Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • 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
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
  • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
  • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

• the present invention relates to indane amide derivatives, processes for their preparation and their use in treating NK 3 mediated disease states.
• the mammalian peptide Neurokinin B belongs to the Tachykinin (TK) peptide family which also include Substance P (SP) and Neurokinin A (NKA).
• TK Tachykinin
• SP Substance P
• NKB Neurokinin A
• NK 3 receptor antagonists are known (Drapeau, 1990 Regul. Pept., 31, 125-135), and findings with peptidic NK 3 receptor agonists suggest that NKB, by activating the NK 3 receptor, has a key role in the modulation of neural input in airways, skin, spinal cord and nigro-striatal pathways (Myers and Undem, 1993, J. Phisiol., 470, 665-679; Counture et al., 1993, Regul. Peptides, 46, 426-429; Mccarson and Krause, 1994, J. Neurosci., 14 (2), 712-720; Arenas et al., 1991, J. Neurosci., 11, 2332-8).
• NK 3 antagonists which are far more stable from a metabolic point of view than the known peptidic NK 3 receptor antagonists and are of potential therapeutic utility in treating pulmonary disorders (asthma, chronic obstructive pulmonary diseases -COPD-, airway hyperreactivity, cough), skin disorders and itch (for example, atopic dermatitis and cutaneous wheal and flare), neurogenic inflammation and CNS disorders (Parkinson's disease, movement disorders, anxiety).
• the present invention is to a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein
• (R 1 ) a is independently hydrogen, lower alkyl, halo-substituted alkyl, alkenyl, alkoxy, halogen, hydroxy, optionally substituted aryl, cycloalkyl, cycloalkenyl, O-CH 2 -COOR, -COOR, -C(O)N(R'R") or SO 2 N(R'R"), -S(O) n -alkyl or -S(O) n -aryl, wherein n is 0, 1 or 2 and a is 1 to 3 and wherein R, R' and R" are independently, hydrogen or lower alkyl;
• R 2 and R 3 are independently hydrogen, lower alkyl, halo-substituted alkyl, alkenyl, alkoxy, halogen, hydroxy, optionally substituted aryl, cycloalkyl, cycloalkenyl, -O-CH 2 -COOR, COOR, -C(O)N(R'R") or SO 2 N(R'R"), -S(O) n -alkyl or -S(O) n -aryl, wherein n is 0, 1 or 2, and wherein R, R' and R" are independently, hydrogen or lower alkyl or, together R 2 and R 3 form a -O-(C ⁇ 2 ) r -O- moiety, wherein r is 1-3, or, together with the carbons to which they are bound, form a 5-, 6- or 7-membered ring;
• R 4 and R 5 are independently hydrogen, lower alkyl, halo-substituted alkyl, alkenyl, alkoxy, halogen, hydroxy, optionally substituted aryl, cycloalkyl, cycloalkenyl, -O-CH 2 -COOR, COOR, -C(O)N(R'R") or SO 2 N(R'R"), -S(O) n -alkyl or -S(O) n -aryl, wherein n is 0, 1 or 2, and wherein R, R' and R" are independently, hydrogen or lower alkyl or, together R 4 and R 5 form a -O-(CH 2 ) r -O" moiety, wherein r is 1-3, or, together with the carbons to which they are bound, R 4 and R 5 form a 5-, 6- or 7-membered ring;
• R 6 and R 7 are independently hydrogen, -C(O)-optionally substituted aryl, -
• R 8 and R 9 are independently hydrogen, -C(O)-optionally substituted aryl, - SO 2 -optionally substituted aryl, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted alkenyl, or, R 8 and R 9 , together with the nitrogen to which they are bound, form a 5-, 6-, or 7-membered ring; or, R 6 and R 7 , together with the nitrogen to which they are bound, form a 5-, 6-, or 7-membered ring; and
• the present invention is to a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
• the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as an active therapeutic substance.
• the activity of the compounds of formula (I) as NK 3 antagonists in standard tests indicates that they are of potential therapeutic utility in the treatment of pulmonary disorders (asthma, COPD, airway hyperreactivity, cough), skin disorders and itch (atopic dermatitis, cutaneous wheal and flare), neurogenic inflammation and CNS disorders (Parkinsons disease, movement disorders, anxiety) (hereinafter referred to as the 'Conditions'). Therefore, in yet another aspect, the present invention is to a method for treating NK 3 -mediated disease states in mammals, preferably humans, comprising administering to said mammal in need thereof, an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
• lower alkyl or “alkyl” are used herein at all occurrences to mean a straight or branched chain radical of 1 to 6 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.
• alkenyl is used herein at all occurrences to mean a straight or branched chain radical of 2-6 carbon atoms, unless the chain length is limited thereto, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl, and the like.
• alkoxy is used herein at all occurrences to mean a straight or branched chain radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n- propoxy, isopropoxy, and the like.
• halo-substituted alkyl is used herein at all occurrences to mean an alkyl moiety as defined above which has one or more halogen atoms substituted on the alkyl chain, including, but not limited to trifluoromethyl (CF 3 ).
• aryl or “heteroaryl” are used herein at all occurrences to mean a 5-14-membered optionally substituted aromatic ring(s) or ring systems which may include bi- or tri-cyclic systems and, wherein one or more heteroatoms are selected from oxygen, nitrogen or sulfur.
• Representative examples include, but are not limited to, phenyl, naphthyl, pyridyl, quinolinyl, thiazinyl, isoquinoline, imidazole, pyrimidine, oxazole, thiadiazole, triazole, benzimidazole, furanyl, and the like.
• heteroatom is used herein at all occurrences to mean an oxygen atom, a sulfur atom or a nitrogen atom.
• R 1 and R 2 are optionally bound to the nitrogen, wherein R 1 and R 2 are independently, hydrogen, lower alkyl, or together with the nitrogen to which they are bound, form saturated or unsaturated 5-, 6-, or 7-membered ring.
• 5-, 6- or 7-membered ring is used herein at all occurrences to mean that the substituents, together with the nitrogen or carbons to which they are bound, form a saturated or unsaturated cyclic ring structure optionally containing at least one heteroatom selected from oxygen, nitrogen or sulfur, including, but not limited to morpholine, piperizine, piperidine, pyrrolidine, pyridine, cyclohexyl, cyclopentyl, and the like.
• arylalkyl and heteroarylalkyl are used herein at all occurrences to mean an aryl or heteroaryl moiety, respectively, that is connected to core molecular structure by a C 1-6 alkyl moiety as defined above, such as a benzyl or a phenethyl group.
• halogen is used herein at all occurrences to mean chloro, fluoro, iodo and bromo.
• Optional substituents include, but are not limited to, alkyl; halo-substituted alkyl; alkenyl; alkynyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; halogen; NO 2 ; - OR b ; -SR b ; -N(R b ) 2 ; -NHC(O)R b ; -CO 2 R 15 or -CON(R b ) 2 , wherein R b is hydrogen, (C 1 - C 4 ) alkyl, aryl, including, but not limited to, phenyl, arylalkyl, including, but not limited to benzyl, 7
• optional substituents for use herein include alkyl, preferably, C 1 to C 4 alkyl, alkoxy, preferably methoxy and ethoxy, NO 2 , halogen, aryl, preferably phenyl and arylalkyl, preferably benzyl.
• alkyl preferably, C 1 to C 4 alkyl
• alkoxy preferably methoxy and ethoxy
• NO 2 halogen
• aryl preferably phenyl and arylalkyl, preferably benzyl.
• optionally substituted lower alkyl optionally substituted alkenyl
• optionally substituted arylalkyl optionally substituted
• heteroarylalkyl referred to in the definition of R 6 and R 7
• suitable optional substituents on the aliphatic (alkyl) or olefinic (alkenyl) moieties include, but are not limited to one or more of the following moieties: alkoxy; hydroxy; optionally substituted aryl, preferably optionally substituted phenyl; COOR wherein R is hydrogen or lower alkyl; -NR 6 R 7 or -SO 2 NR 6 R 7 , wherein R 6 and R 7 are as defined above; acylsulfonamide (e.g., -C(O)NH-SO 2 -alkyl); and aroylsulfonamide (e.g., -C(O)NH-SO 2 -aryl).
• Suitable optional substituents on the aryl or heteroaryl portion are one or more of the following moieties: hydrogen; lower alkyl; halo-substituted alkyl; alkenyl; alkoxy; -O-(CH 2 )r-O, wherein r is 1 to 3; halogen; hydroxy; optionally substituted aryl; cycloalkyl; cycloalkenyl; -COOR; -C(O)N(R"R"); -SO 2 N(R'R "); -S(O) n -alkyl or -S(O) n -aryl, wherein n is 0, 1 or 2 and wherein R, R' and R" are independently, hydrogen or lower alkyl; NO 2 ; aroylamido (e.g., -NH-C(O)-aryl); and acylamido (e.g., -NH-C(O)-alkyl).
• aroylamido
• cycloalkyl is used herein at all occurrences to mean cyclic radicals, preferably of 3 to 7 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
• cycloalkenyl is used herein at all occurrences to mean cyclic radicals, preferably of 3 to 7 carbons having olefinic character, i.e., one or more double bonds, including but not limited to cyclopropenyl, cyclopentenyl, cyclohexenyl, and the like.
• salts include, but are not limited to, salts with inorganic acids such as hydrochloric, sulfate, phosphate, diphosphate, hydrobromide, and nitrate or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methansulfonate, p-toluenesulfonate, palmitate, salicylate and stearate.
• inorganic acids such as hydrochloric, sulfate, phosphate, diphosphate, hydrobromide, and nitrate
• organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methansulfonate, p-toluenesulfonate, palmitate, salicylate and stearate.
• R 1 ) a is suitably, independently hydrogen, lower alkyl, halo-substituted alkyl, alkenyl, alkoxy, halogen, hydroxy, optionally substituted aryl, cycloalkyl, cycloalkenyl, O-CH 2 -COOR, -COOR, -C(O)N(R'R") or SO2N(R'R"), -S(O) n -alkyl or -S(O) n -aryl, wherein n is 0, 1 or 2 and a is 1 to 3 and wherein R, R' and R" are independently, hydrogen or lower alkyl.
• R 1 represents one to three various, independently chosen substituents that may be on the core indane aromatic ring.
• R 1 is preferably hydrogen or hydroxy, more preferably, hydrogen.
• R 2 and R 3 are suitably, independently hydrogen, lower alkyl, halo- substituted alkyl, alkenyl, alkoxy, halogen, hydroxy, optionally substituted aryl, cycloalkyl, cycloalkenyl, -O-CH 2 -COOR, -COOR, -C(O)N(R'R") or SO 2 N(R'R"), S(O) n -alkyl or -S(O) n -aryl, wherein n is 0, 1 or 2, and wherein R, R' and R" are independently, hydrogen or lower alkyl; or, together R 2 and R 3 form a -O-(CH 2 ) r O- moiety, wherein r is 1-3; or, together with the carbons to which they are bound, form a 5-, 6- or 7-membered ring.
• R 2 and R 3 are preferably alkoxy or, together they form a -O-(CH 2 ) r -O- moiety, wherein r is 1-3.
• R 2 and R 3 are more preferabl methoxy, ethoxy, or, together they form a -O-(CH 2 ) r -O- moiety, wherein r is 1.
• R and R 3 most preferably together form a methylenedioxy moiety, i.e., a -O-(CH 2 ) r -O- moiety, wherein r is 1.
• R 4 and R 5 are suitably, independently hydrogen, lower alkyl, halo-substituted alkyl, alkenyl, alkoxy, halogen, hydroxy, optionally substituted aryl, cycloalkyl, cycloalkenyl, -O-CH 2 -COOR, -COOR, -C(O)N(R"R") or SO 2 N(R'R"),-S(O) n -alkyl or -S(O) n -aryl, wherein n is 0, 1 or 2, and wherein R, R' and R" are independently, hydrogen or lower alkyl; or, together R 4 and R 5 form a -O-(CH 2 ) r -O- moiety, wherein r is 1-3; or, together with the carbons to which they are bound, R 4 and R 5 form a 5-, 6- or 7-membered ring.
• R 4 and R 5 are preferably alkoxy or, together they form a -O-(CH 2 ) r - O- moiety, wherein r is 1-3.
• R 4 and R 5 are more preferably methoxy, ethoxy or, together they form a -O-(CH 2 ) r -O- moiety, wherein r is 1.
• R 4 and R 5 most preferably together form a methylenedioxy moiety, i.e., a - O-(CH 2 ) r -O- moiety, wherein r is 1.
• R 6 and R 7 are suitably, independently hydrogen, -C(O)-optionally substituted aryl, -SO 2 -optionally substituted aryl, optionally substituted lower alky optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted alkenyl, or NR 8 R 9 , wherein R 8 and R 9 are independently hydrogen, -C(O)-optionally substituted aryl, -SO 2 -optionally substituted aryl, optionally substituted lower alky optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted alkenyl, or, R 8 and R 9 , together with the nitrogen to which they are bound, form a 5-, 6-, or 7- membered ring; or, R 6 and R 7 , together with the nitrogen to which they are bound, form a
• R 6 and R 7 are preferably, independently hydrogen; optionally substituted alkyl, wherein the optional substituents on the alkyl portion are alkoxy, hydroxy, optionally substituted aryl, COOR wherein R is hydrogen or lower alkyl, -NR 6 R 7 or -SO 2 NR 6 R 7 , wherein R 6 and R 7 are as defined above, acylsulfonamide, and aroylsulfonamide, [preferably the optional substituents on the alkyl portion are optionally substituted phenyl and COOR, wherein R is hydrogen, methyl or ethyl, preferably R is hydrogen or methyl];
• optionally substituted arylalkyl wherein the optional substituents on the aryl portion are hydrogen, lower alkyl, alkenyl, alkoxy, halogen, hydroxy, optionally substituted aryl, optionally substituted heteroaryl, cycloalkyl, cycloalkenyl, -COOR, - C(O)N(R'R") or SO 2 NCR'R”), wherein R, R' and R" are independently, hydrogen or lower alkyl, -S(O) n -alkyl or -S(O) n -aryl, wherein n is 0, 1 or 2, NO 2 , aroylamido and acylamido, [preferably the optional substituents on the aryl portion are NO 2 , methylenedioxy, or alkoxy; or, together with the nitrogen to which they are bound, R 6 and R 7 form a 5-, 6- or 7-membered ring, preferably a pyrrolidino or a piperazino
• NK 3 antagonists are of potential therapeutic utility in the treatment of pulmonary disorders (asthma, COPD, airway hyperreactivity, cough), skin disorder and itch (atopic dermatitis, cutaneous wheal and flare), neurogenic inflammation and CNS disorders (Parkinsons disease, movement disorders, anxiety) (hereinafter referred to as the 'Conditions') in mammals, preferably human. Therefore, the present invention provides a method for treating NK 3 -mediated disease states comprising administering to a mammal in need thereof, an effective amount of an NK 3 receptor antagonist compound of formula (I).
• the present invention provides a method for antagonizing the NK 3 receptor comprising administering to a mammal in need thereof, an effective amount of an NK 3 receptor antagonist compound of formula (I).
• the mammal is a human.
• the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as an active therapeutic substance.
• the present invention further provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• the present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of the conditions.
• Such a medicament, and a composition of this invention may be prepared by admixture of a compound of the invention with an appropriate carrier. It may contain a diluent, binder, filler, disintegrant, flavoring agent, coloring agent, lubricant or preservative in conventional manner.
• a pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields.
• preparations may be in a pack form accompanied by written or printed instructions for use as an agent in the treatment of the conditions.
• the suitable dosage range for the compounds of the invention depends on the compound to be employed and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to absorbability and the frequency and route of administration.
• the compound or composition of the invention may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage.
• the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may be designed to give slow release of the active ingredient
• the pharmaceutical carrier employed may be, for example, either a solid or liquid.
• solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
• liquid carriers are syrup, peanut oil, olive oil, water and the like.
• the carrier or diluent may include time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
• 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 carrier will vary widely but preferably will be from about 25 mg. to about 1000 mg.
• the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
• the compounds of formula (I) may also be administered topically to a mammal in need of treatment for NK 3 -mediated disease states.
• the compounds of formula (I) may be administered topically in the treatment or prophylaxis of NK 3 -mediated disease states, including, but not limited to the above-mentioned conditions.
• the amount of a compound of formula (I) (hereinafter referred to as the active ingredient) required for therapeutic effect on topical administration will, of course, vary with the compound chosen, the nature and severity of the disease state being treated and the mammal undergoing treatment, and is ultimately at the discretion of the physician.
• a suitable dose of an active ingredient is 1.5 mg to 500 mg for topical administration, the most preferred dosage being 1 mg to 100 mg, for example 5 to 25 mg administered two or three times daily.
• topical administration non-systemic administration and includes the application of a compound of formula (I) externally to the epidermis, to the buccal cavity and instillation of such a compound into the ear, eye and nose, and where the compound does not significantly enter the blood stream.
• systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration.
• an active ingredient may be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation.
• the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e.g. from 1% to 2% by weight of the formulation although it may comprise as much 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.
• topical formulations of the present invention both for veterinary and for human medical use, comprise an active ingredient together with one or more acceptable carriers) therefor and optionally any other therapeutic ingredient(s).
• the carriers) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious 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 sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous or alcoholic solution of a bactericidal 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 sterilized by autoclaving or maintaining at 98- 100°C for half an hour.
• the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
• bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine 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 comprise a sterile aqueous solution optionally containing a bactericide 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 moisturizer 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. They 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 comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, com, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol.
• the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof.
• suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof.
• Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
• 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 amount of a compound of formula (I) administered by inhalation is from about 0.1 mg to about 100 mg per day, preferably about 1 mg to about 10 mg per day.
• this invention relates to a method of treating NK 3 -mediated disease states such as pulmonary disorders (asthma, COPD, airway hyperreactivity, cough), skin disorders and itch (atopic dermatitis, cutaneous wheal and flare), neurogenic inflammation and CNS disorders (Parkinsons disease, movement disorders, anxiety).
• pulmonary disorders asthma, COPD, airway hyperreactivity, cough
• skin disorders and itch atopic dermatitis, cutaneous wheal and flare
• neurogenic inflammation and CNS disorders Parkinsoninsons disease, movement disorders, anxiety.
• formula (I) compound can be administered to such mammal in a conventional dosage form prepared by combining the formula (I) compound with a conventional pharmaceutically acceptable carrier or diluent according to known techniques. It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.
• the formula (I) compound is administered to a mammal in need of treatment for pulmonary disorders (asthma, COPD, airway hyperreactivity, cough), skin disorders and itch (atopic dermatitis, cutaneous wheal and flare), neurogenic inflammation and CNS disorders (Parkinsons disease, movement disorders, anxiety), in an amount sufficient to decrease symptoms associated with these disease states.
• pulmonary disorders asthma, COPD, airway hyperreactivity, cough
• skin disorders and itch atopic dermatitis, cutaneous wheal and flare
• neurogenic inflammation and CNS disorders Parkinsoninsons disease, movement disorders, anxiety
• the route of administration may be oral or parenteral.
• parenteral as used herein includes intravenous, intramuscular, subcutaneous, intra-rectal, intravaginal or iniraperitoneal administration.
• the subcutaneous and intramuscular forms of parenteral administration are generally preferred.
• the daily parenteral dosage regimen will preferably be from about 30 mg to about 300 mg per day of active ingredient [i.e., the compound of formula (I)].
• the daily oral dosage regimen will preferably be from about 100 mg to about 2000 mg per day of active ingredient
• the optimal quantity and spacing of individual dosages of a formula (I) compound will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of the formula (I) compound 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.
• the compounds of this invention are prepared by treating the carboxylic acid 1 (for a preparation of appropriate carboxylic acids see PCT/US92/09427, published May 13, 1993 as WO 93/08799) with, for example, thionyl chloride to obtain the acid chloride 2. This is treated with either an excess of a commercially available or conventionally made amine or a mixture of an amine and another base such as a tertiary amine to give the final product of formula (I). It will be recognized that a variety of indanecarboxylic acids and a variety of amines may be used to give many different indaneamides of formula (I).
• indaneamides disclosed herein may be prepared by other conventional methods for making amides, including mixed anhydride synthesis and dicyclohexylcarbcdiimide mediated process, and others as disclosed in Larock, Comprehensive Organic
• Example 1(a) The compound of Example 1(a) was dissolved in Et 2 O (5mL) and rapidly stirred at room temperature (hereinafter "RT”). A solution of 40% methylamine in water (3mL) was added dropwise. After the addition was completed, the mixture was stirred for 2h. The precipitated product was collected by filtration, washed with water (5 mL), then with Et 2 O (5 mL). After drying, the title compound (0.054g, 72%) was obtained as a white solid. Melting point (hereinafter "mp") 189-190°C.
• Example 3 Following the procedures of Example 1 and Example 2, except using the appropriate indanecarboxylic acid and the appropriate amine in the place of those used in Example 3, the following were prepared:
• the present invention also provides a method for the treatment and/or prophylaxis of the Conditions in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
• NK 3 ligands The activity of the compounds of me present invention, as NK 3 ligands, is determined by their ability to inhibit the binding of the radiolabelled NK 3 ligands, [ 125 I]-[Me-Phe 7 ]-NKB or [ 3 H]-Senktide, to guinea-pig and human NK 3 receptors (Renzetti et al, 1991, Neuropeptide, 18, 104-114; Buell et al, 1992, FEBS, 299(1), 90-95; Chung et al, 1994, Biochem. Biophys. Res. Commun., 198(3), 967-972).
• the binding assays utilized allow the determination of the concentration of the individual compound required to reduce by 50% the [ 125 I]-[Me-Phe 7 ]-NKB and [ 3 H]-Senktide specific binding to NK 3 receptor in equilibrium conditions.
• Binding assays provide for each compounds tested means of IC 50 values of 2-5 separate experiments performed in triplicate or in quadruplicate.
• the most potent compounds of me present invention show IC 50 values in the range up to 10 micromolar.
• the NK 3 -antagonist activity of the compounds of the present invention is determined by tiieir ability to inhibit Senktide induced contraction of the guinea-pig ileum (Maggi et al, 1990, Br. J. Pharmacol., 101, 996-1000) and human NK 3 receptors-mediated Ca ++ mobilization (Mochizuki et al, 1994, J. Biol. Chem., 269, 9651-9658).
• Guinea-pig functional assay provide for each compound tested means of Kg values of 3-8 separate experiments, where Kg is the concentration of the individual compound required to produce a 2-fold rightward shift in the dose-response curve of Senktide.
• Human receptor functional assay allows the
• the therapeutic potential of the compounds of the present invention in treating the conditions can be assessed using rodent disease models.

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• 1995
  • 1995-10-13 JP JP8520428A patent/JPH10512855A/ja active Pending
  • 1995-10-13 EP EP95938210A patent/EP0799225A4/en not_active Withdrawn
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