en) 1972-11-08 1976-10-05 Pfizer Inc. P-biphenyl esters of 15-substituted-ω-pentanorprostaglandins
JPS4993342U (en) 1972-12-05 1974-08-13
JPS5253841Y2 (en) 1972-12-12 1977-12-07
JPS49100071U (en) 1972-12-20 1974-08-28
JPS49101356U (en) 1972-12-20 1974-08-31
JPS5320995Y2 (en) 1972-12-23 1978-06-02
JPS49101356A (en) 1973-02-07 1974-09-25
JPS49102647A (en) 1973-02-14 1974-09-27
JPS5118118Y2 (en) 1973-07-17 1976-05-14
FR2239458B3 (en) 1973-07-31 1976-07-16 Aries Robert
US3931282A (en) 1974-02-21 1976-01-06 Syntex (U.S.A.) Inc. 11α-Hydroxymethyl prostaglandins
JPS50157344A (en) 1974-03-20 1975-12-19
GB1458315A (en) 1974-04-22 1976-12-15 Ici Ltd Prostanoic acid derivatives
JPS50142539U (en) 1974-05-13 1975-11-25
JPS50157344U (en) 1974-06-12 1975-12-26
US3964455A (en) * 1974-12-19 1976-06-22 General Motors Corporation Valve control mechanism
DE2460990A1 (en) 1974-12-21 1976-07-01 Hoechst Ag New prostaglandin analogs and methods for their production
JPS5186449U (en) 1974-12-30 1976-07-10
US3934013A (en) * 1975-02-21 1976-01-20 Syntex (U.S.A.) Inc. Pharmaceutical composition
GB1506816A (en) * 1975-03-31 1978-04-12 Upjohn Co Prostaglandins
JPS5328160Y2 (en) 1975-05-16 1978-07-15
GB1517562A (en) 1975-06-13 1978-07-12 Ici Ltd Prostane derivatives
GB1520522A (en) * 1975-06-16 1978-08-09 Ono Pharmaceutical Co 16-methyleneprostaglandins
ES449162A1 (en) 1975-06-23 1977-12-16 Syntex Inc A process for the preparation of a compound or racemi-co-antimerico 8r.
JPS582925B2 (en) 1975-07-21 1983-01-19 Kaken Seiyaku Kk
US4005133A (en) 1975-10-14 1977-01-25 The Upjohn Company PGF2.sub.α, L-Arginine salt
US4128577A (en) 1975-12-29 1978-12-05 The Upjohn Company 15-Methyl- and 16-phenoxy-PGF2 α, amides
US4596812A (en) * 1976-05-24 1986-06-24 The Upjohn Company Methods and solutions for treating male pattern alopecia
US4139619A (en) * 1976-05-24 1979-02-13 The Upjohn Company 6-Amino-4-(substituted amino)-1,2-dihydro-1-hydroxy-2-iminopyrimidine, topical compositions and process for hair growth
US4051238A (en) 1976-06-03 1977-09-27 The Upjohn Company Treatment of genital tract diseases of domestic animals with prostaglandins
US4268522A (en) * 1976-06-14 1981-05-19 Pfizer Inc. 13,14-Dihydro-15-alkenyl- and 13,14-dihydro-15-alkynyl prostaglandins and analogs thereof
DE2737808A1 (en) 1976-08-27 1978-03-16 Pfizer 2-substituted heterocyclic aryl-omega-pentanorprostaglandine
DE2737807A1 (en) 1976-08-27 1978-03-09 Pfizer C. deeply 1 -p-biphenyl of omega-pentanorprostaglandinen
US4171331A (en) 1978-06-05 1979-10-16 Miles Laboratories, Inc. 1 And 2-substituted analogues of certain prostaglandins
US4178457A (en) 1978-07-10 1979-12-11 Syntex (U.S.A.) Inc. (dl)-16-Phenoxy- and 16-substituted phenoxy-9-keto prostatrienoic acid derivatives and processes for the production thereof
US4206151A (en) * 1978-12-21 1980-06-03 American Cyanamid Company 15-Deoxy-16-hydroxy-16-vinyl or cyclopropyl prostan-1-ols of the E, A and F series
US4311707A (en) * 1979-02-12 1982-01-19 American Cyanamid Company Process for topically producing cutaneous vasodilation for the treatment of vasospastic or ischemic conditions
GB2048254B (en) 1979-04-02 1983-05-25 Upjohn Co 19,20 -didehydro-19-hydroxy and 19-oxo-prostaglandin derivatives
JPS5829710Y2 (en) 1979-05-25 1983-06-29
US4296504A (en) 1980-07-07 1981-10-27 Lawson Daniel C Toilet seat lock
JPS6032763Y2 (en) 1980-09-06 1985-09-30
JPH0222226Y2 (en) 1981-02-04 1990-06-14
JPH0216288B2 (en) 1981-09-25 1990-04-16 Upjohn Co
US4543353A (en) 1981-11-27 1985-09-24 Farmitalia Carlo Erba S.P.A. Ester and amide derivatives of 13,14-didehydro prostaglandins
US4599353A (en) 1982-05-03 1986-07-08 The Trustees Of Columbia University In The City Of New York Use of eicosanoids and their derivatives for treatment of ocular hypertension and glaucoma
JPS6032763A (en) 1983-07-29 1985-02-19 Nippon Iyakuhin Kogyo Kk Novel 11-oxoprostanoic acid derivative and its use
US4912235A (en) 1983-12-22 1990-03-27 Syntex (U.S.A.) Inc. Processes and intermediates for making 16-phenoxy- and 16-substituted phenoxy-prostatrienoic acid derivatives and their stereoisomers
WO1986000616A1 (en) 1984-07-13 1986-01-30 Gail Sansone Bazzano Substituted pyrimidine oxides useful for hair growth promotion
JPH0334934Y2 (en) 1984-07-31 1991-07-24
ES545700A0 (en) 1984-07-31 1986-06-16 Syntex Inc Process for preparing derivatives of acids 11-subbed-2-16-phenoxy and 16-substituted phenoxy-prostatrienoicos
JPH0341464B2 (en) * 1984-11-21 1991-06-24
JPH0473406B2 (en) 1985-03-22 1992-11-20 Kenichi Katsu
US4757089A (en) 1985-06-14 1988-07-12 Massachusetts Eye And Ear Infirmary Increasing aqueous humor outflow
US5863948A (en) * 1985-06-14 1999-01-26 Massachusetts Eye And Ear Infirmary Increasing aqueous humor outflow
FI872552A (en) * 1986-06-09 1987-12-10 American Cyanamid Co Prostaglandinkomposition Foer lokalt bruk.
US5041439A (en) 1986-06-13 1991-08-20 The Procter & Gamble Company Penetrating topical pharmaceutical compositions
US4883819A (en) 1986-07-31 1989-11-28 The Trustees Of Columbia University In The City Of New York Use of A, B and C prostaglandins and derivatives thereof to treat ocular hypertension and glaucoma
JPS63211231A (en) 1987-02-27 1988-09-02 Sumitomo Pharmaceut Co Ltd Remedy for male infertile animal
US4952581A (en) 1987-04-03 1990-08-28 The Trustees Of Columbia University In The City Of New York Use of a prostaglandin in combination with an adrenergic blocking agent for reduction of intraocular pressure
GB8713747D0 (en) 1987-06-12 1987-07-15 Unilever Plc Skin treatment composition
US5166178B1 (en) 1987-09-18 1998-07-21 R Tech Ueno Ltd Ocular hypotensive agents
DE3876050T2 (en) * 1987-09-18 1993-03-25 R Tech Ueno Ltd Ocular hypotensivagenzien.
DE3872701T2 (en) 1987-10-07 1992-12-03 Kabi Pharmacia Ab Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension.
DE68908950D1 (en) 1988-05-11 1993-10-14 Ueno Seiyaku Oyo Kenkyujo Kk Use of 15-keto-prostaglandin E or F compounds for uterine contractions.
JPH0222226A (en) 1988-07-12 1990-01-25 Ono Pharmaceut Co Ltd Remedy for osteopathic disease containing pgd analog compound as active ingredient
US5296504A (en) * 1988-09-06 1994-03-22 Kabi Pharmacia Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension
US6187813B1 (en) 1990-04-10 2001-02-13 Pharmacia & Upjohn Aktiebolag Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension
US5321128A (en) * 1988-09-06 1994-06-14 Kabi Pharmacia Ab Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension
US5194429A (en) * 1988-10-01 1993-03-16 K.K. Ueno Seiyaku Oyo Kenkyujo Ocular hypotensive agents
FR2647675B1 (en) 1989-06-05 1994-05-20 Sanofi Use of a derivative of the statin in the treatment of ocular affections
US4968812A (en) 1989-06-23 1990-11-06 Shell Oil Company Spirolactonelactams
JPH0737389B2 (en) 1989-08-29 1995-04-26 久光製薬株式会社 Prostaglandin e1-containing ointment
JPH0737390B2 (en) 1989-08-29 1995-04-26 久光製薬株式会社 Ointment composition
CA1339132C (en) 1989-09-12 1997-07-29 Johan W. Stjernschantz Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension
CA2030345C (en) * 1989-11-22 1998-12-08 Ryuji Ueno Use of 15-keto-prostaglandin compound for improvement of encephalic function
JPH0627942Y2 (en) 1989-12-14 1994-07-27 松下電器産業株式会社 Condenser with a fuse holder
JPH0720909Y2 (en) 1989-12-14 1995-05-15 松下電器産業株式会社 condenser
CA2039420C (en) * 1990-04-04 1996-12-10 Ryuji Ueno Treatment of cataract with 15-keto-prostaglandin compounds
US5302617A (en) * 1990-04-27 1994-04-12 Kabushikikaisha Ueno Seiyaku Oyo Kenkyuio Biochemical treatment with 15-dehydroxy-16-oxoprostaglandin compounds
DE4024347A1 (en) 1990-07-27 1992-01-30 Schering Ag Cyclopentane derivatives, methods for their manufacture and their pharmaceutical use
JPH04300833A (en) 1991-03-29 1992-10-23 Green Cross Corp:The Prostaglandin e1-containing fat emulsion-loaded aerosol
US5312832A (en) * 1991-05-17 1994-05-17 Allergan, Inc. Ocular hypotensive 2-decarboxyl-2-acylthioalkyl prostaglandin derivatives
CN1282249A (en) 1997-12-18 2001-01-31 内森·厄尔·斯科特 Prostaglandin E/F & alpha combination for treating impotence and enhancing sexual arousal
US5288754A (en) * 1992-02-04 1994-02-22 Allergan, Inc. Polar C-1 esters of prostaglandins
US5641494A (en) * 1992-03-20 1997-06-24 Janssen Pharmaceutica N.V. Agent for regulating the greasiness of the skin
US5409911A (en) * 1992-09-11 1995-04-25 Merck & Co., Inc. Prostaglandin analog for treating osteoporosis
US5688819A (en) 1992-09-21 1997-11-18 Allergan Cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents
US5352708A (en) * 1992-09-21 1994-10-04 Allergan, Inc. Non-acidic cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents
CA2146127C (en) 1992-10-13 2000-06-13 Louis Desantis, Jr. Combinations of prostaglandins and clonidine derivatives for the treatment of glaucoma
US5332730A (en) 1992-10-16 1994-07-26 Allergan, Inc. Azido derivatives of cyclopentane heptanoic or heptenoic acid
EP0705277B1 (en) 1993-06-25 1998-10-21 Merck Frosst Canada Inc. Prostaglandin receptor ep3 and dna encoding it
FR2711060B1 (en) 1993-10-13 1995-11-17 Oreal A method for modifying hair growth and / or hair and compositions used for this purpose.
WO1995011003A1 (en) 1993-10-20 1995-04-27 Pharmacia Ab New use of prostaglandins
WO1995011033A1 (en) 1993-10-22 1995-04-27 Commonwealth Scientific And Industrial Research Organisation Polyoxometallates in the treatment of flavivirus infections
WO1995012401A1 (en) * 1993-11-03 1995-05-11 Pharmacia Ab Method and means for prevention of cataract
US5431881A (en) 1993-12-10 1995-07-11 Palacios; Henry J. Treatment of hair loss and dermatological problems
US6124344A (en) 1993-12-28 2000-09-26 Allergan Sales, Inc. Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents
US5458883A (en) * 1994-01-12 1995-10-17 Duke University Method of treating disorders of the eye
US5462968A (en) 1994-01-19 1995-10-31 Allergan, Inc. EP2 -receptor agonists as agents for lowering intraocular pressure
US5698733A (en) 1994-09-30 1997-12-16 Alcon Laboratories, Inc. Use of 9-deoxy prostaglandin derivatives to treat glaucoma
US6169111B1 (en) * 1995-06-07 2001-01-02 Alcon Laboratories, Inc. Conformationally rigid aryl prostaglandins for use in glaucoma therapy
FR2730811B1 (en) 1995-02-17 1997-03-21 Oreal Method to diagnose and / or follow the development of a capillary disorder and / or measure the effectiveness of a treatment applied to combat a capillary disorder
DE69613693D1 (en) 1995-05-18 2001-08-09 Allergan Sales Inc 2-heteroarylalkenylderivate the cyclopentano-heptane (heptaene) acid as a therapeutic agent for the treatment of elevated intraocular pressure
US5716609A (en) * 1995-07-25 1998-02-10 Panacea Biotec Limited Therapeutic anti-inflammatory and analgesic composition containing nimesulide for use transdermally and a process for the manufacture thereof
US5661178A (en) 1995-09-01 1997-08-26 Allergan Method for effecting vasodilation with (1,5-inter)aryl prostaglandin derivatives
US6251436B1 (en) 1995-09-29 2001-06-26 L.A.M. Pharmaceutical Corporation Drug preparations for treating sexual dysfunction
WO1997015319A1 (en) 1995-10-23 1997-05-01 Queen's University At Kingston Method and pharmaceutical composition for chondrostimulation with a prostaglandin (e.g. misoprostol) and tgf-beta, optionally in combination with igf-1
US6441047B2 (en) 1995-11-17 2002-08-27 Alcon Manufacturing Ltd.. Combination therapy for treating glaucoma
WO1997023225A1 (en) 1995-12-22 1997-07-03 Alcon Laboratories, Inc. Combinations of dp and fp type prostaglandins for lowering iop
US5814660A (en) 1995-12-22 1998-09-29 Alcon Laboratories, Inc. 9-oxa prostaglandin analogs as ocular hypotensives
US5866602A (en) 1995-12-22 1999-02-02 Alcon Laboratories, Inc. Keto-substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives
WO1997023226A1 (en) 1995-12-22 1997-07-03 Alcon Laboratories, Inc. Combinations of prostaglandins and miotics for lowering intraocular pressure
CA2244089C (en) 1996-02-19 2009-06-02 Monash University Dermal penetration enhancers and drug delivery systems involving same
US5741810A (en) 1996-02-29 1998-04-21 Allergan Cyclopentane heptan(ene)oic acid, 2- heteroarylalkenyl derivatives as therapeutic agents
US5990168A (en) 1996-04-18 1999-11-23 Alberta Cancer Board Methods and compositions for the treatment of ataxia telangiectasia
JP3049593B2 (en) 1996-05-01 2000-06-05 日本ソシア株式会社 Hair growth tonic
ES2182088T3 (en) 1996-06-10 2003-03-01 Sucampo Ag Endothelin antagonist.
WO1998000100A1 (en) 1996-07-03 1998-01-08 The Board Of Regents Of The University Of Oklahoma Enhancement of skin pigmentation by prostaglandins
DE69714274T3 (en) 1996-09-17 2006-06-01 Asahi Glass Co., Ltd. Fluorinated prostaglandin and drug
JP4004109B2 (en) 1996-09-17 2007-11-07 参天製薬株式会社 Fluorine-containing prostaglandin derivative and pharmaceutical
US5827508A (en) 1996-09-27 1998-10-27 The Procter & Gamble Company Stable photoprotective compositions
EP0948333A1 (en) 1996-11-01 1999-10-13 Alcon Laboratories, Inc. Use of a combination of carbonic anhydrase inhibitors and prostaglandins for treating glaucoma
CA2269853A1 (en) 1996-11-12 1998-05-22 Paul W. Zinke Use of cis-.delta.4 analogs of prostaglandins as ocular hypotensives
US6353000B1 (en) 1996-11-12 2002-03-05 Alcon Laboratories, Inc. 11-halo prostaglandins for the treatment of glaucoma or ocular hypertension
JP2001505556A (en) 1996-11-12 2001-04-24 アルコン ラボラトリーズ,インコーポレイテッド As antiglaucoma agent 15-fluoro prostaglandin
US6353014B1 (en) 1996-11-12 2002-03-05 Alcon Laboratories, Inc. 15-ketal postaglandins for the treatment of glaucoma or ocular hypertension
WO1998027053A1 (en) 1996-12-18 1998-06-25 Ono Pharmaceutical Co., Ltd. Sulfonamide and carboxamide derivatives and drugs containing the same as the active ingredient
EP0946501B1 (en) 1996-12-20 2006-05-31 Pfizer Inc. Prevention of loss and restoration of bone mass by certain prostaglandin agonists
EP0951282B1 (en) 1996-12-20 2008-04-02 Pfizer Inc. Prevention and treatment of skeletal disorder with ep2 receptor subtype selective prostaglandin e2 agonists
EP0860430B1 (en) 1997-02-04 2002-06-12 Ono Pharmaceutical Co., Ltd. Omega-cycloalkyl-prostaglandin E2 derivatives
DE69823852T2 (en) 1997-02-04 2005-05-19 Johnstone, Murray A., Seattle A method for promoting hair growth and development of the hair system
DK1008588T3 (en) 1997-02-10 2003-07-28 Ono Pharmaceutical Co 11,15-O-dialkyl prostaglandin E derivatives, to processes for their preparation and pharmaceutical compositions comprising them as an active ingredient
KR20000065039A (en) 1997-02-27 2000-11-06 히라이 가쯔히꼬 Pulmonary circulation improvers
EP0968183A2 (en) 1997-03-07 2000-01-05 Alcon Laboratories, Inc. 13-thia prostaglandins for use in glaucoma therapy
JP3217293B2 (en) * 1997-04-17 2001-10-09 株式会社アールテック・ウエノ Hair growth and hair tonic
RU2218159C2 (en) 1997-04-22 2003-12-10 Фармациа Энд Апджон Аб APPLICATION OF α-METHYL-P-TYROSINE FOR INHIBITION OF PRODUCING IRIS MELANIN
WO1998053809A1 (en) 1997-05-30 1998-12-03 Merck & Co., Inc. Ophthalmic compositions for treating ocular hypertension
US6531485B2 (en) 1997-06-23 2003-03-11 Pfizer Inc. Prostaglandin agonists
CN1169528C (en) 1997-07-11 2004-10-06 法玛西雅和厄普约翰公司 Prostaglandin derivatives devoid of side-effects for treatment of glaucoma
WO1999012556A1 (en) 1997-09-08 1999-03-18 The Public Health Research Institute Of The City Of New York, Inc. HIV-1 gp120 V1/V2 DOMAIN EPITOPES CAPABLE OF GENERATING NEUTRALIZING ANTIBODIES
WO1999012553A1 (en) 1997-09-08 1999-03-18 Idec Pharmaceuticals Corporation Methods for producing human antibodies in scid mice using dendritic cells
WO1999012561A9 (en) 1997-09-09 2000-03-16 Hoffmann La Roche FRACTURE HEALING USING PTHrP ANALOGS
ES2288766T3 (en) 1997-09-09 2008-01-16 Curis, Inc. Synergistic effects of morphogens op / bmp and neurotrophic factors GDNF / NGF.
CA2303763C (en) 1997-09-09 2007-04-24 The Procter & Gamble Company Aromatic c16-c20-substituted tetrahydro prostaglandins useful as fp agonists
CN1269720A (en) 1997-09-09 2000-10-11 普罗克特和甘保尔公司 Method of increasing bone volume
EP1011698A4 (en) 1997-09-09 2004-05-12 Univ Western Australia Chemical supplementation of bone
JP2001515866A (en) 1997-09-09 2001-09-25 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア Inhibition of apoptosis using a prosaposin receptor agonist
US6066751A (en) 1997-09-09 2000-05-23 The Procter & Gamble Company Process for making epoxide intermediates
KR20010023840A (en) 1997-09-09 2001-03-26 데이비드 엠 모이어 Method of increasing bone volume using non-naturally-occurring fp selective agonists
WO1999012899A1 (en) 1997-09-09 1999-03-18 The Procter & Gamble Company A process for making prostaglandin f analogs
DK1011689T3 (en) 1997-09-10 2007-05-21 Merial Ltd The use of 9a-azalides as veterinary antimicrobial agents
WO1999012558A1 (en) 1997-09-10 1999-03-18 Allegheny University Of The Health Sciences Inhibitors of collagen assembly
JP2001515869A (en) 1997-09-11 2001-09-25 アメリカ合衆国 Cytotoxic t lymphocytes response mucosal
US6331319B1 (en) 1997-09-11 2001-12-18 Purdue Research Foundation Galactosidase modified submucosal tissue
EP1024821A1 (en) 1997-09-12 2000-08-09 Smithkline Beecham Corporation Novel prokaryotic polynucleotides, polypeptides and their uses
EP0970697A4 (en) 1997-09-17 2001-02-21 Toray Industries Cervical maturing agent
WO1999015502A1 (en) 1997-09-19 1999-04-01 Shionogi & Co., Ltd. Compounds having [2.2.1]bicyclo skeleton
US6124314A (en) 1997-10-10 2000-09-26 Pfizer Inc. Osteoporosis compounds
DE69836752T2 (en) 1997-10-10 2007-10-11 Pfizer Inc. Prostaglandin agonists and their use for the treatment of bone diseases
EP1027057A4 (en) 1997-10-28 2003-01-02 Vivus Inc Treatment of female sexual dysfunction
CA2315221A1 (en) 1997-10-30 1999-05-14 Vaysman, Pyotr Method and composition for treatment of sexual dysfunction
WO1999025357A1 (en) 1997-11-14 1999-05-27 United Therapeutics Corporation USE OF 9-DEOXY-2', 9-α-METHANO-3- OXA-4,5,6- TRINOR-3, 7-(1',3'-INTERPHENYLENE) -13,14-DIHYDRO- PROSTAGLANDIN F1 TO TREAT PERIPHERAL VASCULAR DISEASE
US6099870A (en) 1997-12-18 2000-08-08 Johnson & Johnson Consumer Companies, Inc. Methods for improving the health of hair and scalp
WO1999032441A1 (en) 1997-12-22 1999-07-01 Alcon Laboratories, Inc. 13-oxa prostaglandins for the treatment of glaucoma and ocular hypertension
WO1999032641A1 (en) 1997-12-22 1999-07-01 Unilever N.V. A process for site-directed integration of multiple copies of a gene in a mould
US5955575A (en) 1997-12-22 1999-09-21 Hopital Sainte-Justine Antagonists of G-protein-coupled receptor
US6262293B1 (en) 1997-12-25 2001-07-17 Ono Pharmaceutical Co., Ltd. ω-Cycloalkly-prostaglandin e2 derivatives
GB9802599D0 (en) 1998-02-07 1998-04-01 Glaxo Group Ltd Medical use
EP1071648A2 (en) 1998-03-13 2001-01-31 Merck Frosst Canada & Co. Carboxylic acids and acylsulfonamides, compositions containing such compounds and methods of treatment
US6444840B1 (en) 1998-03-31 2002-09-03 The Procter & Gamble Co. C11 oxymyl and hydroxylamino prostaglandins useful as FP agonists
ES2244208T3 (en) 1998-03-31 2005-12-01 Duke University Prostaglandins and hydroxylamino oximyl c11 fp used as antagonists.
CA2324343C (en) 1998-03-31 2005-05-31 The Procter & Gamble Company C11 oxymyl and hydroxylamino prostaglandins useful as medicaments
DE69929594T2 (en) 1998-05-25 2006-12-07 Sato, Fumie, Fujisawa Hypnotics prostaglandin enhaltend
US6458549B2 (en) 1998-06-11 2002-10-01 Winthrop-University Hospital Methods of diagnosing renal salt wasting syndrome and Alzheimer's disease and methods of treating the same
US5942545A (en) 1998-06-15 1999-08-24 Macrochem Corporation Composition and method for treating penile erectile dysfunction
US6187818B1 (en) 1998-06-17 2001-02-13 Pharmacia & Upjohn Company Prostaglandins formulation and process
WO2000002450A1 (en) 1998-07-08 2000-01-20 Fibrogen, Inc. Method for treatment of fibrosis related diseases by the administration of prostacyclin derivatives
KR20010021835A (en) 1998-07-14 2001-03-15 제임스 에이. 아노 Prostaglandin product
WO2000003980A1 (en) 1998-07-15 2000-01-27 Ono Pharmaceutical Co., Ltd. 5-THIA-φ-SUBSTITUTED PHENYL-PROSTAGLANDIN E DERIVATIVES, PROCESS FOR PRODUCING THE SAME AND DRUGS CONTAINING THE SAME AS THE ACTIVE INGREDIENT
EP1109546A1 (en) 1998-07-21 2001-06-27 MERCK & CO., INC. Ophthalmic compositions for treating ocular hypertension
CA2337349A1 (en) 1998-07-21 2000-02-03 Merck & Co., Inc. Ophthalmic compositions for treating ocular hypertension
US6284234B1 (en) * 1998-08-04 2001-09-04 Johnson & Johnson Consumer Companies, Inc. Topical delivery systems for active agents
WO2000009557A1 (en) 1998-08-12 2000-02-24 Kazusa Dna Research Institute Foundation Novel gene and protein pgth encoded thereby
US6586468B1 (en) 1998-09-14 2003-07-01 Ono Pharmaceutical Co., Ltd. ω-substituted phenyl-prostaglandin E derivatives and drugs containing the same as the active ingredient
WO2000016760A3 (en) 1998-09-23 2000-06-08 Fujisawa Pharmaceutical Co New use of prostaglandin e2 antagonists
US6121253A (en) 1998-11-20 2000-09-19 Merck Frosst Canada & Co. Prostaglandin conjugates for treating or preventing bone disease
CN1345303A (en) 1999-03-01 2002-04-17 辉瑞产品公司 Oxamic acids and derivatives as thyroid receptor ligands
EP1159265B1 (en) 1999-03-05 2004-11-24 Duke University C-16 unsaturated fp-selective prostaglandins analogs
DE60015508D1 (en) 1999-03-05 2004-12-09 Univ Durham C-16 ungesätigte fp-selective prostaglandin analog
EP1169061A1 (en) 1999-03-12 2002-01-09 Alcon Laboratories, Inc. Combination therapy for treating glaucoma
US6894175B1 (en) 1999-08-04 2005-05-17 The Procter & Gamble Company 2-Decarboxy-2-phosphinico prostaglandin derivatives and methods for their preparation and use
US6548535B2 (en) 2000-01-18 2003-04-15 Merck & Co., Inc. Method for treating ocular hypertension
US20020013294A1 (en) 2000-03-31 2002-01-31 Delong Mitchell Anthony Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
US20020146439A1 (en) 2000-03-31 2002-10-10 Delong Mitchell Anthony Compositions and methods for treating hair loss using oximyl and hydroxylamino prostaglandins
CN1366458A (en) * 2000-03-31 2002-08-28 东丽株式会社 Hair growth and hair formation controlling agents
US20020037914A1 (en) 2000-03-31 2002-03-28 Delong Mitchell Anthony Compositions and methods for treating hair loss using C16-C20 aromatic tetrahydro prostaglandins
US20020172693A1 (en) 2000-03-31 2002-11-21 Delong Michell Anthony Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
FR2812193B1 (en) 2000-07-28 2003-10-24 Oreal Using receptor antagonist ep-2 prostaglandins and / or EP-4 to alleviate, reduce or stop the growth of hair and hairs in cosmetic preparations
FR2812191B1 (en) 2000-07-28 2003-10-17 Oreal Using receptor agonists of prostaglandin e2 (EP-3) to mitigate, reduce or stop hair growth and hair in cosmetic preparations
FR2812190B1 (en) * 2000-07-28 2003-01-31 Oreal Use of non-prostanoic receptor agonists ep-2 prostaglandins and / or EP-4 as a cosmetic agent to mitigate, reduce or to stop hair loss and hair
US20040082013A1 (en) 2002-01-24 2004-04-29 Regan John W Methods for screening for substances which inhibit fp prostanoid receptor interaction with a compound having pgf2alpha activity and methods of treating cancer
ES2284646T3 (en) 2001-02-22 2007-11-16 Jagotec Ag Statin-fibrate combination with side effects-fed fasting reduced.
US7157590B2 (en) 2001-05-31 2007-01-02 Finetech Laboratories Ltd. Process for the preparation of 17-phenyl-18,19,20-thinor-pgf 2a and its derivatives
US20030199590A1 (en) 2002-07-25 2003-10-23 Cagle Gerald D Prostaglandin analogues for promotion of hair growth
EP1298223A3 (en) 2001-09-28 2003-07-23 Pfizer Products Inc. Methods related to the A-C repeat Z-sequence upstream from the aldose reductase gene
ES2271381T3 (en) 2001-12-19 2007-04-16 Astrazeneca Ab Substituted phenylpropionic acid derivatives as activated receptor alpha agonists peroxisome proliferator (PPAR) human.
US7351404B2 (en) 2002-02-04 2008-04-01 Allergan, Inc. Method of enhancing hair growth
JP2005531516A (en) 2002-03-18 2005-10-20 ファイザー・プロダクツ・インク Method of treatment by selective ep4 receptor agonists
US7186707B2 (en) 2002-04-01 2007-03-06 University Of Florida Prodrugs for use as ophthalmic agents
GB0208785D0 (en) 2002-04-17 2002-05-29 Medical Res Council Treatment methtods
US7320967B2 (en) * 2002-04-23 2008-01-22 L'oreal Cosmetic composition, method of cosmetic treatment and preparation of a composition for promoting the growth and/or preventing or delaying the loss of hair
US6573294B1 (en) 2002-05-14 2003-06-03 Allergan, Inc. 8-azaprostaglandin analogs as agents for lowering intraocular pressure
US7521530B2 (en) 2002-06-11 2009-04-21 Universite De Montreal Peptides and peptidomimetics useful for inhibiting the activity of prostaglandin F2α receptor
US7589233B2 (en) 2003-07-29 2009-09-15 Signature R&D Holdings, Llc L-Threonine derivatives of high therapeutic index
US7045634B2 (en) 2003-09-05 2006-05-16 Allergan, Inc. Prostamide receptor antagonists
US20050058614A1 (en) * 2003-09-15 2005-03-17 Allergan, Inc. Methods for the treatment of gray hair using cyclopentane(ene) heptan(en)oic acid amides
US7070768B2 (en) 2003-09-25 2006-07-04 Allergan, Inc. Method for imparting artificial tan to human skin
US20050112075A1 (en) 2003-11-25 2005-05-26 Hwang Cheng S. Reduction of hair growth
US8415364B2 (en) 2003-11-26 2013-04-09 Duke University Method of preventing or treating glaucoma
EP1812017A2 (en) 2004-10-21 2007-08-01 Duke University Ophthamological drugs
US7288029B1 (en) 2005-01-19 2007-10-30 Gkn Driveline North America, Inc. Propshaft with crash-worthiness
GB0506759D0 (en) 2005-04-02 2005-05-11 Medical Res Council Combination treatment methods
WO2007123818A3 (en) 2006-04-18 2008-12-11 Nitromed Inc Organic nitric oxide enhancing salts of prostaglandins, compositions and methods of use
US20070254920A1 (en) 2006-04-26 2007-11-01 Aerie Pharmaceuticals, Inc. Prodrug derivatives of acids using alcohols with homotopic hydroxy groups and methods for their preparation and use
US7868032B2 (en) 2006-10-18 2011-01-11 Allergan, Inc. Prostamide receptor antagonists
US20090018204A1 (en) 2007-07-13 2009-01-15 Brinkenhoff Michael C Composition and method for enhancing hair growth
US8623918B2 (en) 2008-10-29 2014-01-07 Novaer Holdings, Inc. Amino acid salts of prostaglandins
US8722739B2 (en) * 2008-10-29 2014-05-13 Novaer Holdings, Inc. Amino acid salts of prostaglandins
CA2739571A1 (en) 2008-10-29 2010-08-26 Aerie Pharmaceuticals, Inc. Amino acid salts of prostaglandins
WO2010108012A1 (en) 2009-03-18 2010-09-23 Duke University Compositions and methods for promoting nasal patency and treating neurogenic bladder using prostaglandins

Patent Citations (86)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3776939A (en) * 1958-05-28 1973-12-04 S Bergstrom Dihydro-pgf1a
US3839409A (en) * 1958-05-28 1974-10-01 Kemiska Inst Karolinska I Pge3 esters and alkanoates
US3598858A (en) * 1958-05-28 1971-08-10 Sune Bergstrom Pge2 and pge3
US3691216A (en) * 1958-05-28 1972-09-12 Sune Bergstrom Pge2 methyl ester and pge2 methyl ester diacetate
US3706789A (en) * 1958-05-28 1972-12-19 Sune Bergstrom Pgf{11 {60
US3776938A (en) * 1958-05-28 1973-12-04 S Bergstrom Dihydro-pge1
US3852337A (en) * 1958-05-28 1974-12-03 Kemiska Institutionen Karolins Pgf tetraols and alkanoyl esters
US3435053A (en) * 1966-06-06 1969-03-25 Upjohn Co Cyclopenta(b)pyrans
US3524867A (en) * 1966-06-06 1970-08-18 Upjohn Co Process for producing cyclopenta (b)pyrans
US3882241A (en) * 1969-12-01 1975-05-06 Upjohn Co Use of prostaglandins E and F for prevention of pregnancy in humans
US3896156A (en) * 1970-06-30 1975-07-22 Upjohn Co Dihydroprostaglandin e, analogs
US4011262A (en) * 1972-07-13 1977-03-08 Pfizer Inc. 13,14-Dihydro-15-substituted-ω-pentanorprostaglandins of the two series
US3882245A (en) * 1972-11-01 1975-05-06 Upjohn Co Use of prostaglandins in combating shock
US4024179A (en) * 1972-11-08 1977-05-17 Pfizer Inc. Substituted ω-pentanorprostaglandins
US3966792A (en) * 1973-02-28 1976-06-29 Ono Pharmaceutical Co., Ltd. Prostaglandin compounds
US3984455A (en) * 1973-07-16 1976-10-05 The Upjohn Company Prostaglandin E1 analogs
US4004020A (en) * 1973-12-21 1977-01-18 Schering Aktiengesellschaft Novel prostanoic acid derivatives and process for the preparation thereof
US3928588A (en) * 1974-02-22 1975-12-23 Upjohn Co Method of reducing the undesirable gastrointestinal effects of prostaglandin synthetase inhibitors
US4061671A (en) * 1974-04-03 1977-12-06 Hoechst Aktiengesellschaft Analogues of prostaglandins
US4128720A (en) * 1975-02-14 1978-12-05 Ono Pharmaceutical Company Prostaglandin analogues
US4217360A (en) * 1975-02-27 1980-08-12 Schering Aktiengesellschaft Novel 1,3-benzodioxaneprostanoic acid derivatives and process for the preparation thereof
US4073934A (en) * 1975-04-18 1978-02-14 Schering Aktiengesellschaft Novel acetylenic prostaglandin analogs
US4158667A (en) * 1976-02-04 1979-06-19 The Upjohn Company 6-Keto PGF analogs
US4284646A (en) * 1976-08-06 1981-08-18 Schering Aktiengesellschaft Prostanoic acid derivatives and their preparation
US4489092A (en) * 1976-08-06 1984-12-18 Schering Aktiengesellschaft Prostanoic acid derivatives and their preparation
US4499293A (en) * 1976-09-22 1985-02-12 The Upjohn Company PGI2 Salts
US4123441A (en) * 1976-09-22 1978-10-31 The Upjohn Company Enlarged-hetero-ring prostacyclin analogs
US4089885A (en) * 1976-11-05 1978-05-16 American Home Products Corporation Prostaglandin derivatives
US4225507A (en) * 1979-07-05 1980-09-30 The Upjohn Company 19-Hydroxy-19-methyl-PGI2 compounds
US4225508A (en) * 1979-07-05 1980-09-30 The Upjohn Company 19-Hydroxy-PGI2 compounds
US4621100A (en) * 1981-09-25 1986-11-04 The Upjohn Company Treatment of osteoporosis with prostaglandins
US4704386A (en) * 1985-08-29 1987-11-03 G. D. Searle & Co. 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[(phenylsulfinyl-, and phenylsulfonyl)alkanoyl]hydrazides
US4889845A (en) * 1986-06-09 1989-12-26 American Cyanamid Company Vehicle for topical application of pharmaceuticals
US5280018A (en) * 1986-06-09 1994-01-18 American Cyanamid Company Vehicle for optical application of pharmaceuticals
US5663203A (en) * 1986-09-11 1997-09-02 Schering Aktiengesellschaft Agents containing prostacyclin derivatives for topical application
US5500230A (en) * 1987-01-23 1996-03-19 The General Hospital Corporation Method for treatment of glaucoma with nitrogen containing guanylate cyclase activators
US5219885A (en) * 1987-02-16 1993-06-15 Froelich Juergen Prostaglandin E1 derivatives as pharmaceutically active agents, and pharmaceutical compositions containing these compounds, especially for transcutaneous administration
US5973002A (en) * 1987-02-16 1999-10-26 Froelich; Juergen C. Prostaglandin E1 derivatives as pharmacologically active agents, especially for transcutaneous administration
US5464868A (en) * 1987-02-16 1995-11-07 Froelich; Juergen C. Prostaglandin E1 derivatives for transdermal administration and methods of treatment therewith
US5681850A (en) * 1987-02-16 1997-10-28 Froelich; Juergen C. Method of treatment of impotence with prostaglandin E1 derivatives
US5770759A (en) * 1987-04-30 1998-06-23 R-Tech Ueno, Ltd. Prostaglandins of the F series
US5578618A (en) * 1988-09-06 1996-11-26 Pharmacia Aktiebolag Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension
US6030999A (en) * 1988-09-06 2000-02-29 Pharmacia & Upjohn Aktiebolag Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension
US5063057A (en) * 1990-09-26 1991-11-05 Elizabeth Arden Co., Division Of Conopco, Inc. Cosmetic capsules
US5576315A (en) * 1991-05-03 1996-11-19 G.D. Searle & Co. Substituted dibenzoxazepine compounds and methods for treating osteoporosis and ischemia
US5578643A (en) * 1992-05-20 1996-11-26 Loyola University Of Chicago Protective prostaglandins for use in conjunction with chemotherapeutic agents
US5578640A (en) * 1992-05-20 1996-11-26 Loyola University Of Chicago Protective prostaglandins for use in conjunction with chemotherapeutic agents
US5605931A (en) * 1992-05-20 1997-02-25 Loyola University Of Chicago Protective prostaglandins for use in conjunction with chemotherapeutic agents
US5422371A (en) * 1992-05-27 1995-06-06 Arch Development Corp. Methods and compositions for inhibiting 5α-reductase activity
US5508303A (en) * 1992-05-29 1996-04-16 Toray Industries, Inc. Hair-growing composition
US6013823A (en) * 1992-06-08 2000-01-11 New Pharma International Corp. Trans-pentavalent 2-15-deoxy-16-hydroxy-16-methyl-PGE1 methyl ester (B-407)
US5834498A (en) * 1992-09-21 1998-11-10 Allergan Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents
US6037364A (en) * 1992-09-21 2000-03-14 Allergan Sales, Inc. Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents
US5340813A (en) * 1992-11-09 1994-08-23 Cell Therapeutics, Inc. Substituted aminoalkyl xanthine compounds
US5567079A (en) * 1992-11-17 1996-10-22 Felder; Anton Method for the hydraulic branching of an open stream and hydraulically working channel branch
US5670506A (en) * 1993-04-05 1997-09-23 Cell Therapeutics, Inc. Halogen, isothiocyanate or azide substituted xanthines
US5719140A (en) * 1993-04-30 1998-02-17 G.D. Searle & Co. 2, 3-, 4-, 5-, 6-, 7-, 8-, 9- and /or 10-substituted dibenzoxazepine compounds, pharmaceutical compositions and methods of use
US6031079A (en) * 1993-05-26 2000-02-29 Merck Frosst Canada, Inc. Purified prostaglandin receptor EP1
US5985597A (en) * 1993-05-26 1999-11-16 Merck Frosst Canada, Inc. DNA encoding prostaglandin receptor EP1
US5840847A (en) * 1993-06-25 1998-11-24 Merck Frosst Canada, Inc. Purified prostaglandin receptor FP
US5869281A (en) * 1993-06-25 1999-02-09 Merck Frosst Canada Inc. DNA encoding prostaglandin receptor FP
US5889052A (en) * 1993-08-03 1999-03-30 Alcon Laboraties, Inc. Use of cloprostenol and fluprostenol analogues to treat glaucoma and ocular hypertension
US5759789A (en) * 1993-08-31 1998-06-02 Merck Frosst Canada, Inc. Prostaglandin receptor EP2
US5605814A (en) * 1993-08-31 1997-02-25 Merck Frosst Canada Inc. DNA encoding human prostaglandin receptor EP2
US5516652A (en) * 1993-10-06 1996-05-14 Merck Frosst Canada Inc. DNA encoding prostaglandin receptor IP
US6025375A (en) * 1993-12-20 2000-02-15 Fujisawa Pharmaceutical Co., Ltd. 4,5-diaryloxazole derivatives
US5587391A (en) * 1993-12-28 1996-12-24 Allergan Cyclopentane(ene) heptenoic or heptanoic acids and derivatives thereof useful as therapeutic agents
US6031001A (en) * 1994-09-21 2000-02-29 Synphra Ab Use of prostaglandins
US5885974A (en) * 1994-12-06 1999-03-23 Michael M. Danielov Therapeutic methods utilizing naturally derived bio-active complexes and delivery systems therefor
US6043264A (en) * 1995-01-06 2000-03-28 Toray Industries, Inc. Benzene-condensed heterocyclic derivatives and their uses
US5958723A (en) * 1995-01-26 1999-09-28 Merck Frosst Canada & Co. DNA encoding prostaglandin receptor DP
US5885766A (en) * 1995-02-17 1999-03-23 Societe L'oreal S.A. Method of screening of substances for their effect on the expression of mediators of inflammation in a hair follicle
US5990346A (en) * 1995-06-26 1999-11-23 Teijin Limited Prostaglandins and processes for production thereof
US5972965A (en) * 1995-07-21 1999-10-26 Fujisawa Pharmaceutical Co., Ltd. 4,5-diaryl oxazole derivatives
US6025392A (en) * 1995-12-22 2000-02-15 Alcon Laboratories, Inc. substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives
US5994397A (en) * 1995-12-22 1999-11-30 Alcon Laboratories, Inc. Substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives
US5703108A (en) * 1996-02-28 1997-12-30 Pfizer Inc. Bone deposition by certain prostaglandin agonists
US5658897A (en) * 1996-04-08 1997-08-19 Allergan Cyclopentane(ene) heptanoic or cyclopentane(ene) heptenoic acid, 2-hydrocarbyl phosphinyloxyalkyl or phosphonamidoalkyl as therapeutic agents
US5792851A (en) * 1996-09-03 1998-08-11 Albert Einstin College Of Medicine Of Yeshiva University, A Division Of Yeshiva University Human prostaglandin transporter
US5892099A (en) * 1997-01-27 1999-04-06 Ono Pharmaceutical Co., Ltd. 3,7-dithiaprostanoic acid derivative
US6030959A (en) * 1997-04-04 2000-02-29 Monsanto Company Gastro-specific prodrugs
US6037368A (en) * 1997-05-09 2000-03-14 Mount Sinai School Of Medicine 8-iso- prostaglandins for glaucoma therapy
US6048895A (en) * 1997-09-09 2000-04-11 The Procter & Gamble Company Aromatic C16-C20 substituted tetrahydro prostaglandins useful as FP agonists
US5977173A (en) * 1997-09-09 1999-11-02 Wos; John August Aromatic C16 -C20 -substituted tetrahydro prostaglandins useful as FP agonists
US5877211A (en) * 1997-11-21 1999-03-02 Allergan EP2 receptor agonists as neuroprotective agents for the eye
US6372730B1 (en) * 1999-08-04 2002-04-16 The Procter & Gamble Company 2-decarboxy-2-phosphinico Prostaglandin F analogs

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE43372E1 (en) 1999-03-05 2012-05-08 Duke University C16 unsaturated FP-selective prostaglandins analogs
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US8541466B2 (en) 2000-03-31 2013-09-24 Duke University Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
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US8618086B2 (en) 2000-03-31 2013-12-31 Duke University Compositions and methods for treating hair loss using C16-C20 aromatic tetrahydro prostaglandins
US20090286769A1 (en) * 2000-03-31 2009-11-19 Duke University Compositions and methods for treating hair loss using non-naturally occurring prostaglandins
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US20060121069A1 (en) * 2000-03-31 2006-06-08 Duke University Compositions and methods for treating hair loss using oximyl and hydroxylamino prostaglandins
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US20090318542A1 (en) * 2004-10-21 2009-12-24 Toone Eric J Ophthamological drugs
US20060135609A1 (en) * 2004-10-21 2006-06-22 Duke University Ophthamological drugs
US8642644B2 (en) 2004-10-21 2014-02-04 Duke University Ophthamological drugs
US20090298928A1 (en) * 2004-12-29 2009-12-03 R-Tech Ueno, Ltd. Composition and method for scalp and hair treatment
US20070298134A1 (en) * 2004-12-29 2007-12-27 R-Tech Ueno, Ltd. Composition and Method for Scalp and Hair Treatment
US9241918B2 (en) 2005-03-16 2016-01-26 Allergan, Inc. Enhanced bimatoprost ophthalmic solution
US8586630B2 (en) 2005-03-16 2013-11-19 Allergan, Inc. Enhanced bimatoprost ophthalmic solution
US8772338B2 (en) 2005-03-16 2014-07-08 Allergan, Inc. Enhanced bimatoprost ophthalmic solution
US8524777B2 (en) 2005-03-16 2013-09-03 Allergan Inc. Enhanced bimatoprost ophthalmic solution
US8933127B2 (en) * 2005-03-16 2015-01-13 Allergan, Inc. Enhanced bimatoprost ophthalmic solution
US8933120B2 (en) 2005-03-16 2015-01-13 Allergan, Inc. Enhanced bimatoprost ophthalmic solution
US9155716B2 (en) * 2005-03-16 2015-10-13 Allergan, Inc. Enhanced bimatoprost ophthalmic solution
US20070254920A1 (en) * 2006-04-26 2007-11-01 Aerie Pharmaceuticals, Inc. Prodrug derivatives of acids using alcohols with homotopic hydroxy groups and methods for their preparation and use
US8623918B2 (en) 2008-10-29 2014-01-07 Novaer Holdings, Inc. Amino acid salts of prostaglandins
US8722739B2 (en) 2008-10-29 2014-05-13 Novaer Holdings, Inc. Amino acid salts of prostaglandins
US20100105775A1 (en) * 2008-10-29 2010-04-29 Delong Mitchell A Amino acid salts of prostaglandins
US9006291B2 (en) 2009-02-03 2015-04-14 Pharma Patent Holding Inc. Composition, method and kit for enhancing hair
US9522153B2 (en) 2009-12-22 2016-12-20 Allergan, Inc. Compositions and methods for lowering intraocular pressure
US9801891B2 (en) 2009-12-22 2017-10-31 Allergan, Inc. Compositions and methods for lowering intraocular pressure

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