AU1216299A - Quinoline derivatives as tachykinin NK3 receptor antagonists - Google Patents

Description

R.guiitiofl 3.2

AUSTRALIA

Patents Act 1990 COMPLETE

SPECIFICATION

FOR A STANDARD

PATE-NT

DIVISIONAL

APPLICATION

Name of Applicant: Smith~line Beecham Farmaceutiel of Via ZamLeti02 Baranzate di Bollate, Milan, Italy Actual Inventors: FARINA, Carlo GIARDINA, Giuseppe Arnaldo Maria GRUGNI, Mario RAVEGLIA, Luca Francesco Address for Service: DAVIES ICOLLISON CAVE, Patent Attorneys, of 1 Little Collins Street, Melbourne, Victoria 3000, Australia "pjnlinederi1vatives as tachykinin

NK

3 receptor antagonists" invention Title: The following statement is a full description of thsivention, icluding the best metho of performing it known to us:

V.

pO0-,p~aPSBFA!.Ni -DIfV IlA- QULNOLMN DERIVATES AS TACHYKEIN~

NK

3 RECEpTOR

ANTAGONISTS

This specification relates to a divisional application derived from Australian Patent Application No. 26164/95, 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 Neurolkinin B (NKB) belongs to the Tachykiflin (TK) peptide t0 family which also include Substance P (SP) and Neurokiflin A (NKA). Pharmtacological and molecular biolog-ical evidence has shown the existence of three subtypes of TK receptor

(NK

1

NK

2 and NQ 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_ Automl Phzarmicol., 13, 23- 93).

selective peptidic

NK

3 receptor antagonists are known (Drapeau, 1990, Regui.PePt., 31, 125-135), and findings with peptidic

NK

3 receptor agonists suggest that NKB, by ativating 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 ljndem, 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).

H-owever, the peptide-like nature of the known antagonists makes them likely to beA too labile from a metabolic, point of view to serve as practica hrpui gns 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 tha the known peptidic

NK

3 receptor antagonists, and are of potential. therapeutic utility in treating pulmonary disorders (asthma, chronic obstructive pulmonlary diseases -COPD-, airway hyperreactiitY, cough), skin disorders and itch (for example, atopic dermatitis and cutaneous whea and flare), neurogeflic

IB-

inflammation 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).

10 S According to the present invention there is provided a compound, or a solvate or salt thereof, of formula 1 e t i Ri 2

R~

N-C-A

RI

N RS in which: opinal sbtiuedsngeor fusd rngroylcuphavingamatc caatr, containinfg from 5 to 12 rng atosn dcomprising up t orhmo atoms in the or each rdng selected from S 4

N;

Ris inea orbranchd Cj.

8 alkylC -7cycloalkyl.C47 cYcloalkylalkyl. OPtiona substituted phenyl or phenyl C alkyl, an optionally substituted five-meinbered heteroiatic ring comprising up to four heteratomn selected from 0 and N, ~hYdroxy C 1 -6 alkyl amino C 1 -6 alkyl, C 1 -6 alicylanioalkl, di C 1alkylaminoalkyl. C j6 acylaminoalkyl,

C

1 lkoxOyalkyl,

C

1 -6 alkylcarbonyl4 15 C 1 6 alkylaininocarboflyl, di C 1 6 alkylamiflocarbonyl, halogeno C 1 6 akl ri i group -(CH 2 when cyclized onto Ar, where p is 2 or 3.

R, and R 2 which may be the same or different, are independently hydrogen or C 1 _6 linear or branched alkcyl, or together form a -(CHZ)n- group in which n represents 3,4. or 5; or R 1 together with R forms a group -ACH2)q-. 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, C 2 aley.arl 1 akx.hdrx.hloemD cyan~qo. carboxy, carboxarnido, suiphonanido, CI-6~ aikoxycarboflyl, rifluorometliyl, acyloxy. phthalimido. amino, mono- and di-CI-6 alyaio

-O(CH

2 )r-NT 2 in which ris 2.3. o 0 4 and Tishydrogen orC-6 alylor it forms with the adjacent nitrogen a group VI

VI

or~ V (01I V CC in which V and VI axe indepenetly hydrogen or Oxygen and u is 0.1 or 2; -O(CH2)-OW 2 in whcsis 23or 4and W ydoe C.6 aB* r hydroxyalkyl. arninoalkti, mono-Or di-alikylf olk~Oyl, acylarnino, 2 alkylsulphoflylamiflo. aminoacyiamino. Mono- or di-alky mioacylamino.b with up to four R 3 substituents being present in the quinoline nucleus; or R 4 is a group -(CH2)r- when cyclized onto RS as aryl, in which t is 1, 2, or 3; Re, is branched Or linear C 1 -6 alkyl, C 3 -7 cYcIoaikYl, C4-7 cycloalkylalkyl, 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 mn the or each ring selected from S, 0, N, X is 0, S, or N-CaN.

Examples of Ar are phenyl optionally substituted by hydroxy, halogen, C 1.

alkoxy or C 1.

6 alkyl. Examples of halogen arm chlorine and fluorine, an example of

C

1 6 alkoxy is methoxy and an example of Cl-6 alkyl is methyl Examples of Ar as a heterocyclic group are thienyl and pyridyL Examples of Ar as a C5 7 cycloalkidienyl group is cyclohexailieflyl.

Examples of R are as follows: Cl-.

8 alkyl: methyl, ethyl, n-propyl, iso-propyl, n-butyl, heptyl; phenyl Cl..6 alkyl: benzyl; ,:hydroxy C 1- alkyl: CH 2 OH, CHiCH20H, CH(Me)OH; amino C 1 6 alkl(Y: -CH 2

NH

2 di Cl alainoalkyl:

-CH

2 NMe2;

C

1 6 alkoxylalkyl:

CH

2 OMe; Cl 1 6 alkylcazbonyh COMe;, Cl-6 alkoxycarbonyt COOMe;

C

1 -6 alkoxycarbonyl

C

1 -6 alkyl: CH 2 COOMe;

C

1 6 alkYlaMinocaeDonYL CONHMe; di C 1- alkylaminocarbonyl: CONMe2. CO(1-pyrrolidinyl); halogen CI-6 alkyl: urifluoromethyl; -4CH2)p- wheni cyclized onto An Example of RI and R 2 as C.6 alkyl s metyl; -J 30 example of R, together with R farming a gmoup..(CH2)q- is spizocycIopemn~fe.

Exmples of R 3 and R 4 are methyl ethyl, n-proyl. n-butyl, medhoxy.

hydroxy. amino, chlorine, flumrne, bromine, acetyloxy. 2..(dimstylamlino~etboxy.

2.{1.phtbAloyl)etO)XY, aminoetholy, 2..(1.pyfoiTOU yCehMx, phtiloyl yiehyai mland pbeyl.2 Examples of R 5 ame cyclohCXYL. phenyl. optionallysbiue s defined for 3 Ar above; examples of R 5 as a heterocyclic group are fuiyl. thienyl, PYrryL thiazOlyl.

benzofuzyl and pyridyl.

A'preferred group of compounds of formula M ame those in which' is phenyl, optionally substituted by C 1-6 alkyl orhalogen; thienyl or a -ycloalkdieflyl group; P, is C 1 aly C 1 -6 alkoxycarboflyl. C 1 6 alkylcaxt'ofyl, hydro'xy C 1 alkyl; RI and R 2 are each hydrogen or C 1 -6 Aikyl;

R

3 is hydrogen. hydroxy. halogen. C 1 -6 alko'XY, C 1- 6 alkYl; R4 is hydrogen, Cp- 6 alkyl, Cl-6 alkoxy, hydroxy, amino, halogen, aioalkoxy. mono- or di..alkylanoalkoxy, mono- or di-alkylainioalkl.

phthaloyakoxy, mono- or dli-aULkylmin3cY~l~ifl and acylamino; 15R 5 is phenyl, tbienyl, furyl. pyrryl and tiazolyL A Afer preferred group fcomposof fomla m thosen whch: Ar is phenyl, 2-,chiorophenyl, 2-rhienyl or cyclohexadiefyl; R is methyl, ethyl, n-propyl. -COOWe, -COMe; RI and R 2 are echb hydrogen or methyl;

R

3 is hydrogen. methoxy, or hydroxy; o

R

4 is hydrogen, methyl ethyL. methoxy. hydruxy. amino, chlooine, bromine, dimethylamifloethoxy, 2-(1-phthaloyl)ethoxy, aminoethoxy, 2-(1pyrliiy~ehxy ie.*aio* poy dmtylmno..laio scetylamino. and dimethylaminomethyL.

R

5 is phenyL 2-tbienyl. 2-f inyl. 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 (1a):

N-C-Z

H

(1a) i in which: PR.R3adR am as de find in fom l and and~ 4. wbi1 may b Arasdeiw n foml 7 them e or different, are each A s- 4 A paru-cularly preferred group of compounds of formula tIa) are those of formula (1b) in which the group R is oriented downlward and H upward.

N-C

R

4

H

R3 (1b) Th copounS o forula(I) r teir salts or solvates are preferably in I ~pharmaceutically acceptable or substantiOlY pure form. BY Pharmacuticaly acceptable form is meant iner aias, of a pha uetically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carrieas, and including no material considered toxic at normal dosage levels.

10 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 pharmacenticallY acceptable form is the crystalline form, including such form in pharmaceutlical composition. In the case of salts and solvates the additional ionic and solvent moieties must also be non-toxic.

Examples of pharmaceutically acceptable salts of a compound of formula (1) include the acid addition salts wit the conventhionafl pharmaceutilcal acids, for example maleic, hydrochloric, hydrobromiic. phosphoric, acetic, fumaric, salicylic.

civic, lactc, mandelic, tarmarc. succinic, benzoic, ascorbic, and methanestulphoic.

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 stmtoisomicl form. IThe invention extends to alsuch forms and to mixtre heref. including racemates.

ThIle ineto loprovides a process for the preparaton of a compound of formula MI which comprise reacting a compound of formula(i)

R

2 or~ apru rao onetbet R R 2 and Ar i as cdmpond fof formula X' OH S Fr4 N R's or an active derivative thereot~ in which RV 3

R!

4 R:5 and Xare R 3

R

4

R

an sdfndfrfrua()o rupcnetbet 3 4 5adX ofr a compound of formula (1c) 2 R' R' R 4 N R? (Ic0 and optionally thereafter performing one or more of the following steps: where R! to R 5 ,Ae andX) ae other than R, to R 5 Arand X convetngany one of R!,R to R! 5 ,rand X to R, Rto R 5 Arand X toobtaina compound Of formula ()where R'.TV to R5, Ar' and XareRP, R, to R 5 Ar and X, converting any on fR ,t 5 r n oaohrR ,t 5 radXt banacmon of formula forming a salt and/or solvate of the obtained compound of formula (1c).

Suitable active derivatives of the compounds. of formula (ED are acid halides (preferably chlorides), acid azides or acid anhydrides. Another suitable derivative is a mixed anhydride formed between the acid and an alkyl chicroformate; another suitable derivative is an activated ester such as a cyanomethyl. ester, thiophenyl. estr, p-nitrophenyl esm.r p-nitrothiopheayl. e=te, 2,4fi-ridulorqphnyI es=e, pentachiorophenyl ester, pentalluoropbenyl emte. N-hydroxy-phtalimido ester Nhyiroxypiperidine ester. N-hydroxysn~~tflde ester, N-hydroxy beuzotriazole estr or the carboxy group may be activated using a carbodlimide or N.'Mcarbonyldiimidazole.

For example, In standard methods well known to thos silled in the art, the compounds of formula (MI) may be couipled: with an acid cbloride inthe presemltof aninorganic or organic base in a suitable aptotic solven such as dimethylf raide (DMF) at a temperature in a 6 range from -70 to 5 0 C (preferably in a range from -10 to with the acid in the presence of a suitable condensing agent, such as for example NXN-cnrbonyl dfiiridazole (CDI) or a carbodinide such as dicyclohexylcubodifde (DCC) or N-iehlmnpoy-'ehlmofmd and N-hydroxybenzotriZOe (HOBT) to maxizise yields and avoid racemizalion processes (Synthesis, 453, 1972) in an aprotic solvent such as a mixt of acetuifule (MeCN) and tenraliydrofumn C1XF) in a ratio from 9 to 7 respectively, at a temperaxure in a range from -70 to 501C (preferably in a range from -10 to 250Q) (wee Scheme 1).

-7 o IH r COOMAe fromP -2 t70 0 with mixedt arad generated infi fomteai and aecn a~Iky (o compound of formula or one compound of formuda may be-converted to another compound of formula by inteiconversiofl of suitable substituenEs. Thus, cerain compounds of formula aI) and (1c) are useful inermediates in forming other compounds of the preset invention- For example R! 2 may be hydrogen and converted to R 2 aIYl group, for example methyl, by conventional amnide alicylation procedures (Zabicky, The chemiwy of amides; Interscience, London, 1970, p. 749). When K~ is oxygen, it may be converted to X sulphur by standard tbioamide formation reagents. SUCh 2s P 2

S

5 (Oxeni. Rev., 61, 45, 191 or Angew. Ozem., 78, 517, 1966) or the Lawesson reagent (Tetrahedrm 41, 5061,.195). When Ar'or IVS is a methoxy substiarted phenyl, it may be converted to another Ar' or R'S hydroxy substituted pheiiyl by standard demethylation procedures via Lewis acids, such as boron trbromide (Syndzesis. 249, 1M6) or mineral acids, such as hydrobtumic or hydroiodic acid. When R is an alkoxycarbonyl group, for example' methoxycarboflyL it may be converted to another R. such as I. ~~ethoxycarboflyl by rransesteriicaiofl with an appropriat alcohol at a temperatue in a range from 20 to 120 0 C, carboxy by hydrolysis in acidic or basic medium, aminocabonyl, alkylarninocabonyl or diakyllflinocaboflyl by tranamidation with wrimonia, a primary Amie or a secondary amine in methanol as solvent at a tempertumif in a range from 10 to 120 0 C optionally in the presnce of a catalytic amount of NaCN OtC1mL 52, 2033, 1-97) or by using trimethylauminium (Me 3 AI) (Terraledro Lerrer, 48, 417 1. 1M7, hydroxyntethyl by a selective metal hydride reduczion soch as lithium borohydride reduction (Termazedron, 35, 567, M99) or sodium borohydride reduction in THF MeO (i ChmL Soc. Japan, 57, 1948, 1M8 or Syndi Commzm., 12. 463,.1M8). alkarbonyl by acyl chloride formation and susq ent n with alympsmhalides in THF as solvent at4- 8A a temperatre in a range from -78 to 3 0 C (Terrahedron Letters, 4303. 1979) or with alklcdmiif haids o dalycadia in the pres n= Of M90I 2 or LiCI Org.

Giem.., 47,2590, 1982). Another group which R! as methoxycarbonyl can be converted into is a substituted heteroaromatic ring, such as an oxadiazoic (J Med.

(Them., 34, 2726, 1991).

Scheme 2 summarizes some of the above, described procedures to convert a compound of fomua(1c) or iwhicI is oxygen R!isCOOMe AYandRW, to

WS

5 are as descdibed for formula to another compound of formula Scheme 2

R

1 N Fr, Me ORe (;r2 O PC 1 2 C 2

.H

2 0 iFr Fo FFrN

W

3 N &M r W W 5 M.To The cmpouds offormla maybe cnvered lo ther phr etiay accptale cidad i 3nslsb ecinwt the aprprat orai or minr

H

aciCs Solate o th conp ItaSo ml maFefredb rsaliaino 4 0n~ i~ mt ea pr pit ov o o Nx r pe h dae may e f r e Mrhl F1 r 9 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 stereoisomeric form and the process of the invention may produce racemates as well as enaniomerically pure forms. To obtain pure enantiomers, appropriate enantiomerically pure primary or secondary amines of formula (HId) or (Hle) Re, R1 (e) are reacted with compounds of formula to obtain compounds of formula (rd) or (re).

R'

R'

"N R R

R'

(Id) (re) 20 Compounds of formula (Pd) or (Fe) may subsequently be converted to compounds of formula (Id) or (le) by the methods of conversion mentioned before.

R2

R

N RFI R (Id) Compounds of formula (II) are known compounds or can be prepared from known compounds by known methods. oye For example, the compound of fo la in which X' is oxygen, R' 3 b r R h opndo om~a, R4 ":l F4 .Rs

R,

7 and R' 5 are hydrogen is described in Pfitzinger, J. PrakL Owem, 38, 582. 1882 and in Pfitzinger, J. Proct Ctem, 56, 293, 1897; the compound of formula in which Xr is oxygen. R 3 and R! 4 axe hydrogen and R' 5 is 2-pyridyl is described in Risaliti, Ric.

ScienL, 28, 561, 1958; the compound of formula in which X is oxygen. R'3 and

RV

4 are hydrogen and R'S is rn-and p-chlorophenyl, o-fiuoropheflyl and 3,4dichiorophenyl are described in Brown et aL, J. Am. Chiem. Soc., 68, 2705, 1946: the compound of formula in which IC is oxygen RV3 and R' 4 are hydrogen and R' 5 is p-methoxyphenyi is described in Ciusa and Lumzatt. Gaz. 0dm. fAL, 44,64, 1914; the compound of formula in which rC is oxygen. R! 3 and R!4 are hydrogen and

R!

5 is m-trifluoromethylphenyl is described in Shargier and Lalezari J. Chem Eag.

Data, 8, 276, 1963; the compound of formula in which YC is oxygen, R! 3 and R!4 are hydrogen and R! 5 is p-fluorophenyl is described in Ru Hoi et aL, Rec Tray. OzimL 68, 781, 1%9; the compound of formula in which IC is oxygen, R! 3 and R' 4 are hydrogen and R' 5 is p-methylphenyl is described in Prevost er aL, Compt RenA Acad Sci., 258, 954, 1964; the compound of formula in which XC is oxygen, R' 3 and R! 4 are hydrogen and W' 5 is p-bromophenyl is described in Nicolai et aL, Eur. J.

:Med Chem, 27, 977, 1992; the compound of formula (11 in which KC is oxygen, R! 4 and R! 5 are hydrogen and W' 3 is 6-methyl is described in Buchmann and Hown, Am Cwm Soc., 68, 27 18, 1M4; the compound of formula in which rC is oxygen. R! 4 and R! 5 are hydrogen and W 3 is 8-rntro is described in Buchmn et a4 J Ant- Chem Soc., 69,380,1947; the compound of formula CIH), in which IC is oxygen,

R!

4 is hydrogen. R' 3 is 6-chioro, R5 is p-chlorophenyl. is described in Lutz ez aL, J.

Am Chenm Soc., 68, 1813.194M; the compound of formula in which Xr is oxygen 1

R!

3 and R' 4 ame hydrogen and W 5 is 2-thiazolyl is described in Ear. Pat Appl. EP 112,776: compounds of formula in which IC is oxygen. R' 3 is 8trifluoromethyL. R!4 is hydrogen and R! 5 are phenyl, o- and p-flnorophenyl. 3,4dichiorophenyl. p-mnethoxypheuyl are described in Nicolai at aL, Eurf. Med. Clien, 27,977,19M; compounds of formula in which IC is oxygen. R: 3 is 6-bromo. R'4 is hydrogen and R' 5 are phenyl or p-fluorophenyl are described in Nicolai et aL, Bur.

3. 30 J Med Cien, 27, 977, M9; other compounds of formula (U1) are described in Ger.

Offen. DE 3,721,=Z and in Ear. Pat AppL EP 384,313.

Compounds of formula (1l, Hd) and (Mfe) are commercially available compounds or can be prepared from known compounds by known methods (for example, compounds of formula in which RW is alkoxycarbonyl RW 1 arnd R! 2 ar 35 hydrogen and AxMis as defined for the compounds of formula wre described in Laebigs Ann. der Omie, 523, 199.19IM.

The activity of the compounds of formula as NK 3 receptor antagnists in stndard tests indicates that they are of potential theraputic utility in the treatment of -I 1both 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 pharmacetically 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 15 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.

20 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, S ,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 S 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 exam'pls sYrup. acacia, gelatin, sorbitol, tragacantli, or polyvinylpyrrolidoile; fillers, for exampl lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettiig lubricants, for example magnesium stearale; disinteprats. for examiple starch.

polyvinyl-pyrrolidone, sodium starch glycollat or miCrOCryTMlhlifie cellulose; or pharmacemutically acceptable setting agents such as sodium lauryl sulphate.

Solid compositions may be obtained by conventional methods of blending.

filling, tabletting or the lio. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of filers.

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 stearare 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 15 form of an ingestible capsule, freape of gelatin containing the compound, if desired with a carrer 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 reconstitutioni 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, hydroxethylcellulose.

carboxymethylcellulose, aluminium. stearaxe gel, hydrogenated edible fats; emulifyin agents, for example lecithin, sorbima monooleate, or acacia; aqueous or non-aqueous vehicles, which include edble oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerin, or propylen glycoL, or ethyl 1~ alcohol, glycerine, water or normal saine; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid: and-if desired conventional flavouring or colourin~g agents.

The compounds of this invention may also be administered by a non-oral re In accordance with routine Pharmaceuticalprcdrteom sionma be formulated, for example for rectal administration as a suppository. They may also be formulated for pre-sentation in an injectable form in ant aqueous or not!-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile.

W pyrogen-free water or a pasenterally acceptable oil or a mixtue of liquids. The liquid may contain bacteriostafic agents, anti-oxidants orotiher presarvatives, buffers or solutes to render the solution isotonic with the blood, ticening agents, suspeding agents or other pharmacetiially acceptable additives. Such forms will be presented iunit dose fozim suc a s -ampo ules ordsoale injection devices or in multi- dose ~~forms Suich a a bottle from which th prpit oemybe 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 Prefered spray formulations comprise micronised compound particles in combination with a surfactant, solvent or a dispersing agent to prevent the sedimenation 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 formulaiion. 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 15 percutaneous absorption, pressure sensitive adhesives known in the art such as natural rubber or silicone can be used.

i 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 adminisration. A unit dose will generaly contain from 20 to 1000 mg and .r 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 adminstered once or more times Sa 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 give the preceding daily dose.

No unacceptable toxicological effects are expected with compounds of the Iinvention 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 mamals, paricularly humans, which comprises adminstering to the mammal in need of such treatment andior prophylaxis an effective amountof a compound of formula or a ph rmaceudcally acceptable salt or solvate thereof She invention further provides a method for the reatmnt and/or prophylaxis of the Secondary Conditins in mammals, particularly humans, which comprises administering to the m o mmal in need of such treament and/or prophylais an Seffective amount of anNK 3 receptorantagoni 1The activiy of the compounds ofthpsent invenon, as NK 3 ligands, is eterined by t bility o inhiR ding of radiolabelled NK 3 i 125I Me-Pe7]-lKB or 3 H-Senktide, to ginea-pig and human N 3 e eptoss S14 (Renze~i eE al, 1991, Neuropeptide, 18, 104-114; Buell et at, 1992, FEBS, 299(l), Chung et al, 1994, Biochera Biophys. Res. CommuyL, 198(3), 967-972).

The binding assays utilized allow the determination of the concentration of the individual compound required to reduce by 50% the 25 1]HMe-Phe 7 i-NKB and 3 H]-Senktide specific binding to NK 3 receptor in equilibrium conditions (1C50).

Binding assays provide for each compound tested a mean IC 50 value of 2-isepanute experiments performed in dupicate or triplicate. The most poten compounds of the present invention show IC 50 values in the range 1-1000 nM; in particular, in guineapig cortex membranes by displacement of 3 Hh-Senktide. the COMPOUnds of the Examples 22,47,48, and 85 display Kis (aM) of 5.6,8.8, 12.0 and 4.8 respectively The NX 3 -antagonist activity of the compounds of the present invention is determined by their ability to inhibit senkide-induced contration of the guinea-pig ileum (Maggi er al, 1990, Br. J. PharmacoL, 101, 996-1000) and rabbit isolated idis sphincter muscle (Hall ce al., 1991, Eur. I. PharmacoL, 199, 9-14) and human NK 3 ;*X15 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 zightward shift in the concentration-response curve of senktide. Human receptor functional assay allows the determination of the concentration of the individual comp ound required to reduce by 50% (IC 50 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 ths specification and the claims which follow, unless the context requires other-wise, the wod "cmneand 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 groupj of integers or, steps

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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, receptor antagonist.

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

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. 25

4. Use according to claim 3 in the manufacture of a medicament for use in the treatment of skin disorders and itch. DATED this 14th day of January, 1999. SMITHKLINE BEECHAM FARMACEUTCI S p A. DAVIES COLLISON CAVE Patent Attorneys for the Applicant 1 I1