Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
  • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/04—Antipruritics

Definitions

• the present invention relates to compounds which are of use in the treatment and management of pruritis.
• Pruritis is a common symptom of many inflammatory skin diseases, notably psoriasis and atopic dermatitis. This symptom has historically been difficult to model. Recently, a behavioral model for peripherally evoked itch was published (Woodward et al., Characterization of a behavioral model for peripherally evoked itch suggests platelet-activating factor as a potent pruritogen. J. Pharmacol. Exp. Therap. 272:758- 765, 1995). This model has lead to additional modifications as will be shown herein. As little effective treatment for this condition exists, there remains a need for treatment, in this field, for compounds which are capable of anti-pruritic activity.
• This invention relates to the novel use of PDE4 inhibitors, preferably compounds of Formula (I) for the prophylaxis, treatment and management of pruritis in a mammal, including humans, in need of such treatment, which method comprises administering to such mammal, an effective amount of a compound of Formula (I).
• PDE4 inhibitors preferably compounds of Formula (I) for the prophylaxis, treatment and management of pruritis in a mammal, including humans, in need of such treatment, which method comprises administering to such mammal, an effective amount of a compound of Formula (I).
• the compounds of the present invention of Formula (I) are described herein.
• Figure I demonstrates the anti-pruritic activity of compound I. 1 ,3-di- cyclopropylmethyl-8-amino xanthine in an arachidonic acid induced pruritis model.
• PDE4 inhibitors as a class of compounds, regardless of structure possess anti-pruritis activity As pruritis is a key symptom of many different disease states, the use of PDE4 inhibitors in the managment of pruritic activity is of great value. While it is recognized that PDE4 compounds are of many different structural classes, they all share a common feature, inhibition of the PDE4 isoenzymes.
• PDE4 compounds for use herein include, but are not limited to, those desc ⁇ bed in WO 92/00968, PCT/US91/08229, WO 92/05175, WO 92/05176, WO 92/11260, WO 93/01014, PCT/US92/03613, WO 93/07111, PCT/US93/02045, WO 93/19748, WO 93/19750, WO 93/19751, WO 93/19747, WO 93/19749, WO 93/19720, WO 94/20079, WO 95/00139, WO 95/08581, WO 95/09308, WO 95/09623, WO 95/09836, WO 95/09624, WO 95/09837, WO 95/0
• CP 80633 is describ-sd in J.M. Hanifin et al. J. Invest. Dermatol. 107:51-56 (1996).
• the method of use does net include the compound CP80633.
• the compounds of Formula (I) may also be used in association with the vete ⁇ nary treatment of mammals, other than in humans, in need of such treatment for pruritis Treatment, may be therapeutically or prophylactically in animals
• Patent 5,734,05 1 are represented by the structure
• Rl and R 2 are each independently alkyl or a moiety of the formula -(CH 2 ) m -A, m is a number from 0 to 3, A is an unsubstituted or substituted cyclic hydrocarbon radical R3 is halogen, nitro, or -NR 4 R 5 ;
• R4 and R 5 are independently hydrogen, alkyl, alkylcarbonyl or together with the nitrogen to which they are attached forming an optionally substituted heterocyclic ring; and the pharmaceutically acceptable salts thereof.
• both Ri and R2 represent -(CH2) m -A.
• the A moiety represents a C 3 -8 cycloalkyl group, particularly a C3- 6 cycloalkyl and preferably unsubstituted. More preferably A is a cyclopropyl or cyclobutyl moiety.
• m is zero or one.
• Suitable optional substituent groups for any cyclic hydrocarbon include a Ci ⁇ alkyl moiety or halogen atom.
• a preferred group for Ri or R 2 is an alkyl group of 1 to 6 carbons, specifically methyl, ethyl, propyl or n-butyl. More preferred is n-butyl.
• R 3 is halogen
• the preferred substitution is bromine or chlorine
• R3 is -NR 4 R 5
• R 4 and R5 represent alkyl or alkylcarbonyl
• one of R4 or R 5 is hydrogen
• Suitable heterocyclic groups include saturated or unsaturated heterocylic groups having single or fused rings, each ring having 5 to 7 ring atoms which ring atoms optionally comprise up to two additional hetero atoms selected from 0, N, or S.
• Preferred heterocyclic groups include single rings comprising 5 to 7 ring atoms, more preferably 5 to 6 ring atoms,and most preferably 6 ring atoms
• Preferred heterocyclic groups are pyrrolidinyl, piperidinyl, or morpholinyl rings
• 1,3-d n-butyl-8-nitro xanthine 1,3-d •cyclopropylmethyl-8-nitro xanthine, 1,3-d cyclobutylmethyl-8-nitro xanthine; 1,3-d cyclopentylmethyl-8-nitro xanthine; 1,3-d cyclohexylmethyl-8-nitro xanthine, 1,3-d n-butyl-8-amino xanthine; 1,3-d -cyclopropylmethyl-8-amino xanthine, 1,3-d -cyclobutylmethyl-8-amino xanthine, 1,3-d -cyclopentylmethyl-8-amino xanthine; 1,3-d -cyclohexylmethyl-8-amino xanthine, 1,3-d: -cyclopropyl-8-amino xanthine; 1,3-d -n-butyl-8-acetamido
• the most preferred compound of Formula (I) for use in the method of this invention is l,3-di-cyclopropylmethyl-8-amino xanthine or a pharmaceutically acceptable salt thereof.
• alkyl groups as used herein alone or when used as part of another group (for example as in alkylcarbonyl) is meant to include both straight or branched chain radicals of 1 to 12 carbon atoms, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, tert-butyl, and the like.
• cyclic hydrocarbon unless specified otherwise, as used herein is meant a single ring or a fused rings of 3 to 8 carbon atoms. Cyclic hydrocarbons may comprise up to 8 carbons in each ring.
• cycloalkyl or “cycloalkyl alkyl” as used herein is meant to be interchangeable with the term “cyclic hydrocarbon”
• Cycloalkyl and cycloalkyl-alkyl groups are meant to include, but not limited to cyclopropyl, cyclopropyl-methyl, cyclopentyl or cyclohexyl.
• halo as used herein is meant all halogens, i.e.. chloro, fluoro, bromo and iodo.
• the compounds of Formula (I) or a pharmaceutically acceptable salt thereof can also be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by excessive or or unregulated pruritic activity.
• the compounds of Formula (I) may be used topically in the treatment or prophylaxis of topical disease states which have a pruritic component.
• the compounds of Formula (I) are disclosed in Maschler et al.. Great Britain Patent Application No. 8906792.0 filed on March 23, 1989, and US Patent 5,734,051 for the treatment of disorders associated with increased numbers of eosinophils, such as proliferative skin disease states, i.e. psoriasis, atopic dermatitis, non-specific dermititis, primary irritant contact dermatitis, allergic contact dermititis, or allergic disorders such as atopy, uticaria, eczema, rhinitis, serborrheic dermatitis, and mange in domestic animals.
• proliferative skin disease states i.e. psoriasis, atopic dermatitis, non-specific dermititis, primary irritant contact dermatitis, allergic contact dermititis, or allergic disorders such as atopy, uticaria, eczema, rhinitis, serborrheic dermatiti
• the compounds of Formula (I) are also disclosed in PCT/US91/08734, and PCT US93/01496 published as WO 93/06699 whose dislosures are incorporated herein by reference in its entirety, for the treatment of tumour necrosis mediated diseases.
• the compounds of Formula (I) may, be administered concurrently with another agents useful for the treatment or managment of pruritis, such as steroids.
• a monokine activity interfering agent required for therapeutic effect will, of course, vary with the agent chosen, the route of administration desired, the nature and severity of the disease, and the particular condition of the mammal, specifically human, undergoing treatment, and is ultimately at the discretion of the physician. It will also be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of the agent will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques.
• the optimal course of treatment i.e., the number of doses of the agent given per day for a defined number of days
• the compounds of Formula (I) may be administered orally (when active by this route), topically, parenterally or by inhalation in conventional dosage forms prepared by combining such agent with standard pharmaceutical earners according to conventional procedures in an amount sufficient to produce therapeutic activity
• the pharmaceutical earner employed can be readily determined by one of skill in the art who will recognize that such determination will depend upon vanous well- known factors such as the nature, quantity and character of the particular monokine activity mterfenng agent being employed and the form and route of administration desired
• the earners employed may be those desenbed elsewhere herein
• the pharmaceutical composition of the present invention will comprise an effective, non-toxic amount of a compound of Formula (I) and a pharmaceutically acceptable earner or diluent
• the compounds of Formula (I) are administered in conventional dosage forms prepared by combining a compound of Formula (I) in an amount sufficient to produce activity, respectively, with standard pharmaceutical earners according to conventional procedures These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropnate to the desired preparation
• the pharmaceutical earner employed may be, for example either a solid or liquid Exemplary of solid earners are lactose, terra alba, sucrose talc, gelatin, agar pectin, acacia, magnesium stearate, steanc acid and the like Exemplary of liquid earners are syrup, peanut oil, olive oil, polyethylene glycol, coconut oil, water and the like
• the earner or diluent may include time delay mate ⁇ al well known to the art such as glyceryl monostearate or glyceryl di
• compositions of Formula (I) and their pharmaceutically acceptable salts can be employed in a wide vanety of pharmaceutical forms
• the preparation of a pharmaceutically acceptable salt will be determined by the nature of the compound itself, and can be prepared by conventional techniques readily available to one skilled in the art
• a solid earner if a solid earner is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge
• the amount of solid earner will vary widely but preferably will be from about 25 mg to about 1 gram
• the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, stenle injectable liquid such as an ampule or nonaqueous liquid suspension
• any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
• composition is in the form of a soft gelatin shell capsule
• any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell
• a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, polyethylene glycol, coconut oil, glycerine or water with a flavouring or colouring agent.
• the amount of a compound of Formula (I) required for therapeutic effect on topical administration will, of course, vary with the compound chosen, the nature and severity of the inflammatory condition and the animal undergoing treatment, and is ultimately at the discretion of the physician.
• parenteral' as used herein includes intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration
• the subcutaneous and intramuscular forms of parenteral administration are generally preferred. Appropriate dosage forms for such administration may be prepared by conventional techniques.
• Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyviny'pyrrolido ⁇ c, lecithin, arachis oil, or sesame oil
• a parenterally acceptable oil for example polyethylene glycol, polyviny'pyrrolido ⁇ c, lecithin, arachis oil, or sesame oil
• the daily dosage regimen for parenteral administration is suitably about 0 001 mg/Kg to 40 mg/Kg, preferably about 0 01 mg/Kg to 20 mg/Kg, of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base
• the compounds of Formula (I) may be administered orally
• the daily dosage regimen for oral administration is suitably about 1 mg/kg to 1 OOOmg day
• the dosage is suitably about 001 mg/kg to 40mg/kg, preferably about 0 01 to 20 mg/Kg of a compound of formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base
• the active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit activity
• the compounds of Formula (I) may also be administered by inhalation
• inhalation is meant intranasal and oral inhalation administration
• Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
• the daily dosage regimen for inhalation administration is suitably about 001 mg/kg to 40mg/kg, preferably 0 01 to 20 mg/Kg of a compound of formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base
• Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or t ⁇ chlorofluoromethane
• the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to himself a single dose
• the compounds of Formula (I) may also be administered topically
• Bv topical administration is meant non-systemic administration and includes the application of a
• systemic administration oral, intravenous, intrapentoneal and intramuscular administration
• the active ingredient may compnse, for topical administration, from 0 001% to 10% w/w e g from 1% to 2% by weight of the formulation although it may compnse as m u ch as 10% w/w but preferably not in excess of 5% w/w and more preferably from 0 1% to 1% w/w of the formulation
• the topical formulations of the present invention comprise an active ingredient together with one or more acceptable carner(s) therefor and optionally any other therapeutic ⁇ ngred ⁇ ent(s)
• the car ⁇ er(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deletenous to the recipient thereof
• Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose
• Drops according to the present invention may comprise ste ⁇ le aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactencidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent
• the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and ste ⁇ lized by autoclaving or maintaining at 98-100°C for half an hour
• the solution may be sten zed by filtration and transfened to the container by an aseptic technique
• bactencidal and fungicidal agents suitable for inclusion in the drops are phenylmercu ⁇ c nitrate or acetate (0 002%), benzalkonium chlonde (0 01%) and chlorhexidme acetate (0 01%)
• Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol
• Lotions according to the present invention include those suitable for application to the skin or eye
• An eye lotion may compnse a stenle aqueous solution optionally containing a bactencide and may be prepared by methods similar to those for the preparation of drops
• Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moistu ⁇ zer such as glycerol or an oil such as castor oil or arachis oil
• Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application
• Thev may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery with a greasy or non-greasy basis
• the basis may compnse hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap, a mucilage, an oil of natural o ⁇ gm such as almond, corn, arachis, castor or olive oil, wool fat or its denvatives, or a fatty acid such as stenc or oleic acid together with an alcohol such as propylene glycol or macrogols
• the formulation may incorporate any suitable surface active agent such as an anionic, catiomc or non-ionic surfactants such as sorbitan esters or polyoxyethylene denvatives thereof Suspending agents
• the form and character of the pharmaceutically acceptable earner or diluent is dictated by the amount of active ingredient, a compound of Formula (I), with which it is to be combined, the route of administration and other well-known vanables
• the optimal quantity and spacing of individual dosages of a compound of Formula (I) or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration and the particular patient being treated, and that such optimums can be determined by conventional techniques
• the optimal course of treatment 1 e the number of doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
• Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of liquid formulations are given below.
• a solution containing a compound of Formula (I) is prepared by dissolving the compound in water, or other suitable carrier, with or without a preservative, such as benzoic acid, to deliver the desired amount of drug per use
• the compound is present in an amount from about lO ⁇ g to about 30 ⁇ g/ per ml of carrier
• a solution containing a compound of Formula (I) is prepared by dissolving the compound in an amount from about 1 to about lOmg per ml of PEG 400 with or without BHA/BHT preservatives
• the solution can alternatively be filled into a soft gelatin capsule to prepare a solid oral dosage form or used as a syrup
• a solid dosage form containing a compound of Formula (I), such as 1,3-di- cyclopropylmethyl-8-amino xanthine has been prepared by mixing 50mg of the compound with various concentration (mg) of mannitol, hydroxypropylmethylcellulose, calipharm, Starch 1500, and magnesium sterate (as a lubricant), to fill capsules of an appropriate size or the composition may, if desired, be compressed into tablets
• a compound of Formula (I) such as 1,3-di- cyclopropylmethyl-8-amino xanthine
• the mouse model takes advantage of the cutaneous inflammatory response to arachidonic acid which is preceeded by scratching and rubbing behavior indicative of pruritis.
• mice were administered a topical dose of arachidonic acid (2 mg/ear) in 20 ul cold acetone to the left ear.
• the treated mice were then placed individually into 4L beakers. After a 2 min accommodation period, the episodes of scratching and head shaking were counted over a 10 min period.
• the data were analysed by calculating the mean and standard error. A statistical difference in the mean values was determined using Student's t-test.
• the biochemical pharmacology of the inflammatory response to arachidonic acid has implicated mast cell degranulation and eicosanoid inflammatory mediator release (e.g. leukotrienes and prostanoids). Tachykinins and platelet activating factor may also be involved in this response.
• PDE4 phosphodiesterase type 4
• BRL 61063 is the same as Compound I.

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• 1998
  • 1998-10-15 AR ARP980105131A patent/AR015966A1/es not_active Application Discontinuation
  • 1998-10-16 CN CN98810066A patent/CN1306426A/zh active Pending
  • 1998-10-16 BR BR9814080-9A patent/BR9814080A/pt not_active IP Right Cessation
  • 1998-10-16 KR KR1020007004053A patent/KR20010031149A/ko not_active Application Discontinuation
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  • 1998-10-16 JP JP2000516677A patent/JP2001520196A/ja not_active Withdrawn
  • 1998-10-16 HU HU0003792A patent/HUP0003792A3/hu unknown
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