AU4263200A - Quinoline-4-carboxamide derivatives, their preparation and their use as neurokinin 3 (NK-3)- and neurokinin 2 (NK-2) receptor antagonists - Google Patents

Description

-1-

AUSTRALIA

PATENTS ACT 1990 DIVISIONAL

APPLICATION

NAME OF APPLICANTS: SmithKline Beecham S.p.A.

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

INVENTION TITLE: Quinoline-4-carboxamide derivatives, their preparation and their use as neurokinin 3 and neurokinin 2 (NK-2) receptor antagonists The following statement is a full description of this invention, including the best method of performing it known to us: Q:\OPER\MJC\10318-97 DIVFILE.DOC 23/6/00 -1- QUINOLINE-4-CARBOXAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS NEUROKININ 3 AND NEUROKININ 2 (NK-2) RECEPTOR

ANTAGONISTS

This application is a divisional of Australian Patent Application No. 10318/97, the entire contents of which are incorporated herein by reference.

The present invention relates to novel compounds, in particular to novel quinoline derivatives, to processes for the preparation of such compounds. to pharmaceutical compositions containing such compounds and to the use of such compounds 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 (NKI, NK2 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, JPhysiol., 470, 665-679; Counture et al., 1993, Regul. Pepides. 46, 426-429; Mccarson and Krause, 1994, J. Neurosci., 14 712-720; Arenas et al. 1991, JNeurosci., 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 ofnon-peptide NK-3 antagonists which are S. far more stable from a metabolic point of view than the known peptidic NK-3 receptor antagonists and are of potential therapeutic utility. These compounds also have NK-2 25 antagonist activity and are therefore considered to be of potential use in the prevention and treatment of a wide variety of clinical conditions which are characterized by overstimulation of the tachykinin receptors, in particular NK-3 and NK-2.

These conditions include respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma, airway hyperreactivity, cough; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis and inflammatory pain; neurogenic inflammation or peripheral neuropathy, allergies such as eczema and rhinitis; ophthalmic diseases such as ocular inflammation, conjunctivitis, vernal conjuctivitis and the like; cutaneous diseases, skin disorders and itch, such as cutaneous wheal and flare, contact dermatitis, atopic dermatitis, urticaria and other eczematoid dermatitis; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systhemic lupus erythematosis; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and urinary incontinence; renal disorders and disorders of the bladder function, (hereinafter referred to as the 'Primary Conditions').

Certain of these compounds also show CNS activity and hence are considered to be of particular use in the treatment of disorders of the central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders such as AIDS related dementia, senile dementia of the Alzheimer type, Alzheimer's disease, Down's syndrome, Huntington's disease, Parkinson's disease, movement disorders and convulsive disorders (for example epilepsy); demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as diabetic neuropathy, AIDS related neuropathy, chemotherapy-induced neuropathy and neuralgia; addiction disorders such as alcoholism; stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; eating disorders (such as food intake disease); fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of the blood flow caused by vasodilation and vasospastic diseases such as angina, migraine and Reynaud's disease and pain or nociception, for example, that is attributable to or associated with any of the foregoing conditions especially the transmission of pain in migraine, (hereinafter referred to as the 'Secondary Conditions').

The compounds of formula are also considered to be useful as diagnostic tools for assessing the degree to which neurokinin-3 receptor activity (normal, overactivity or underactivity) is implicated in a patient's symptoms.

According to the present invention there is provided a compound, or a solvate or a salt thereof, of formula

R

O NH- Ar

R

R

R

3 wherein, Ar is an optionally substituted aryl or a C5-7 cycloalkdienyl group. or an optionally substituted single or fused ring aromatic heterocyclic group,; R is C 1 -6 alkyl, C 3 7 cycloalkyl,

C

3 7 cycloalkylalkyl, optionally substituted S phenyl or phenyl C1-6 alkyl, an optionally substituted five-membered heteroaromatic ring comprising up to four heteroatoms selected from O and N, hydroxy C -6 alkyl, amino C 1 6 alkyl, C.- 6 alkylaminoalkyl. di C 1 -6 alkylaminoalkyl, C -6 acylaminoalkyl, Ci -6 alkoxyalkyl, C -6 alkylcarbonyl, carboxy, C 1 -6 alkoxycarbonyl,

C

1 -6 alkoxycarbonyl

C.-

6 alkyl, aminocarbonyl,

C

1 6 alkylaminocarbonyl, di C 1 6 alkylaminocarbonyl, halogeno C 6 alkyl; or R is a group -(CH 2 wherein p is 2 or 3 which group forms a ring with a carbon atom of Ar;

R

1 represents hydrogen or up to four optional subtitutents selected from the list consisting of: C 6 alkyl, C 6 alkenyl, aryl, C1- 6 alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulphonamido. C -6 alkoxycarbonyl, trifluoromethyl, acyloxy, phthalimido, amino or mono- and di-C 1-6 alkylamino;

R

2 represents hydrogen,

C

1 .6-alkyl, hydroxy, halogen, cyano, amino, mono- or di-C -6-alkylamino, alkylsulphonylamino, mono- or di-Ci.6-alkanoylamino wherein any alkyl group is optionally substituted with an amino group or with a mono- or dialkylamino group, or R 2 is a moiety -X-(CH 2 )n-Y wherein X is a bond or and n is an integer in the range of from 1 to 5 providing that when X is n is only an integer from 2 to 5 and Y represents a group NY 1

Y

2 wherein Y 1 and Y 2 are independently selected from hydrogen,

C

1 -6-alkyl, C1-6-alkenyl, aryl or aryl-C 6 -alkyl or Y is hydroxy, halogen or an optionally substituted N-linked single or fused ring, heterocyclic group,

R

3 is branched or linear C 1 -6 alkyl, C 3 7 cycloalkyl,

C

4 7 cycloalkylalkyl, optionally substituted aryl, or an optionally substituted single or fused ring aromatic heterocyclic group; and

R

4 represents hydrogen or C 1 -6 alkyl.

Suitably, Ar represents optonally substituted phenyl, preferably unsubstituted phenyl.

When R represents C1-6 alkylcarbonyl, an example is acetyl.

When R represents C 1 -6 alkoxycarbonyl, an example is methoxycarbonyl.

Suitably, R represents C alkyl, for example ethyl.

Preferably, R is ethyl.

Suitably, R 1 represents hydrogen or C.

6 alkyl for example methyl.

.Preferably, RI is hydrogen.

hen R 2 represents halogen it is suitably fluorine.

When R 2 represents mono- or di-C l-6-alkanoylamino, the alkanoyl group is 25 favourably an N-hexanoyl group suitably substituted with an amino group on the terminal carbon atom.

When Y is an optionally substituted N-linked single or fused heterocyclic group, any single or fused ring is suitably saturated or unsaturated and consisting of 5- or 6- ring atoms, said ring atoms optionally comprising 1 or 2 additional heteroatoms selected from O orN.

When Y is an N-linked single or fused heterocyclic group, one or two ring atoms are optionally substituted with one or two oxo groups or one or two hydroxy,

C

1 -6 alkoxycarbonyl,

C

1 6 alkyl. aryl or a single or fused ring aromatic heterocyclic group, or the substituents on adjacent ring atoms form a carbocyclic ring; said aryl or aromatic heterocyclic groups being optionally substituted with one or two C1- 6 alkyl, alkoxy, hydroxy, halogen or halogenalkyl groups.

Preferably, Y represents an N-linked single or fused heterocyclic group, any single or fused ring being saturated or unsaturated and consisting of 5- or 6- ring atoms, said ring atoms optionally comprising I or 2 additional heteroatoms selected from O or N and wherein one or two ring atoms are optionally substituted with one or two oxo groups or one or two hydroxy,

C

1 -6 alkoxycarbonyl, C -6 alkyl, aryl or a single or fused ring aromatic heterocyclic group, or the substituents on adjacent ring atoms form a carbocyclic ring; said aryl or aromatic heterocyclic groups being optionally substituted with one or two C -6 alkyl, alkoxy, hydroxy, halogen or halogenalkyl groups.

When Y represents the above mentioned heterocyclic group having an OH or an oxo substituent on one or two of the ring atoms, said atoms are preferably positioned adjacent to the linked N atom.

A suitable N-linked single ring 6- membered saturated heterocyclic group comprising an additional heteroatom is a morpholino group or a piperizinyl group, for example an optionally substituted 4 -phenylpiperazinyl group.

Suitable N-linked fused ring heterocyclic groups comprise a 5-or 6- membered saturated or unsaturated heterocyclic ring fused to a benzene ring.

A suitable N-linked fused ring heterocyclic group comprising a 6- membered saturated heterocyclic ring fused to a benzene ring is a 2 ,3 ,4tetrahydro)isoquinolinyl group.

A suitable N-linked fused ring heterocyclic group comprising a 5- membered saturated heterocyclic ring fused to a benzene ring is a 2-isoindolinyl group.

A suitable N-linked fused ring heterocyclic group comprising a 6- membered unsaturated heterocyclic ring fused to a benzene ring and having an oxo substituent on one saturated ring atom is a 1,4-dihydro-3(2H)-isoquinolinon-2-yl group or a 3,4- 25 dihydro- (2H)-isoquinolinon-2-yl group.

A suitable N-linked fused ring heterocyclic group comprising a 6- membered unsaturated heterocyclic ring fused to a benzene ring and having an oxo substituent on two saturated ring carbon atoms is an homophthalimido group.

When R2 represents a moiety -(CH2)n-Y, examples of Y include an amino group or a mono- or di-Cl.6-alkylamino group. A further example of Y in the moiety -(CH2)n-Y is a morpholino group or a 4 -phenylpiperazine group or an N-methyl-Nbenzylamino group.

A preferred value for the moiety -X-(CH 2 )n-Y is a moiety of formula a

-X-(CH

2 N

N-T

(a) (a) wherein T represents C1-6 alkyl, C 1 -6 alkoxycarbonyl, aryl or an aromatic heterocyclic group and either X is O and n is 2 or 3 or X is a bond and n is 1, 2 or 3.

Suitably X is O. Suitably X is a bond.

When T represents a C1-6 alkyl group, it is preferably a methyl group.

When T represents an aryl group it is suitably an optionally substituted phenyl group, preferably a phenyl group substituted with one or more, for example up to 3, alkoxy groups, especially methoxy groups, especially when substituted at position 2 relative to the point of attachment on the piperazinyl group.

When T represents an aromatic heterocyclic group, a suitable group is a 6 membered aromatic heterocyclic group having 2 nitrogen atoms, suitably a pyrimidine group and preferably a 2 -pyrimidine group.

A further preferred value for the moiety -X-(CH2)n-Y is a moiety of formula 0

-X-(CH

2 )n Nt T1 a a.

*aa.

a wherein X is O or a bond, n is 1, 2 or 3, T 1 and T 2 each independently represents hydroxy,

C

1 -6 alkoxycarbonyl,

C

1 -6 alkyl, aryl or a single or fused ring aromatic heterocyclic group, or T 1 and T 2 together with the carbon atoms to which they are attached form a carbocyclic ring; said aryl or aromatic heterocyclic groups being 20 optionally substituted with one or two C -6 alkyl, alkoxy, hydroxy, halogen, halogenalkyl groups; or one ofT I or T 2 is an oxo group and the other is selected from the above mentioned groups as appropriate.

Preferably,

T

1 and T 2 together with the carbon atoms to which they are attached form a carbocyclic ring, in particular a cyclohexyl ring.

When R2 represents a moiety -(CH2)n-Y, n is suitably an integer 1 or 2, for example 1.

Examples of the moiety -(CH2)n-Y include aminomethyl and methylaminomethyl, a further example is morpholinomethyl.

When

R

2 represents a moiety -O-(CH2)n-Y, examples of Y include OH, -2- 30 isoindolinyl, homophthalimido, 2 ,3 4 -tetrahydro)isoquinolinyl, 1,4-dihydro- 3 2 H)-isoquinolinon-2-yl and, especially, 3,4-dihydro- 2 H)-isoquinolinon-2-yl. Further examples of Y in the moiety O-(CH2)n-Y are: phthalimido; 3 -hydroxy-3,4-dihydro- 1( 2 H)-isoquinolinon-2-yl; 1-( 2 H)-isoquinolinon-2-yl (a favoured group); succinimido; maleimido; 2.2-dimethyl-4-oxo- 3 -imidazolidinyl; 4 2 -methoxyphenyl) piperazin-l-yl (a favoured group); 4 3 -chlorophenyl)piperazin-1-yl (a favoured group); 4 -phenylpiperazin- 1-yl (afavoured group), 4 2 -pyrimidinyl)piperazin-1-yl (a favoured group); 2-phenyl-4oxo-3-imidazolidinyl and 2, 2 -dimethyl-5-phenyl-4-oxo-3-imidazolidinyl.

When R 2 represents a moiety -O-(CH2)n-Y, n is suitably an integer 2 or 3.

Preferably,

R

2 represents a moiety -X-(CH2)n-Y.

In one aspect X is a bond.

Suitably, X represents O. When R 4 is CI- 6 alkyl, an example is methyl.

Preferred compounds of formula are those wherein: Ar is phenyl, R is ethyl, R 1 is hydrogen,

R

2 is a moiety -X-(CH2)n-Y wherein X is, preferably, O or a bond, n is 1.2 or 3 and Y is a moiety formula or as defined above; in particular should be mentioned the compounds of examples 18, 30, 33 and The compounds of formula may have at least one asymmetric centre for example the carbon atom labelled with an asterisk in the compound of formula and therefore may exist in more than one stereoisomeric form. The invention extends to all such stereoisomeric forms and to mixtures thereof, including racemates. In particular, the invention includes compounds wherein the asterisked carbon atom in formula has the stereochemistry shown in formula (Ia): Ar NH-7 4 R R4 N R 3 (la) wherein Ar, R, R 1

R

2

R

3 and R 4 are as defined in relation to formula 20 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, having 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.

S 25 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 additional 30 ionic and solvent moieties must also be non-toxic.

Suitable salts are pharmaceutically acceptable salts.

Suitable pharmaceutically acceptable salts 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.

Suitable pharmaceutically acceptable salts include salts of acidic moieties of the compounds of formula when they are present, for example salts of carboxy groups or phenolic hydroxy groups.

Suitable salts of acidic moieties include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2 -hydroxyethylamine, bis-( 2 -hydroxyethyl)-amine or tri-( 2 -hydroxyethyl)-amine cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl-p-phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine collidine, quinine or quinoline. Suitable solvates are pharmaceutically acceptable solvates.

Suitable pharmaceutically acceptable solvates include hydrates.

The term 'alkyl' (unless specified to the contrary) when used alone or when forming part of other groups (such as the 'alkoxy' group) includes straight- or branched-chain alkyl groups containing 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms, examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group.

The term 'carbocylic' refers to cycloalkyl and aryl rings.

The term 'cycloalkyl' includes groups having 3 to 12, suitably 4 to 6 ring carbon atoms.

25 The term 'aryl' includes phenyl and naphthyl, preferably phenyl which unless S*specified to the contrary optionally comprise up to five, preferably up to three substituents selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxyalkyl, hydroxy, amino, nitro, cyano, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups.

30 The term 'aromatic heterocyclic group' includes groups comprising aromatic heterocyclic rings containing from 5 to 12 ring atoms, suitably 5 or 6, and comprising up to four hetero-atoms in the or each ring selected from S, O or N.

Unless specified to the contrary, suitable substituents for any heterocyclic group includes up to 4 substituents selected from the group consisting of: alkyl, alkoxy, aryl and halogen or any two substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, may form an aryl group, preferably a benzene ring, and wherein the carbon atoms of the aryl group represented by the said two substituents may themselves be substituted or unsubstituted.

When used herein the term "halogen" refers to fluorine, chlorine, bromine and iodine, preferably fluorine or chlorine.

When used herein the term "acyl" includes residues of acids, in particular a residue of a carboxylic acid such as an alkyl- or aryl- carbonyl group.

The invention also provides a process for the preparation of a compound of formula or a salt thereof and/or a solvate thereof, which process comprises reacting a compound of formula

(III):

H Arj HIN R,

R

4 wherein RL and Ar' are R, R 4 and Ar as defined for formula or a group or atom convertible to R, R 4 and Ar respectively, with a compound of formula or an active derivative thereof: o OH

R'

I 2 N R' 3 (II) wherein R'l, R'-2 and R' 3 are Rl, R 2 and R 3 respectively as defined in relation to formula or a group convertible to RI, R 2 and R 3 to form a compound of formula (Ib): H At' I R' R' 2 N 3 (Ib) wherein Ar', R'l, R' 2

R'

3 and R' 4 are as defined above, and optionally thereafter .*"carrying out one or more of the following optional steps: converting any one of Ar', R'I, R' 2

R'

3 and R' 4 to Ar, R, RI, R 2

R

3 or R 4 respectively as required, to obtain a compound of formula (ii) converting a compound of formula into another compound of formula and (iii) preparing a salt of the compound of formula and/or a solvate thereof.

Suitable groups convertible into other groups include protected forms of said groups.

Suitably Ar', R'I or R' 3 each represents Ar, R, R

I

or R 3 respectively or a protected form thereof.

Suitably R' 2 represents a group other than a protected form which is convertible into R 2 by conventional procedures.

Suitably, R' 4 represents hydrogen, so that compounds of formula wherein the required R 4 is alkyl are conveniently prepared from the corresponding compound wherein

R

4 is hydrogen.

It is favoured if the compound of formula (II) is present as an active derivative.

A suitable active derivative of a compound of formula (II) is a transient activated form of the compound of formula (II) or a derivative wherein the carboxy group of the compound of formula (II) has has been replaced by a different group or atom, for example by a carboxy halide, preferably a chloride, or an azide or a carboxylic acid anhydride.

Other suitable active derivatives include: a mixed anhydride formed between the carboxyl moiety of the compound of formula (II) and an alkyl chloroformate; 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, Nhydroxy-phtalimido ester, N-hydroxypiperidine ester, N-hydroxysuccinimide ester, Nhydroxy benzotriazole ester; alternatively, the carboxy group of the compound of formula (II) may be activated using a carbodiimide or N,N'-carbonyldiimidazole.

The reaction between the compound of formula (II) or the active derivative thereof and the compound of formula (III) is carried out under the appropriate conventional conditions for the particular compounds chosen. Generally, when the 25 compound of formula (II) is present as an active derivative the reaction is carried out using the same solvent and conditions as used to prepare the active derivative, preferably the active derivative is prepared in situ prior to forming the compound of formula (Ib) and thereafter the compound of formula or a salt thereof and/or a solvate thereof is prepared.

For example, the reaction between an active derivative of the compound of Sformula (II) and the compound of formula (III) may be carried out: by first preparing an acid chloride and then coupling said chloride with the compound of formula (III) 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 to 50°C (preferably in a range from -10 to 20°C); or by treating the compound of formula (II) with a compound of formula (III) 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 Ndimethylaminopropyl-N'-ethylcarbodiimide preferably in the presence of Nhydroxybenzotriazole (HOBT) to maximise yields and avoid racemization processes (see Synthesis, 453, 1972), in an aprotic solvent, such as a mixture of acetonitrile (MeCN) and tetrahydrofuran (THF), for example a mixture in a volume ratio of from 1:9 to 7:3 (MeCN:THF), at a temperature in the range of from -70 to 50 0 C (preferably in a range of from -10 to 25 0

C).

A preferred reaction is set out in Scheme 1 shown below: Scheme 1 H Ar' O OH 0 N R'

R'

2 Ar' DCC, HOBT R- R' 4 RI H

R'

N R R' MeCN/THF 3:7 N R' 0-20'C (11) (111) (Ib) wherein Ar', R' 1

R'

2

R'

3 and R' 4 are as defined above. It will be appreciated that a compound of formula (Ib) 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 (Ib) are useful intermediates in forming other compounds of the present invention.

Accordingly, in a further aspect the invention provides a process for preparing a compound of formula or a salt thereof and/or a solvate thereof, which process comprises converting a compound of the above defined formula (Ib) wherein at least one 20 of Ar', R' t

R'

2

R'

3 or R' 4 is not Ar, R, RI, R 2

R

3 or R 4 respectively, thereby to provide a compound of formula and thereafter, as required, carrying out one or more of the following optional steps: converting a compound of formula into another compound of formula and preparing a salt of the compound of formula and/or a solvate thereof.

25 Suitably, in the compound of formula (Ib) the variables Ar', R' 1 and R' 3 are Ar, R, RI or R 3 respectively or they are protected forms thereof, R' 2 is a group or atom which may be converted into a variable R 2 by one or more steps and R' 4 is hydrogen which thereafter is converted as required into a C -6 alkyl group.

Favourably,

R'

2 represents OH, CH 3 or an amino group.

30 R'2 can also represent a moiety -X-(CH2)n-Y' wherein X and n are as defined in relation to the compounds of formula and Y' is a group Y which is convertible into another group Y, for example Y' represents

NH

2 The conversion of any group Ar', R'l or R' 3 into Ar, R, R I or R 3 which as stated above are usually protected forms of Ar. R, R, or R 3 may be carried out using appropriate conventional conditions such as the appropriate deprotection procedure.

The conversion of any group

R'

2 into R 2 (including the conversion of any group Y' into another group Y in the above mentioned moiety -X-(CH2)nl-y') may be carried out using appropriate conventional reagents and conditions: For example, when

R'

2 is OHf, the compounds of formula (Ib) can be converted to compounds of formula as described in Schemes 2a and 2b.

Scheme 2a COOEt KI K 2 C0 3 THF r.t.

0 1 12X$ (C 2 )X er 0 KI. K 2 C0 3 THF, reku 2. NH 2

NH

2

'H

2 0 ElOH reflux 4h, I NaSH 4 refiux 3h, 0 NH <Al' R- (CH,)y OH N

R'

3 H

CCH

2 )clL 2 -0 R- (CH 2 )X (a(CH 2 )rL 3 'N NH 2 KI TEA DMF 80 0 C 31, S.

S

*SSS

*5

S

*SSS

SSSS

*5

S

S

S

S *5 Swann 0 Toluene 4A Mot. slaves M3 reflux H NYIa~ e.g. HN'IXU 4NaCNBH 3 r MOH a~t 0, CHO (CH 2 )y 0 N R' 0 0

-N

N. (C" 2

)X

N

R'

3 0 1. NaSH 4 WOK-N1 2 O r.

2. kCI TEA r.t 3. H 2 PdIC 5% ACOHITFA SOOC 0 NH -r<At 0 b R-1

(CH

2 N R 3 0 S cheme 2b -1 1-

K

2

C

3 0 NH r OH THF. AR' R'H CI-(C_)x-NYl "Y2 a O(C2)x-NY,"Y2 N 3 R' 0

R-

(Ib)

(IV)

wherein Ar',

R'

1

R'

2 and R' 3 are as defined above, L 1 is a leaving group or atom, such as a halogen atom for example bromine,

L

2 and L 3 each independently represent a leaving group or atom, preferably the same leaving group or atom, such as a halogen atom for example bromine, q is an integer I or 2, r is zero or an integer 1, x is an integer in the range of from 2 to 5, y is an integer in the range of from 1 to 4, Y 1 a and Y2 a together with the nitrogen to which they are attached represent an N-linked single or fused ring heterocyclic group, any single or fused ring being saturated or unsaturated and consisting of 5- or 6- ring atoms, said ring atoms optionally comprising 1 or 2 additional heteroatoms selected from O or N and wherein one or two ring atoms are optionally substituted with one or two oxo groups or one or two hydroxy, C1-6 alkoxycarbonyl, C I 6 alkyl, aryl or a single or fused ring aromatic heterocyclic groups, said aryl or aromatic heterocyclis groups being optionally substituted with one or two C 1 -6 alkyl, alkoxy, hydroxy, halogen, halogenalkyl groups.

In Scheme 2a,as illustrated, an example of HN Y 1 aY 2 a is 1,2,3,4tetrahydroisoquinoline.

The reactions in Schemes 2a and 2b illustrate that when R 2 is OH the compound 0 of formula (Ib) can be converted into a compound wherein

R

2 is -O-(CH2)n-Y' wherein n is as defined in relation to the compounds of formula and Y' is Y as defined in relation Sto formula or is a group convertible thereto, by reaction with a compound of formula

(IV):

Ll-(CH2)n-Y'

(IV)

25 wherein n and Y' are as defined and illustrated above and L 1 is a leaving group or atom, such as a halogen atom, for example bromine and chorine The particular reaction conditions used depends upon such factors as the specific nature of the required conversion and the nature of the compound of formula (IV) but generally the appropriate conventional conditions are employed. For example: As is shown in Scheme 2a, when R' 2 is OH, it can be converted to 2 -aminoalkoxy by reaction with 2 -bromoalkylphthalimide and potassium carbonate

(K

2 CO3) in boiling THF to obtain the phthalimido derivative which is, in turn, hydrolized with hydrazine hydrate in alcoholic medium.

-12- The primary amine when R' 2 is O(CH2)n

NH

2 wherein n is as defined above) can be converted to a cyclic tertiary amine by reacting with an o-dibromoalkyl benzene in DMF at 800 C, using TEA to trap the forming hydrogen bromide. The primary aminoalkoxy quinoline can also be tranformed in an homophthalimidoalkoxy quinoline, by refluxing with homophthalic anhydride in toluene, azeotroping the forming water with a Dean-Starck apparatus or using 4A molecular sieves. The carbonyl at position 3 of the homophthalimido group can be reduced to hydroxy with sodium borohydride (NaBH 4 in methanol at room temperature; subsequently, the hydroxy group can be eliminated by reaction with mesyl chloride (MsCI) and TEA and the forming double bond can be reduced with hydrogen using a palladium on carbon catalyst Pd on C) in a mixture of acetic acid and trifluoroacetic acid (AcOH/TFA).

The hydroxy group at position 3 of the quinoline ring can also be alkylated with a bromoalkyl ester, for example ethyl bromoacetate, and K 2

CO

3 in THF at room temperature; the resulting ester moiety can be reduced to alcohol with a selective metal borohydride, such as NaBH 4 in boiling t-BuOH/MeOH (Bull. Chem. Soc. Japan, 1984, 57, 1948 or Synth. Commun., 1982, 12, 463). The hydroxy moiety may then be oxidized to the corresponding aldehyde in standard Swern conditions, with oxalyl chloride/DMSO at -60 0 C in CH 2 C1 2 (Tetrahedron, 1978, 34, 1651). Reductive amination of the so formed aldehyde with a c clic secondary amine, such as 1, 2 3 4 -tetrahydroisoquinoline and NaCNBH 3 in methanol at room temperature Am. Chem. Soc., 1971, 93, 2897) affords the corresponding 1,2,3,4-tetrahydroisoquinolinylalkoxy derivative.

In Scheme 2bit is illustrated that the compound of formula (Ib) wherein

R

2 is OH can be reacted with a compound of formula (IV) wherein Y is an N-linked single or fused ring heterocyclic group as defined in relation to Y of formula to provide the respective compound of formula wherein Y is the said N-linked single or fused ring heterocyclic group. In Scheme 2b the heterocyclic group HNYlaY 2 a is, for example, an N linked piperazine. The reaction is carried out using conventional alkylation conditions in an aprotic solvent such as tetrahydrofuran, preferably in the presence of a base, for example potassium carbonate, usually at an elevated temperature, conveniently at the reflux 30 temperature of the solvent.

When R' 2 is CH 3 compounds (Ib) can be converted to other compounds of formula as described in Scheme 3.

Scheme 3 -13- 0 NH -Ar' Ar R' 0 NH-_ NBS cat. (PCO)202

C

C3 CICH 2

CH

2 Ci, 80*c NYaY 2 a e.g.

'N R' 3 MeOH (Ib)

(I)

wherein Ar', R'I, R' 2 and R' 3 are as defined above and wherein Y a and Y 2 a are as defined in relation to Scheme 2a or 2b.

In particular, when R' 2 is CH 3 it can be transformed to a (monoalkyl) or (dialkyl) aminomethyl quinoline derivative by reacting the intermediate bromomethyl derivative (prepared using N-bromosuccinimide in dichloroethane in the presence of a catalytic amount of benzoylperoxide) with the appropriate amines, to yield, for example the 3morpholinomethyl derivative.

When R' 2 is NH2, compounds (Ib) can be converted to other compounds of formula using the appropriate conventional procedures.

In particular, when R' 2 is NH 2 it can be converted to a (monoalkyl) or (dialkyl)amino acylamino group by reaction with an o-chloroacylchloride and subsequent displacement of the chlorine atom or with potassium phthalimide in refluxing

DMF,

followed by hydrolisis with hydrazine hydrate in alcoholic medium, or with the appropriate mono- or di-alkylamine in methanol as solvent at a temperature from 200 to 100 0

C.

In a further particular aspect, there is provided a process for the preparation of compounds of formula wherein Ar is phenyl, R is C1-6 alkyl, R 4 is hydrogen or C -6 alkyl and R 2 represents a moiety -(CH2)n-NHY 3 wherein Y 3 is a group -CR(Ar)(R4) wherein Ar and R are as last above defined and n is as defined in relation to formula .which process comprises: halogenating a compound of formula (II) wherein R' 1 and R' 3 are as defined above 25 and R' 2 is -(CH2)n-1-CH 3 and thereafter reacting the halogenated product with a compound of formula

H

2 N 4 Ar'

(V)

30 wherein Ar', R' and R' 4 are as last above defined or are protected forms thereof..

000 30 S. The compound of formula (II) is preferably in an activated form, as described above, and especially as a tert butvl ester.

-14- The halogenation reaction is effected by use of conventional halogenating reagents, such as the use of N-bromosuccinamide for bromination usually in an inert solvent such as carbon tetrachloride, at any temperature providing a convenient rate of formation of the required product, suitably at an elevated temperature such as the reflux temperature of the solvent.

The reaction between the said halogenated product, and the compound of formula is suitably carried out in a protic solvent, usually an alkanolic solvent such as ethanol, at a temperature in the range of from 0°C to The conversion of R' 4 when representing hydrogen into a C 1 -6 alkyl group is carried out using the appropriate conventional procedure, for example the procedure shown in Scheme 4: Scheme 4 NH-KAr' Ar' COMe 0 NH R- 4 R 2. (uOH.S.

4

R

2 COMe N NR'3 t- R' N wherein Ar', R'2 R' 3 and R' 4 are as defined above.

Suitable conversions of one compound of formula into another compound of formula include conversions wherein one group R, RI, R 2

R

3 or R 4 is converted into another group R, RI, R 3 or R 4 respectively, said conversions conveniently proceeding via appropriate groups Ar', R'I, R' 2

R

3 and R' 4 using conventional methodology, for example those methods described in the reaction Schemes herein.

S :-Examples of conversions of one compound of formula into another compound of formula include those wherein R 2 is converted into other values ofR 2 Thus when R, is a group -O-(CH2)n-NH- 2 wherein n is as defined in relation to formula suitable conversions into other values ofR- are illustrated in Scheme Scheme o NH<A r 0 0. '-NH 2 N (CH 2 x= 2-4 OEN 3

R-

2) QS.C 0EOHC A 1) o 2s00 3) Na. TH, Z 2) 200C. ttMh HN COo 0 NH 0 FMOC Ar' 0 SR ,N Et* DMF 0 OR' R' N (CH 2 X X0(C- N R 0

M

2 CO NcHO n NeOH /MeOH N R' 3 N R'3 wherein Ar', RI', R 2 and R 3 are as defined in relation to the compounds of formulae (II) and (III).

The reaction of the compound of formula wherein R 2 is a group -O-(CH2)n-NH2 (the 'primary amine') with FMOC protected glycinyl chloride or an appropriately substituted derivative thereof to provide a compound having an N- linked 4-oxoimidazolidinyl group, or a substituted derivative thereof, is conveniently carried out in an inert solvent such as methylene dichloride at any temperature providing a convenient rate of formation of the required product, usually at reduced to ambient temperature, for example in the range of 0 0 C to ambient temperature to initially provide S" an aminoacetylaminoethoxy intermediate or an appropriately substituted derivative thereof. Ring closure of this intermediate is effected by treatment with an appropriate aldehyde or ketone depending upon the nature of the required ring. Thus, when the required ring is a 2,2-dimethyl substituted ring then acetone is used, usually in an nbutanol solvent at reflux, or when a 2-phenyl substituted ring is required then benzaldehyde is used, in refluxing methanol.

Alternatively, when the primary amine intermediate is reacted with succinic anhydride in an aromatic hydrocarbon solvent such as toluene, usually at an elevated temperature, for example the reflux temperature of the solvent, the 3-carboxypropanoyl intermediate produced can be cyclised to provide a succinamido group by heating with tetrahydronaphthaline.

*A compound wherein Y is a 1, 4 -dihydro-3(2H)-isoquinolinon-2-yl group or a derivative thereof is prepared from the primary amine intermediate by reaction with an appropriate isochromanone in an alkanolic solvent, such as ethanol suitably absolute -16ethanol, at an elevated temperature such as the reflux temperature of the solvent to provide a 2 2 -hydroxymethyl)phenylacetyl intermediate which is cyclised first by activation, for example by chlorinating the hydroxymethyl group with thionyl chloride, followed by treatment with a base such as sodium hydride in tetrahydrofuran to effect cyclisation; preferably the cyclisation carried out in the presence of a catalytic amount of 1,3-dimethyl-2-imidazolidinone.

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 enantiomerically pure forms. Accordingly, a pure enantiomer of a compound of formula is obtained by reacting a compound of the above defined formula (II) with an appropriate enantiomerically pure primary amine of formula (IIIa) or (IIIc): H

H

Ar' H Ar' H R' H' N R'

R'H

R'4 R' (IIIa) (IIIc) wherein R'4and Ar' are as defined above, to obtain a compound of formula (I'a) or H Ar' H Ar' O N R' 0 N R' R'l 1 R' I R:N R' N R'3 (I'c) 20 wherein Ar', R'I, R'2, R' 3 and R' 4 are as defined above.

Compounds of formula or may subsequently be converted to compounds of formula (Ia) or (Ic) by the methods of conversion mentioned before: H Ar H Ar *I O0 N "R R 4

R

SRNR

5Ia)N

R

N 3 N R3 25 (Ia) (Ic) -17wherein Ar, R, R 1

R

2

R

3 and R 4 are as defined above.

Suitably, in the above mentioned compounds of formulae (III'a) and (III'c) R 4 represents hydrogen.

An alternative method for separating optical isomers, for example for those compounds of formula wherein R 4 is different from hydrogen, is to use conventional, fractional separation methods in particular fractional crystallization methods. Thus, a pure enantiomer of a compound of formula is obtained by fractional crystallisation of a diastereomeric salt formed by reaction of the racemic compound of formula with an optically active strong acid resolving agent, such as camphosulphonic acid, in an appropriate alcoholic solvent, such as ethanol or methanol, or in a ketonic solvent, such as acetone. The salt formation process should be conducted at a temperature between and 80 0 C, preferably at 50 0

C.

In the case in which other basic functionalities, such as primary, secondary or tertiary amine, are present in the molecule, a wider range of optically active acid resolving agents become available, including tartaric acid, O,O'-di-p-toluoyltartaric acid and mandelic acid.

The compounds of formula (II) wherein R 2 is CH 3 OH or NH 2 and protected forms of such compounds are either known compounds or they are prepared according to methods used to prepare known compounds, for example 3 -methyl-2-phenyl-4-quinoline carboxylic acid (R 2 is CH 3 CAS [43071-45-0]) is prepared in accordance with the methods described in Synthesis (1993), page. 993; 3 -hydroxy-2-phenyl-4-quinoline carboxylic acid (R 2 is OH, CAS [485-89-2]) is prepared in accordance with the methods described in U.S. Patent 2,776,290 (1957); and 3 -amino- 2 -phenyl-4-quinoline carboxylic (R2 is NH 2 CAS [36735-26-9]) is prepared in accordance with the methods described in Chemical Abstract 77:61 7 69u Khim. Geterotsikl. Soedin. (1972), 4, 525-6).

Compounds of formula (III) and are commercially available compounds (particularly when R' alkyl) or they can be prepared from known compounds by known methods. for example, compounds of formula (III) in which R' is alkoxycarbonyl and R' 4 is hydrogen 30 and Ar' is as defined for the compounds of formula are described in Liebigs Ann. der Chemie, 523, 199, 1936.

The compounds of formula (IV) are known compounds or they are prepared using methods analogous to those used to prepare known compounds, for example those Sdisclosed in in USP4386091(Mead Johnson) and USP4487773 (Mead Johnson).

It will be appreciated that in any of the above mentioned reactions any reactive group in the substrate molecule may be protected according to conventional chemical practice.

Suitable protecting groups in any of the above mentioned reactions are those used conventionally in the art. Thus, for example suitable hydroxyl protecting groups include 40 benzyl or trialkylsilyl groups.

The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected. Thus for example a benzyloxy group may be prepared by treatment of the appropriate compound with a benzyl halide, such as benzyl bromide, and thereafter, if required, the benzyl group may be conveniently removed using catalytic hydrogenation or a mild ether cleavage reagent such as trimethylsilyl iodide or boron tribromide.

As indicated above, the compounds of formula have useful pharmaceutical properties, accordingly 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 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, flavouring agent, colouring 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.

if 25 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 30 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.

-19- The compositions, for example those suitable for oral administration. may 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, 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 coconut oil, oily esters, for example 25 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 30 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 S. 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 35 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 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 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 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 V 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 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 or a pharmaceutically acceptable salt or solvate thereof.

The activity of the compounds of the present invention, as NK 3 ligands, is 35 -determined by their ability to inhibit the binding of the radiolabelled

NK

3 ligands. [125I].

S Me-Phe7-NKB 3 H]-Senktide, to guinea-pig and human

NK

3 receptors (Renzetti et al, 1991, Neuropeptide, 18, 104-114; Buell et al, 1992, FEBS, 299(1), 90-95; Chung et al, 1994, Biochem. Biophys. Res. Commun.. 198(3), 967-972).

The binding assays utilized allow the determination of the concentration of the individual compound required to reduce by 50% the 12 5 I]-[Me-Phe7]_NKB and [3H]- Senktide specific binding to NK 3 receptor in equilibrium conditions Binding assays provide for each compound tested a mean IC 5 0 value of separate experiments performed in duplicate or triplicate. The most potent compounds of the present invention show

IC

5 0 values in the range 0.1-1000 nM. The NK3 -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.

As stated above, the compounds of formula are also considered to be useful as diagnostic tool. Accordingly, the invention includes a compound of formula for use as diagnostic tools for assessing the degree to which neurokinin-3 receptor activity (normal, overactivity or underactivity) is implicated in a patient's symptoms. Such use comprises the use of a compound of formula as an antagonist of said activity, for example including but not restricted to tachykinin agonist-induced inositol phosphate turnover or electrophysiological activation, of a cell sample obtained from a patient. Comparison of such activity in the presence or absence of a compound of formula will disclose the degree of NK-3 receptor involvement in the mediation of agonist effects in that tissue.

The following Descriptions illustrate the preparation of the intermediates, whereas the Examples illustrate the preparation of the compounds of the present invention. The compounds of the Examples are summarised in Tables 1-3 below.

a -22- .i.

go DESCRIPTION 1 3-Morpholinomethyl-2-phenylquinoline-4-carboxylic acid hydrochloride 5.60 g (21.27 mmol) of 3-methyl-2-phenylquinoline-4-carboxylic acid (CAS [43071-45were dissolved in 100 ml of CH 2

CI

2 7.60 g (42.50 mmol) of N-bromosuccinimide and 0.52 g (2.00 mmol) of dibenzoyl peroxide were added and the suspension was refluxed for 24 hours.

SAfter cooling, the reaction mixture was evaporated in-vacuo to dryness, dissolved in 100 ml of THF and added to 50 ml (573.92 mmol) of morpholine. Then, it was stirred at room 35 temperature overnight, evaporated in-vacuo to dryness and purified by gradient flash column chromatography on 230-400 mesh silica gel using a mixture of CH2CI2/MeO

H

95:5 containing 0.5% NH 4 0H as starting eluent and a mixture of CH2CI2/MeOH -23- 80:20 containing 2% NH40H as final eluent. The product obtained was dissolved in acetone and acidified with HCl/Et2O; the precipitate so formed was recovered by suction filtration; 0.85 g of the title compound were obtained as a white solid.

C2 1

H

2 0N 2 03 -HCI M.P. =173-1751C M.W. 384.87 I.R. (Nujol): 3700-3100; 2750-2000; 1710; 1630 cm-1.

DESCRIPTION 2 (S)-N-(a-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide 2.49 g (9.4 mmol) of 3 -hydroxy-2-phenylquinoline-4-carboxylic acid (CAS [485-89-2]) were suspended in 150 ml of a 7/3 mixture of THF/CH 3 CN; 1.40 g (10.3 mmol) of 1hydroxybenzotriazole (HOBT) and 1.27 g (9.4 mmol) of (S)-a-ethylbenzylamine dissolved in 20 ml of CH2CI 2 were added and the reaction mixture was stirred at room temperature for 30 minutes. 2.13 g (10.3 mmol) of dicyclohexylcarbodiimide

(DCC)

dissolved in 20 ml of CH 2 C1 2 were added dropwise. The reaction was left at room temperature overnight, quenched with 20 ml of H20, evaporated in-vacuo to dryness and dissolved in EtOAc. The precipitated dicyclohexylurea was filtered off and the organic layer was washed with H 2 0, 20% citric acid, sat. sol. NaHCO 3 sat. sol. NaC1. The organic layer was separated, dried over Na 2

SO

4 and evaporated in-vacuo to dryness; the residue was purified by gradient column chromatography on 60-240 mesh silica gel using a mixture of hexane/EtOAc 9:1 as starting eluent and a mixture of hexane/EtOAc 7:3 as final eluent. The crude product was recrystallized from i-PrOH to yield 1.75 g of the title compound as a white solid.

C2 5

H

22

N

2 0 2 M.P. 68-168.4oC M.W. 382.47 20 -28.5 MeOH) 30 Elemental analysis: Calcd. C, 78.51; H, 5.80; N, 7.33; Found C, 78.49; H, 5.84; N, 7.26.

I.R. (KBr): 3370; 1625; 1525 cm- 1 300 MHz 1 H-NMR (DMSO-d 6 6 9.80 1H); 9.11 1H); 8.00-7.94 3H); 7.61- 3• 7.42 8H); 7.38 (dd, 2H); 7.28 (dd, 1H); 5.06 (dt, 35 1H); 1.82 (ddq, 2H); 0.97 3H).

MS (El; TSQ 700; source 200 C;70 V; 200 uA): 382 264; 247; 219.

DESCRIPTION 3 (S)-N-(a-ethylbenzyl)-3-(ethoxycarbonylmethoxy)-2-phenyuinoline-4-carboxamide g (5.2 mmol) of (S)-N-(a-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (compound of Description 2) were dissolved, under nitrogen atmosphere, in 20 ml of THF; 2.0 g (14.5 mmol) of K 2 CO3, 0.87 ml (7.8 mmol) of ethyl bromoacetate and a catalytic amount of KI were added and the mixture was stirred at room temperature for 2 hours and 30 minutes.

After filtering off the inorganic salts, the solution was evaporated in-vacuo to dryness, dissolved in EtOAc and washed with water; the organic layer was separated, dried over Na 2

SO

4 and evaporated in-vacuo to dryness to obtain 3.3 g of a yellow oil.

This oil was purified by flash column chromatography on 230-400 mesh silica gel, eluting with a mixture of hexane/EtOAc 7:3 containing 0.5% NH 4 0H The crude solid obtained was triturated with i-Pr20/i-PrOH, filtered, washed and dried to yield 2.1 g of the title compound as a white solid.

C2 9

H

2 8

N

2 0 4 M.P. 103-105'C M.W. 468.56 [a]D 20 -42.5 MeOH) Elemental analysis: Calcd. C, 74.34; H, 6.02; N, 5.98; Found C, 74.44; H, 6.01; N, 6.00.

I.R. (KBr): 3320-3140; 3100-3020; 2980-2920; 1758; 1630; 1550 cm-1 300 MHz 1 H-NMR (DMSO-d 6 6 9.28 1H); 8.08 1H); 8.05-7.98 2H); 7.80- 7.71 1H): 7.60 2H); 7.55-7.48 3H); 7.43 (d.

25 2H); 7.35 (dd, 2H); 7.28 (dd, 1H); 5.06 (dt, 1H); 4.26 (ABq, 2H); 4.04 2H); 1.86-1.67 2H); 1.12 (t, 3H); 0.96 3H).

MS (EI; TSQ 700; source 180 C;70 V; 200 uA): 468 439; 334; 306; 278.

30 DESCRIPTION 4 o° (S)-N-(a-ethylbenzyl)-2-phenyl-3-(2-phthalimidoethoxy)quinoline-4-carboxamide S1.90 g (5.0 mmol) of (S)-N-(a-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (product of Description 2) were dissolved in 20 ml of THF.

35 3.80 g (14.9 mmol) of N-(2-bromoethyl)phthalimide dissolved in 15 ml of THF, 2.00 g (14.5 mmol) of K 2

CO

3 and 0.25 g of KI were added and the suspension was stirred at room temperature for 2.5 hours and then refluxed for 2 hours.

Additional 1.90 g (7.4 mmol) of N-( 2 -bromoethyl)phthalimide and a catalytic amount of KI were added and the reaction refluxed for 3.5 hours; additional 0.50 g (2.0 mmol) of N- (2-bromoethyl)phthalimide and a catalytic amount of KI were added and the reaction refluxed for 5 hours.

The inorganic salts were filtered off and the reaction mixture evaporated in-vacuo to dryness, dissolved in CH2C1 2 and washed with water; the organic layer was separated, dried over Na2SO 4 and evaporated in-vacuo to dryness. The residue was purified by flash column chromatography on 230400 mesh silica gel, eluting initially with a mixture of hexane/ethyl acetate 8:2 containing 0.5% NH 4 0H and then with a mixture of hexane/ethyl acetate 3:2 containing 0.5% NH 4 0 H The crude solid obtained (2.60 g) was triturated with i-Pr 2 O, filtered, washed and dried to yield 2.5 g of the title compound.

C35H2 9

N

3 0 4 172-175oC M.W. 555.64 [a(]o 2 -16.3 MeOH) I.R. (KBr): 3280; 3060; 2960; 1780; 1715; 1660; 1530 cm- 1 300 MHz IH-NMR (DMSO-d 6 5 9.27 1H); 8.03 1H); 7.92-7.84 4H); 7.78- 7.69 3H); 7.60-7.53 2H); 7.46-7.38 4H); 7.27 (dd, 1H); 7.13-7.04 3H); 4.96 (dt, IH); 3.92- 3.78 2H); 3.72-3.55 2H); 1.78 (dq, 2H); 0.93 3H).

MS (EI; TSQ 700; source 180 C;70 V; 200 uA): 555 526, 421, 174.

S. 25 DESCRIPTION (S)-N-(a-ethylbenzyl)-3-(2-aminoethoxy)-2-phenyiquinoline-4-carboxamide .yir 2.2 g (3.9 mol) of(S)-N-(ethbenyl)-2-phenyl-3(2phthaliidoethoxy) quinoline- 4 -carboxamide (compound of Description 4) were dissolved in 150 ml of 96% EtOH; the S 30 solution was heated to reflux; 0.38 ml (7.8 mmol) of hydrazine hydrate were added and the reaction mixture refluxed for 4 hours.

Additional 0.4 ml (8.2 mmol), 0.2 ml (4.1 mnmol), 0.2 ml (4.1 mmol), 0.4 ml (8.2 mmol), 0.4 ml (8.2 mmol) of hydrazine hydrate were added every 12 hours while refluxing the reaction mixture. Then it was evaporated in-vacuo to dryness and 20 ml of H20 were .I 35 added; it was cooled with an ice bath and 10 ml of conc. HCI were added.

The reaction mixture was refluxed for I hour and then, after cooling, the phthalhydrazide was filtered off. The resulting aqueous filtrate was washed with EtOAc, basified with 2N -26- NaOH and extracted with EtOAc. The organic layer was washed with sat. sol. NaCI, dried over Na 2

SO

4 and evaporated in-vacuo to dryness. The residue was purified by flash column chromatography on 230-400 mesh silica gel, eluting with a mixture of EtOAc/MeOH 96:4 containing 1.2% NH 4 0 H to yield 1.2 g of the title compound.

C27H27N302 M.P. 62-66 0

C

M.W. 425.54 I.R. (KBr):.3360; 3250; 3060: 3020; 2960; 2920; 2870; 1640; 1540 cm- 1 S 300 MHz IH-NMR (DMSO-d 6 8 9.45 1H); 8.09 1H); 8.00 (dd, 1H); 7.94 (s br, 3H); 7.76 (ddd, 1H); 7.65-7.51 4H); 7.48-7.40 (m, 3H); 7.31 (dd, 1H); 5.09 (dt, 1H); 3.83 2H); 2.72 (m, 2H); 1.93-1.80 2H); 0.99 3H).

MS (FAB POS; thioglycerine matrix; FAB gas Xe; 8 kV; source 50): 426 DESCRIPTION 6 (S)-N-(a-ethylbenzyl)-3-formylmethoxy-2-phenyquinoline-4-carboxamide 0.64 ml (7.4 mmol) of oxalyl chloride were dissolved, under nitrogen atmosphere, in 5 ml of dry CH 2

CI

2 The solution was cooled at -55C and 0.53 ml (7.4 mmol) of DMSO dissolved in 1.5 ml of dry CH 2

CI

2 were added dropwise, keeping the temperature at The solution was maintained under stirring for 7 minutes, then 2.1 g (4.9 mmol) of (S)-N-(a-ethylbenzyl)-3-(2-hydroxyethoxy)-2-phenylquinoline-4-carboxamide i (compound of Example 2) dissolved in 50 ml of dry CH2C12 were added dropwise, maintaining the temperature between -55 and -50C. After 30 minutes 4.6 ml (33.0 25 mmo) o TEA er adde

A

der 30 minutes 4.6 mi (33.0 mmol) of TEA were added dropwise and the temperature was allowed to raise to room emperature. 10 ml of H20 ere added, the organic layer was separated and washed with

H

2 0, 20% citric acid. sat. sol. NaHCO 3 sat. sol. NaCI, dried over Na 2

SO

4 filtered and evaporated in-vacuo to dryness.

S The residue was purified by gradient flash column chromatography on 230-400 mesh silica gel using as starting eluent a mixture of hexane/EtOAc 70:30 containing

NH

4 OH and as final eluent EtOAc containing 0.5% NH 4 0H The crude product was triturated with i-Pr20 to yield 0.53 g of the title compound, used without further purification.

C2 7 H2 4

N

2 0 3 35 M.W. =424.50 EXAMPLE 1 (S)-N-(a-ethylbenzyl)-3-morpholinomethyl-2-phenylquinoline4-carboxamide 0.8 g (2.1 mmol) of 3 -morpholinomethyl-2-phenylquinoline-4-carboxylic acid hydrochloride (compound of Description 1) were dissolved, under nitrogen atmosphere, in 25 ml of a 8:2 mixture of THF/CH 3 CN; after cooling at -10 0 C, 0.31 g (2.3 mmol) of 1hydroxybenzotriazole (HOBT), 0.29 ml (2.9 mmol) of TEA and 0.34 g (2.5 mmol) of(S)c-ethylbenzylamine were added. The reaction mixture was stirred for 5 minutes at a temperature between -10 and then 0.47 g (2.3 mmol) of dicyclohexylcarbodiimide (DCC) were added.

The temperature was allowed to raise to room temperature and the reaction was maintained under stirring for 6 hours and on standing overnight; then it was evaporated in-vacuo to dryness, dissolved in CH 2 C12, and washed with sat. sol. NaHCO 3 The organic layer was evaporated in-vacuo to dryness, dissolved in IN HCI, washed with ibasified with sat. sol. NaHCO 3 and extracted with CH 2 C12. The solvent was evaporated in-vacuo to dryness and the residue was chromatographed on 60-240 mesh silica gel, eluting with a mixture ofhexane/EtOAc 7:3 containing 1% NH40H first and then with a mixture ofhexane/EtOAc 3:2 containing 1% NH40H The crude product was dissolved in acetone and the solution acidified with HCI/Et 2 0; the solid was recovered by suction filtration and triturated with warm toluene to yield 0.43 g of the title compound as a pale yellow solid.

C

3 0

H

3 1

N

3 0 2

-HCI

M.P. 173-176 0

C

M.W. 502.06 [a1 0 20 +11.0 MeOH) I.R. (Nujol): 3600-3300; 3150; 2750-2020; 1655; 1630; 1545 cm- 1 300 MHz 1 H-NMR (DMSO-d 6 6 9.42 (d br, 1H); 8.09 1H); 7.85 (ddd, 1H); 7.79 (d br, 1H); 7.66-7.11 11H); 5.04 (dt, 1H); 4.05 (s br, 2H); 3.46 4H); 2.50-2.30 4H); 2.10-1.84 2H); 0.99 3H).

S 30 MS (El; TSQ 700; source 180 C;70 V; 200 uA): 465 380; 330; 261; 217.

EXAMPLE 2 (S)-N-(a-ethylbenzyl)-3-(2-hydroxyethoxy)-2-phenylquinoline-4-carboxamide 35 0.65 g (1.4 mmol) of (S)-N-(a-ethylbenzyl)-3-(ethoxycarbonylmethoxy)-2-phenyl quinoline-4-carboxamide (compound of Description 3) were dissolved, under nitrogen atmosphere, in 50 ml of t-BuOH; 55 mg (1.4 mmol) of NaBH4 were added and the mixture was heated to reflux. 7 ml of MeOH were added dropwise, the reaction was refluxed for 3 hours and then quenched with 5 ml of sat. sol. NH 4 CI, evaporated in-vacuo to dryness, dissolved with CH 2 Cl 2 and washed with sat. sol. NaC. The extracted organic layer was dried over Na 2

SO

4 filtered and evaporated in-vacuo to dryness to yield 0.75 g of a crude product which was purified by gradient flash column chromatography on 230- 400 mesh silica gel using a mixture of hexane/EtOAc 80:20 containing 0.5% NH 4 0

H

as starting eluent and a mixture of hexane/EtOAc 50:50 containing 0.5% NH 4 0H as final eluent. The purified product obtained was triturated with warm i-PrOH to yield 0.28 g of the title compound as a white solid.

C2 7

H

2 6

N

2 0 3 M.P. 129-1300C M.W. 426.52 [aiD 20 -41.2 MeOH) Elemental Analysis: Calcd. C, 76.03; H, 6.14; N, 6.57; Found C, 76.02; H, 6.17; N, 6.58.

I.R. (KBr): 3240; 3060; 2980-2920; 1625; 1550 cm-1 300 MHz IH-NMR (DMSO-d 6 6 9.30 1H); 8.07-7.90 3H); 7.76-7.67 1H); 7.60-7.49 5H); 7.45 2H); 7.39 (dd, 2H); 7.29 (dd, 1H); 5.08 (dt, 1H); 4.57 1H); 3.69 2H); 3.34 (dt, 2H); 1.82 2H); 0.99 3H).

MS (EI; TSQ 700; source 180 C;70 V; 200 uA): 426 397; 292; 264 EXAMPLE 3 (S)-N-(a-ethylbenzyl)-3-hdroxy-7-methyl-2-phenylquinoline-4-carboxamide g (1.8 mmol) of 3-hydroxy-7-methyl-2-phenylquinoline-4-carboxylic acid were issolved, under nitrogen atmosphere, in 35 ml of dry THF and 20 ml of CH 3 CN. 0.25 g (1.8 mmol) of (S)-a-ethylbenzylamine and 0.45 g (3.4 mmol) of HOBT were added; the solution was cooled at 0°C and 0.41 g (2.0 mmol) of DCC, dissolved in 12 ml of dry 30 CH 2 C1 2 were added dropwise. The mixture was stirred 1 hour at 0C, 2 hours at room temperature and 2 hours at 40 0 C; after cooling the precipitated dicyclohexylurea was filtered off and the filtrate was evaporated in-vacuo to dryness. The residue was dissolved ,in CH2C1 2 and washed with 20% citric acid, sat. sol. NaHC0 3 and sat. sol. NaCI; the organic layer was dried over Na2SO 4 filtered and evaporated in-vacuo to dryness. The 35 crude product was purified by flash column chromatography on 230-400 mesh silica gel eluting with CH 2 C1 containing 0.5% NH 4 0H the product was further purified by preparative HPLC to yield 30 mg of the title compound as a white solid.

C26H 2 4

N

2 0 2 M.P. =111-114°C M.W. 396.48 I.R. (KBr): 3310; 3100-3020; 2980-2820; 1625; 1578; 1555; 1540 cm-1 300 MHz IH-NMR (DMSO-d 6 5 9.60 (s br, 1H); 9.02 (s br, 1H); 7.96 (d br, 2H); 7.76 (s br, 1H); 7.54-7.24 10H); 5.05 (dt, 1H); 2.47 (s, 3H); 1.80 2H); 0.95 3H).

MS (EI; TSQ 700: source 180 C;70 V; 200 uA): 396 367; 278; 261; 233.

EXAMPLE 4 (S)-N-(a-ethylbenzyl)-3-fluoro-2-phenyIquinoline4-carboxamide 0.54 g (4.0 mmol) of (S)-a-ethylbenzylamine and 0.7 ml (5.0 mmol) of TEA were dissolved, under nitrogen atmosphere, in 10 ml of dry CH2C1 2 1.14 g (4.0 mmol) of 3fluoro-2-phenylquinoline-4-carbonylchloride (obtained from the corresponding carboxylic acid by reaction with oxalyl chloride in CH 2 C12 at room temperature), dissolved in 20 ml of a 1:1 mixture of dry CH2CI 2 /DMF, were added dropwise and the reaction was maintained at room temperature overnight.

The reaction mixture was evaporated in-vacuo to dryness and the residue dissolved in EtOAc and washed with H 2 0, 5% citric acid, sat. sol. NaHCO 3 and sat. sol. NaCI. The organic layer was dried over Na-SO 4 filtered and evaporated in-vacuo to dryness. The residual oil was purified by gradient flash column chromatography on 230-400 mesh silica gel using hexane as starting eluent and a mixture of hexane/EtOAc 9:1 as final eluent to yield 0.5 g of the title compound.

25 C25H 2 1

FN

2 0 M.P. 67-68 0

C

M.W. 384.46 20 22.8 (c 0.5, MeOH) I.R. (KBr): 3250; 3060; 2960; 2930; 1640; 1600; 1550 cm-1 30 300 MHz IH-NMR (DMSO-d 6 6 9.50 1H); 8.17 1H); 8.01 2H); 7.81 (dd, 1 7.76-7.66 2H); 7.64-7.56 3H); 7.46-7.35 4H); 7.29 (dd, 1H); 5.10 (dt, 1H); 1.88-1.74 (m, 2H); 0.99 3H).

35 MS (EI; TSQ 700; source 180 C:70 V; 200 uA): 384 355; 250; 222.

EXAMPLE (S)-N-(a-ethylbenzyl)-3-[2-(2-isoindolinyl)ethoxyj-2-phenylquinoline- 4 -carboxamide dihydrochloride g (3.5 mmol) of (S)-N-(a-ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4carboxamide (compound of Description 5) and 1.0 g (3.9 mmol) of ac,a-dibromo-o.

xylene were dissolved in 150 ml of DMF; 1.1 ml (7.8 mmol) of TEA and a catalytic amount of KI were added and the mixture was heated to 80 0 C for 3 hours. The reaction mixture was evaporated in-vacuo to dryness, dissolved in 10% HCI and washed with hexane. Then it was basified with 20% NaOH and extracted with CH 2 C1 2 the organic layer was washed with sat. sol. NaCI, dried over Na 2

SO

4 filtered and evaporated invacuo to dryness. The residue was purified by flash column chromatography on 230-400 mesh silica gel eluting with a mixture of hexane/EtOAc 7:3 containing 0.5% NH40

H

the product was further purified by preparative HPLC, dissolved in EtOAc and the solution acidified with HCI/Et 2 0 to yield 100 mg of the title compound as a gray solid.

C

3 5

H

3 3

N

3 0 2 -2HC1 M.P. 95 0 C dec.

M.W. 600.59 I.R. (KBr): 3700-3100; 3080-3020; 2980-2820; 2740-2020; 1650; 1550 cm- 1 300 MHz 1 H-NMR (DMSO-d 6 6 11.38 (s br, 1H); 9.49 1H); 8.10 1H); 7.95 (m, 2H); 7.78 (ddd, 1H); 7.67-7.55 5H); 7.48-7.22 (m, 9H); 5.06 (dt, 1H); 4.50-3.50 2H); 4.30-4.12 (m, 2H); 4.12-3.97 2H); 3.28 2H); 1.98-1.72 (m, 2H); 0.94 3H).

MS (EI; TSQ 700: source 180 C;70 V; 200 uA): 527 525; 383; 249.

EXAMPLE 6 (S)-N-(a-ethylbenzyl)-3-(2-homophthalimidoethoxy)-2-phenylquinoline-4carboxamide 0.95 g (2.2 mmol) of the compound of Description 5 and 0.47 g (2.9 mmol) of omophthalic anhydride were dissolved in 20 ml of toluene; some triturated molecular sieves were added and the solution was refluxed, under magnetic stirring, distilling away the forming H 2 0 with a Dean-Stark apparatus.

The reaction was refluxed for 13 hours then, after cooling, the molecular sieves were filtered off and it was evaporated in-vacuo to dryness. The residue was dissolved in CH2C12 and washed with H20, 20% citric acid, sat. sol. NaHCO 3 and sat. sol. NaCI; the organic layer was dried over Na2SO 4 filtered and evaporated in-vacuo to dryness. The -31crude product was purified by gradient flash column chromatography on 230-400 mesh silica gel using a mixture of hexane/EtOAc 70:30 containing 0.5% NH 4 0H as starting eluent and a mixture of hexane/EtOAc 50:50 containing 0.5% NH 4 0H as final eluent. The crude product was triturated with warm i-Pr20/i-PrOH to yield 0.55 g of the title compound as a white solid.

C

3 6

H

3 1

N

3 0 4 M.P. 159-161 0

C.

M.W. 569.67 [Ct]D 20 -29.7 MeOH) Elemental analysis: Calcd. C, 75.90; H, 5.48; N, 7.38; Found C, 75.73; H, 5.45; N, 7.36.

I.R. (KBr): 3360; 3100-3020; 2980-2820; 1715; 1668; 1610; 1510 cm-1 300 MHz 1 H-NMR (DMSO-d 6 5 9.25 1H); 8.05 1H); 8.00 1H); 7.79 2H); 7.71 2H); 7.58-7.35 8H); 7.27-7.23 4H); 4.98 (dt, 1H); 4.09-3.79 6H); 1.79 2H); 0.93 (t, 3H).

MS (El; TSQ 700; source 180 C;10 V; 200 uA): 569 382; 187.

EXAMPLE 7 (S)-N-(a-ethylbenzyl)-2-phenyl-(2-(1,2,3,4-tetrahydro-2-isoquinolinyl)ethoxy] quinoline-4-carboxamide hydrochloride 0.5 g (1.2 mmol) of (S)-N-(a-ethylbenzyl)-3-formylmethoxy-2-phenylquinoline-4- 2 carboxamide (compound of Description 6) and 0.3 ml (2.4 mmol) of 1,2,3,4- 25 tetrahydroisoquinoline were dissolved, under nitrogen atmosphere, in 10 ml of CH 3

CN:

Some triturated molecular sieves were added and the solution was maintained under stirring at room temperature for 30 minutes; 0.2 g (3.2 mmol) of NaCNBH 3 were then Sadded in 30 minutes. The reaction mixture was maintained at room temperature overnight, then was quenched with 15% NaOH, keep under stirring for 20 minutes and evaporated in-vacuo to dryness. The residue was dissolved in 10% HC1, washed with Et,2, basified with 15% NaOH and extracted with Et2O. The organic layer was washed with H 2 0, dried over Na2SO 4 filtered and evaporated in-vacuo to dryness. The residue was purified by flash column chromatography on 230-400 mesh silica gel eluting with a mixture of hexane/EtOAc 7:3 containing 0.5% NH 4 0H to obtain 140 mg of a product which was dissolved in MeOH and acidified with HCl/Et 2 0. The solvent was evaporated in-vacuo to dryness and the residue was triturated with warm to yield 120 mg of the title compound.

-32- C3 6

H

35 N-0 2

*-HCI

M.P. =120-130OC dec.

M.W. =578. 16 [aID 2 1 14.8 5, MeOH) L-R. (KBr): 3 700-3 100; 3 080-3 000; 2980-2820; 2800-2020; 1670-1640; 1550 cm- 1 300 MHz IH-NMR (DMSO-d 6 6 10.89 (s br, 9.60 11H); 8.09 IH); 7.95 (mn, 2Hf); 7.78 (ddd, 1f1); 7.65-7.52 (in, 511); 7.44-7.22 (in, 8H); 7.08 (d br, 4.30-4.00) (in, 4ff); 3.50-2.90 (mn, 6ff); 1.80 (in, 2Hf); 0.90 (in, 3H).

MS (El; TSQ 700; source 180 C;70 V; 200 UA): 541 383; 247; 159; 146; 132.

DESCRIPTION 7 -hyd roxyethyl)benzyl3hydroxy 2 phen 1*1*n--croxmd Prepared as described in Description 2 from 0.98 g (3.7 iniol) of 3 -hydroxy-2..

phenyiquinoline-4-carboxylic acid (CAS [485-89-2]), 1.5 g (3.9 imol) of I-amino-l-.

phenyl-2-propanol (diastereomeric mixture) (Viscontini, 1'961, Helvetica Chimnica Acta, 71, 631), 0.95 g (7.1 inmol) of HOBT, 0.51 ml (4.6 mmol) of N-methylmorpholine and 0.84 g (4.1 minol) of DCC in 50 ml of a 2:1 mixture of THF and CH 3

CN.

The work-up of the reaction mixture was carried out in the same manner as described in Description 2. The residual oil was purified by flash column chromatography on 230-400 mesh silica gel eluting with a mixture of EtOAc/MeOff 98:2 containing 0.5%

NH

4 0H toobtain a crude product which was triturated with i-PrOff to yield 690 mng of the title compound.

2~ C2S)H-2 2 N-,0 3 M..=398.46 I.R. (KBr): 3410; 3320; 3 100-3000; 1635; 1580 cm- 1 3 00 MI-z I H-NMR (DMS O-d 6 6 9.70 (s br, I 9.15 (s br, 1ff); 7.99 1ff); 7.98 (dd, ~2ff); 7.67 IH); 7.59-7.42 7ff); 7.35 (dd, 2H); 7.28 (dd, IH); 5.16 (dd, IH); 4.99 (s br, 1ff); 4.02 (dq, 1H); 1. 10 3ff).

MS (El; TSQ 700; source 180 C;70 V; 200 uA): 398 354; 248; 106.

:DESCRIPTION 8 35 (S)-N-(ac-ethybezl?)3[1 2 2 '-hydroxymethylph enylacetyl)am in oethoxyj -2phenylquinline..4-carboxamide -33- 0.7 g (4.7 mmiol) of isochromanone were dissolved in 25 ml of abs. EtOH; 2.0 g (4.7 mmol) of (S--aehlezl--2aiotoy--hnlunln--abxmd (compound of Description 5) were added and the reaction was refluxed for 12 hours.

Additional 0.3 g (2.0 mmol) of isochromanone were added and the reaction mixture was refluxed for 5 hours; additional 0.5 g (3.4 mniol) of isochromanone were added and the reaction refluxed for 10 hours. After cooling, it was evaporated in vacuo to dryness and the residue was purified by gradient flash column chromatography on 230-400 mesh silica utilising a mixture of hexane/EtOAc 50:50 containing 0.5% NH 4 0H- as starting eluent and a mixture of hexane/EtOAc 20:80 containing 0.5% NH 4 0H as final eluent. The crude product so obtained was triturated with i-Pr2O/i-PrOH to yield 1.8 g of the title compound.

C3 6

H

3 5

N

3 0 4 M.P. 160-163*C M.W. =573.69 -3 1.5 MeOH) Elemental analysis: Calcd. C, 75.36; H, 6.15; N, 7.32; Found C, 75.09; H, 6.14; N, 7.34.

I.R. (KBr): 3600-3 100; 3100-3000; 1641; 1558 cm-1.

300 MHz I 1 H-NMR (DMSO-d 6 5 9.3 0 INH); 8.08 I1H); 7.98 (in, 2H); 7.89 (t br, 11-1); 7.73 (ddd, IH); 7.59 (in, 2H); 7.57-7.48 (in, 31-); 7.45 (in, 2H); 7.41-7.33 (in, 3H); 7.28 (dd. IN); 7.19 (dd, I 7.15 (dd, I1H); 7.09 (dd, INH); 5.09 I H); 5.08 (dt, IN); 4.48 1H); 3.70-3.59 (in, 2H); 3.37 (s, 2H); 3.12-2.92 (in, 1.90-1.75 (in, 2H); 0.99 (t, 1 5 3H).

9 MS (El; TSQ 700; source 180 C;70 V; 200 uA): 555; 438; 411; 382; 247; 218; 192; 174; 119.

DESCRIPTION 9 (S)-N-(a-ethylbenzy).3[2.(3carboxypropanoy)a min oethoxyI.

2 .phenylq uinoline- 4 .9 carboxamide 2.0 g (4.7 mrnol) of (S)-N-(cx-ethyl benzyl)-3-(2aiinoethoxy)-2phelylquinoline-4carboxainide (compound of Description 5) and 0.6 g (6.2 innol) of succinic anhydride 35 were dissolved in 50 ml of toluene; some triturated molecular sieves were added and the reaction mixture was refluxed in a Dean Stark apparatus for 4 hours. The reaction mixture was evaporated in vacuo to dryness, dissolved in 100 ml of CH 2 Cl-) and washed with sat.

-34sol. NaCI, 20% citric acid and sat. sol. NaCi. The organic layer was dried over Na 2

SO

4 and evaporated in vacuo to dryness to yield 2.3 g of the crude product which was purified by flash column chromatography on 23 0-400 mesh silica gel, eluting initially with a mixture CH2CI2)/MeOH 9:1 and then with a mixture of CH2CI 2 /MeciH 8:2. The crude solid obtained was triturated with i-Pr2O/i-PrOH, filtered, washed and dried to yield 1.4 g of the title compound.

C3 1

H

3 1

N

3 0 M.P. I I 18-122*C M.W. =525.60 [cc]D 2 0 -32.1 MeOI-) I.R. 3600-3 120; 3 100-3000; 1740-1700; 1680-1600 cm- 1 300 MHz I H-NMR (DMS0-cl 6 5 11.98 (s br, 1FH); 9.28 I 8.07 111); 7.99 (dd, 2H); 7.73 (ddd, IH); 7.66 (t br, IH); 7.61-7.48 (in, 7.46 7.39 (dd, 2H); 7.30 (dcl. 114); 5.05 (dt, 1Ff); 3.69-3.57 (in, 2H); 3.12-2.91 (in, 2H); 2.34 (in, 2Hf); 2.21 (mn, 1.90-1.75 (in. 2H); 1.00 3H).

MS (FAB POS; thioglycerine matrix; FAB gas Xe; 8 kV; source 50): 526 383; 291.

DESCRIPTION (SZ)-N-(a-ethylbeinzyl)..3- f2 (3..carboxyproe yamiothxl-2pn q uin olin e- 4 -carboxamide *2.0 g (4.7 rnmol) of -ethyl benzyl)-3 2 -amninoethoxy)-2 -phenyl quino line4- 5 carboxaiie (compound of Description 5) and 0.61 g (6.2 mmol) of inaleic anhydride .were dissolved in 50 ml of toluene. Some molecular sieves were added and the reaction mixture was refluxed for 5 hours. After cooling, the reaction mixture was evaporated in vacuo to dryness. dissolved in CH 2 C1 2 and washed with sat. sol. NaCI, 20% citric acid.

sat. sol. NaCI. The organic layer was dried over Na,)SO 4 and evaporated in vacuo to dryness. The crude product was purified by flash column chromatography on 230-400 mesh silica gel, eluting with a mixture of i-Pr2O/EtOAc 70:30 containing 0.5% of formic acid, and then triturated with i-Pr 2 O to yield 2.0 g of the title compound.

a.C I. CH-) 9

N

3 0 =158-162oC 523.59 [a]D 20 38.6 MeOHf) Elemental analysis: Calcd. C. 71.11; H, 5.58; N, 8.03; Found C, 70.90; H, 5.56; N, 7.95.

I.R. (KBr): 3280; 3150-3000; 1710; 1640-1620 cm- 1 300 MHz 1 H-NMR (DMSO-d 6 6 14.80 (s br, 1H); 9.30 1H); 9.08 (t br, 1H); 8.07 (d, 1H); 7.94 (dd, 2H); 7.79-7.70 1H); 7.60 2H); 7.52-7.38 7H); 7.29 (dd, 1H); 6.32 1H); 6.27 1H); 5.07 (dt, 1H); 3.76-3.64 2H); 3.28-3.00 2H); 1.90-1.74 2H); 1.00 3H).

MS (El; TSQ 700; source 180 C;70 V; 200 uA): 425; 407.

DESCRIPTION 11 (S)-N-(a-ethylbenzyl)-3-(2-aminoacetylaminoethoxy)-2-phenylquinoline-4carboxamide g (7.1 mmol) of (S)-N-(a-ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4carboxamide (compound of Description 5) were dissolved, under nitrogen atmosphere, in 60 ml of CH2C1 2 1.2 ml (8.5 mmol) of TEA were added; the solution was cooled to 0 0

C

and 2.7 g (8.5 mmol) of 9 -fluorenylmethoxycarbonyl)glycinyl chloride (FMOC-glycinyl chloride), dissolved in 60 ml of CH 2 Cl 2 were added dropwise. The reaction mixture was stirred at room temperature for 3 hours and then washed with sat. sol. NaCI, 20% citric acid, sat. sol. NaHCO 3 sat. sol. NaCI, dried over Na 2

SO

4 and evaporated in vacuo to dryness. The crude product was purified by gradient flash column chromatography on 230-400 mesh silica gel, utilising a mixture of hexane/EtOAc 1:1 as starting eluent and a mixture of EtOAc/MeOH 9:1 as final eluent. The product (5.0 g) was dissolved in 100 ml of a 10% solution of diethylamine in DMF and stirred at room temperature for minutes. The reaction mixture was then evaporated in vacuo and purified by gradient S: 25 flash column chromatography on 230-400 mesh silica gel, utilising a mixture of EtOAc/MeOH 9:1 as starting eluent and a mixture of EtOAc/MeOH 7:3 as final eluent, to yield 0.6 g of the title compound.

C2 9

H

3 0

N

4 0 3 M.P. 55-60 0 C dec.

30 482.58 [ajD 20 -33.7 MeOH) Elemental analysis: Calcd. C, 72.12; H, 6.27; N. 11.61; Found C, 70.12; H, 6.45; N. 10.81.

I.R. (KBr): 3500-3110; 3100-3000; 1680-1650; 1638 cm- 1 300 MHz 1 H-NMR (DMSO-d 6 6 9.29 1H); 8.06 IH); 7.98 (dd, 2H); 7.74 (ddd, 1H); 7.68 (t br. 1H); 7.60-7.38 9H); 7.30 (dd, 1H); 5.09 (dt, IH). 3.70-3.55 (in, 3.18-3.00 (in, 211); 2.99 211); 1.90-1.78 (in, 211); 1 .00 311).

MS (El; TSQ 700; source 180 C;70 V; 200 uA): 482 382; 291; 264; 247;219;190; 141; 119; 101; 91.

DESCRIPTION 12 (S--(-tybny)31-S--aiohnlctlmnehxl2 phenylq uinoline-4-carboxamide The reaction to obtain the FMOC-protected title compound was conducted as described in Description 11, starting from 2.8 g (6.7 nimol) of (S)-N-(a-ethylbezyly3-( 2 amnehx)2peyqunln--abxmd (compound of Description 1.1 ml mmol) of TEA and 3.1 g (8.0 inmol) of (S)-FMOC-phenylglycinyl chloride. The reaction was stirred at room temperature for 20 hours and worked up as described in Description I11 to yield 4.5 g of the FMOC protected title compound, which was deprotected by stirring at room temperature for 30 minutes with 90 ml of a 10% solution of diethylamnine in DMF. The reaction mixture was then evaporated in vacuc and purified by gradient flash column chromatography on 230-400 mesh silica gel, utilising EtOAc as starting eluent and a mixture of EtOAc/MeOI- 9:1 as final eluent, to yield, after trituration with i-Pr 2 O, 1.4 g of the title compound.

C

3 5H 3 4

N

4

O

3 M.P. =140-145'C =558.68 [aID 7.0 MeGH) 5 Elemental analysis: Calcd. C, 75.25; H, 6.13; N, 10.03; a. Found C, 72.70; H, 6.11; N, 9.80.

I.R. (KBr): 3440-3110; 3100.3000; 1650-1630; 1585 cm- 1 300 MHz I H-NMR (DMSO-d 6 8 9.30 I1H); 8.08 11H); 7.97 (dd, 2H1); 7.92 (t br, 111); 7.72 (dd, 7.60-7.48 (in, 5H); 7.45 2H); 7.38 (dd, 2H); 7.30-7.20 (in, 611); 5.09 (dt, 1H); 4.21 (s, I 3.65 3.07 (dt, 2.10 (s br, 211); 1.90- 1 .75 (mn, 211); 0.95 311).

MIS (El; TSQ 700; source 180 C;70 V; 200 uA): 541; 453; 382; 292;291; 247; 219; 106.

35 DESCRIPTION 13 (S)-N-(a-ethylbenzv).3[2..(R)-a-aminophenl JIaiothxl2 phnlunfne-abxmd -37- The reaction was conducted exactly as described in Description 12, utilising the FMOC-phenylglycinyl chloride instead of the The same amounts of all the reagents were used. 0.8 g of the title compound were obtained.

C35H34N403 M.P. 92-94°C M.W. 558.68 [a]D 2 0 -52.8 MeOH) Elemental analysis: Calcd. C, 75.25; H, 6.13; N, 10.03; Found C, 74.15; H, 6.19; N, 9.91.

I.R. (KBr): 3440-3110; 3100-3000; 1670-1630 cm-1.

300 MHz IH-NMR (DMSO-d6): 5 9.30(d, 1H); 8.07 1H); 7.96 2H); 7.90 (t br, 1H); 7.72 1H); 7.60-7.50 5H); 7.44 2H); 7.38 (dd, 2H); 7.29-7.19 6H); 5.09 (dt, 1H); 4.20 (s, 1H); 3.60 2H); 3.16-2.91 2H); 2.11 (s br, 2H); 1.90-1.75 2H); 0.96 3H).

MS (EI; TSQ 700; source 180 C;70 V; 200 uA): 541; 453; 382; 292;291; 247; 219; 106.

DESCRIPTION 14 2-ethoxycarbonylmethyl-1,2,3,4-tetrahydroisoquinoline g (45.0 mmol) of 1,2,3,4-tetrahydroisoquinoline were dissolved, under nitrogen .q.

i atmosphere, in 60 ml of dry THF. 17.34 g of K2CO 3 and 5.0 ml (45.2 mmol) of ethyl bromoacetate were added and the reaction mixture was stirred at room temperature 2 5 overnight. The inorganic salts were filtered off and the solvent was evaporated in vacuo to dryness. The residue was dissolved in CH2CI 2 and washed with sat. sol. NaCI, 5% citric acid, sat. sol. NaHC03 and sat. sol. NaCI; the organic layer was dried over Na-SO 4 and evaporated in vacuo to dryness to yield 6.6 g of the title compound which was used without further purification.

30 CI3H17NO2 M.W. 219.28 I.R. (KBr): 3100-3000; 1752 cm-1.

DESCRIPTION 2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline -38- 1.9 g (50.0 mmol) of LiAIH 4 were suspended, under nitrogen atmosphere, in 100 ml of dry THF; the reaction mixture was cooled at 0°C and 5.0 g (22.8 mmol) of 2ethoxycarbonylmethyl-1,2, 3 4 -tetrahydroisoquinoline (compound of Description 14), dissolved in 100 ml of dry THF, were added dropwise. The reaction was stirred at room temperature for 2 hours, ice-cooled and quenched with 2.5 ml of H 2 0, 7.5 ml of NaOH, 2.5 ml of H20, stirred for 30 minutes and filtered. The filtrate was evaporated in vacuo to dryness, dissolved in CH 2

CI

2 and washed with sat. sol. NaCI. The organic layer was dried over Na2SO 4 and evaporated in vacuo to dryness to yield 3.9 g of the title compound which was used without further purification.

C

1 1

HI

5

NO

M.W. 177.24 I.R. (KBr): 3700-3100; 3100-3000; 1586 cm-1.

DESCRIPTION 16 2 2 -hydroxyethyl)-3,4-dihydro- (2H)-isoquinolinone 3.8 g (21.4 mmol) of 2-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline (compound of Description 15), 20.0 g (53.6 mmol) of ethylenediaminetetraacetic acid disodium salt dihydrate and 17.1 g (53.6 mmol) of mercury (II) acetate were dissolved in 95 ml of H 2 0.

65 ml of 2N NaOH were added and the reaction was refluxed for 4 hours. After cooling, the reaction was extracted with CH 2

CI

2 washed with 5% HCI, sat. sol. NaHCO 3 sat.

:sol. NaCI, dried over Na 2

SO

4 and evaporated in vacuo to dryness to yield 2.6 g of the S* title compound which was used without further purification.

CllH 13 NO2 S 25 M.W. 191.23 I.R. (KBr): 3700-3100; 1633; 1604; 1576 cm- 300 MHz 1H-NMR (CDC1 3 6 8.10 1H); 7.40-7.10 3H); 3.90 (s br, 2H); 3.85- 3.60 4H); 3.20 (s br, 1H); 3.05-2.95 2H).

MS (EI; TSQ 700; source 180 C;70 V; 200 uA): 191 173; 160.

DESCRIPTION 17 2 2 -chloroethyl)-3,4-dihydro-1( 2 H)-isoquinolinone o* 2.5 g (13.1 mmol) of 2-(2-hydroxyethyl)-3,4-dihydro-l(2H)-isoquinolinone (compound of Description 16) were dissolved in 150 ml of CHCI 3 1.24 ml (17.0 mmol) of SOCI2 dissolved in 30 ml of CHCI 3 were added dropwise and the reaction mixture was heated to 55 C for 2 hours and then evaporated in vacuo to dryness. The residue was dissolved in -39- EtOAc, basified with sat. sol. K 2

CO

3 extracted and washed twice with sat. sol. NaCI.

The organic layer was dried over Na 2

SO

4 and evaporated in vacuo to dryness to yield 2.7 g of the title compound which was used without further purification.

C

1

IH

2

CINO

M.W. 209.67 I.R. (KBr): 3700-3300; 1647; 1605; 1582 cm-1.

300 MHz 1H-NMR (CDC1 3 8 810 IH); 7.45-7.10 3H); 3.85-3.60 6H); 3.00 2H).

MS (EI; TSQ 700; source 180 C;70 V; 200 uA): 209 174; 160.

DESCRIPTION 18 3-(N-benzyl-N-methylamino)methyl-2-phenylquinoline4-carboxylic acid 10.0 g (37.98 mmol) of 3-methyl-2-phenylquinoline-4-carboxylic acid (CAS [43071-45were dissolved in 500 ml of dichloroethane.

13.7 g (76.12 mmol) of N-bromosuccinimide and 1.0 g (3.85 mmol) of dibenzoyl peroxide were added and the solution refluxed for 8 hours.

The reaction mixture was evaporated in vacuo to dryness and the residue was dissolved in 250 ml of THF; 20 ml (155.50 mmol) of N-benzyl-N-methylamine were added and the solution stirred for 24 hours at room temperature.

The precipitated material was filtered off and the filtrate was evaporated in vacuo to dryness. The residue was dissolved in 300 ml of 10% K 2 C0 3 and evaporated in vacuo to dryness. The dark oil was dissolved in 200 ml of acetone, the precipitate was filtered off 2 and the filtrate was evaporated in vacuo to dryness. 100 ml of water were added to the S 25 residue and the solution, acidified with 6N HCI, was evaporated in vacuo to dryness.

The residue was dissolved in 28% NH 4 0H and the solution was evaporated in vacuo to dryness. The crude product was flash chromatographed on 230-400 mesh silica gel, eluting with a mixture of EtOAc/MeOH 85:15 containing 1.5% of 28% NH 4 0H to afford 8.0 g of the title compound as a white solid.

C2 5 H2 2

N

2 0 2 M.P. 250 °C M.W. 382.46 I.R. (KBr): 3650-3200; 1700; 1660; 1627 cm- 1 35 300 MHz 1 H-NMR (CDC1 3 6 8.45 1H); 8.05 1H); 7.70-7.05 12H); 4.20 (s br, 2H); 3.70 (s br, 2H); 3.40 s br, 1H); 2.00 3H).

EXAMPLE 8 (R,S)-N-(a-acetylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide Prepared as described in Description 6 from 0.24 ml (2.8 mmol) of oxalyl chloride, 0.4 ml (5.6 mmol) of DMSO, 0.69 g (1.7 mmol) of (R,S)-N-[a-(1-hydroxyethyl)benzyl]-3hydroxy-2-phenylquinoline-4-carboxamide (compound of Description 7) and 1.7 ml (12.2 mmol) of TEA.

The work-up of the reaction mixture was carried out in the same manner as described in Description 6. The residue was purified by flash column chromatography on 230-400 mesh silica gel eluting initially with a mixture of petroleum ether/EtOAc 80:20 containing 0.5% NH 4 OH and then with a mixture of petroleum ether/EtOAc 70:30 containing 0.5% NH 4 OH to obtain a crude product which was triturated with ito yield 96 mg of the title compound as a white solid.

C

2 5

H

2 0 N20 3 163-166 0

C

396.45 I.R. (KBr): 3400-3000; 1725, 1630, 1570, 1550 cm- 1 300 MHz 1 H-NMR (DMSO-d 6 6 9.75 (s br, 1H); 9.55 (s br, 1H); 7.95 3H); 7.82 1H); 6.60-6.32 10H); 5.82 1H); 2.19 (s, 3H).

MS (EI; TSQ 700; source 180 C;70 V; 200 uA): 396 353; 248; 220; 106.

EXAMPLE 9 S*i a -ethylbenzyl)-3-(3-phthalimidopropoxy) 2-phenylquinoline-4-carboxamide 25 4.0 g (10.5 mmol) of (S)-N-(a-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (product of Description 2) were dissolved in 450 ml of THF.

13.8 g (54.1 mmol) of N-(2-bromopropyl)phthalimide, dissolved in 35 ml of THF, 4.21 g (30.5 mmol) of K2CO 3 and 0.53 g of KI were added and the suspension was refluxed for 20 hours.

The inorganic salts were filtered off and the reaction mixture evaporated in vacuo to dryness, dissolved in CH2C 2 and washed with water; the organic layer was separated, dried over Na2SO 4 and evaporated in vacuo to dryness. 2.0 g of the residue were purified by flash column chromatography on 230-400 mesh silica gel, eluting initially with a 3 mixture ofhexane/EtOAc 8:2 containing 0.5% NH40H and then with a mixture of 35 hexane/EtOAc 3:2 containing 0.5% NH 4 0H The crude solid so obtained was triturated with i-Pr20, filtered, washed and dried to yield 1.1 g of the title compound.

C

3 6

H

3 1

N

3 0 4 -41- M.P. 125-1280C M.W. 569.60 [a 20= -38.2 MeOH) Elemental analysis: Calcd. C, 75.91; H, 5.49; N, 7.38; Found C, 75.53; H, 5.50; N, 7.26.

I.R. (KBr): 3400-3120; 3100-3000; 1770; 1740-1700; 1635; 1580 cm-1.

300 MHz 1 H-NMR (DMSO-d 6 6 9.23 1H); 8.05 1H); 7.89 (dd, 2H); 7.86 (m, 4H); 7.72 (ddd, IH); 7.59 2H); 7.40 4H); 7.30 3H); 7.16 (dd, 1H); 5.03 (dt, 1H); 3.61 2H); 3.31 (dt, 2H); 1.90-1.58 4H); 0.96 3H).

MS (El; TSQ 700; source 180 C;70 V; 200 uA): 569 188; 160.

EXAMPLE a -ethylbenzyl)-3-{2-f3-(R,S)-hydroxy-3,4-dihydro- (2H)-isoquinolinon-2-ylJ ethoxy)-2-phenylquinoline-4-carboxamide (diastereomeric mixture) g (4.4 mmol) of N a -ethylbenzyl)-3-(2-homophthalimidoethoxy)-2phenylquinoline-4-carboxamide (compound of Example 6) were dissolved, under nitrogen atmosphere, in 25 ml of MeOH; the solution was cooled to 0OC and 0.25 g (6.6 mmol) of NaBH 4 were added. The temperature was allowed to raise to room temperature and after 30 minutes additional 0.25 g (6.6 mmol) of NaBH 4 were added and the reaction mixture was maintained under stirring for 1 hour and 15 minutes. Additional 0.5 g (13.2 mmol) of NaBH 4 were added and the reaction mixture was allowed to stand at room S temperature overnight. 2 ml of 30% NaOH were added, the organic solvent was S* 25 evaporated under reduced pressure, and the aqueous solution was extracted with CH2C2, washed with sat. sol. NaCI, dried over Na 2

SO

4 and evaporated in vacuo to dryness. The crude product was purified by gradient flash column chromatography on 230-400 mesh silica gel, utilising a mixture of petroleum ether/EtOAc 7:3 containing 0.5% NH 4 0

H

as starting eluent and a mixture of petroleum ether/EtOAc 3:7 containing

NH

4 OH as final eluent.

The crude solid so obtained was triturated with i-Pr20, filtered, washed and dried to yield 1.2 g of the title compound.

C3 6

H

3 3

N

3 0 4 M.P. =100-110°C 35 M.W. 571.68 Elemental analysis: Calcd. C, 75.64; H, 5.82; N, 7.35; Found C, 74.44; H, 5.95; N, 7.12.

-42- 1.R. 3600-3200; 3 100,3000; 1732; 1635; 1610; 1580 cm-1.

300 MHz I1--NMR (DMSO-d 6 5 9.29 and 9.25 I 8.05 I1-H); 7.92 (in, 2H-); 7.86 (dd, 1I); 7.70 (ddd, IH); 7.56-7.22 (mn. 13H-); 5.96 5-92 IH); 5.094.84 21); 3.99-381 2H); 3.24-3.05 (in, 21-1); 2.90-2.80 (in, 1.90-1.65 (in, 21H); 0.92 and 0.78 31-).

MS (El; TSQ 700; source 180 C;70 V; 200 uA): 553; 382; 219; 190; 172.

EXAMPLE I1I (S)-N(cethvbenzy1)..-3-aminopmop) 2 heyqion4-abxm hydrochloride 4.1 g (7.4 inmol) of (S)-N-(a-ethybezyl)-3 3 -phthalimidopropoxy)2phenylqinlin 4 -carboxainide (compound of Ex. 9) were dissolved in 200 ml of 96% EtOll and 0.71 ml (13.65 m~mol) of hydrazine hydrate were added to the boiling solution. The reaction mixture was refluxed for 24 hours, then additional 0.71 ml (13.65 inmol) of hydrazine hydrate were added and the solution refluxed for 4 hours. After cooling, the reaction mixture was evaporated in vacuo to dryness; 50 ml of H 2 0 were added and the solution was acidified to p1-=1 with 37% HCI. The mixture was refluxed for I hour, the insoluble material was filtered off and 3 0% NaOH- was added to pH-= 10. The solution was extracted with EtOAc, washed with sat. sol. NaCJ, dried over Na2SO 4 and evaporated in vacuc to dryness. The crude product was purified by gradient flash column chromatography on 9* 230-400 mesh silica gel, utilising a mixture of EtOAc/MeOH 95:5 containing

NH-

4 0H as starting eluent and a mixture of EtOAc/MeGH 85:15 containing

NH

4 0H as final eluent.

The crude solid so obtained was triturated with a warm mixture of i-Pm~ 0/EtOAc, 9999 filtered, washed and dried to yield 1.4 g of the title compound as a free base. 0.9 g of this free base were dissolved in EtOAc, acidified with H-Cl/Et 2 O, evaporated in vaczuo to dryness and triturated with a mixture of EtOAc/acetone to yield 0.8 g of the title 999 30 compound.

C2-8H2 9

N

3 0-)HCI M.P. =160-165'C dec.

9999M.W. =476.02 [all) 0 28.6 MeOH-) S 35 1.R. (KBr): 1653; 1550 cm- 1.

300 MHz I1--NMR (DMSO-d 6 5 9.32(d, INH); 8.08 I 7.92 (mn, 7.80-7.70 (mn, 7.60-7.50 (mn, 5H); 7.47-7.39 (mn, 7.31 (dd, -43- 1K); 5.08 (dt, 3.57 2H); 2.50 (in. 2H-I); 1.91- 1.60 (in, 4H); 0.99 3H).

MS (El; TSQ 700; source 180 C;70 V; 200 UA): 439 394; 383; 304; 277; 26 1; 248; 219; 119.

EXAMPLE 12 carboxamide 0.8 g (1.4 iniol) of (S--aehlezl--2[-R,)hdoy34dhdo12) isoquinolinon-2-yl]ethoxy)--he} inln-4croxmd (compound of Example were dissolved in 20 ml of dry CH 2

CI

2 The solution was cooled to -10 0 C, 0.21 ml mimol) of TEA were added and a solution of 0. 12 ml (1 .5 mmol) of methanesulfonyl chloride in 2.5 ml of CH-)CI 2 was added dropwise. The temperature was allowed to raise to 25'C and the reaction mixture was stirred overnight. 5 ml of sat. sol. NaHCO 3 were added, the organic layer was extracted, washed with sat. sol. NaCI, dried over Na 2

SO

4 and evaporated in vacuc to dryness. The crude product was purified by flash column chromatography on 230-400 mesh silica gel, eluting with a mixture of hexane/EtOAc 7:3 containing 0.5% NH 4 0H The crude solid so obtained was triturated with a warm mixture of i-Pi-2O, filtered, washed and dried to yield 0.4 g of the title compound.

C

36

H

3 1

N

3 0 3 M.P. =60'C dec.

M.W. 553.67 2 0 +9.7 MeGH) Elemental analysis: Calcd. C, 78.09; H, 5.64; N, 7.59; Found C, 76.86; H, 6.05; N, 7.00.

1.R. (KBr): 3350-3 120; 3 100-3000; 2968; 2874; 1653; 1594 cm- 1 300 MHz I 1 H-NMR (DMSO-d 6 8 9.29(d, 1KH); 8.14 1KH); 8.03 IlH); 7.79-7.68 (mn, 5H); 7.60 2H); 7.52 (dd, 1K); 7.48-7.39 4H); 30 7.29 (dd, 1K); 7.11 (dd, 1K); 7.00 (in, 3H): 6.57 (d, lH); 5.03 (dt. IH); 3.95-3.74 (in, 4K); 1.89-1.71 (in, 9 0.90 3K).

MS (El; TSQ 700: source 180 C;70 V; 200 uA): 553 249; 172.

35 EXAMPLE 1 (S)-N-(cz-ethylbenzyl).3-[ (S)-a-ethylbenzylj aminonmethyl-2..phenylquinoline4-.

carboxamide hydrochloride -44g (15.50 mmol) of t-butyl 3-ehl2peNIunln--abxlt (obtained by reaction of 3-ehl2peyqioie4cro,, chloride with t-BuOH), 3.0 g (17.00 mniol) of N-bromosuccinimide and a catalytic amount of dibenzoyl peroxide were dissolved in 100 ml Of CC1 4 and the slurry was refluxed for 3 hours.

g (8.43 mmol) of N-bromosuccinimide were added and the slurry refluxed for additional 2 hours; then, evaporated in vacuo to dryness to yield 11.1 g of a crude material. 1 .0 g of this residue was dissolved in 30 ml of abs. EtOH; 1. 0 g (7.40 mmol) of (S)-(-)-ca-ethylbepnzylamine were added and the solution was stirred at room temperature forlIhour.

The reaction mixture was evaporated in vacuo to dryness. The crude product was purified by gradient chromatography on 70-23 0 mesh silica gel, eluting with CH2CI 2 /MeOH (from 0 to to afford 0.6 g of the title compound as a free base. This was dissolved in Et-,O and the solution acidified with H-CI/Et 2 O to yield the corresponding hydrochloride.

which was recrystallized from EtOAc to obtain 0.25 g of the title compound as a white powder.

C35H3 5

N

3 0.HCI M.P. =193-195 0

C

M.W. -550.15 [a]JD 2 1= -59.8 (c MeOH) Elemental analysis: Calcd. C, 76.4 1; H, 6.60; N, 7.64; Cl, 6.45; Found C, 76.03; H, 6.66; N. 7.52; Cl, 6.53.

1.R. (KBr): 3441; 3173; 3056; 2968-2582; 1665; 1649; 1539 cm-l.

300 M7' 1 HNM DM d37K. on the free base): 6 8.8 8 (d br, I 8.02 IlH); 25 -3)0MzIHNR(MOd, 7.80-7.65 (in, 4H); 7.55-7.28 (in, 7.20-7. (mn, 3H); 7.00 2H); 5.12 (dt, lH); 4.60 (d, 2H); 3.20 (in, IH); 2.00-1.80 (mn, 3H); 1.65-1.30 (in, 2H); 1 .00 3H); 0.68 3H).

MIS (CI; isobutane gas reagent; P 4000 inTorr; source 150 514(MH+); 394; 379; 349; 30 1 36.

EXAMPLE 14 (S)-N-Qx-ethylbenzyl)..3.

12 4 -dihydro-3(2H)..isoq uinolinon-2y)ethoxy..2 phenylq uinioline-4..carboxamide 1.2 g (2.1 iniol) of (S--c-tybny)3[-2'hdoyehlhnlctl amnehx]2pevqunln--abxmd (compound of Description 8) were dissolved in 30 ml of CHC13; HCl/Et 2 0 was added to pH=4 and a solution of 0.2 ml (2.7 mmol) of SOC12 in 6 ml of CHCI 3 was added dropwise. The reaction mixture was warmed to 50C for 5 hours; additional 0.1 ml (1.4 mmol) of SOCI 2 were added and the reaction refluxed for 1 hour. The mixture was evaporated in vacuo to dryness, dissolved in EtOAc, washed with sat. sol. K 2 CO3, with sat. sol. NaCI, dried over Na 2

SO

4 and evaporated in vacuo to dryness to yield 1.3 g of (S)-N-(a-ethylbenzyl)-3-[2-( 2 chloromethylphenylacetyl)aminoethoxyj-2-phenylquinoline-4-carboxamide as a white solid. This product was dissolved in 25 ml of dry THF and added dropwise to a suspension of 100 mg (4.2 mmol) of NaH in 10 ml of dry THF and 1 ml of 1,3-dimethyl- 2 -imidazolidinone. The reaction mixture was stirred at room temperature for 4 hours and then quenched with H 2 0, evaporated in vacuo to dryness dissolved in EtOAc and washed with sat. sol. NaCI. The organic layer was dried over Na 2 S

O

4 and evaporated in vacuo to dryness. The crude product was purified by flash column chromatography on 230-400 mesh silica gel, eluting with a mixture of hexane/EtOAc 1:1 to yield 113 mg of the title compound.

C

3 6

H

3 3

N

3 0 3 M.P. 153-156°C M.W. 555.68 [a]D 2 0 -20.8 MeOH) I.R. (KBr): 3300-3100; 3100-3000; 1660; 1640; 1550 cm- 1 300 MHz 1 H-NMR (DMSO-d 6 6 9.30 1H); 8.05 1H); 7.82 2H); 7.72 (ddd, 1 7.60 (m 7.46-7.36 5H); 7.31-7.22 (m, 6H); 7.16 m 1H); 5.05 (dt, 1H); 4.26 (Abq, 2H); 7.80-7.70 2H); 3.44 2H); 3.34 2H); 1.89- 25 1.72 2H); 0.94 (t,3H).

MS (EI; TSQ 700; source 180 C:70 V; 200 uA): 382 264; 247; 219; 172; 119; 91.

EXAMPLE (S)-N-(a-ethylbenzyl)-3-(2-succinimidoethoxy)-2-phenylquinoline-4-carboxamide 0.8 g of (S)-N-(a-ethylbenzyl)-3 2 3 -carboxypropanoyl)aminoethoxy]-2phenylquinoline-4-carboxamide (compound of Description 9) and 4 ml of tetrahydronaphthalene were heated to 140°C for 2.5 hours and, subsequently, to 200°C for 2 hours. After cooling, 80 ml of EtOAc were added and the solution was washed with 35 sat. sol. NaCI, sat. sol. NaHCO 3 20% citric acid, sat. sol. NaCI, dried over Na2SO 4 and evaporated in vacuo to dryness. The residue was purified by flash column -46chromatography on 230-400 mesh silica gel, eluting with a Mixture of hexane/EtOAc 1: 1 to yield 148 mg of the title compound.

C3IH 2 9

N

3 0 4 M.P. =80*C dec.

M.W. =507.59 [allD2 _25.4 MeOW) I.R. (KBr): 3280; 3100-3000; 1710-1690; 1670-1635; 1530 cm 1 300 MHz I H-NMR (DMSO-d 6 6 9.29 I 8.05 1WH); 7.84 (dd, 2H); 7.73 (ddd, 1W); 7.58 (in, 2H); 7.56-7.50 (in. 3H); 7.47 2H); 7.40 (dd, 7.28 (dd, 1W); 5.08 (dt, IW); 3.77-3.70 3.46-3.32 (in, 2H); 2.54 4H); 1.90-1.78 (in, 2H); 1.00 3H).

MS (El; TSQ 700; source 180 C;70 V; 200 uA): 507 478; 374; 221; 126.

EXAMPLE 16 (S)-N-(a-ethylbenzI)-3.{2.maleimidoethoxy).

2 .phenylq uinoline-4..carboxamide 0.3 g (5.73 inrol) of (S)N(-tybny)3[-3croyrpnv~mnehx] 2-hnlunln--abxmd (compound of Description 10) were dissolved in 3 ml of acetone. 1.6 ml (11.5 inmol) of TEA were added and the reaction mixture was heated to reflux. 0.82 ml (8.6 inmol) of acetic anhydride were added dropwise to the boiling solution which was refluxed for 22 hours. After cooling, the reaction mixture was poured into ice, stirred for 30 minutes and then extracted with EtOAc. The organic layer was washed wihst o.NaCI, 20 ircacid, st o.NaHCO 3 adsat. sol. NaCi, dried over Na2 SO 4 and evaporated in vacuc to dryness. The residue was purified by gradient flash colun chromatography on 230-400 mesh silica gel, utilising a mixture of hexane/EtOAc 80:20 as starting eluent and EtOAc as final eluent to yield, after trituration with i-Pr2)O, 100 mg of the title compound.

*59C3

IH-)

7

N

3 0 4 M.W. 505.57 [i 2 0 -21.7 MeOW) Elemental analysis: Calcd. C, 73.65; H, 5.3 8; N, 8.3 1; S. Found C, 72.50; H, 5.59; N, 7.8 1.

00. 35 I.R. (KBr): 3 400-3 100; 3100-3000; 1710; 1660-1625 cm-.

300 MHz I H-NMR (DMSO-d 6 6 9.27 1W); 8.05 1W); 7.31 (dd, 7.73 (ddd, 1W); 7.58 (mn, 2H); 7.48-7.38 (in, 7H); 7.29 (dd, 1W);- -47- 6.95 2H); 5.05 (dt, lIH); 3.80-3.70 (in, 2H); 3.51- 3.35 (in, 2H); 1.88-1.78 (in, 2H); 0.99 3H).

MS (El; TSQ 700; source 180 C;70 V; 200 uA): 505 476; 372; 220; 124.

EXAMPLE 17 g (1.0 minol) of (S--aehlezl--2aioctlmnehx)2 phenylquinoine4caboxamid (compound of Description 11), were dissolved in 100 ml of n-BuOH; 3.5 ml of acetone were added and the reaction mixture was refluxed for hours. The solvent was evaporated in vacuo to dryness and the crude product was purified by gradient flash column chromatography on 230-400 mesh silica gel, utilising a mixture of EtOAc/MeOH 9:1 as starting eluent and a mixture of EtOAc/MeOH 6:4 as final eluent, to yield, after trituration with i-Pr- 2 O, 0.36 g of the title compound.

C

3 2H 3 4

N

4 0 3 M.P. 160-162"C M.W. 522.65 [aCID 2 0 _50.0 MeOH) Elemental analysis: Calcd. C, 73.54; 6.56; N, 10.72; Found C, 72.87; H, 6.60; N, 10.63.

I.R. (KBr): 3285; 3100-3000; 1679; 1650-1625; 1587 cm-1.

300 MHz IH-NMR (DMSO-d 6 8 9.28 8.06 7.93 (dd, 2H); 7.74 (ddd, IH); 7.61-7.49 (in, 7.47 7.39 (dd, 2H); 25 7.29 (dd, I 5. 10 (dt, IJH); 3.64 2H); 3. 10 (s br, 3.10-2.90 (in, 2H); 2.79 (s br, IR); 1.90-175 (i, 2H); 1.00 3H); 1.00 3H); 0.95(s, 3H).

MS (El; TSQ 700; source 180 C;70 V; 200 uA): 522 383; 360; 248; 141.

30 EXAMPLE 18 (S)-N-(a-ethyl benzy 3 4 (2m eth oxypheny)p iperazin- I -yIj pro poxy) 2 p h e y l q i n o i n -4 a rb x a m d e d ih y d r o c h l oo n d e (compound of Description 1.0 g (3.7 mmol) of 1-( 2 -methoxyphenyl)..-(3.

chloropropyl)pperzne and 1.6 g (11.7 mniol) of K'2C0 3 were suspended in 20 ml of THF and the reaction mixture was refluxed for 17 hours. Additional 1.1 g (4.1 minol) of -48- 1-(2-methoxyphenyl)-4-(3-chlroropy)piperazine and a catalytic amount of KI were added and the reaction refluxed for 4 hours. The inorganic salts were filtered off the filtrate was evaporated in vacuo to dryness and purified by flash column chromatography on 230-400 mesh silica gel, eluting with a mixture of CH2CI2/MeOH 98:2 containing 0.5% NH40H to obtain 0.6 g of free base which was dissolved in MeOH and acidified to pH=1 with HCI/Et20. The solvent was removed in vacuo and the product was triturated with warm EtOAc to yield 0.6 g of the title compound.

C

3 9H 4 2N 4 0 3 .2HCI M.P. 151-155 0

C

687.71

[IID

2 0 -7.7 MeOH) I.R. (KBr): 3600-3300; 3300-3 100; 3100-3000; 2800-2000; 1659 cm- 1 300 MHz 1 H-NMR (DMSO-d 6 6 10.85(s br, IH); 9.36 1H); 8.09 1H); 7.95 (d, 2H); 7.76 (ddd, 1H); 7.66-7.53 5H); 7.48-7.41 (inm, 4H); 7.31 (dd, 11); 7.08-6.90 4H); 5.11 (dt, 1H); 3.82 3H); 3.69 2H); 3.45 (d br, 2H); 3.28 (dd br, 2H); 3.08-2.89 4H); 2.86-2.70 2H); 1.91-1.76 4H); 1.02 3H).

MS TSQ 700; source 180 C;70 V; 200 uA): 614 599; 452; 382; 317; 268; 247; 205; 190; 136.

EXAMPLE 19 (S)-N-(a-ethylbenzyl)-3- {2-12-(R,S)-phenyl-4-oxo3-imidazolidinyllethoxy}-2- S :phenylquinoline-4-carboxamide (diastereomeric mixture) 25 0.8 g (1.7 mmol) of (S)-N-(a-ethylbenzyl)-3-(2-aminoacetylaminoethoxy)-2penylquinoline-4-carboxamid (compound of Description 11) were dissolved in 8 md of MeOH; 0.25 ml (2.5 mmol) of benzaldehyde were added and the reaction mixture was refluxed for 10 hours. The solvent was evaporated in vacuo to dryness and the residue 30 was purified by gradient flash column chromatography on 230-400 mesh silica gel, utilising a mixture of hexane/EtOAc 1:1 gl .:utilising a mixture of hexane/EtOAc 1:1 as starting eluent and a mixture of EtOAc/MeOH 9:1 as final eluent, to yield 0.52 g of the title compound.

C

3 6

H

34

N

4 0 3 80-85'C dec.

5 570.69 [1ID 2 0 -45.6 MeOH) I.R. (KBr): 3400-3120: 3100-3000; 1710-1685; 1680-1650; 1650-1630 cm- 1 -49- 300 MHz IH-NMR (DMSO-d 6 TFA): 6 9.20 and 9.10 8.05 IH); 7.80-7.70 3H); 7.60-7.20 15H); 5.88 and 5.80 (s, IH); 4.95 (dt, 1 4.00 (dd, 1H); 3.85 (dd. 3.75-3.63 (mn, 11); 3.61-3.40 3H); 1.80-1.68 2H); 0.91 and 0.81 3H).

MS (EI; TSQ 700; source 180 C;70 V; 200 uA): 570 467; 435; 408; 383; 334; 305; 264; 247; 219; 189; 118; 91.

EXAMPLE (S)-N-(a-ethylbenzyl)-3-2-2,2-dimethyl-5-(S)-phenyl-4-oxo-3imidazolidinyllethoxy}-2-phenylquinoline- 4 -carboxamide g (0.9 mmol) of (S)-N-(a-ethylbenzyl)-3-[2-(S)-a-aminophenylacetylaminoethoxy]- 2-phenylquinone-4-carboxamide (compound of Description 12) were dissolved in 10 ml of n-BuOH; 3.5 ml of acetone were added and the reaction mixture was refluxed for 17 hours. The solvent was evaporated in vacuo to dryness and the residue was triturated with i-Pr 2 0 to yield 440 mg of the title compound.

C3 8

H

3 8

N

4 0 3 M.P. 167-168oC 598.74 [l]D 20 -42.2 MeOH) I.R. (KBr): 3280; 3100-3000; 1690-1670; 1660-1640; 1581 cm-1.

300 MHz IH-NMR (DMSO-d 6 8 9.29 1H); 8.06 1H); 7.94 (dd, 2H); 7.73 (ddd.

S 25 1H); 7.62-7.20 15H); 5.09 (dt, 1H); 4.49 1H); 3.70 2H); 3.29 1H); 3.06 2H); 1.90-1.74 (m, 2H); 1.12 3H); 1.02 3H): 0.96 3H).

MS (EI; TSQ 700; source 180 C;70 V; 200 uA): 598 583; 463; 452; 436; 146.

EXAMPLE 21 30 (S)-N-(a-ethylbenzyl)-3- 2 2 -dimethyl-5-(R)-phenyl-4-oxo-3imidazolidinyljethoxy-2-phenylquinoline4-carboxamide g (0.9 mmol) of (S)-N-(a-ethylbenzyl)-3-2-(R)-a-aminophenylacetylaminoethoxy- S-phenylquinoline-4-carboxamide (compound of Description 13) were dissolved in 10 ml of n-BuOH; 3.5 ml of acetone were added ant the reaction mixture was refluxed for 17 hours. The solvent was evaporated in vacuo to dryness and the residue was purified by gradient flash column chromatography on 230-400 mesh silica gel, utilising a mixture of hexane/EtOAc 1:1 as starting eluent and EtOAc as final eluent, to yield 0.41 g of the title compound.

C

3 8

H

3 8

N

4 0 3 M.P. =147-150 0

C

M.W. =598.74 [CCzD 20 =-42.4 MeOJ-) l.R. (KBr): 3272; 3 100-3000; 1700-1670; 1660-1630; 1586 cm-I. 300 MHz I H-NMR (DMSO-d 6 5 9.3 0 I 8.08 I 7.95 (dd. 7.74 (ddd, 1H); 7.62-7.22 (in, 15H); 5.09 (dt, I 4.46

INH);

3.78-3.65 (mn, 2H); 3.23 3.19-3.08 (in, 1I); 3.05-2,93 (mn, 1H); 1.90-1.75 (in, 2H); 1.10 3H); 1.03 0.99 3H).

MS (El; TSQ 700; source 180 C-70 V; 200 uA): 598 583; 463; 452; 436; 146.

EXAMPLE 22 (S)-N-(a-ethylbenzyI)..3.[2..(3,4..dhydro..l( 2 I)-isoquinolinon-2-y)ethoxy-2- 1.0 g (2.61 minol) of (S--aehlezl--yrx--hnlunln--abxmd (compound of Description 2) were dissolved, under nitrogen atmosphere, in 12 ml of dry THF. 1.1 g of K 2 C0 3 and 130 ing of KI were added and then 1.1 g (5.2 mmol) of 2-(2- *chloroethy)-'3,4dihyd.

0 I 2 H)-isoquinolinone (compound of Description 17), dissolved *in 9 ml of THF, were added dropwise. The reaction was refluxed for 4 hours, filtered and 25 evaporated in vacuc to dryness. The residue was dissolved in CH 2

CI

2 and washed with sat sol. NaCi; the organic layer was dried over Na 2

SO

4 and evaporated in vacuo to dryness. The crude product was purified by gradient flash column chromatography on 23 0-400 mesh silica gel, utilising a mixture of hexane/EtOAc 1:1 as starting eluent and EtOAc as final eluent, to yield 1.2 g of the title compound.

30 C3 6

H

3 3

N

3 0 3 M.P. 71 *C dec.

555.67 [OCtD =-24.2 MeOH) 1.R. (KBr): 3-360-3 120; 3 100-3000; 1660; 1650-1610; 1600; 1580 cm-1.

300 MHz 1 H-NMR (DMSO-d 6 6 9.29 I 8.05 I 7.90 2H); 7.84 I H); 7.71 (ddd, IH); 7.57 2H); 7.49 (dd, IN); 7.44-7.24 (mn, IOH); 4.99 (dt, IH); 3.90-3.78 (in, 2H); 3.60-3.49 1H); 3.40-3.25 3H); 2.81 2H); 1.88-1.67 (m, 2H); 0.87 (t,3H).

MS (El; TSQ 700; source 180 C;70 V; 200 uA): 555 393; 174.

EXAMPLE 23 (S)-N-(a-ethylbenzyl)-3-(N'-benzyl-N'-methylamino)methyl-2-phenylquinoline-4carboxamide g (20.90 mmol) of 3-(N-benzyl-N-methylamino)methyl-2-phenylquinoline-4carboxylic acid (compound of Description 18), 5.7 g (41.8 mmol) of ethylbenzylamine and 5.7 g (41.80 mmol) of HOBT were dissolved in 60 ml of CH 2 C1 2 11.9 g (57.90 mmol) of DCC dissolved in 20 ml of CH 2

CI

2 were added and the solution was stirred at room temperature overnight.

ml of 20% citric acid were added and the solution stirred at room temperature for 2 hours. The precipitated dicyclohexylurea was filtered off and the slurry, basified with solid K 2 C0 3 was diluted with 50 ml of H 2 0 and 50 ml of CH 2 C12. The organic phase was separated and the aqueous phase extracted with CH 2 C1 2 the organic phase was dried over Na 2

SO

4 and evaporated in vacuo to dryness.

The crude product was flash chromatographed on 230-400 mesh silica gel, eluting with a mixture of hexane/EtOAc 8:2 to afford 4.5 g of crude material which was treated with the precipitated title compound was filtered, triturated with pentane and filtered again to yield 1.6 g of the pure title compound as a white powder.

C

34

H

3 3

N

3 0 M.P. 76-78 °C 25 M.W. 499.65

IC

2 -43.1 (c 1.2 MeOH) I.R. (KBr): 3290; 3061; 3029; 2970-2789; 1633; 1537 cm- 1 300 MHz 1 H-NMR (DMSO-d 6 5 8.90 1H); 8.05 1H); 7.80-7.05 16H); 6.85 2H); 5.15 1H); 3.75 2H); 3.15 2H); 1.90 2H); 1.65 3H); 0.95 (t 3H).

MS (EI; TSQ 700; source 180 C;70 V; 200 uA): 408; 380; 273.

EXAMPLE 24 .(-)-N-(a-acetylbenzyl)-3-methyl-2-phenylquinoline--carboxamide S 3.8 g (10.0 mmol) of (-)-a-aminoacetophenone D-10-camphosulfonate (Benjamin,

B.M.,

Collins, 1961, J. Am. Chem. Soc., 83, 3662) were dissolved in 1000 ml of 96% EtOH. 270 mg of PtO 2 were added and the reaction mixture was hydrogenated in a Parr apparatus at 10 psi for 10 minutes. The catalyst was filtered off and the solvent was evaporated in vacuo to dryness to yield 4.0 g of the corresponding 1-amino-l-phenyl-2propanol D-10-camphosulfonate. 1.5 g (3.9 mmol) of this compound were dissolved in a 1:1 mixture of CH2C12/CH 3 CN; 1.36 ml (9.7 mmol) of TEA were added and the reaction mixture was cooled to -150C. 1.32 g (4.7 mmol of 3 -methyl-2-phenylquinoline-4carbonyl chloride (obtained from the corresponding carboxylic acid (CAS [43071-45-0]) by reaction with oxalyl chloride in CH 2

CI

2 at room temperature), dissolved in 50 ml of a 1:4 mixture of CH2CI 2 /DMF, were added dropwise, maintaining the temperature below 10'C. The reaction mixture was stirred for 2 hours at 0 0 C and then maintained at room temperature overnight. The inorganic salts were filtered off, the filtrate was evaporated in vacuo to dryness, dissolved in CH 2

CI

2 and washed with sat. sol. NaHC0 3 20% citric acid, sat. sol. NaHC0 3 sat. sol. NaC1. The organic layer was dried over Na 2

SO

4 and evaporated in vacuo to dryness. The crude product was purified by gradient flash column chromatography on 230-400 mesh silica gel, utilising a mixture of CH2C12/MeOH 99:1 containing 0.5% NH 4 0H as starting eluent and a mixture of CH2CI 2 /MeOH 98:2 containing 0.5%

NH

4 0H as final eluent, to yield 0.86 g of hydroxyethyl)benzyl]-3-methyl-2-phenylquinoline-4-carboxamide 0.24 ml (2.8 mmol) of oxalyl chloride were dissolved, under nitrogen atmosphere, in 6 ml of dry CH 2

CI

2 The solution was cooled to -55C and 0.40 ml (5.6 mmol) of DMSO, i dissolved in 1.1 ml of dry CH2Cl 2 were added dropwise maintaining the temperature below -50C. The reaction was stirred at -55°C for 9 minutes, then 0.69 g (1.7 mmol) of N-[c-(1-hydroxyethyl)benzyl]-3-methyl-2 -phenylquinoline-4-carboxamide, dissolved in 20 ml of dry CH2C 2 were added keeping the temperature between -50 and -55 0

C.

2 After 30 minutes at -55'C, 1.7 ml (12.2 mmol) of TEA were added without exceeding then the reaction mixture was allowed to reach room temperature and stirred for additional 15 minutes.

The reaction was quenched with 5 ml of H20 and extracted with CH2C12; the organic layer was washed with H20, 20% citric acid, sat. sol. NaHCO 3 and brine; the organic 30 layer was separated, dried over Na-S0 4 and evaporated in vacuo to dryness.

The residual oil was purified by gradient flash column chromatography on 230-400 mesh ilica gel, utilising a mixture of petroleum ether/EtOAc 8:2 containing 0.3% NH 4 0H as starting eluent and a mixture of petroleum ether/EtOAc 6:4 containing as final eluent, to yield 0.44 g of the title compound as an amorphous solid..

C2 6

H

2 2

N

2 0 2 M.P. 55-88 0

C

-53- M.W. 394.48 [all)D 20 96.0 (c =0.5 MeOH) e.e. =74% (chiral

I-PLC)

1.R. (KBr): 3420-3120; 3 100-3000; 1730; 1670-1630; 1580 cm-I.

300 MHz 1 1--NMR (DMSO-d 6 6 9.51 1H); 8.00 1H); 7.81 (m br, 7.71 (ddd, 7.58-7.32 (in, I ii); 5.95 1I); 2.28 (s br, 3Hi); 2.18 3H).

MS (El; TSQ 700; source 180 C;70 V; 200 uA): 394 35 1; 246; 217.

EXAMPLE (+--c-ctlezl--ehl--hnlunln--abxmd Prepared as described in Example 24. 1.69 g of (+)-a-aminoacetophenone hydrochloride (Benjamin, Collins, 1961, J Am. Chem. Soc., 83, 3662) were converted into 1. 7 g of the corresponding I -amino- I -phenyl-2-propanol hydrochloride. 1.6 g (8.5 inmol) of this compound were acylated with 2.9 g (10.2 mniol) of 3-ehl2peyqioie4 carbonyl chloride in the presence of 3 ml (21.2 mmol) of TEA to afford 1.9 g of 1hyrxehlbnyj3mty--peyqioie4croaie 1.9 g (4.8 mmol) of this compound were oxidised in the Swern conditions described in Example 24 (0.7 ml of oxalyl chloride, 1. 16 ml of DMSO, 3.5 ml of TEA) to yield 1.4 g of the title compound as :an amorphous solid.

a. a.C 2 6

H

2 2

N

2 0 2 M.P. 72-95*C M.W. 394.48 [aiD 2 0 +83.7 (c =0.5 MeOH) e.e. =60% (chiral

HPLC)

I.R. (KBr): 3420-3120; 3100-3000; 1730; 1670-1630; 1580 cm- 1 3 00 MHz I'H-NMR (DMS O-d 6 6 9.51 lI 8.00 I1H); 7.81 (m br, I 7.71 (ddd, IFI); 7.58-7.32 (in, 1111); 5.95 2.28 (s br, 3H); 30 2.18 3H).

MS (El; TSQ 700; source 180 C;70 V; 200 uA): 394 351; 246; 217.

EXAMPLE 26 (R,S)-N-Icx-(m ethoxya rbo nyl)acc(m ethyl) benzyll 2.phenylq uinoine4-carboxa mide Prepared as described in Description 2 from 1.0 g (4.0 inmol) of 2 -phenylquinoline-4 carboxylic acid, 0.9 g (4.2 inmol) of methyl cz-methylphenylglicinate hydrochloride [obtained from the corresponding acid (Steinger, Organic Synthesis. Coll. Vol. 3, 88) by reaction with MeOH and SOC1 2 1.0 g (7.7 mmol) of HOBT, 0.55 ml (5.0 mmol) of N-methylmorpholine and 0.92 g (4.4 mmol) of DCC in 50 ml of a 2:1 mixture of THF and CH 3

CN.

The work-up of the reaction mixture was carried out in the same manner as described in Description 2. The residue was purified by gradient flash column chromatography on 230-400 mesh silica gel, utilising a mixture of petroleum ether/EtOAc 9:1 containing 0.3% NH 4 0H as starting eluent and a mixture of petroleum ether/EtOAc 8:2 containing 0.5% NH 4 0H as final eluent, to yield, after trituration with i-Pr20, 38 mg of the title compound.

C

2 6

H

2 2

N

2 0 3 M.P. 154-157 0

C

M.W. 410.48 I.R. (KBr): 3400-3100; 3100-3000; 1740; 1660; 1600 cm- 1 300 MHz IH-NMR (DMSO-d 6 6 9.48 1H); 8.31 2H); 8.20 1H); 8.14 1H); 8.14 1H); 7.84 (dd, 1H); 7.69 (dd, 1H); 7.63-7.51 5H); 7.41 (dd, 2H); 7.35 (dd, 1H); 3.77 3H); 0(s, 3H).

MS (EI; TSQ 700; source 180 C;70 V; 200 uA): 410 351; 232; 204.

EXAMPLE 27 :I :(R,S)-N-[a-(methoxycarbonyl)-a-(methyl)benzylj-3-methyl-2-phenylquinoline-4carboxamide 5.9 g (27.4 mmol) of methyl a-methylphenylglicinate hydrochloride (see literature 25 reference of Example 26) by reaction with MeOH and SOC12) were dissolved in 100 ml of dry Et 2 0; 9.6 ml (68.9 mmol) of TEA were added and the solution was cooled to 0°C.

8.6 g (30.4 mmol) of 3-methyl-2-phenylquinoline-4-carbonyl chloride (obtained from the corresponding carboxylic acid (CAS [43071-45-0]) by reaction with oxalyl chloride in

CH

2 C1 2 at room temperature), dissolved in 180 ml of a 1:1 mixture of CH 2

CI

2

/DMF,

30 were added dropwise maintaining the temperature below 5 0 C. The reaction was then maintained at room temperature overnight. The solvent was evaporated in vacuo to dryness, the residue was dissolved in CH 2 Cl 2 and washed with sat. sol. NaHCO 3 citric acid, sat. sol. NaHCO 3 sat. sol. NaCI. The organic layer was dried over Na2SO 4 evaporated in vacuo to dryness and purified by gradient flash column chromatography on 230-400 mesh silica gel, utilising a mixture of petroleum ether/EtOAc 8:2 containing 0.3% NH 4 0H as starting eluent and a mixture of petroleum ether/EtOAc 7:3 containing 0.3% NH40H as final eluent, to yield, after trituration with i-Pr2O, 23 mg of the title compound.

C

2 7

H

2 4

N

2 0 3 192-195°C 424.50 I.R. (KBr): 3400-3100; 3100-3000; 1741; 1658 cm- 1 300 MHz IH-NMR (DMSO-d 6 6 9.50 1H); 8.03 1H); 7.76 (dd, 1H); 7.68 (dd, IH); 7.60-7.49 8H); 7.42-7.31 3H); 3.78 (s br, 3H); 2.40 (s br, 3H); 2.05 (s br, 3H).

MS (EI; TSQ 700; source 180 C;70 V; 200 uA): 424 365; 246; 217.

EXAMPLE 28 (R,S)-N-[a-(acetyl)-a-(methyl)benzyl]-3-methyl-2-phenylquinoline-4-carboxamide 265 mg (0.78 mmol) of Bu 4

NHSO

4 were suspended in 1.5 ml of CH 2

CI

2 250 mg (0.63 mmol) of (R,S)-N-(a-acetylbenzyl)-3-methyl-2-phenylquinoline-4-carboxamide (racemate of Example 24), 0.1 ml (1.6 mmol) of Mel and 0.6 ml of 10% NaOH were added and the reaction mixture was allowed to stand at room temperature overnight. The reaction mixture was washed twice with sat. sol. NH 4 CI and then with sat. sol. NaCI, dried over Na 2

SO

4 and evaporated in vacuo to dryness. The residue was dissolved in a 1:1 mixture of hexane/EtOAc and the insoluble inorganic salts were filtered off. The filtrate was evaporated in vacuo to dryness and then purified by gradient flash column chromatography on 230-400 mesh silica gel, utilising a mixture of petroleum ether/EtOAc 8:2 containing 0.3% NH 4 0H as starting eluent and a mixture of 25 petroleum ether/EtOAc 7:3 containing 0.4% NH 4 0H as final eluent, and then by preparative HPLC to yield, after trituration with i-Pr20, 17 mg of the title compound.

C

2 7

H

2 4

N

2 0 2 M.P. 167-169 0

C

M.W. 408.50 30 I.R. (KBr): 3290; 3100-3000; 1720; 1641; 1580 cm-1 300 MHz 1 H-NMR (DMSO-d 6 5 9.43(s br, 1H); 8.04 1H); 7.88 (s br, 1H); 7.77 (dd, 7.67 (dd, IH); 7.62-7.49 7H); 7.42 (dd, 2H); 7.34 (dd, 1H); 2.40 (s br, 3H); 2.17 3H); 2.01 (s, 3H).

MS (El: TSQ 700; source 180 C;70 V; 200 uA): 408 365; 246; 217.

*6 C A

CC.

C C

C

C CC CCC C *CC CCt C CC C C C C C C C C C CC C CCC C CC CCC TABLE I a

.S

0S*

S

S S

S

.0 00:..

S* 0. *5 S S S S S S TABLE I (continued) Ex AR Ph Et1 RI R2 R4

OH

H 0--

(S)

11 Ph Et H OCH 2

CH

2

CH

2

NH

2 H (S) 12 Ph Et H2 H (S) 13 Ph Et H CH 2 NHCH(Et)Ph H (S) 14 Ph Et H O-vt$ H (S) Ph Et H O H (S) 16 Ph Et H H (S) Molecular formula

C

36

H

3 3

N

3 0 4

C

2 8

H

2 9

N

3 0 2

HCI

C

36

H

3 1

N

3 0 3

C

3 5

H

3 5

N

3 0 -HI

C

36

H

33

N

3 0 3 Melting point cc 100110 [aID 2 0 c=O.5, MeOl

I

160-165 -28.6 60 dec.

193-195 153-156 +9.7 -59.8 -20.8 7y; I

C

3 1 2 9

N

3 0 4 80 dec. -25.4

C

3 1

H

27

N

3 0 4 74-78 -21.7 I III In

NH

N)d

C

3 2

H

3 4

N

4 0 3 160-162 I I I

T-

18 I Ph

H

O N N)

MOO

C

39

H

42 N 0 3 .21HCI I 151-155 50.0 7.7

MOO

I

TABLE 1 (continued) I I I I nx A 1 r R 2

R

4 j Molecular I formula Melting point 0C 80-85 dec.

laiD 20 c=0.5, McOll -45.6

N)

_j

C

36

H

34

N

4 0 3 0 0 N N

C

3 8

H

3 8

N

4 0 3 167-168 -42.2 21 Pb Et H 07vN/H HI C 38

H

38

N

4 0 3 147-150 -42.4 22 Ph Et H H C 3 6

H

3 3

N

3 0 3 71 dec. -24.2 23 Ph Et H CH 2

N(CH

3 )CH1 2 Ph H

C

34

H

33

N

3 0 76-78 43.1# 24 Ph COCH 3 H CH 3 H C 2 6

H

22

N

2 0 2 55-88 -96.0 Ph COCH 3 H CH 3 H C 2 6

H

22

N

2 0 2 72-95 83.7 26 Ph C0 2

CH

3 H H CH 3

C

2 6

H

22

N

2 0 3 154-157 27 Ph CO 2 CH 3 H CH 3

CH

3

C

2 7 2 4

N

2 0 3 192-195 H C2H4N0 Ph I COCH- I CH-i CH~ IR.S~ CI~?U~lhT~n, 1L7 tLn CHi (R S) C A m-dV 1 1<7 1 IC J J~ 1 14L /g-ff 4 Nc 1.2, MeOH 00* 'a 0. to to to Following synthetic procedures described in Examples 1-28, the compounds listed below have been prepared: TABLE 2 Ar o NH+

R

4 R

R

N Ar U U U U U U U U U U U UU U.

U

U

U U U UU U U U U U U U. *UU U U U U U *U U U U U U U U U U U

U

UUU U UU

*UU

0 N N-COO-tBu N N-COO-isu

C

3 8H39C1N 2 0 2 .2HCI

C

39

H

42

N

4 0 3 2HC1 C39H4 2

N

4 0 2

C

3 7

H

4 4 N40 4 C3211 3 6

N

4 0 2 .3HCI

C

3 6

H

3 8N60 2 C38H 4 5

N

3 0 2

.HCI

C

34

H

2 9

N

5 0 4 Oe 9@ S S S

S

S. 9 S S S S S S S S

S

S S 55 S S S S 5** S. S 5 5 S S S S S S S S 55 S S S 55 S S S S S *5

S

S S S S S S S S S S S S 5 S 55* 55 Table 3. Analytical and spectroscopic data of compounds of Examples 29-46.

Ex. ElIem en t al 1 an al1 y s i s 2F9_ IR (Kbr); cm' 3293; 3060-2824; 1633; 1599; 1533.

3 700-3 100; 3 100-2850; MS (El; source 200 300 Mf~z 1 l[ NMR (DMS0), 0 C; 70eV; 200 1A)30k 408; 380;273; 261; (33 8.68(d,IH); 7.72(m,2H; 216; 91. 7 5 7 -7.42(m,SH; 7.3 7(dd,2 H); 7.2 8(dd, 11-H); 5.40(ddt, I H); 2 6 3(d,2H;2.50(s,3H); 2.10-I 8 2(m,2fH);- 540 378: 259; (3 53K): 8.84(d br, IH); 8.02(d,

IH);

216; 161; 132; 119; 7 7 5(m,2H); 7 6

O-

7 .52(m,3H); 7.49-7.42 105;91; 56. 7.36(dd,2H); 7.25(dd, IH); 7.19- 7.1 2(m,2H); 6.79(d,2H); 6.72(dd, I H); S. I0(dt, IH); 3.58(s,2H); 2.80(t,4H); 2.21 2 .10(m,4H): 2.02 l.9iH;0.98(t,3H).

522 452; 383; 1 2 .20(s br,2H); 9.3 7(d, IH); 8.09(d,lIH); 139; 113; 91; 70. 7.92(d,2H); 7.76(ddd, IH): 7.62-7.50 7.49-7.4 1 7 3 2(m, I H); 12(dt, I 3.70-3 6 0(m,414I); 3.60-3.3 3 3 5- 3 .20(m,2H); 2.8 1 2.8 l- 2 .60(m,2H); 1.90-1 .72(m,4H); In 99(t,

H).

31 Calcd. C,62.71; H,6.54; N,8.86; Found C,56.69; 1H,6.5 1; N,7.94; CI, 15.06.

0 Oe.

~0* 00 0 0 0** 0e* 0** 0* 000 0 0.

*00 000 Ex. Elemental analysis 32 Calcd. C,65.94,, H,5.97; N,8.09; CI,15.36; Found C,65.42; H,6.03; N,7.91; CI, 13.3 6.

33 Calcd. C,67.52; H,6.34; N,8.29; C1, 13.1 1; Found C,64.99; 11,6.44; N,7.89; Cl, 12.65.

34 Caled. C,65.94; H,5.97; N,8.09; Ci,15.36; Found C,64.89; H,6.04; N,7.83; Cl, 13.86.

JR (Kbr); cm- 1 3700-3 150; 3150-2800; 2750-2000; 1654; 1588; 1547.

3 700-3 150; 3150-2800; 2750-2000; 1658; 1600; 1538.

3700-3150; 3150-2800; 2750-2000; 1654; 1595; 1539.

MS (El; source 200 C; 70eV; 200 pA) 618 452; 247; 209; 119; 91.

584 366; 337; 232; 206; 175.

7 .5O- 7 .40(m,5H); 7.39-7.29 7.20(d, IH); 7.11 (dd, IH); 5.11 (dt, 11H); 3 75 -3.63(m,2H); 3.40-3.29 (m,411); 3. 19(dd,2H); 3 .OO-2.75(m,4H); 1.90-1 7 5(m,4H); I .01(t,3H).

11. 19(s br, IH); 9.3 9(d, IH); 8. 10(d, IH); 7.94(dd,2H); 7.76(ddd, IH); 7.66- 7 5 7 4 9 -7.40(m,4H); 7.33- 7 .26(m,3H); 7.O1(d,2H); 6.88(dd,1H); 3.29(dd,2-U; 3.13(dd,2H); 2.95- 2 .82(m,2H); 2 82 2 .68(m,211); 1.91 1 .75(m,41H); 0.99(t,3 H).

()18 452; 13 8; 11 .13 (s br, IH); 9.3 8(d, IH); 8. 10(d, IH); 104. 7.98(d,2 7.78(ddd, I 7.6 1- 7.50(m,5H); 7 .50-7.40(m,4H); 7.30- 7.2 1 (m,214); 7 .00(s, I 6.95(d, 11-1); 6.85(d,2H); 5.l10(dt, IH); 3.82(d,2H); 3.72- 3 .62(m,2H); 3,28(dd,2H); 3.1 9(dd,21l); 2 9 O-2.70(m,4H); 1,90-1 .70(m,41-); O.98(t,3 H).

1 .0 .0 I Elemental analysis IR (Kbr); cm1 Calcd. C,65.94; H,5.97; N,8.09; 1650; 1495; 1240.

CI,15.36; Found C,64.99; 1,6.22; N,7.82; C1, 13.65.

MS (El; source 200 70 eV; 200 jiA) A) 619 641 (MNa+); B (ESI DAU+ 619) 237; 210.

A) 6 15 63 7 (MNa+); B (ESI DAU+ 615) 233.

36 Calcd. C,68.1 1; N,8.15; Cl, 10.3 1; Found C,66.66; H,6.70; N,7.87; Cl, 9.78.

1650; 1450; 1240; 1020.

300 MIz H NMR (DMS0), 303 k 10.7 1 (s br, IH); 9.3 7(d, I 8.08(d, I H); 7.93(dd,2H); 7.76(ddd, IH); 7.65- 7.52(m,5H); 7 .48-7.40(m,4H); 7.33- 7.28(m, IH); 7.30(d,2H); 7.02(d,2H); 5.10(dt, IfM; 3.78(d,2H); 3.71-3.63 3.3 1 (dd,2H); 3. 1 0(dd,2H); 2.95- 2.70 1.90-1 .75(m,4H); I .00(t,3H).

I 1.00(s br, IH); 9.3 8(d, IH); 8.09(d, IH); 7.94(dd,2H); 7.75(ddd, I 7.68- 7.52(m,5H); 7 4 9-7.41(m,4H); 7.3 1 (dd, I 6.99(d,2H); 6.89(d,2-H); 3.71(s,3H); 3.71-3.65 3.60(d,2H); 3.30(dd,2H); 3.10(dd,2H); 3 .00-2.85(m,2H); 2.85- 2.70(m.2H); 1.90-1.78 0.99(t,3H).

10 O80(s br, I 9.3 8(d, I 8.09(d, I H); 7.94(dd,2H); 7.76(ddd, IH); 7.65- 7.52(m,5H); 7 .48-7.40(m,4H); 7.3 0(dd, 1ff); 7.09(d,2H); 6.90(d,2H); 5.10(dt,IH); 3 75 -3.62(m,4H); 3.29(dd,I1H); 3.05(dd,1I1H); 2.97- 2.70(m,6H'; 2.23(s,3H); 1.90-1 .75(m,4H); 0.99(t,3H).

i Calcd. C,67.89; H,6.50; N,8.12; Cl1, 12.84; Found C,64.53; H,6.65; N,7.53; Cl, 12.95 1660; 15 10; 1440. 1 A) 599 B (CID Offset 46 V) 217; 189.

I I 9 9@ @9 *9 @9 9 9 9@ 9e* 9 9. 9@# @9 9 9 999 p 9 9 9.

*99 @9 9..

Elemental analysis IR (Kbr); cm-1 MS (El; source 200 0 C; 70eV; 200 [A) 73290; 2970; 1690; A) 609 631 1640; 1530; 1420; (MNa+) 1170.

39 Calcd. C,62.18; 11,6.36; N,9.06; C1, 17. 21; Found C,5 7.72; H,6.58; N,8.3 1; C1, 16.11I.

Calcd. C,63.78; H,6.02; N,12.40; C1,13.07; Found C,60.79; H,6.46; N,1 1.81; CI, 13. 10.

1650; 1450; 1300.

1660; 1540; 1350.

FA) 509 531 (MNa+); B (ESI DAU+ 509) 127.

A) 587 609 300 IIz 1 H NMR (DMS0), 303 k 9.28(d, I 8.06(d, I 7.92(dd,2H); 7.72(ddd, IHM; 7 6 3 7 7.45(d,2H); 7.3 8(dd,2H); 7.28(dd, I H); 5.09(dt, IH); 3.69-3.58 (m,2H); 3 .17(m,4H); 2 .0 1(m,6H); 1.89-1.74 1.5I-1.41(m,2H); I.39(s,9H); 0.90(t,3

H).

I 1.99(s br, IH); 10. 09(s br, IH); 9 .89(s br, IH); 9.3 8(d, IH); 8.09(d,'I

H);

7.92(dd,2H); 7.75 (ddd,1IH); 7.64- 7.48-7.41 7.32(m,1IH); 5. 10(dt, IH); 3.72-3.62 3

.S

3 -3.30(m,6H); 3.30- 3.O5(m,2H); 2.82-2.62 (m,214); 1.9 1.

I .75(m,4H); 0.99(t,3H).

I 1.30(s br, IH); 9.3 8(d, IH); 8.49(d,2H); 8.09(d, I 7.92(dd,2H); 7.75(ddd, I H); 7 65 7 .50(m,5H); 7 4 8 -7.38(m,4H); 7.2 7(dd, I1H); 6,79(dd, I 5. 1 0(dt, I H); 5.65(d,2H); 3.75-3.62 (m,2H); 3.39(dd,2H); 3.29(dd,2f{); 2.8 1-2.65 1.90-1 .75(m,4H); 0.99(t,3

H).

B (ESI DAU+ 587) 205.

S 04* 9 9 *9 1 *s

S..

909 99 9 9 9 b 99 99* 9 9 9 499 9 99 9 9ie 9 9 9 9 9 9* 9.

9 *9 999 Ex.

41 42 43 Elemental analysis JR (Kbr); cm-1 11650; 15501450; 1300.

MS (El; source 200 70 eV; 200 vA) A) 576 (MII+); B (ESI DAU+ 576) 194; 166, 219; 190; 163 3280; 1728; 1660- 1640.

300 MI1zz 1 H NMR (DM50S), 303 k 10. 19(s br, I1H); 9.3 5(d, 111); 8.09(d, I H); 7.93(dd,2H); 7.75(ddd, IH); 7.65- 7.53(m,5H); 7 4 7-7.39(m,4H); 7.3 0(dd, I 5. 1 0(dt, 11H); 3.72- 3.60(m,2H); 2.99(dd,2H); 2.79- 2.62(m,4H); 1.88-1 .72(m,4H); I .68(d,2H); I .53(ddd,2H); 1.45-I .35(m,8H); I .22(m,2H); 0.99(t,3 H).

9.27(d, I 9.0 1 8.06(d, I H); 7.91 7.71 (ddd, IH); 7.5 8(m,2H); 7.48-7.3 1 (m,711); 7.2 1I(dd, IH); 5.08(dt,]IH); 3 .69(t,2H); 3.51-3.35 (m,2 H); 1.90-1 .69(m,4H); 0.97(t,3 H).

9.50 (2d,IH); 7.70-8.10 (m,314); 7.10-7.55 11); 6 4 8 -6.90 5.30 (s,IH); 4.85-5.15 (m,214); 1.65-1.95 0.90 (2t,3H).

8.89 I 8. 01 I 7.74 (in, 2 H); 7.62 (dd, 2H); 7.5 7-7.44 (in, 7.39 (dd, 2H); 7.29 (dd, 111); 7.20-7. 10 (mn, 311); 6.89 2H); 5.13 (dt, I 3.70 (s, 211); 3. 10 21- 2.02-1.80 211); 1.68 3H); 0.98 314).

3230; 1660; 1550. A) 447 B3 (ES! DAU+-447) 261; 119; 91.

408; 273; 380.

44 3498; 3185; 2968-2637; 1650; 1535.

Ex.

46 Elemental analysis :IR (Kbr); cm 1 MS (El; source 200 300 MIHzH NMR (DMS0), 303 k 0 C; 70 eV;20A 3419; 3163; 3 059-2933; 514; 223; 2 10; 132; 9.52 I 8. 10 I 7.86 (dd, 2H); 1656; 1542. 91. 7.79 (ddd, I 7.63 (in, 2H); 7.49-7.36 (in, 16H); 7.30-7.20 (in, 3H); 5.01 (dt, 1H); 4.09 (in, 4H); 3.99 (mn, 2 3.00 (in, 2H); 1.8 1-1.71 (in, 2H); 0.82 3H).

3388; 2930; 1630; 438 383; 320; 303; 9.48(d, IH); 8.91 (s br, IH); 8.09(d, IH); 1563. 291; 247; 219; 204; 7.98(dd,2H); 7.76(ddd, IH); 7.6 1(m,2H); 119; 105; 91; 56. 7 .58-7.50(m,3H); 7 48 -7.25(m,8H); 7.2 1 5.07(dt, I1H); 3.98-3.85 2.85(s br,6H); 1.90-1 .74(m,2H); 0.93(t,3H).

*Nujol moul. A) ESI POS; TSQ 700; solvent: methanol/ spray:4.5 kV/ skimmer: 60 eV/ capillary 220 TC.

Table 4. Pharmacolagical data Example n. Binding affinity in hNK-3-CHOa ICso (nM) 2 1.6 1.2 6 0.8 9 3.2 11 2.6 14 1.7 17 3.4 18 0.4 21 0.9 22 1.3 30 1.1 31 3.3 33 0.7 34 0.8 40 1.1 42 2.7

S..

a hNK-3-CHO human neurokinin-3 receptors expressed in radioligand used was 2 5 I]-[Me-PheT]-NKB.

CHO cell lines; 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.

-69-

Claims (13)

1. A compound of formula R 0 NH- Ar R R 1 R2 N (RI or a salt thereof, or a solvate thereof, wherein, Ar is an optionally substituted aryl or a C 5 7 cycloalkdienyl group, or an optionally substituted single or fused ring aromatic heterocyclic group,; R is C1- 6 alkyl, C 3 7 cycloalkyl, C 3 7 cycloalkylalkyl, optionally substituted phenyl or phenyl C -6 alkyl, an optionally substituted five-membered heteroaromatic ring comprising up to four heteroatoms selected from O and N, hydroxy C1-6 alkyl, amino C -6 alkyl, C 1 -6 alkylaminoalkyl, di C -6 alkylaminoalkyl, C -6 acylaminoalkyl, C1-6 alkoxyalkyl, C -6 alkylcarbonyl, carboxy, C1-6 alkoxycarbonyl, C1-6 alkoxycarbonyl C -6 alkyl, aminocarbonyl, C1-6 alkylaminocarbonyl, di C1-6 alkylaminocarbonyl, 15 halogeno C 1 .6 alkyl; or R is a group -(CH 2 wherein p is 2 or 3 which group forms a ring with a carbon atom ofAr; R 1 represents hydrogen or up to four optional subtitutents selected from the list consisting of: C -6 alkyl, C -6 alkenyl, aryl, Cl6 alkoxy, hydroxv, halogen, nitro, cyano, carboxy, carboxamido, sulphonamido, C -6 alkoxycarbonyl, trifluoromethyl, acyloxy, phthalimido, amino or mono- and di-C 1-6 alkylamino; R 2 represents hydrogen, C 1

6-alkyl, hydroxy, halogen, cyano, amino, mono- or di-C i- 6 -alkylamino, alkylsulphonylamino, mono- or di-C .6-alkanoylamino wherein any Salkyl group is optionally substituted with an amino group or with a mono- or di- alkylamino group, or R 2 is a moiety -X-(CH 2 )n-Y wherein X is a bond or and n is an 25 integer in the range of from 1 to 5 providing that when X is n is only an integer from 2 to 5 and Y represents a group NY Y 2 wherein Y 1 and Y 2 are independently selected from hydrogen, C 1 6 -alkyl, C1.6-alkenyl, aryl or aryl-C 1 -6-alkyl or Y is hydroxy, halogen or an optionally substituted N-linked single or fused ring, heterocyclic group, R3 is branched or linear C 1 -6 alkyl, C 3 7 cycloalkyl, C4- 7 cycloalkylalkyl, optionally substituted aryl, or an optionally substituted single or fused ring aromatic heterocyclic group; and R4 represents hydrogen or C 1 -6 alkyl. 2. A compound according to claim 1, wherein Ar represents phenyl. 3. A compound according to claim 1 or claim 2, wherein R represents ethyl. 4. A compound according to any one of claims 1 to 3, wherein R 2 represents a moiety -X-(CH2)n-Y. A compound according to any one of claims 1 to 4, wherein the moiety -X- (CH2)n-Y is a moiety of formula N N-T (a) wherein T represents C 1 -6 alkyl, C1-6 alkoxycarbonyl, aryl or an aromatic heterocyclic group and either X is O and n is 2 or 3 or X is a bond and n is 1, 2 or 3. 6. A compound according to claim 5, wherein T represents a methyl group.

7. A compound according to claim 5, wherein T represents a phenyl group, substituted with one or more alkoxy groups.

8. A compound according to claim 5, wherein T represents a pyrimidine group.

9. A compound according to claim 1, wherein -X-(CH2)n-Y is a moiety of formula 0 N T T2 (b) 20 wherein X is O or a bond. n is 1, 2 or 3, T 1 and T2 each independently represents hydroxy, C 1 -6 alkoxycarbonyl, C 1 -6 alkyl, aryl or a single or fused ring aromatic heterocyclic group, or T 1 and T 2 together with the carbon atoms to which they are attached form a carbocyclic ring; said aryl or aromatic heterocyclic groups being optionally substituted with one or two C 1 -6 alkyl, alkoxy, hydroxy, halogen, 25 halogenalkyl groups; or one of T 1 or T 2 is an oxo group and the other is selected from the above mentioned groups as appropriate. A compound according to claim 9, wherein TI and T 2 together with the carbon atoms to which they are attached form a carbocyclic ring.

11. A compound according to claim 9, wherein R- represents n is an integer 1 or 2.

12. A compound according to claim 1, wherein: Ar is phenyl, R is ethyl, R I is hydrogen, R 2 is a moiety -X-(CH2)n-Y wherein X is 0 n is 1, 2 or 3 and Y is a moiety formula as defined in claim 5 or a moiety of formula as defined abovein claim 9. -71-

13. A compound according to claim 1 as described in Examples 1-46 herein, or a salt thereof, or a solvate thereof

14. A compound according to claim 1 as described in Examples 18, 30, 33 and herein, or a salt thereof, or a solvate thereof A process for the preparation of a compound of formula or a salt thereof and/or a solvate thereof, which process comprises reacting a compound of formula (III): H Ar' H R' R 4 (III) wherein R 4 and Ar' are R, R 4 and Ar as defined for formula or a group or atom convertible to R, R 4 and Ar respectively, with a compound of formula (II) or an active derivative thereof: 0 OH S R 2 15 N R I 15 R 3 (II) .o wherein R' 1 R' 2 and R' 3 are R 1 R 2 and R 3 respectively as defined in relation to formula or a group convertible to RI, R 2 and R 3 to form a compound of formula (Ib): H Ar N R R'4 R', 2 0 N R3 (Ib) wherein Ar', R'l, R' 2 R'3and R' 4 are as defined above, and optionally thereafter carrying out one or more of the following optional steps: converting any one of Ar', R'i, R' 2 R' 3 and R' 4 to Ar, R, R 1 R2, R 3 or R4 respectively as required, to obtain a compound of formula (ii) converting a compound of formula into another compound of formula and (iii) preparing a salt of the compound of formula and/or a solvate thereof. -72-

16. A pharmaceutical composition comprising a compound of formula or a pharmaceutically acceptable salt thereof, or a pharmaceutcally acceptable solvate thereof and a pharmaceutically acceptable carrier.

17. A method for the treatment and/or prophylaxis of the Primary and Secondary Conditions in mammals, which method comprises administering to the mammal in need of such treatment and/or prophylaxis an effective, non-toxic amount of a compound of formula or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

18. A compound of formula or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance.

19. A compound of formula or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, for use for the treatment and/or prophylaxis of Primary and Secondary Conditions. The use of a compound of formula or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, in the manufacture of a 20 medicament for the treatment of the Primary and Secondary Conditions. DATED this 23 rd day of June, 2000 SmithKline Beecham S.p.A. by DAVIES COLLISON CAVE Patent Attorneys for the Applicant C.. C C -73-