Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/06—Antiglaucoma agents or miotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
  • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
  • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams

Definitions

• Ocular hypotensive agents are useful in the treatment of a number of various ocular hypertensive conditions, such as post-surgical and post- laser trabeculectomy ocular hypertensive episodes, glaucoma, and as presurgical adjuncts.
• Glaucoma is a disease of the eye characterized by increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) may be either open-angle or acute or chronic angle- closure. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract.
• the increased intraocular tension is due to the obstruction of aqueous humor outflow.
• chronic open-angle glaucoma the anterior chamber and its anatomic structures appear normal, but drainage of the aqueous humor is impeded.
• acute or chronic angle-closure glaucoma the anterior chamber is shallow, the filtration angle is narrowed, and the iris may obstruct the trabecular meshwork at the entrance of the canal of Schlemm. Dilation of the pupil may push the root of the iris forward against the angle, and may produce pupilary block and thus precipitate an acute attack. Eyes with narrow anterior chamber angles are predisposed to acute angle-closure glaucoma attacks of various degrees of severity.
• Secondary glaucoma is caused by any interference with the flow of aqueous humor from the posterior chamber into the anterior chamber and subsequently, into the canal of Schlemm.
• Inflammatory disease of the anterior segment may prevent aqueous escape by causing complete posterior synechia in iris bombe, and may plug the drainage channel with exudates.
• Other common causes are intraocular tumors, enlarged cataracts, central retinal vein occlusion, trauma to the eye, operative procedures and intraocular hemorrhage.
• glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision.
• topical ⁇ -adrenoreceptor antagonists have traditionally been the drugs of choice for treating glaucoma.
• Eicosanoids and their derivatives are currently commercially available for use in glaucoma management.
• Eicosanoids and derivatives include numerous biologically important compounds such as prostaglandins and their derivatives.
• Prostaglandins can be described as derivatives of prostanoic acid which have the following structural formula:
• prostaglandins are known, depending on the structure and substituents carried on the alicyclic ring of the prostanoic acid skeleton. Further classification is based on the number of unsaturated bonds in the side chain indicated by numerical subscripts after the generic type of prostaglandin [e.g. prostaglandin Ei (PGE-
• prostaglandin Ei
• PGE2 prostaglandin E2
• PPF2 ⁇ prostaglandin F2 ⁇
• Prostaglandin EP 2 selective agonists are believed to have several medical uses.
• U.S. Patent No. 6,437,146 teaches the use of prostaglandin EP 2 selective agonists "for treating or preventing inflammation and pain in joint and muscle (e.g., rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenile arthritis, etc.), inflammatory skin condition (e.g., sunburn, burns, eczema, dermatitis, etc.), inflammatory eye condition (e.g., conjunctivitis, etc.), lung disorder in which inflammation is involved (e.g., asthma, bronchitis, pigeon fancier's disease, farmer's lung, etc.), condition of the gastrointestinal tract associated with inflammation (e.g., aphthous ulcer, Chr
• United State Patent No 6,710,072 teaches the use of EP2 agonists for the treatment or prevention of "osteoporosis, constipation, renal disorders, sexual dysfunction, baldness, diabetes, cancer and in disorder of immune regulation... various pathophysiological diseases including acute myocardial infarction, vascular thrombosis, hypertension, pulmonary hypertension, ischemic heart disease, congestive heart failure, and angina pectoris.”
• X is S or O
• R is a hydrocarbyl or a hydroxyhydrocarbyl moiety comprising from 1 to 12 carbon atoms;
• D is independently a moiety comprising from 1 to 6 non-hydrogen atoms; and n is an integer from 0 to 4.
• A may be a group which is related to one of these three moieties in that any carbon is substituted with S or O.
• A may be an S substituted moiety such as one of the following or the like. ,CH,
• A may be an O substituted moiety such as one of the following or the like.
• A may have both an O and an S substituted in the chain, such as one of the following or the like.
• A is -(CH2)m-Ar-(CH 2 ) 0 - wherein Ar is substituted or unsubstituted phenyl or monocyclic heteroaryl, the sum of m and o is from 1 to 4, and wherein one CH 2 may be substituted with S or O.
• A comprises from 1 to 4 CH 2 moieties and Ar, e.g.
• A comprises O, from O to 3 CH 2 moieties, and Ar, as in for example, -0-Ar-, Ar-CH 2 -O-, -O-Ar-(CH 2 ) 2 -, -0-CH 2 -Ar-, -O-CH 2 -Ar-(CH 2 ) 2 , and the like; or A comprises S, from O to 3 CH 2 moieties, and Ar, as in for example, -S-Ar-, Ar-CH 2 -S-, -S-Ar-(CH 2 ) 2 -, -S-CH 2 -Ar-, -S-CH 2 -Ar-(CH 2 ) 2) and the like.
• Ar is substituted or unsubstituted phenyl or substituted or unsubstituted monocyclic heteroaryl.
• Ar is substituted or unsubstituted phenyl, thienyl, furyl, or pyridinyl.
• Ar is phenyl (Ph).
• A is -(CH 2 ) 2 -Ph. While not intending to limit scope of the invention in any way, substituents may have 4 or less heavy atoms, or in other words, non hydrogen atoms. Any number of hydrogen atoms required for a particular substituent will also be included.
• the substituent may be C 4 or lower hydrocarbyl, including C 4 or lower alkyl, including methyl, ethyl, propyl isomers including isopropyl, butyl isomers including f-butyl, and alkenyl, alkynyl, and the like; C 3 or lower hydrocarbyloxy including alkoxy such as methoxy, ethoxy, etc.; CF 3 ; halo, such as F, Cl, or Br; hydroxyl; NH 2 and alkylamine functional groups up to C 3 ; other N or S containing substituents; and the like.
• A is -(CH 2 )m-Ar-(CH 2 )o- wherein Ar is phenyl, the sum of m and o is from 1 to 3, and wherein one CH 2 may be substituted with S or O.
• A is -CH 2 -Ar-OCH 2 -.
• A is -CH 2 -Ar-OCH 2 - and Ar is phenyl.
• Ar is attached at the 1 and 3 positions, such as when A has the structure shown below.
• D is a moiety comprising from 1 to 6 non-hydrogen atoms, in other words, there are from 1 to 6 atoms which are not hydrogen, and any number of hydrogen atoms required to form the complete substituent.
• a methyl substituent has 1 carbon atom and 3 hydrogen atoms.
• substituents include other hydrocarbyl moieties comprising from 1 to 6 carbon atoms including alkyl such as ethyl, propyl, isopropyl, butyl and isomers thereof, pentyl and isomers thereof, hexyl and isomers thereof; cyclic and unsaturated hydrocarbyls having 1 to 6 carbon atoms; CO 2 H and salts thereof; alkoxy up to C 5 such as methoxy, ethoxy, propoxy, isopropoxy, a butoxy isomer, or a pentoxy isomer; carboxylic acid esters; CN; NO 2 ; CF 3 ; F; Cl; Br; I; sulfonyl esters; SO 3 H and salts thereof; and the like.
• D may be in any reasonable position on the phenyl ring.
• n is 0. In other compounds n is 1 , in other compounds n is 2, and in other compounds n is 3.
• a hydrocarbyl moiety refers to a moiety consisting of only carbon and hydrogen. While not intending to limit the scope of the invention in any way, examples of different types of hydrocarbyl moiety are as follows.
• Hydrocarbyl is a moiety consisting of only carbon and hydrogen, and includes, but is not limited to alkyl, alkenyl, alkynyl, and the like, and in some cases aryl, and combinations thereof.
• Alkyl is hydrocarbyl having no double or triple bonds including:
• linear alkyl such as methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, and the like;
• branched alkyl such as isopropyl, branched butyl isomers (i.e. sec- butyl, tert-butyl, etc), branched pentyl isomers (i.e. isopentyl, etc), branched hexyl isomers, and higher branched alkyl fragments;
• cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.; and alkyl fragments consisting of both cyclic and noncyclic components, whether linear or branched, which may be attached to the remainder of the molecule at any available position including terminal, internal, or ring carbon atoms.
• Alkenyl is hydrocarbyl having one or more double bonds including linear alkenyl, branched alkenyl, cyclic alkenyl, and combinations thereof in analogy to alkyl.
• Alkynyl is hydrocarbyl having one or more triple bonds including linear alkynyl, branched alkynyl, cyclic alkynyl and combinations thereof in analogy to alkyl.
• Aryl is an unsubstituted or substituted aromatic ring or ring system such as phenyl, naphthyl, biphenyl, and the like.
• Aryl may or may not be hydrocarbyl, depending upon whether it has substituents with heteroatoms.
• Arylalkyl is alkyl which is substituted with aryl. In other words alkyl connects aryl to the remaining part of the molecule. Examples are -CH 2 - Phenyl, -CH 2 -CH 2 -Phenyl, and the like. Arylalkyl may or may not be hydrocarbyl, depending upon whether it has substituents with heteroatoms.
• alk(poly)enyl which is similar to alkenyl, except that more than one double bond is present.
• hydrocarbyl is alkynyl or an alk(poly)ynyl, which is similar to alkenyl or alk(poly)ynyl except that one or more triple bonds are present.
• a hydrocarbyl moiety comprising a cyclic structure comprises a cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl(poly)enyl, cycloalkyl(poly)ynyl, aryl, and the like; and may consist of only the ring or may be a combination of the ring and one or more of the linear, branched, or cyclic hydrocarbyl fragments; or may be a fused polycyclic structure.
• hydrocarbyl having no ring has 12 or fewer carbon atoms
• hydrocarbyl having one or more rings has 18 or fewer carbon atoms.
• a hydroxyhydrocarbyl moiety consists of a combination of a hydrocarbyl moiety and a hydroxyl group. In other words, a hydrogen atom of the hydrocarbyl moiety is substituted with a hydroxyl group. The hydroxyhydrocarbyl moiety attaches to the remainder of the molecule at a carbon atom.
• R is a hydrocarbyl or a hydroxyhydrocarbyl moiety comprising from 1 to 12 atoms
• R may also be a different moiety which may be considered hydrocarbyl or hydroxyhydrocarbyl according to the description given herein.
• R is not methyl, ethyl.
• R comprises from 4 to 12 carbon atoms.
• R is a hydroxyhydrocarbyl having the hydroxyl group attached to the carbon atom which is also attached to the remainder of the molecule.
• the hydroxyl group and the remainder of the molecule are on geminal positions on the hydrocarbyl moiety.
• This type of hydroxyhydrocarbyl moiety is referred to as a 1- hydroxyhydrocarbyl moiety herein.
• Non-linear hydroxyhydrocarbyl is hydroxyhydrocarbyl wherein the hydrocarbyl portion is not linear, i.e. it has branching and/or a ring.
• R is hydroxyhydrocarbyl where there are two carbon atoms connecting the hydroxyl group to the remaining part of the molecule.
• These particular hydroxyhydrocarbyl are called 2- hydroxyhydrocarbyl herein.
• 2- hydroxyhydrocarbyl For example, -CH 2 CH 2 OH and -C(CH 3 ) 2 CH 2 OH are 2-hydroxyhydrocarbyl. While not intending to limit the scope of the invention in any way, an example of a structure where R is 2-hydrocarbyl is shown below.
• R 3 , R 4 , and R 5 are independently H or Ci -6 alkyl.
• R 4 and R 5 may be two separate moieties.
• R 4 and R 5 may be methyl, and no bond would be present where indicated by the dashed line.
• R 4 and R 5 may form a ring.
• a compound such as the one shown below is possible, wherein x is from 1 to 6.
• R comprises from 6 to 9 carbon atoms and a cyclic structure. In other compounds, R comprises from 1 to 5 carbon atoms. In certain compounds R is hydroxyalkyl having from 1 to 5 carbon atoms. In other compounds R is a 1 -hydroxyhydrocarbyl moiety comprising from 6 to 9 carbon atoms and a cyclic structure. In other compounds R is a 1 - hydroxyhydrocarbyl moiety comprising from 6 to 9 carbon atoms and a cyclic structure comprising from 4-7 carbon atoms. In other words, the cyclic structure part of R is a cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl fragment.
• the cyclic structure part of R may also be a cycloalkenyl or cycloalkynyl fragment such as cyclopentene or cyclohexene.
• R is a hydrocarbyl moiety comprising from 1 to 5 carbon atoms.
• R is methyl, ethyl, propyl, isopropyl, a butyl isomer such as t- butyl, or a pentyl isomer.
• R is t-butyl.
• Certain useful compounds comprise
• a "pharmaceutically acceptable salt” is any salt that retains the activity of the parent compound and does not impart any additional deleterious or untoward effects on the subject to which it is administered and in the context in which it is administered compared to the parent compound.
• a pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into a salt.
• Pharmaceutically acceptable salts of acidic functional groups may be derived from organic or inorganic bases.
• the salt may comprise a mono or polyvalent ion.
• the inorganic ions lithium, sodium, potassium, calcium, and magnesium.
• Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules.
• Hydrochloric acid or some other pharmaceutically acceptable acid may form a salt with a compound that includes a basic group, such as an amine or a pyridine ring.
• a prodrug is a compound which is converted to a therapeutically active compound after administration, and the term should be interpreted as broadly herein as is generally understood in the art. While not intending to limit the scope of the invention, conversion may occur by hydrolysis of an ester group or some other biologically labile group. Generally, but not necessarily, a prodrug is inactive or less active than the therapeutically active compound to which it is converted.
• the compounds disclosed herein are useful for the prevention or treatment of glaucoma or ocular hypertension in mammals, or for the manufacture of a medicament for the treatment of glaucoma or ocular hypertension.
• the compounds disclosed herein may also be useful for the stimulation of hair growth or stimulate conversion of vellus hair to terminal hair in mammals, or for the manufacture of a medicament for the stimulation of hair growth or stimulate conversion of vellus hair to terminal hair.
• the compounds disclosed herein will be selective EP 2 agonists. Therefore, they are also useful for the treatment of those diseases disclosed in the art as being amenable to treatment by prostaglandin EP 2 agonist, such as the ones listed previously.
• a drug to be administered systemically it may be confected as a powder, pill, tablet or the like, or as a solution, emulsion, suspension, aerosol, syrup or elixir suitable for oral or parenteral administration or inhalation.
• non-toxic solid carriers include, but are not limited to, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, the polyalkylene glycols, talcum, cellulose, glucose, sucrose and magnesium carbonate.
• the solid dosage forms may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
• a time delay material such as glyceryl monostearate or glyceryl distcarate may be employed. They may also be coated by the technique described in the U.S. Pat. Nos.
• Liquid pharmaceutically administrable dosage forms can, for example, comprise a solution or suspension of one or more of the presently useful compounds and optional pharmaceutical adjutants in a carrier, such as for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.
• a carrier such as for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.
• the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like.
• auxiliary agents are sodium acetate, sorbitan monolaurate, triethanolamine, sodium acetate, triethanolamine oleate, etc.
• Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 16th Edition, 1980.
• the composition of the formulation to be administered, in any event contains a quantity of one or more of the presently useful compounds in an amount effective to provide the desired therapeutic effect.
• Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously.
• Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol and the like.
• the injectable pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like.
• the amount of the presently useful compound or compounds administered is, of course, dependent on the therapeutic effect or effects desired, on the specific mammal being treated, on the severity and nature of the mammal's condition, on the manner of administration, on the potency and pharmacodynamics of the particular compound or compounds employed, and on the judgment of the prescribing physician.
• the therapeutically effective dosage of the presently useful compound or compounds is preferably in the range of about 0.5 or about 1 to about 100 mg/kg/day.
• a liquid which is ophthalmically acceptable is formulated such that it can be administered topically to the eye.
• the comfort should be maximized as much as possible, although sometimes formulation considerations (e.g. drug stability) may necessitate less than optimal comfort.
• the liquid should be formulated such that the liquid is tolerable to the patient for topical ophthalmic use.
• an ophthalmically acceptable liquid should either be packaged for single use, or contain a preservative to prevent contamination over multiple uses.
• solutions or medicaments are often prepared using a physiological saline solution as a major vehicle.
• Ophthalmic solutions should preferably be maintained at a comfortable pH with an appropriate buffer system.
• the formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
• Preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate.
• a useful surfactant is, for example, Tween 80.
• various useful vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyi methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
• Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
• buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
• an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
• excipient components which may be included in the ophthalmic preparations are chelating agents.
• a useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.
• ingredients are usually used in the following amounts:
• Ingredient Amount (% w/v) active ingredient about 0.001 -5 preservative 0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01 -10 pH adjustor q.s. pH 4.5-7.5 antioxidant as needed surfactant as needed purified water as needed to make 100%
• Topical formulations may generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.
• the actual dose of the active compounds of the present invention depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
• the compounds disclosed herein can be useful in the treatment of baldness and/or hair loss.
• Alopecia baldness
• baldness is a deficiency of either normal or abnormal hair, and is primarily a cosmetic problem in humans. It is a deficiency of terminal hair, the broad diameter, colored hair that is readily seen.
• vellus hair is a fine colorless hair which may require microscopic examination to determine its presence. This vellus hair is a precursor to terminal hair.
• the compounds described herein can be used to stimulate, such as the conversion of vellus hair to growth as terminal hair, as well as increasing the rate of growth of terminal hair.
• the utility of the compounds described herein for the simulation of hair growth was discovered as follows. [0098] In the course of treating patients having glaucoma, treatment may only be appropriate in one eye. Within the course of daily practice, it was discovered that a patient who had been treated with bimatoprost, a prostaglandin analogue, developed lashed that were longer, thicker, and fuller in the treated eye than in the non-treated eye. On examination, the difference was found to be very striking. The lashes were longer and had a fuller, denser appearance in the treated eye.
• the compounds described herein are prostaglandin analogues and therefore have similar activities as bimatoprost, contain structural similarities, and therefore are expected to stimulate hair growth and stimulation of the conversion of vellus hair to terminal hair.
• the compounds described herein and their prodrugs can be used for the stimulation of hair growth.
• hair growth includes hair associated with the scalp, eyebrows, eyelids, beard, and other areas of the skin of animals.
• the compound is mixed with a dermatologically compatible vehicle or carrier.
• vehicle which may be employed for preparing compositions as described herein, may comprise, for example, aqueous solutions such as e.g., physiological salines, oil solutions, or ointments.
• vehicle furthermore may contain dermatologically compatible preservatives such as e.g., benzalkonium chloride, surfactants like e.g., polysorbate 80, liposomes or polymers, for example, methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone and hyaluronic acid; these may be used for increasing the viscosity.
• soluble or insoluble drug inserts when the drug is to be administered.
• dermatological compositions can be formulated for topical treatment for the stimulation of hair growth which comprises an effective hair growth simulating amount of one or more compounds as defined above and a dermatologically compatible carrier.
• Effective amounts of the active compounds may be determined by one of ordinary skill in the art, but will vary depending on the compound employed, frequency of application and desired result.
• the compound will generally range from about 0.0000001 to about 50% by weight of the dermatological composition.
• the compound will range from about 0.001 to about 50% by weight of total dermatological composition, more preferably from about 0.1 to about 30% by weight of the composition.
• the application of the present compounds for stimulation of hair growth finds applications in mammalian species, including both humans and animals.
• the compounds described herein can be applied for example, to the scalp, face beard, head, pubic area, upper lip, eyebrows, and eyelids.
• animal raised for their pelts, e.g., mink the compounds described herein can be applied over the entire surface of the body to improve the overall pelt for commercial reasons.
• the process can also be used for cosmetic reasons in animals, e.g., applied to the skin of dogs and cats having bald patches due to mange or other diseases causing a degree of alopecia.
• compositions contemplated for the stimulation of hair growth include pharmaceutical compositions suited for topical and local action.
• topical as employed herein relates to the use of a compound, as described herein, incorporated in a suitable pharmaceutical carrier, and applied at the site of thinning hair or baldness for exertion of local action.
• topical compositions include those pharmaceutical forms in which the compound is applied externally by direct contact with the skin to be treated.
• Conventional pharmaceutical forms for this purpose include ointments, liniments, creams, shampoos, lotions, pastes, jellies, sprays, aerosols, and the like, and may be applied in patches or impregnated dressings depending on the part of the body to be treated.
• composition embraces formulations (including creams) having oleaginous, water-soluble and emulsion-type bases, e.g., petrolatum, lanolin, polyethylene glycols, as well as mixtures of these.
• the compounds can be applied repeatedly for the sustained period of time topically on the part of the body to be treated, for example, the eyelids, eyebrows, skin or scalp.
• the preferred dosage regimen will generally involve regular, such as daily, administration for a period of treatment of at least one month, more preferably at least three months, and most preferably, at least six months.
• the active compounds can be formulated in aqueous solutions, creams, ointments, or oils exhibiting physologicla acceptable osmolarity by addition of pharmaceutically acceptable buffers and salts, such formulations may or may not, depending on the dispenser, contain preservatives such as benzalkonium chloride, chlorhexidine, chlorobutanol, parahydroxybenzoic acids and phenylmercuric salts such as nitrate, chloride, acetate, and borate, or antioxidants, as well as additives like EDTA, sorbitol, boric acid and the like as additives.
• preservatives such as benzalkonium chloride, chlorhexidine, chlorobutanol, parahydroxybenzoic acids and phenylmercuric salts such as nitrate, chloride, acetate, and borate, or antioxidants, as well as additives like EDTA, sorbitol, boric acid and the like as additives.
• aqueous solutions may contain viscosity increasing agents such as polysaccharides, e.g., methylcellulose, mucopolysaccharides, e.g., hyaluronic acid and chondroitin sulfate, or poly alcohol, e.g., polyvinylalcohol.
• viscosity increasing agents such as polysaccharides, e.g., methylcellulose, mucopolysaccharides, e.g., hyaluronic acid and chondroitin sulfate, or poly alcohol, e.g., polyvinylalcohol.
• Various slow releasing gels and matricies may also be employed as well as soluble and insoluble ocular inserts, for instance, based on substances forming in situ gels.
• various amounts of the drug and different dose regimens may be employed.
• the daily amount of compound for treatment of the eyelid may be about 0.1 ng to about 100 mg per eyelid.
• the compound can be advantageously formulated using ointments, creams, liniments or patches as a carrier of the active ingredient.
• these formulations may or may not contain preservatives, depending on the dispenser and nature of use.
• preservatives include those mentioned above, and methyl-, propyl-, or butyl- parahydroxybenzoic acid, betain, chlorhexidine, benzalkonium chloride, and the like.
• matricies for the slow release delivery may also be used.
• the dose to be applied on the scalp is in the range of about 0.1 ng to about 100 mg per day, more preferably about 1 ng to about 10 mg per day, and most preferably about 10 ng to about 1 mg per day depending on the compound and the formulation.
• the compound may be administered once or several times daily with or without antioxidants.
• A is -(CH 2 )B-, cis or -CH 2 C ⁇ C-(CH 2 ) 3 -, wherein 1 or 2 carbon atoms may be substituted with S or O; or A is -(CH 2 ) m -Ar- (CH 2 ) o - wherein Ar is substituted or unsubstituted phenyl or monocyclic heteroaryl, the sum of m and o is from 1 to 4, and wherein one CH 2 may be substituted with S or O;
• X is S or O;
• R is a hydrocarbyl or a hydroxyhydrocarbyl moiety comprising from 1 to 12 carbon atoms;
• D is independently a moiety comprising from 1 to 6 non-hydrogen atoms; and n is an integer from 0 to 4.
• Another embodiment is a compound comprising
• Another embodiment is a compound comprising
• Another embodiment is a compound comprising
• Another embodiment is a compound comprising
• Another embodiment is a compound comprising
• R is alkyl having from 3 to 6 carbon atoms.
• Another embodiment is a compound comprising
• Another embodiment is a compound comprising or a pharmaceutically acceptable salt, or a prodrug thereof; wherein Y is as described above.
• Another embodiment is a compound comprising
• Y is as described above; and m is an integer having a value of from 0 to 3.
• Another embodiment is a compound comprising
• Another embodiment is a compound comprising
• Another embodiment is a compound comprising
• Another embodiment is a compound comprising
• Another embodiment is a compound comprising
• Another embodiment is a compound comprising
• Another embodiment is a compound comprising
• Another embodiment is a compound comprising
• Another embodiment is a compound comprising
• Another embodiment is a compound comprising
• Another embodiment is a compound comprising or a pharmaceutically acceptable salt or a prodrug thereof; wherein R 3 , R 4 , and R 5 are independently H or C 1 - 6 alkyl.
• R 4 and R 5 are methyl in the structure above.
• Another embodiment is a compound comprising
• Another embodiment is a compound comprising
• Another embodiment is a compound comprising
• Another embodiment is a compound comprising
• Another embodiment is a compound comprising
• Another embodiment is a compound comprising Y or a pharmaceutically acceptable salt or a prodrug thereof, wherein Y is as described above.
• Other compounds comprise
• n is 0 in any structure shown above.
• R comprises from 6 to 9 carbon atoms and a cyclic structure in any structure shown above.
• R is a 1 -hydroxyhydrocarbyl moiety in any structure shown above.
• R comprises from 1 to 5 carbon atoms in any structure shown above.
• R consists of t-butyl in any structure shown above.
• R is 1 -hydroxyalkyl in any structure shown above.
• A is -(CH 2 ) m -Ar-(CH 2 ) 0 - wherein Ar is phenyl, the sum of m and o is from 1 to 4, and wherein one CH 2 may be substituted with S or O in any structure shown above.
• A is -CH 2 -Ar-O-CH 2 - in any structure shown above.
• R is 2-hydroxyhydrocarbyl in any structure shown above.
• Glaucoma or Ocular Hypertension are Glaucoma or Ocular Hypertension
• a corresponding embodiment is contemplated drawn to administering the compound to a mammal for the treatment of glaucoma or ocular hypertension.
• Inflammatory Bowel Disease For each embodiment drawn to a compound, a corresponding embodiment is contemplated drawn to administering the compound to a mammal for the treatment of inflammatory bowel disease.
• said inflammatory bowel disease is colitis.
• said inflammatory bowel disease is Crohn's disease.
• a corresponding embodiment is contemplated drawn to administering the compound to a mammal for the stimulation of hair growth or the stimulation of the conversion of vellus hair to terminal hair.
• One embodiment is a use of a compound in the manufacture of a medicament for the treatment of inflammatory bowel disease.
• One embodiment is a use of a compound in the manufacture of a medicament for the stimulation of hair growth or the stimulation of the conversion of vellus hair to terminal hair.
• said compound can be used in the manufacture of a medicament for the treatment of glaucoma, treatment of inflammatory bowel disease, and/or stimulation of hair growth or the stimulation of the conversion of vellus hair to terminal hair, said compound comprising:
• X is S or O
• R is a hydrocarbyl or a hydroxyhydrocarbyl moiety comprising from 1 to 12 carbon atoms;
• D is independently a moiety comprising from 1 to 6 non-hydrogen atoms; and n is an integer from O to 4.
• said compound comprises
• said compound comprises
• said compound comprises
• said compound comprises or a pharmaceutically acceptable salt, or a prodrug thereof; wherein Y and R are as described above.
• said compound comprises
• R is alkyl having from 3 to 6 carbon atoms.
• said compound comprises
• said compound comprises
• said compound comprises
• Y is as described above; and m is an integer having a value of from 0 to 3.
• said compound comprises
• said compound comprises
• said compound comprises
• said compound comprises
• said compound comprises or a pharmaceutically acceptable salt, or a prodrug thereof, wherein Y is as described above.
• said compound comprises
• said compound comprises
• said compound comprises
• said compound comprises
• said compound comprises
• said compound comprises or a pharmaceutically acceptable salt or a prodrug thereof; wherein R 3 , R 4 , and R 5 are independently H or Ci -6 alkyl.
• R 4 and R 5 are methyl in the structure above.
• said compound comprises
• said compound comprises
• said compound comprises
• said compound comprises
• said compound comprises
• said compound comprises
• said compound comprises
• said compound comprises
• n is 0 in any structure shown above.
• R comprises from 6 to 9 carbon atoms and a cyclic structure in any structure shown above.
• R is a 1-hydroxyhydrocarbyl moiety in any structure shown above.
• R comprises from 1 to 5 carbon atoms in any structure shown above.
• R consists of t-butyl in any structure shown above.
• R is 1 -hydroxyalkyl in any structure shown above.
• A is -(CH 2 )B-, cis or -CH 2 C ⁇ C-(CH 2 ) 3 - in any structure shown above.
• A is -(CH 2 ) m -Ar-(CH 2 ) 0 - wherein Ar is phenyl, the sum of m and o is from 1 to 4, and wherein one CH 2 may be substituted with S or O in any structure shown above.
• A is -CH 2 -Ar-O-CH 2 - in any structure shown above.
• R is 2-hydroxyhydrocarbyl in any structure shown above.
• said inflammatory bowel disease is colitis.
• said inflammatory bowel disease is Crohn's disease.
• Triethylamine (15 ⁇ l_) and ethyl chloroformate (15 ⁇ l_) are added sequentially to a solution of compound 1 (10.5 mg) in CH 2 CI 2 (0.2 ml_) at room temperature. After 2.5 h, triethylamine (15 ⁇ l_) and ethylene glycol (200 ⁇ l_) are added. After stirring overnight at room temperature, the reaction mixture is partitioned between H 2 O (5 ml_) and CH 2 CI 2 (5 ml_). The phases are separated and the aqueous phase is extracted with CH 2 CI 2 (2x5 mL).
• Triethylamine (6.5 ⁇ l_) and ethyl chloroformate (7 ⁇ l_) are added sequentially to a solution of compound 1 (20 mg) in CH 2 CI 2 (0.47 mL) at room temperature. After 2.5 h, triethylamine (6.5 ⁇ L) and 4-(2-hydroxyethyl)- morphine (58 ⁇ L) are added. After stirring overnight at room temperature, the reaction mixture is partitioned between H 2 O (5 mL) and CH 2 CI 2 (5 mL). The phases are separated and the aqueous phase is extracted with CH 2 CI 2 (2x5 mL).
• HEK-293 cells stably expressing the human or feline FP receptor, or EPi, EP 2 , or EP 4 receptors are washed with TME buffer, scraped from the bottom of the flasks, and homogenized for 30 sec using a Brinkman PT 10/35 polytron.
• TME buffer is added to achieve a final 40 ml volume in the centrifuge tubes (the composition of TME is 100 mM TRIS base, 20 mM MgCI 2 , 2M EDTA; 10N HCI is added to achieve a pH of 7.4).
• the cell homogenate is centrifuged at 19000 r.p.m. for 20 min at 4° C using a Beckman Ti-60 rotor. The resultant pellet is resuspended in TME buffer to give a final 1 mg/ml protein concentration, as determined by Biorad assay.
• Radioligand binding competition assays vs. [ 3 H-]17 -phenyl PGF 20 (5 nM) are performed in a 100 ⁇ l volume for 60 min. Binding reactions are started by adding plasma membrane fraction. The reaction is terminated by the addition of 4 ml ice-cold TRIS-HCI buffer and rapid filtration through glass fiber GF/B filters using a Brandel cell harvester. The filters are washed 3 times with ice-cold buffer and oven dried for one hour. Non-specific binding is determined with 10 uM unlabeled 17 -phenyl PGF 20 -
• [00209] [ 3 H-] PGE 2 (5 nM; specific activity 180 Ci mmol) is used as the radioligand for EP receptors. Binding studies employing EP 1 , EP 2 , EP 31 EP 4 are performed in duplicate in at least three separate experiments. A 200 ⁇ l assay volume is used. Incubations are for 60 min at 25°C and are terminated by the addition of 4 ml of ice-cold 50 mM TRIS-HCI, followed by rapid filtration through Whatman GF/B filters and three additional 4 ml washes in a cell harvester (Brandel). Non-specific binding is determined with 10 "5 M of unlabeled PGE 2 ,.
• HEK-293(EBNA) cells stably expressing one type or subtype of recombinant human prostaglandin receptors (prostaglandin receptors expressed: hDP/Gqs5; JiEP 1 ; hEP 2 /Gqs5; hEP 3A /Gqi5; hEPVGqs ⁇ ; hFP; hlP; hTP), are cultured in 100 mm culture dishes in high-glucose DMEM medium containing 10% fetal bovine serum, 2 mM l-giutamine, 250 ⁇ g/ml geneticin (G418) and 200 ⁇ g/ml hygromycin B as selection markers, and 100 units/ml penicillin G, 100 Cg/ml streptomycin and 0.25 ⁇ g/ml amphotericin B.
• Cells are seeded at a density of 5x10 4 cells per well in Biocoat® Poly-D-lysine-coated black-wall, clear-bottom 96-well plates (Becton- Dickinson) and allowed to attach overnight in an incubator at 37 °C. Cells are then washed two times with HBSS-HEPES buffer (Hanks Balanced Salt Solution without bicarbonate and phenol red, 20 mM HEPES, pH 7.4) using a Denley Cellwash plate washer (Labsystems).
• HBSS-HEPES buffer Hanks Balanced Salt Solution without bicarbonate and phenol red, 20 mM HEPES, pH 7.4
• Cells are excited with an Argon laser at 488 nm, and emission is measured through a 510-570 nm bandwidth emission filter (FLIPRTM, Molecular Devices, Sunnyvale, CA). Drug solution is added in a 50 ⁇ l volume to each well to give the desired final concentration. The peak increase in fluorescence intensity is recorded for each well.
• FLIPRTM 510-570 nm bandwidth emission filter
• HBSS-HEPES buffer On each plate, four wells each serve as negative (HBSS-HEPES buffer) and positive controls (standard agonists: BW245C (hDP); PGE 2 (hEPi; hEP 2 /Gqs5; hEP 3A /Gqi5; hEP4/Gqs5); PGF 2 ⁇ (hFP); carbacyclin (hiP); U-46619 (hTP), depending on receptor).
• standard agonists BW245C (hDP); PGE 2 (hEPi; hEP 2 /Gqs5; hEP 3A /Gqi5; hEP4/Gqs5)
• PGF 2 ⁇ hFP
• carbacyclin hiP
• U-46619 hTP
• HTS high-throughput
• CoRe concentration-response

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