AU5784501A - Quinoline derivatives as tachykinin NK3 receptor antagonists - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANT: SmithKline Beecham Farmaceutici S.p.A.

ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street Melbourne, 3000.

INVENTION TITLE: "Quinoline derivatives as tachykinin NK 3 receptor antagonists" The following statement is a full description of this invention, including the best method of performing it known to us: I P:\OPER\PDB\SPECI\SKB.DIV -7/8/01 -1A- QUINOLINE DERIVATES AS TACHYKININ NK 3 RECEPTOR ANTAGONISTS This specification relates to a divisional application derived from Australian Patent Application No. 12162/99, the entire contents of which are incorporated herein by reference.

The present invention relates to novel quinoline derivates, processes for their preparation and their use in medicine.

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 (NK,,

NK

2 and NK 3 and NKB binds preferentially to the NK 3 receptor although it also recognises the other two receptors with lower affinity (Maggi et al, 1993, J. Auton. Pharmacol., 13, 23- 93).

Selective peptidic 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. Physiol., 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 novel class of selective, non-peptide 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 p:\OpER\PDB\SKBFARM.DIV 14/1/9 -1Binflammation and CNS disorders (Parkinson's disease, movement disorders, anxiety and psychosis). These disorders are referred to hereinafter as the Primary Disorders.

The novel NK 3 antagonists of the present invention are also of potential therapeutic utility in treating convulsive disorders (for example epilepsy), renal disorders, urinary incontinence, ocular inflammation, inflammatory pain, eating disorders (food intake inhibition), allergic rhinitis, neurodegenerative disorders (for example Alzheimer's disease), psoriasis, Huntington's disease, and depression (hereinafter referred to as the Secondary Disorders).

According to the present invention there is provided a compound, or a solvate or salt thereof, of formula *a N-C -Ar in which: Ar is an optionally substituted phenyl. naphthyl. Or C 5 7 cycloalkdienYl group, or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four heteroatoms in the or each ring selected from S, 0, N; R is linear or branched C 1 g alkyl, C 3 7 cycloalkyl,

C

4 7 cycloalkylaikyl, optionally substituted phenyl or phenyl C 1 alkyl, an optionally substituted five-membered heteroaromatic ring comprising up to four heteroatom selected from 0 and N, hydroxy Cj..

6 akl, amino Cj.

6 alkYl, C 1 -6 alkylaulinoalkyl, di C 1 -6 lkylaminoalkyl, C 1 6 acylaminoalkyl, CI-6 alkoxyalkyl, Cl-6 akl7carbonyl, carbozy, CI-6 alkoxyxcarbonyl, CI-6 alkoxycarbonyl CI-6 aLyl, aminocarbonyl,

C

1 6 alkylaminocaronyl, di C 1 6 alkylaminocarbonyl, halogeno C 1 6 alkyl; Or is a group -(CH2)p- when cydlized onto Ar, where p is 201r3.

R, and R 2 which may be the same or different are independently hydrogen Or Clinea or branched alkyl, or together form a -(CH2)n- group in which n represents 3, 4. Or 5; or R 1 I together with R forms a group in which q is 2, 3, 4 or

R

3 and R 4 which may be the same or different. are independently hydrogen, C 1 -6 linear or branched alkyl, C2- alkenyl. aryl. C 1 6 alkoxy, hydroxy, halogen, nitro.

cyano, carboxy, carboxamido, sulphonamido, C 1 6 alkoxycarbonyL, trifluoromethyl, acyloxy, phthaglimido, amino, mono- and di-Cj..

6 aikylamino, 0O(CH2)r-NT 2 in which r is 2,3, or 4 and T is hydrogen or-C 1 6 alkyl or it forms with the adjacent nitrogen a group VI V N or N V (CH4 Vr' (CH 2 in which V and V 1 are independently hydrogen or Oxygen and u is 0,1 or 2; -0(CH 2 )s-0W 2 in which s is 2.3, or 4 and W is hydrogen or C 1 6 alktyl; hydroxyaikyl, aminoalkyl, mono-or di-alkylaminoalkyl, acylamino, a-lkylsulphonylamino, aminoacylamino, mono- or di-alkylaminoacylamino; with up to four R 3 substituents being present in the quinoline nucleus; or R 4 is a group -(CH2)r- when cyclized onto R 5 as aryL in which t is 1, 2, or 3;

R

5 is branched or linear C 1-6 aL, C 3 7 cycloalkyl, C 4 7 cycloalkylaikyl, Optionally substituted aryl. or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising UP to four hetero-atoms in the Or each ring selected frOM S, 0, N; X is 0, S. or N-CoN.

Examples of Ar are phenyl, optionally substituted by hydroxy, halogen, C 1 6 aikoxy or C 1-6 aIIkyL Examples of halogen are chlorine and fluorine, an example of

C

1 6 alkoxy is methoxy and an example of Cl-6 alkyl. is methyl 'Examp-les of Ar as a heterocycic group are thienyl and pyridyl.

Examples of Ar as a C5- 7 cycloalkdlienyl group is cycohxdeL Examples of R are as follows:

C

1 8 alkyl: methyl, ethyl, n-propyl, iso-propyl, n-butyl, heptyl; phenyl C 1 6 alkyl: benzyl;, hydroxy C 1 -6 alkyl: CH 2 OH, -CH CH 2 OH, CH(Me)OH; amino C 1 -6 alkyl: -CH 2

NH

2 di C 1 6 alkylaminoalkyl: -CH 2 NMe2;

C

1 6 alkoxylalkyl: CH 2 OMe;

C

1 6 alkylcarbonyl: COMe;

*.C

1 6 alkoxycarbonYL COOMe;

C

1 6 alkoxycarbonyl C 1 6 alkyl: CH 2 COOMe;

C

1 6 alkylaminocarbonyl: CONHMe; di C 1 6 alkylaminocarbonyl: CONMe2, CO(l-pyrrolidinyl); halogen C 1 6 alkyl: trifluoromethyl; -(CH2)p- when cyclized onto Ar-.

Example of R 1 and R 2 as C 1 6 alkcyl is methyl; example of R 1 together with R forming a group..(CH2)q- is spirocyclopentane.

Examples of R 3 and R 4 are methyl, ethyl, n-propyl, n-butyl, methoxy, hydroxy, aino, chlorine, fluorine, bromine, acetyloxy, 2-(dimetylamino)ethoxy, 2-(1-phthaloyl)ethoxy, aminoethoxy, 2-(1-pyrrolidinyl)ethoxy. phthaloyl, dimethylaminopropoxy, dimethylaminoacetylamino, acetylamino, dimethylamninomethyl. and phenyl.

Examples of R 5 are cyclohexyl, phenyl optionally substituted as defined for Ar above; examples of R 5 as a heterocyclic group are furyl, thienyl, pyrryl, thiazolyl, benzofuryl and pyridyl.

A'preferred group of compounds of formula are those in which.

Ar is phenyl, optionally substituted by C 1 6 aiyL7 Or halogen; thienyl Or a 7 cycloalkidienyl group; R is C 1 -6 alkyl. CI-6 alkoxycarbonyl, Ci-6 alkylcarbonyl, hydroxy C 1 -6 alkyl; RI and R 2 are each hydrogen or C 1 -6 alkyl;

R

3 is hydrogen, hydroxy, halogen, C1-.6 alkoxy, C 1 6 alkyl;

R

4 is hydrogen, C 1- alkyl, Cj.1- 6 alkoxy, hydroxy, amino, halogen, aminoalkoxy, mono- or di-alkyliinoalkoxy, mono- or di-alkylaminoalkyl, phthaloylalkoxy, mono- or di-alkylaioclmn and acylamino;

R

5 is phenyl, thienyl, furyl, pyrryl and thiazolyl.

A further preferred group of compounds of formula are those in which: Ar is phenyl, 2-chiorophenyl, 2-thienyl or cyclohexadienyl; R is methyl, ethyl, n-propyl, -COOMe, -COMe; RI and R 2 are each hydrogen or methyl;

R

3 is hydrogen, methoxy, or hydroxy;

.R

4 is hydrogen, methyl, ethyl, methoxy, hydroxy, amino, chlorine, bromine, *dimethylaminoethoxy, 2-(l-phthaloyl)ethoxy, aminoethoxy, 2-(1pyrrolidinyl)ethoxy, dimethylamiinopropoxy, dimethylaminoacetylamino, acetylamino, and dimethylaminomethyL

R

5 is phenyl, 2-thienyl, 2-furyL, 2-pyrryL, 2-thiazolyl and 3-thienyl; and X is oxygen.

A preferred sub-group of compounds within the scope of formula above is of formula (Ia):

N-C-Z

R 4

H

R3 (1a) in which:

R

2

R

3 and R 4 are as defined in formula(IM, and Yand Z, which may be the same or different, are each Ar as defined in formula A particularly preferred group of compounds of formula (Ia) are those of formula (Ib) in which the group R is oriented downward and H upward.

R4

H

S N v (Ib) The compounds of formula or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.

A substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula or its salt or solvate.

One preferred pharmaceutically acceptable form is the crystalline form, including such form in pharmaceutical composition. In the case of salts and solvates the 15 additional ionic and solvent moieties must also be non-toxic.

Examples of pharmaceutically acceptable salts of a compound of formula (I) include the acid addition salts with the conventional pharmaceutical acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic, and methanesulphonic.

20 Examples of pharmaceutically acceptable solvates of a compound of formula include hydrates.

The compounds of formula may have at least one asymmetric centre and *therefore may exist in more than one stereoisomeric form. The invention extends to all such forms and to mixtures thereof, including racemates.

The invention also provides a process for the preparation of a compound of formula which comprises reacting a compound of formula (In)

R'

I Re HimN

R'

in which R'I, R' 2 and Ar' are R, R, R 2 and Ar as defined for formula (I) or a group or atom convertible to R, RI, R 2 and Ar, with a compound of formula (II) X' OH R@4 N R's or an active derivative thereof, in which R' 3

R'

4

R'

5 and X are R 3

R

4

R

and X as defined for formula or a group convertible to R3, R4, RS and X. to form a compound of formula (Ic)

R'

1 R X N yA

R'

41 R13 I N R's (Ic) and optionally thereafter performing one or more of the following steps: where R' 1 to R' 5 Ar'and X'are other than R, RI to R 5 Ar and X.

converting any one of R' 1 to R' 5 Ar'and X' to R, RI to R 5 Ar and X to obtain a compound of formula where R' 1 to R' 5 Ar' and X'are R, RI to R 5 Ar and X, converting any oneofR, R toRS, Ar and X to another R, R to R, Ar andXtoobtain a compound of formula forming a salt and/or solvate of the obtained compound of formula (Ic).

Suitable active derivatives of the compounds of formula (II) are acid halides (preferably chlorides), acid azides or acid anhydrides. Another suitable derivative is a mixed anhydride formed between the acid and an alkyl chloroformate; another S suitable derivative is an activated ester such as a cyanomethyl ester, thiophenyl ester, p-nitrophenyl ester, p-nitrothiophenyl ester, 2,4,6-trichlorophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxy-phtalimido ester, Nhydroxypiperidine ester, N-hydroxysuccinimide ester, N-hydroxy benzotriazole ester; or the carboxy group may be activated using a carbodiimide or NN'carbonyldiimidazole.

For example, in standard methods well known to those skilled in the art, the compounds of formula (III) may be coupled: with an acid chloride in the presence of an inorganic or organic base in a suitable aprotic solvent such as dimethylformamide (DMF) at a temperature in a range from -70 to 50 0 C (preferably in a range from -10 to with the acid in the presence of a suitable condensing agent, such as for example N,N'-carbonyl diimidazole (CDI) or a carbodiimide such as dicyclohexylcarbodiimide (DCC) or N-dimethylamninopropyl-NM-ethylcarbodimde and N-hydroxybenzouiazole (HOBT) to maximise yields and avoid racemization processes (Synuhesis, 453, 1972) in an aprotic solvent such as a mixture of acetonitrje (MeCN) and tetrahydrofuran (THF) in a ratio from 1 :9 to 7: 3, respectively, at a temperature in a range from -70 to 50*C (preferably in a range from -10 to (see Scheme 1),

POP.

0 Scheme 1 0 OH '2 COC R, cooM R' X HNA r c, HcBT, R' N Rs R MeCNHF 3:7 v N Rs 0-20"C (III) (c) with a mixed anhydride generated in situ from the acid and an alkyl (for example isopropyl) chloroformate in a suitable aprotic solvent such as dichloromethane at a temperature in a range from -70 to 50 0 C (preferably in a range from -20 to 20 0

C).

It will be appreciated that a compound of formula (Ic) may be converted to a compound of formula or one compound of formula may be converted to another compound of formula by interconversion of suitable substituents. Thus, certain compounds of formula and (Ic) are useful intermediates in forming other compounds of the present invention.

For example R' 2 may be hydrogen and converted to R 2 alkyl group, for example methyl, by conventional amide alkylation procedures (Zabicky, The chemistry of amides; Interscience, London, 1970, p. 749). When X' is oxygen, it may be converted to X sulphur by standard thioamide formation reagents, such as P 2

S

5 (Chem. Rev., 61, 45, 1961 orAngew. Chem., 78, 517, 1966) or the Lawesson reagent (Tetrahedron, 41, 5061, 1985). When Ar' or R 5 is a methoxy substituted phenyl, it may be converted to another Ar' or R' 5 hydroxy substituted phenyl by standard demethylation procedures via Lewis acids, such as boron tribromide (Synthesis, 249, 1983) or mineral acids, such as hydrobromic or hydroiodic acid. When R is an alkoxycarbonyl group, for example methoxycarbonyl, it may be converted to another R, such as ethoxycarbonyl by transesterificaion with an appropriate alcohol at a temperature in a range from 20 to 1200C, carboxy by hydrolysis in acidic or basic medium, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl by transamidation with ammonia, a primary amine or a secondary amine in methanol as solvent at a temperature in a range from 10 to 120 0 C, optionally in the presence of a catalytic amount of NaCN Org. Chem, 52, 2033, 1987) or by using trimethylalnminium (Me 3 AI) (Tetrahedron Leters, 48, 4171, 1977), hydroxymethyl by a selective metal hydride reduction, such as lithium borohydride reduction (Tetrahedron, 35, 567, 1979) or sodium borohydride reduction in THF MeOH (BulL Chem. Soc. Japan, 57, 1948, 1984 or Synth. Commun., 12, 463, 1982), alkylcarbonyl by acyl chloride formation and subsequent reaction with alkylmagnesium halides in THF as solvent at a temperature in a range from -78 to 30 0 C (Tetrahedron Levers, 4303, 1979) or with alkylcadmium halides or dialkylcadmium in the presence of MgC12 or LiCl Org.

ChenL, 47,2590, 1982). Another group which R' as methoxycarbonyl can be converted into is a substituted heteroaromatic ring, such as an oxadiazole Medj Chem., 34, 2726, 1991).

Scheme 2 summarizes some of the above described procedures to convert a compound of formula (Ic) or in which XC is oxygen, R' is COOMe, Ar' and R' 1 to

R'

5 are as described for formula to another compound of formula Scheme 2 Fr 2 U' cooUsN2 UO O N

I

N R' Me COOMe QC N(

CONHM.

HO I Me R'~e S IN I0C.

2 OUiCOH C NIH. 3J. TH R4 R HO OW S 1 O N o N R' R S so1) (COCf 2 2)Mor.t lF. FdC N%+A0r

*A

4 4 N R-4 The compounds of formula (I may be converted into their pharmaceutically acceptable acid addition salts by reaction with the appropriate organic or mineral acids.

Solvates of the compounds of formula may be formed by crystallization or recrystallization from the appropriate solvent For example, hydrates may be formed by crystallization or recrystallization from aqueous solutions, or solutions in organic solvents containing water.

Also salts or solvates of the compounds of formula which are not pharmaceutically acceptable may be useful as intermediates in the production of pharmaceutically acceptable salts or solvates. Accordingly such salts or solvates also form part of this invention.

As mentioned before, the compounds of formula may exist in more than one steroisomeric form and the process of the invention may produce racemaes as well as enantiomerically pure forms. To obtain pure enantiomers, appropriate enantiomerically pure primary or secondary amines of formula (Hid) or (IMe) Re R'e 1"2 Re 2 R HON Are H0 N A R Rol (Hid) (IMIe) are reacted with compounds of formula to obtain compounds of formula (rd) or (re).

:1 2 R 1 12 R R 1 R 1

SR'

3 R 3 N R *5 N Re 9 (Ie) Compounds of formula or (re) may subsequently be converted to *compounds of formula (Id) or (le) by the methods of conversion mentioned before.

R R-R 2 R

R

X N Ar 12.^ Ar N R R3-j KL RL K3L I v Rs v R s (Id) (Ie) Compounds of formula are known compounds or can be prepared from known compounds by known methods.

For example, the compound of formula in which X' is oxygen, R' 3

R

4 and R' 5 are hydrogen is described in Pfitzinger, J. PrakL Chaem, 38, 582, 1882 and in pfitzinger, J. Prakz. Chemz, 56, 293, 1897; the compound of formula in which X' is oxygen, R' 3 and R! 4 are hydrogen and R' 5 is 2-pyridyl is described in Risalizi. Ric Sci era., 28, 561, 1958; the compound of formula in which X' is oxygen, R' 3 and

W'

4 are hydrogen and R' 5 is m- and p-chlorophenyl, o-fluorophenyl and 3,4dichiorophenyl are described in Brown at aL, J. Am. Chemt Soc., 68, 2705,1946; the compound of formula (ED, in which V is oxygen, R' 3 and R! 4 are hydrogen and R' 5 is p-methoxyphenyl is described in Ciusa and T Luua ,o G=Z Chink ItaL, 44, 64, 1914; the compound of formula in which IC is oxygen, R' 3 and R! 4 are hydrogen and

R'

5 is m-trifuoromethylphenyl is described in Shargier and Lalezri J. Chain. Euig.

Data, 8, 276, 1963; the compound of formula in which V' is oxygen, R' 3 and R' 4 are hydrogen and R' 5 is p-fluorophenyl is described in Bu Hoi et aL, Rac Tray. Chin, 68, 781,19-, the compound of formula in which ICis oxygen, R! 3 and R' 4 are hydrogen and R' 5 is p-methylphenyl is described in Prevost et aL, CompL. RM&~ Acad. Sci., 258, 954, 1964; the compound of formula in which X' is oxygen, R' 3 and R' 4 are hydrogen and R' 5 is p-bromophenyl is described in Nicolai et aL, Eur. I.

Med. Chemn, 27, 977,19IM; the compound of formula (1I) in which 3C is oxygen, R! 4 and R' 5 are hydrogen and R' 3 is 6-methyl is described in Bachmann and Howton, I.

Am. Chain Soc., 68,2718,1946; the compound of formula (11) in which IC is oxygen, R' 4 and R' 5 are hydrogen and R' 3 is 8-nitro is described in Buchmann et 4l 1.

Am. Chemn Sac., 69,380,1947; the compound of formula in which IC is oxygen,

RW

4 is hydrogen, R! 3 is 6-chloro, R' 5 is p-chlorophenyl is described in Lutz at aL, J.

Am. Chem. Soc., 68, 1813, 1946; the compound of formula (II0, in which X' is oxygen, R' 3 and R' 4 are hydrogen and R 5 is 2-thiazolyl is described in Ear. Pat.

AppL EP 112,776; compounds of formula in which VXis oxygen. R! 3 is 8wtifluoromethyl, R' 4 is hydrogen and RW 5 are phenyl, o- and p-fluorophenyl, 3,4dichiorophenyl, p-methoxyphenyl are described in Ni1colai et aL, Eur. J. Med. Cham., 27,977,199M; compounds of formula MII, in whichV is oxygen, R' 3 is 6-brorno, R' 4 is hydrogen and R! 5 are phenyl or p-fluorophenyl are described in Nicolai at aL, Eur.

J. Med. Cham., 27, 977, 1M9; other compounds of formula MI) are described in Ger.

Offen. DE 3,721,22 and in Eur. PaL Appl. EP 384,313.

Compounds of formula (hid) and (file) are commercially available compounds or can be prepard from known compounds by known methods (for example, compounds of formula (Mf) in which R' is alkoxycarbonyl, R' 1 and R' 2 are hydrogen and Ai is as defined for the compounds of formula are described in Liebig., Ann. der Chamie, 523, 199, 1936).

The activity of the compounds of formula as NK 3 receptor antagonists in standard tests indicates that they are of potential therapeutic utility in the treatment of both the Primary and Secondary Disorders herein before referred to.

The discovery that NK 3 receptor antagonists have potential therapeutic utility in treating the Secondary Disorders is new, and in a further aspect of the present invention there is provided the use of an NK 3 receptor antagonist for the treatment of the Secondary Disorders. There is also provided the use of an NK 3 receptor antagonist in the manufacture of a medicament for the treatment of any of the Secondary Disorders.

The present invention also provides a compound of formula or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance.

The present invention further provides a pharmaceutical composition comprising a compound of formula or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

The present invention also provides the use of a compound of formula or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of the Primary and Secondary Disorders.

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, flavouring agent, colouring agent, lubricant or preservative in conventional manner.

S: 20 These conventional excipients may be employed for example as in the preparation of compositions of known agents for treating the conditions.

S" 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.

Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.

The compositions, for example those suitable for oral administration, may 12 contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, S polyvinyl-pyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.

Solid compositions may be obtained by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.

When the composition is in the form of a tablet, powder, or lozenge, any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk.

Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. The composition may also be in the form of an ingestible capsule, for example of gelatin containing the compound, if desired with a carrier or other excipients.

Compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; aqueous or non-aqueous vehicles, which include edible oils, for example almond oil, fractionated S 25 coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.

The compounds of this invention may also be administered by a non-oral route. In accordance with routine pharmaceutical procedure, the compositions may be formulated, for example for rectal administration as a suppository. They may also be formulated for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids. The liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi- dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid 13 form or concentrate which can be used to prepare an injectable formulation.

The compounds of this invention may also be administered by inhalation, via the nasal or oral routes. Such administration can be carried out with a spray formulation comprising a compound of the invention and a suitable carrier, optionally suspended in, for example, a hydrocarbon propellant.

Preferred spray formulations comprise micronised compound particles in combination with a surfactant, solvent or a dispersing agent to prevent the sedimentation of suspended particles. Preferably, the compound particle size is from about 2 to 10 microns.

A further mode of administration of the compounds of the invention comprises transdermal delivery utilising a skin-patch formulation. A preferred formulation comprises a compound of the invention dispersed in a pressure sensitive adhesive which adheres to the skin, thereby permitting the compound to diffuse from the adhesive through the skin for delivery to the patient. For a constant rate of percutaneous absorption, pressure sensitive adhesives known in the art such as natural rubber or silicone can be used.

As mentioned above, the effective dose of compound depends on the particular compound employed, the condition of the patient and on the frequency and .route of administration. A unit dose will generally contain from 20 to 1000 mg and 20 preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350,400,450, or 500 mg. The composition may be administered once or more times a day for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg. Alternatively the unit dose will contain from 2 to 20 mg of active ingredient and be administered in multiples, if desired, to 25 give the preceding daily dose.

No unacceptable toxicological effects are expected with compounds of the invention when administered in accordance with the invention.

The present invention also provides a method for the treatment and/or prophylaxis of the Primary and Secondary 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 (1 or a pharmaceutically acceptable salt or solvate thereof The invention further provides a method for the treatment and/or prophylaxis of the Secondary Conditions in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective amount of an NK 3 receptor antagonist.

The activity of the compounds of the present invention, as NK 3 ligands, is determined by their ability to inhibit the binding of the radiolabelled NK 3 ligands, [1 25 1]-[Me-Phe 7 ]-NKB or 3 H]-Senktide, to guinea-pig and human NK 3 receptors 14 (Renzetti et al, 1991, Neuropeptide, 18, 104-114; Buell et al, 1992, FEBS, 299(1), Chung et al, 1994, Biochem. Biophys. Res. Commwn., 198(3), 967-972).

The binding assays utilized allow the determination of the concentration of the individual compound required to reduce by 50% the 1 25]-[Me-Phe 7 ]-NKB and 3 H]-Senktide specific binding to NK 3 receptor in equilibrium conditions Binding assays provide for each compound tested a mean IC 5 0 value of 2-5 separate experiments performed in duplicate or triplicate. The most potent compounds of the present invention show IC 5 0 values in the range 1-1000 nM; in particular, in guineapig cortex membranes by displacement of [3H]-Senktide, the compounds of the Examples 22, 47, 48, and 85 display Kis (nM) of 5.6, 8.8,,12.0 and 4.8 respectively The NK 3 -antagonist activity of the compounds of the present invention is determined by their ability to inhibit senktide-induced contraction of the guinea-pig ileum (Maggi et al, 1990, Br. J. PharmacoL, 101, 996-1000) and rabbit isolated iris sphincter muscle (Hall et al., 1991, Eur. J. PharmacoL, 199,9-14) and human NK 3 receptors-mediated Ca mobilization (Mochizuki et al, 1994, J. BioL Chem., 269, 9651-9658). Guinea-pig and rabbit in-vitro functional assays provide for each compound tested a mean KB value of 3-8 separate experiments, where KB is the concentration of the individual compound required to produce a 2-fold rightward shift in the concentration-response curve of senktide. Human receptor functional assay allows the determination of the concentration of the individual compound required to reduce by 50% (IC 5 0 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 the compounds of the present invention in treating the conditions can be assessed using rodent disease models.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps

Claims (4)

1. A method for the treatment and/or prophylaxis of pulmonary disorders (asthma, chronic obstructive pulmonary diseases -COPD-, airway hyperreactivity, cough), skin disorders and itch (including, atopic dermatitis and cutaneous wheal and flare), neurogenic inflammation and CNS disorders (Parkinson's disease, movement disorders, anxiety and psychosis), convulsive disorders, epilepsy, renal disorders, urinary incontinence, ocular inflammation, inflammatory pain, eating disorders (food intake inhibition), allergic rhinitis, neurodegenerative disorders (including Alzheimer's disease), psoriasis, Huntington's disease, and depression in mammals, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective amount of an NK 3 receptor antagonist.

2. A method according to claim 1 for the treatment and/or prophylaxis of skin disorders and itch. S

3. Use of an NK 3 receptor antagonist in the manufacture of a medicament for use in the treatment of pulmonary disorders (asthma, chronic obstructive pulmonary diseases -COPD-, airway hyperreactivity, cough), skin disorders and itch (including, atopic dermatitis and cutaneous wheal and flare), neurogenic inflammation and CNS disorders (Parkinson's disease, movement disorders, anxiety and psychosis), convulsive disorders, epilepsy, renal disorders, urinary incontinence, ocular inflammation, inflammatory pain, eating disorders (food intake inhibition), allergic rhinitis, neurodegenerative disorders (including Alzheimer's disease), psoriasis, Huntington's disease, and depression.

4. Use according to claim 3 in the manufacture of a medicament for use in the treatment of skin disorders and itch. DATED this 7th day of August, 2001. SMITHKLINE BEECHAM FARMACEUTICI S.p.A. DAVIES COLLISON CAVE Patent Attorneys for the Applicant