COMPOUNDS AND METHODS

Abstract: The present invention relates to indane amide derivatives, processes for their preparation and their use in treating NK3 mediated disease states.

Description: COMPOUNDS AND METHODS ΠEU> 9F Tffl? PWENTΪON; The present invention relates to indane amide derivatives, processes for their preparation and their use in treating NK3 mediated disease states. BACKGROUND OF THE INVENTION: The mammalian peptide Neurokinin B (NKB) belongs to the Tachykinin (TK) peptide family which also include Substance P (SP) and Neurokinin A (NKA). Pharmacological and molecular biological evidence has shown the existence of three subtypes of TK receptor (NKj, NK2 and NK3) and NKB binds preferentially to the NK3 receptor although it also recognizes the other two receptors with lower affinity (Maggi et al., 1993, J. Auton. Pharmacol., 13, 23-93). Selective peptidic NK3 receptor antagonists are known (Drapeau, 1990 Regul. Pept., 31, 125-135), and findings with peptidic NK3 receptor agonists suggest that NKB, by activating the NK3 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). However, the peptide-like nature of the known antagonists makes them likely to be too labile from a metabolic point of view to serve as practical therapeutic agents. We have now discovered a class of selective, non-peptide NK3 antagonists which are far more stable from a metabolic point of view than the known peptidic NK3 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). SUMMARY OF THE INVENTION: In one aspect, the present invention is to a compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula (I) wherein (Rl) a is independently hydrogen, lower alkyl, halo-substituted alkyl, alkenyl, alkoxy, halogen, hydroxy, optionally substituted aryl, cycloalkyl, cycloalkenyl, O-CH2-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 1 and R" are independently, hydrogen or lower alkyl; R2 and R^ 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 SC^NCRTl"), -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^ and R^ form a -0-( Α2)f-0- moiety, wherein r is 1-3, or, together with the carbons to which they are bound, form a 5-, 6- or 7-membered ring; R4 and R^ 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 SC^S 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^ and R^ form a -O-(CH2) O" moiety, wherein r is 1-3, or, together with the carbons to which they are bound, R^ and R^ form a 5-, 6- or 7-membered ring; R6 and R^ are independently hydrogen, -C(O)-optionally substituted aryl, - Sθ2-optionally substituted aryl, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted alkenyl, or NR8R9, wherein R^ and R^ are independently hydrogen, -C(O)-optionally substituted aryl, - SO2-optionally substituted aryl, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted alkenyl, or, R& and R^, together with the nitrogen to which they are bound, form a 5-, 6-, or 7-membered ring; or, R° and R 7 , together with the nitrogen to which they are bound, form a 5-, 6-, or 7-membered ring; and m is 0 to 3; provided that R*> and R? are not each hydrogen when m is 0. In another aspect, the present invention is to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. In still another aspect, 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 NK3 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 NK3-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. DETADLED DESCRIPTION OF THE INVENTION: The terms "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. The term "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. The term "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. The term "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 (CF3). The terms "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. The term "heteroatom" is used herein at all occurrences to mean an oxygen atom, a sulfur atom or a nitrogen atom. When the heteroatom is nitrogen, 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. The term "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. The terms "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 Cι_ $ alkyl moiety as defined above, such as a benzyl or a phenethyl group. The term "halogen" is used herein at all occurrences to mean chloro, fluoro, iodo and bromo. The term "optionally substituted" is used herein at all occurrences to mean that the moieties may or may not be substituted with one to three various functional groups. Optional substituents include, but are not limited to, alkyl; halo-substituted alkyl; alkenyl; alkynyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; halogen; NO2; - OR D ; -SR D ; -N(R b ) 2 ; -NHC(O)R b ; -CC^R 15 or -CON(R* ) 2 , wherein R° is hydrogen, (C\ - C4) alkyl, aryl, including, but not limited to, phenyl, arylalkyl, including, but not limited to benzyl, 7 or heteroaryl. Preferred optional substituents for use herein include alkyl, preferably, C j to C4 alkyl, alkoxy, preferably methoxy and ethoxy, O2, halogen, aryl, preferably phenyl and arylalkyl, preferably benzyl. For the terms "optionally substituted lower alkyl", "optionally substituted alkenyl", "optionally substituted arylalkyl" and "optionally substituted heteroarylalkyl" referred to in the definition of R*> and R 7 , suitable optional substituents on the aliphatic (alkyl) or olefύiic (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 -SC NR O R 7 , wherein R 6 and R 7 are as defined above; acylsulfonamide (e.g., -C(O)NH-Sθ2-alkyl); and aroylsulfonamide (e.g., -C(O)NH-Sθ2-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; -0-(CU2 , wherein r is 1 to 3; halogen; hydroxy; optionally substituted aryl; cycloalkyl; cycloalkenyl; -COOR; -C(O)N(R"R"); -SC^NCRTT); - 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; NO2- aroylamido (e.g., -NH-C(O)-aryl); and acylamido (e.g., -NH-C(O)-alkyl). The term "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. The term "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. As will be understood by those skilled in the art, pharmaceutically acceptable 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. For the compounds of formula (I) various embodiments are as follows. (R*) a is suitably, independently hydrogen, lower alkyl, halo-substituted alkyl, alkenyl, alkoxy, halogen, hydroxy, optionally substituted aryl, cycloalkyl, cycloalkenyl, O-CH -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. It will be recognized that R* 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^ are suitably, independently hydrogen, lower alkyl, halo- substituted alkyl, alkenyl, alkoxy, halogen, hydroxy, optionally substituted aryl, cycloalkyl, cycloalkenyl, -O-CH 2 -COOR, -COOR, -C^NCRTl") or SC^NCRTT), 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^ and R^ form a -O-(CH2 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^ and R^ are preferably alkoxy or, together they form a -O-(CH2)r-0" moiety, wherein r is 1-3. R^ and R^ are more preferabl methoxy, ethoxy, or, together they form a -O-(CH2) r -0- moiety, wherein r is 1. R and R3 most preferably together form a methylenedioxy moiety, i.e., a -O-(CH2) O- moiety, wherein r is 1. R and R^ 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 SC^ 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* and R^ form a -O- CH2 r O- moiety, wherein r is 1-3; or, together with the carbons to which they are bound, R* and R5 form a 5-, 6- or 7-membered ring. R^ and R^ are preferably alkoxy or, together they form a -O-(CH2 rO* moiety, wherein r is 1-3. R^ and R^ are more preferably methoxy, ethoxy or, together they form a -O- CH2 ι-0- moiety, wherei r is 1. R and R^ most preferably together form a methylenedioxy moiety, i.e., a - O-(CH2)r-0~ moiety, wherein r is 1. R6 and R 7 are suitably, independently hydrogen, -C(O)-optionally substituted aryl, -SO2-optionally substituted aryl, optionally substituted lower alky optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted alkenyl, or N 8R9, wherein R& and R^ are independently hydrogen, -C(O)-opύonally substituted aryl, -Sθ2-optionally substituted aryl, optionally substituted lower alky optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted alkenyl, or, R8 and R^, together with the nitrogen to which they are bound, form a 5-, 6-, or 7- membered ring; or, R*> and R 7 , together with the nitrogen to which they are bound, form a 5-, 6-, or 7-membered ring. R^ and R 7 are preferably, independently hydrogen; optionally substituted alkyl, wherein the optional substituents on the alk portion are alkoxy, hydroxy, optionally substituted aryl, COOR wherein R is hydrogen or lower alkyl, -NR 6 R 7 or -S NR O 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 S 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, NO2, aroylamido and acylamido, [preferably the optional substituents on the aryl portion are NO2, methylenedioxy, or alkoxy; or, together with the nitrogen to which they are bound, R6 and R 7 form a 5-, 6- or 7-membered ring, preferably a pyrrolidino or a piperazino ring]. It will be recognized that when m is 0, R*> and R 7 cannot both be hydrogen. Preferred compounds of formula (I) are as follows: (lot, 2β, 3αH+/-)-l-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N, N-dimethyl carboxamide; (lα, 2β, 3αH+/-)-l 4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-methyl-N-(2-phenylethyl) carboxamide; (lα, 2β, 3αH+/-)~1^4--methoxyphenyl)-3-(3,4-methylenedioxyphenyl) dane-2-N--[2-(N,N-diemylaminoethyl)] carrx)xamide; (lα, 2β, 3αH+/->-M4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-[2-(4-nitrophenylethyl] carboxamide; (lα, 2β, 3αH+/-)~ 4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-(2-phenylethyl) carboxamide; (lα, 2β, 3αH+/~)-l- 4-methoxyphenyl)-3-(3,4-methylenedioxyρhenyI) indane-2-N-[(2-methoxyphenyl)methyl] carboxamide; (lα, 2β, 3α)-(+/-)-l-(4-methoxyphenyl 3-(3,4-methylenedioxyphenyl) indane-2-N-[2-(2-methoxyphenyl)ethyl] carboxamide; (lα, 2β, 3α)-(+/-)-l-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-[2-(3,4-metτιylenedioxyphenyl)etJιyl] carboxarriide; (lα, 2β, 3α>-<+''-)-l-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-[2-(3,4-dimethoxyphenyl)ethyl] carboxamide; (lα, 2β, 3α)-(+''-)-l-{4^methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-[3-(N,N-diethylamino)propyl] carboxamide; (lα, 2β, 3α +/-)-l-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) mdane-2-N-[(meώoxycarbonyl)phenylme yl] carix>xamide; (lα, 2β, 3αH^-)- ^methoxyphenyl)-3-(3,4-methylenedioxyphenyl) dane-2-N-[(hydroxycarbonyl)phenylmemyl] caιboxaιm e; (lα, 2β, 3αH+/->~ ^methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-ethyl carboxamide; (lα, 2β, 3αH+/->-M^methoxyphenyl 3-(3,4-methylenedioxyphenyl) indane-2-N-2-methylpropyl carboxamide; (lα, 2β, 3αH+/-)- 4-methoxyphenyl>3-(3,4-methylenedioxyphenyl) mdane-2-N-phenyltααethyl carboxamide; (lα, 2β, 3αH+/->- 4-methoxyphenyl 3-(3,4-methylenedioxyphenyl) indane-2-N-phenyl carboxamide; mp: (lα, 2β, 3αH+/-)-l-<4-methoxyphenyl)-3-(3,4- me ylenedioxyphenyl) dane-2-N-(2-pyridyl) cart)oxamide; (lα, 2β, 3αH+/-)-l-(4-methoxyphenyl)-3-(3,4-methylenedioxy- phenyl)indane-2-N-piperazinyl carboxamide; (lα, 2β, 3αH+/-)~ 4-methoxyphenyl>3-(3,4-methylenedioxy- phenyl)indane-2-N-[(memoxycarbonyl)phenyleΛyl] carrjoxamide; (lα, 2a, 3a +/-)-l-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)- dane-2-N^dirnemylcarboxarnide; (lα, 2β, 3αH+/-)-l-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)- indane-2-carboxylic acid, 2,2-dimethylhydrazide; (lα, 2β, 3αH+/-)-l-(4-hydroxyphenyl)-3-(3,4- me ylenedioxyphenyl)mdane-2-N-memylcarboxamide; (lα, 2β, 3αH+/-)-l » 5-bis(3,4-methylenedioxyphenyl)indane-2-N- methylcarboxamide; and (lα, 2β, 3αH+/-)-5,6-methylenedioxy-l,3-bis(3,4- meΛylenedioxyphenyl>iιιdane-2-N-me ylcarboxamide. The activity of the compounds of formula (I) as NK3 antagonists in standar tests indicates that they 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 mflaπucnation 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 NK3-mediated disease states comprising administering to a mammal in need thereof, an effective amount of an NK3 receptor antagonist compound of formula (I). In addition, the present invention provides a method for antagonizing the NK3 receptor comprising administering to a mammal in need thereof, an effective amount of an NK3 receptor antagonist compound of formula (I). Preferably, the mammal is a human. Accordingly 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 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. These conventional excipients may be employed for example as in the preparation of compositions of known agents for treating the conditions. Preferably, a pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields. For example, such 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. Advantageously, 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. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, 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. In particular, if a solid carrier 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 carrier will vary widely but preferably will be from about 25 mg. to about 1000 mg. When a liquid carrier is used, 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 marnmal in need of treatment for NK3-mediated disease states. Thus, the compounds of formula (I) may be administered topically in the treatment or prophylaxis of NK3- 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 rnammal 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. By topical administration is meant 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. By systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration. While it is possible for an active ingredient to 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. The 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. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of 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. 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. By "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. In one aspect, this invention relates to a method of treating NK3-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). By the term "treating" is meant either prophylactic or therapeutic therapy. Such 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. The route of administration may be oral or parenteral. The term 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 It will be recognized by one of skill in the art that 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. Methods of Preparation: Generally, using conventional techniques known in the art, 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). In addition, it will be recognized that the 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 Transformations. (VCH Publishers, Inc., NY) (1989). Example 1: Preparation of ( lα. 2B. 3αW+/- l-l.(4-rnethoxvphenvn-3-(3.4- methvlenedioxvphenvn indane-2-N-methvlcarboxamide a) (1 α. 2β. 3αW+/- ) 1 -(4-me.hoxvphenv1 3-f3.4-methvlenedioxvphenvl Mndanc-2- carbonyl chloride (lα, 2β, 3α)-(+/-)-l-(4-Methoxyphenyl)-3-(3,4- methylenedioxyphenyl)indane-2-carboxylic acid (0.073g, 0.188 mmol) and thionyl chloride (lmL) was kept at 25° C for 18 h. Thionyl chloride was evaporated and e residue was treated with toluene and evaporated (2x). The product obtained as an oil, was not further purified. b) flα. 2β. 3αι-(-r-/-ι-l-f4-methoxvphenvn-3-f3.4-methvlenedioxvphenvlι indane-2-N-methvl carboxamide The compound of Example 1(a) was dissolved in Et2θ (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 Et2θ (5 mL). After drying, the title compound (0.054g, 72%) was obtained as a white solid. Melting point φereinafter "mp") 189-190°C. Example 2: Preparation of ( α. 2B.3α -l-/-»-l-(4-methoxvphenvl)-3-(3.4- methylenedioxyphenylι indane-2-rN-r(methoxycarbonyl'ιPhenylethyl11 carboxamide a) (la. 2β. 3α +/-)-l-f4-methoxvphenvn-3-f3.4-methvlenedioxvphenvlι indane-2-rN-r(methoxvcarhonvl > rphenvlethvin carboxamide Triemylamine (1 mL) was added to a stirred mixture of the compound of Example 1(a) and DL-phenylalanine methyl ester hydrochloride (commercially available from Chemservice Inc., Westchester, PA, 0.06 lg, 0.283mmol) in methylene chloride (4mL). After 18 h at RT, ediyl acetate (20mL) was added. The mixture was shaken and the layers separated. The ethyl acetate extract was washed with water (lx 20mL), 10% hydrochloric acid (lx20mL), water (lx20mL), dried (MgS04) and concentrated. The residue was chromatographed (Siθ2, 30% ethyl acetate/hexane) to give the title compound (0.087g, 61%) as a white amorphous solid, MS(ES + ion) m/e 550 [MH+]. Example 3 Using procedures analogous to those of Example 1 and Example 2, except using the appropriate amine in the place of me ylamine or DL-phenylalanine methyl ester, the following compounds of formula (I) were prepared: ( 1 α, 2β, 3αH+/-)~ 4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N, N-dimethyl carboxamide; mp: 146-147°C; (lα, 2β, 3αH+/-)-l-(4--methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-methyl-N-(2-phenylethyl) carboxamide; ESMS (+ion) M/e 506[M+H]; (lα, 2β, 3αH+/-)-l-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) mdane-2-N--[2-(N,N-diethylaminoethyl)] carboxamide; ESMS (+ion)M e 487[M+H]; (lα, 2β, 3α)- +/-)-l-(4--metlιoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N--[2-(4-nitrophenylethyl] carboxamide; ESMS (+ion) M/e 536 [M+H]; (lα, 2β, 3αH+/-)-l-<4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-(2-phenylethyl) carboxamide; mp: 159-160°C; (lα, 2β, 3αM+/-)~M^methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-[(2-methoxyphenyl)methyl] carboxamide; mp: 171-173°C; (lα, 2β, 3α "^-)-M^methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-[2-(2-methoxyphenyl)ethyl] carboxamide; mp: 160-162°C; (lα, 2β, 3αH+/->-l-( 4 -memoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-[2-(3,4-methylenedioxyphenyl)ethyl] carboxamide; mp: 143-144°C; (lα, 2β, 3αM+/-)~ ^methoxyphenyl)-3-(3,4-methylenedioxyphenyl) mdane-2-N-[2-(3,4-dimethoxyphenyl)ethyl] carboxamide; mp: 138-140°C; (lα, 2β, 3αH+/ _ )-M^metJioxyphenyl)-3-(3,4-methylenedioxyphenyl) mdane-2-N-[3-(N,N-diethylamino)propyl] carboxamide; ESMS (+ion) M e 501 [M+H]; (lα, 2β, 3αH+/-)-M4-metiιoxyphenyl)-3-(3,4-methylenedioxyphenyl) inc^e-2-N-[(memoxycarbonyl)phenyjj-Qethyl] caι±x)xamide; mp: 144-146°C; (lα, 2β, 3αH+/-)-H -methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-[(hydroxycarbonyl)phenylmethyl] carboxamide; mp: 207-208°C; (lα, 2β, 3αH+/-)-l--< -methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-ethyl carboxamide; mp: 148-150°C; (lα, 2β, 3αH+/-)- 4-meΛoxyphenyl)-3-(3,4-methylenedioxyphenyl) dane-2-N-2-methylpropyl carboxamide; mp: 178-179°C; (lα, 2β, 3αH+/->-M4-memoxyphenyl)-3-(3,4-iι ethylenedioxyphenyl) indane-2-N-phenylmethyl carboxamide; mp: 170-171°C; (lα, 2β, 3αH+/- H4-ιnethoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-phenyl carboxamide; mp: 179- 181 °C; (lα, 2β, 3αH+/-)- 4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-(2-pyridyl) carboxamide; ESMS (+ion) M e 465 [M+H]; (lα, 2β, 3αH+/-)-l-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-piperazinyl carboxamide; mp: 162-164°C; and (lα, 2β, 3αH+/-)-l-(4-methoxyphenyl 3-(3,4-methylenedioxyphenyl) indane-2-N-[(methoxycarbonyl)phenylethyl] carboxamide; mp: 170-172°C. Example 4 Following the procedures of Example 1 and Example 2, except using the appropriate mdanecarboxylic acid and the appropriate amine in die place of those used in Example 3, the following were prepared: (lα, 2a, 3aH+/-)-H4-methoxyphenyl)-3-(3,4- metJ ylenedioxyphenyl)indane-2-N^dimeώylcarboxamide; mp: 222-223°C; (lα, 2β, 3α)-(+/-)~l-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)- indane-2-carboxylic acid, 2,2-dimethylhydrazide; mp: 137-139°C; (lα, 2β, 3αH+/-H~(4-hydroxyphenyl)-3-(3,4- methylenedioxyphenyl)indane-2-N-methylcarboxamide; mp: 187-188°C; (lα, 2β, 3αH+/-)-l » 3-bis(3,4-methylenedioxyphenyl)indane-2-N- methylcarboxamide; mp: 225-225.5°C; and (lα, 2β, 3αH+/-)-5,6-methylenedioxy-l,3-bis(3,4- memylenedioxyphenyl)-indane-2-N-methylcarboxamide; mp: 218-219°C. Biological Assav: The present invention also provides a method for the treatment and/or prophylaxis of die 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. The activity of die compounds of me present invention, as NK3 ligands, is determined by tiieir ability to inhibit die binding of die radiolabelled NK3 ligands, [125η_[Me-Phe ]-NKB or [ 3 H]-Senktide, to guinea-pig and human NK3 receptors (Renzetti et al, 1991, Neuropeptide, 18, 104-114; BueU 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 die determination of the concentration of me individual compound required to reduce by 50% me [^5rj.[Me-Phe 7 ]-NKB and [3H]-Senktide specific binding to NK3 receptor in equilibrium conditions. Binding assays provide for each compounds tested means of IC50 values of 2-5 separate experiments performed in triplicate or in quadruplicate. The most potent compounds of me present invention show IC50 values in die range up to 10 micromolar. The NK3-antagonist activity of d e 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 NK3 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 die 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 d e determination of me concentration of the individual compound required to reduce by 50% (IC50 values) the Ca ++ mobilization induced by the agonist NKB. In this assay, the compounds of the present invention behave as antagonists. The therapeutic potential of die compounds of d e present invention in treating the conditions can be assessed using rodent disease models. The above description fully discloses d e invention including preferred embodiments thereof. Modifications and improvements of die embodiments specifically disclosed herein are witiύn the scope of the following claims. Without further elaboration it is believed that one skilled in the art can, given the preceding description, utilize the present invention to its fullest extent Therefore any examples are to be construed as merely illustrative and not a limitation on d e scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims: What is claimed is: A compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula (I) wherein (R*) a is independendy hydrogen, lower alkyl, halo-substituted alkyl, alkenyl, alkoxy, halogen, hydroxy, optionally substituted aryl, cycloalkyl, cycloalkenyl, O-CH2-COOR, -COOR, -C(O)N(R'R") or -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 independendy, hydrogen or lower alkyl; R 2 and R^ are independendy 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 SC^N RTT), -S(O) n -alkyl or -S(O) n -aryl, wherein n is 0, 1 or 2, and wherein R, R' and R" are independendy, hydrogen or lower alkyl or, together R^ and R^ form a -O-(CH2)rO- moiety, wherein r is 1-3, or, together with die carbons to which diey are bound, form a 5-, 6- or 7-membered ring; R4 and R^ are independendy hydrogen, lower alkyl, halo-substituted alkyl, alkenyl, alkoxy, halogen, hydroxy, optionally substituted aryl, cycloalkyl, cycloalkenyl, -O-CH2-COOR, -COOR, -CXO)N(R"R") or SC^N RTT), -S(O) n -alkyl or -S(O) n -aryl, wherein n is 0, 1 or 2, and wherein R, R' and R" are independendy, hydrogen or lower alkyl or, together R^ and R^ form a -O-(CH2)rO" moiety, wherein r is 1-3, or, together witii the carbons to which they are bound, R^ and R^ form a 5-, 6- or 7-membered ring; R° and R 7 are independendy hydrogen, -C(O)-optionally substituted aryl, - SO2-optionally substituted aryl, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted alkenyl, or NR8R9, wherein R& and R^ are independendy hydrogen, -C(O)-optionally substituted aryl, - Sθ2-optionally substituted aryl, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted alkenyl, or, R and R^, together with the nitrogen to which they are bound, form a 5-, 6-, or 7-membered ring; or, R*> and R 7 , together with the nitrogen to which they are bound, form a 5-, 6-, or 7-membered ring; and m is 0 to 3; provided that R*> and R 7 are not each hydrogen when m is 0. 2. The compound as claimed in claim 1 selected from the group consisting of: (lα, 2β, 3αH+/->-l-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N, N-dimethyl carboxamide; (lα, 2β, 3αH+/-)-l-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-methyl-N-(2-phenylethyl) carboxamide; (lα, 2β, 3αH+/-)-l-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) mdane-2-N--[2-(N,N-diethyteminoemyl)] carboxarnide; (lα, 2β, 3αH+/-)-l-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N~[2-(4-nitrophenylethyl] carboxamide; (lα, 2β, 3αH+/-)-l-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-(2-phcnylethyl) carboxamide; (lα, 2β, 3αH+/->-l-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-[(2-methoxyphenyl)methyl] carboxamide; (lα, 2β, 3αH+/-)-l-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-[2-(2-methoxyphenyl)ethyl] carboxamide; (lα, 2β, 3αH+/-)-l-<4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) mdane-2-N-[2-(3,4-me ylenedioxyphenyl)e yl] carboxamide; (lα, 2β, 3α)-(+/-")-l-(4-methoxyphenyl)-3-(3,4-melhylenedioxyphenyl) dane-2-N-[2-(3,4-dimethoxyphenyl)ethyl] carboxamide; (lα, 2β, 3αH+/->~l-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) mdane-2-N-[3-(N,N-die ylamino)propyl] carboxamide; (lα, 2β, 3αH+/-)-l-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-[(medιoxycarbonyl)phenylmethyl] carboxamide; (lα, 2β, 3αH+/->~ ^memoxyphenyl)-3-(3,4-methylenedioxyphenyl) dane-2-N-[(hydroxycaιixmyl)phenylmethyl] carboxamide; (lα, 2β, 3αH+/->-l-(4--methoxyphenyl)-3-(3,4-meihylenedioxyphenyl) indane-2-N-edιyl carboxamide; (lα, 2β, 3αH+/~)-l-<4-methoxyphenyl)-3-(3,4-medιylenedioxyphenyl) indane- 2-N-2-me ylpropyl carboxamide; (lα, 2β, 3αH+/-)-l-( 4 -methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-phenylmethyl carboxamide; (lα, 2β, 3αH+/->-l- 4 -methoxyphenyl)-3-(3,4-methylenedioxyphenyl) indane-2-N-phenyl carboxamide; mp: (lα, 2β, 3αH+/-)-l-<4-methoxyphenyl)-3-(3,4- mediylenedioxyphenyl)indane-2-N-(2-pyridyl) carboxamide; (lα, 2β, 3αH+/-)-l-(4-methoxyphenyl)-3-(3,4-methylenedioxy- phenyl)indane-2-N-piperazinyl carboxamide; (lα, 2β, 3αH+/-)-l-(4-methoxyphenyl)-3-(3,4-methylenedioxy- phenyl)indane-2-N-[(memoxycarbonyl)phenylediyl] carboxamide; (lα, 2a, 3a)-(+/-)-l-{4— memoxyphenyl)-3-(3,4-methylenedioxyphenyl)- indane-2-N^dimediylcarboxamide; (lα, 2β, 3αH+/-)-l-( 4 -medιoxyphenyl)-3-(3,4-methylenedioxyphenyl)- indane-2-carboxylic acid, 2,2-dimethylhydrazide; (lα, 2β, 3αH+ -)-l-<4-hydroxyphenyl)-3-(3,4- ij-«mylenedioxyphenyl)mdane-2-N-meώylcarboxamide; (lα, 2β, 3α)-(+/-)-1.3-bis(3,4-methylenedioxyphenyl)indane-2-N- mediylcarboxamide; and (lα, 2β, 3αH+/->-5,6-methylenedioxy-l,3-bis(3,4- memyleneώoxyphenyl dane-2-N-methylcarboxamide. 3. A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 1 and a pharmaceutically acceptable carrier. 4. A method for treating NK-3 mediated disease states in mammals, which comprises administering to a mammal in need of such treatment an effective amount of a compound according to claim 1.

Inventors: GIRARD GERALD R, WEINSTOCK JOSEPH, GIRARD, GERALD, R., WEINSTOCK, JOSEPH
Applicants: GIRARD GERALD R, SMITHKLINE BEECHAM CORP, WEINSTOCK JOSEPH, GIRARD, GERALD, R., SMITHKLINE BEECHAM CORPORATION, WEINSTOCK, JOSEPH
Application year: 1995
Main classification: C07D405
IPC codes: A61K31, A61P11, A61P17, A61P25, A61P29, A61P43, C07D317, C07D405