AU1020902A - Method for the synthesis of quinoline derivatives - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANT: SmithKline Beecham Corporation ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street Melbourne, 3000.

INVENTION TITLE: "Method for the synthesis of quinoline derivatives o* 9 oooo 0 9 0 00000 0 00 The following statement is a full description of this invention, including the best method of performing it known to us: METHO0D FOR THEr SYNTHESIS OF

'UFLEDEIAIVES

This application is a divisional of Australian Patent Application No.

93 958/98, the entire contents of -which are incorporated herein by reference.

FIELD OF THE INVENTION This invention relates to novel intermediates and processes for preparing phamaceutically active quinoline compounds, including )-N-(a-ethylbenzyj).3 hyrx--hniunoie4croaie BACKGRO[hUD OF THE INVENTIO Compounds of the structural formula

(I)

0 N-C -Ar N

R

Foml (1) 00090 cylakdey grup ora nFormubtula singeo)ue ightrcci orisn p ptarmac u rl acetable salth or thrf, wheetdn: m,0N isa optionally substituted phenyl group, or a npphnyl C16aklg or notoal 0000 substituted five-membered heteroaromatic ring comprising up to four heteroatom .0.0 ~selected from 0 and N, hydroxy C 1 6 alkyl, di C 1 6 alkylaminoalkcyl, C 1 6 0 acylaminoalkyl,

C

1 6 alkoxyalkyl,

C

1 6 alkylcarbonyl, carboxy,

C

1 6 .25 alkoxycarbonyl, C 1 6 alkoxycarbonyl C 1 6 alkyl, anhinocarbonyl, C 1 -6 alkcylamznocarbonyl, di C 1 6 alkylaiinocarbonyl; or is a group -(CH 2 when cyclized onto Ar, where p is 2 or 3; Rl and R 2 which may be the same or different. are independently hydrogen or C1 -6 linear or branched alkyl, or together form a -(CH2)n. group in which ni represents 3, 4, or 5; or R I together with R forms a group in which q is 2.

3, 4 or

R

3 and R 4 which may be the same or different, are independently hydrogen, C 1 6 linear or branched alkyl, C 1 6 alkenyl, aryl, C 1 6 aikoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamio, sulphonmdo, trifluorornethyl, amino, monoand di-C 16 akylamino, -O(CH2)rNT 2 in which r is 2, 3, or 4 and T is C 1 6 alcyl or it forms a heterocyclic group

V

1

V,

or N V

(CH

2 )u V

CH

in which V and V 1 are hydrogen and u is 0, 1 or 2; -O(CH2) s

-OW

2 in which s is 2, 3, or 4 and W is Ci- 6 alkyl; hydroxyalkyl mono-or di-alkylaminoalkyl, acylamino, alkylsulphonylamino, aminoacylarino, mono- or di-alkylaminoacylamino; with up to four

R

3 substituents being present in the quinoline nucleus; 3; and or R 4 is a group -(CH 2 when cyclized onto R 5 as aryl, in which t is 1. 2, or NK-3 antago and usefl in treatadng pulmony disorders (asthma,

R

5 is branched or linear

C

1 6 alkyl,

C

3 7 cycloalkyl,

C

4 7 cycloalkylalkyl, S" optionally substituted aryl, wherein the optional ubstituent is one of hydroxy, halogen,

CI.

6 alkoxy or C 1 -6 alkyl, or an optionally substituted single or fused ring hetrocyclic group, having aromatic character, containing from 5 to 12 ring atoms (o and comprising up to four hetero-atoms in the or each ring selected from S, O, N; are NK-3 receptor antagonists and are useful in treating pulmonay disorders (asthma 30 urin disorders and itch (for example aopic dermatitis and cutaneous wheal and 999'. flare), neurogenic inflammation, CNS disorders (Parkinson's disease, movement disorders, anxiety), convulsive disorders (for example epilepsy), renal disorders, +urinary incontinence, ocular inflammation, inflammatory pain, eating disorders (food intake inhibition), allergic rhinitis, neurodegenerative disorders (for example Azheimer's disease), psoriasis, Huntington's disease; and depression. A particularly useful NK-3 receptor antagonist falling within the genus of formula is 25 N-thylbenzyl)-3ydroxy2.phenylqinolin 4c arbox ade compounds, and methods for preparing the compounds, are disclosed in Such PCT/EP95/02000, published December 7, 1995, as WO 95/32948, the disclosures of which are incorporated herein by reference.

NK-3 receptor antagonists are useful in treating the symptoms of COPD and urinary incontinence in mammals. An example of such a compound is the potent antagonist (')'(S)-N'(c'ethylbenzyl)-3-hydroxy.2.phnylquinoline.4.arboxamide.

While the route published in PCT/EP95/02000, published December 7, 1995, as WO 95/32948, requires only three steps, the synthesis is plagued with costly starting materials 2acheme c-methoxyacetophenone) and chromatography in the low-yielding final step. As is illustrated in Scheme1, the DCC-mediate (dicyclohexyl carbodiimide) coupling of A-Sc le_1, 3 -hYdroxy.2-phenylqujnoline- 4-carboxylic acid, with I-phenyl propylanmine led to a 30-50%b isolated yield of (-)-(S)-N-(a-thylbenzyl)3hydroxy-2-phenylquinoline-4-carboxaniide along with 10-20% of compound 6 -Scheme 1, (S)-2-Phenyl-.4.[(l phenylpropyl)aminocarbonyl]-3-quinolinyl-3-hydroxy- 2 phenyly 4 -quinolinecarboxyl requiring chromatography for its removal. Without being bound to any particuar theory, (S)-2-Phenyl-4-[[((lphenylpropy )amnobonyl]-3-uinyl-3-hydroxy 2-phnyl-4-quinoline-carboxylate appears to form as a by-product of an attack of the phenolic oxygen of (-)-(S-N-(a-thylbenzyl)-3-hydroxy-phenylquinolin carboxamride to the DCC-activated acid of 3-hydroxy-2-phenylqtinoline 4 carboxylic acid.

Schee 1 1 No 00 I N Ph Given the known synthesis for qioieN- eetratgnsso foml 1.tee a edfra envirommentally favorable, commercially feasible, cheaper and more efficient process, with increased yields, for coupling an ORtho-hydroxy acid with an amine to provide (-)(S)-(a-ethlbenyl)-3-hydroxy-2phnylquinoline-4carboxarflid and related cmons h rsn neto provides new synthetic processes for the synthesis of hylenzyl)-3 hydroxy-2-phenylquinoline-4carboxamide and related compounds', which eliminates the need for the use of U&I~rn 1 a-methoxyactophnone), the need for the use of a chromaography step to remove ESekewe i, (S)-2-Phnyl-4- -peyppl-mnlabnl--qioiy--yrx--hnl4 quinolinecarboxylate, and which increases the yield of desired Product from between and 50% to greater than 70%. 1n addition, according to this invention, the hydrochloride salt of the free base Of (-)-(S)N(aethybezy)3hdroxphnlu'oie4cbxmd and related compounds is optionally prepared, in one reaction vessel, without the need to isolate and purify the free base.

Cragoc et al., J. Org. Chem., 1953, 19, pp. 56 1-569, discloses the reaction of 7 -carboxy-substitutd isatins with substituted phenacyl acetates to provide derivatives of 3 -hydroxycinchoninic acid. Phenacyl acetates are known and/or can be prepared according to Normant et al., Synthesis, 1975, pp. 805-807,* which discloses reacting potassium acetate with alkyl bromides catalyzed by diamines in acetonitrile to provide such acetates. An optimized method for preparing anhydro- O-carboxysalicyhic acid and anhydro-o-cazlboxyglycolic acid is disclosed in Davies, J. Chemn. Soc., 1951, pp. 1357-1359. A preparation for five-muembered ring suffites from the recto of thionyl choieand ahdoyabxlcaisi discussed in Blackboumn et al.. J. Chein. Soc. 1971, pp. 257-259.

None ofteaoectddocuments deciethe methods of the present invention for the synthesis of quinoline NIC-3 receptor antagonists of formula or formula (1a) or the compounds of the invention whiich are useful as intermediates for the synthesis of such quinoline NK-3 receptor antagonists.

SU-MMARY OF THE

INVENION

The objects of this invention are to provide novel intermediates and processes for preparing these intermediates which are useful in the preparation of pharmaceutically active compounds.

Accordingly, in one aspect, this invention is in a method for preparing a compound of formula *R 2.8.

N-C

A

R4R N.

R

Formula

(I)

or a pharmaceutically acceptable salt form thereof, wherein: Ar is an optionally substituted phenyl group, or a naphthyl or C- cycloalicdienyl group, or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atomns in the or each ring selected from S, 0, N; R is linear or branched C 1 8 alkyl, C 3 7 cycloalkyl,

C

4 7 cYcloallcylajkyl, an optionally substituted phenyl group or a phenyl C 1 -6 alkYl group, an optionally substituted five-membered heteroaromatic ring comprising up to four heteroatom selected from 0 and N, hydroxy

C

1 6 alkyl, di C 1 6 alkylanuinoalkyl,

C

1 6 acylaminoalkyl, C 1 6 alkoxyalcyl, C 1 6 alkylcarbonyl, carboxY, C 1 6 alkoxycarbonyl, C 1 6 alkoxycarbonyl C 1 6 alkyl, alninocarbonyl, C 1 6 alkylaminocarbonyl, di CI.

6 ailcylarninocarbanyl; or is a group

-(CH

2 when cyclized onto Ar, where p is 2 or 3; RI and R 2 which may be the same or different, are independently hydrogen or qLj6 inear or brnched klo togehrfoac 2 pi-iirepresents 3, 4, or 5; or R I together with R forms a group in which q is 2, 3 .15

R

3 and R 4 which may be the same or different, are independently hydrogen, 1. 6 linear or branched alkyl, C 1 6 alkenyl, aryl, C 1 6 alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulphonarnido, trifluoromethyl, amino, monoand d-C 1 6 alkylamino, -O(C2)rNT2, in which r is 2, 3, or 4 and T is C 1 6 alkyl or it forms a heterocyclic groui, .N

N

or V (CHOU~ V (CHOU~ in which V and V 1 I are hydrogen and u is 0, 1 or 2;

-O(CH

2 )s-0W 2 in which s is 2, 3, or 4 and W is C 1 6 alkyl; hydroxyalcyl, mono-or di-alkylaminoalkyl, acylanuno, alkylsulphonylamino. aminoacylamino, mono- or di-alkylaninoacylamno; with up to four R 3 substituents being peeti the quinoline nucleus; or R 4 is a group -(CH 2 when cyclized onto R 5 as aryl, in which t is 1, 2, or 3; and

R

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

C

4 7 cycloalkylalkyl, optionally substituted aryl, wherein the optional substituent is one of hydroxy, halogen,

C

1 6 alkoxy or C 1 6 ailkyl, or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atorns in the or each ring selected from S. 0, N; comprising: 1) adding a compound of formula (Mn): Formula to base in a suitable solvent, to form a first reaction mixture, adding to the first reaction mixture a compound of formula

QU:

0 0 OV, 10Formula

(II)

to form a second reaction mixture, and heating the second reaction mixture to form a compound of formula

(TV):

0

OH

SR

4 *N

A

Formula

(WV)

2) isolating the compound Of formula (MV and then reacting the compound .of formula in as suitable solvent. with a base to form a third reaction mixture, cooling the third reaction mixture, and adding a carbonyI-activating agent to form a fourth reaction mixture; 3) adding a compound of formula

IH

N

Ar*AR Formula

(V)

to the fourth reaction mixture to form a fifth reaction mnixture; 4) heating the fifth reaction mixture; and 6 optionally converting the compound of formula to a pharmaceutically acceptable salt, wherein Ar, R, R 1

R

2

R

3

R

4 and R 5 as used in a compound of formulae (II) through (VI) are as defined for a compound of formula In another aspect, this invention is in a method for preparing (-)-(S)-N-(a-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4caroxade comprising: 1) adding isatin to base in a suitable solvent, to form a first reaction mixture, adding to the first reaction mixture an a-acetoxy ketone to form a second reaction mixture, and heating the second reaction mixture to form an a-hydroxy acid; 2) isolating the a-hydroxy acid and then reacting it, in a suitable solvent with a base to form a third reaction mixture, cooling the third reaction mixture, and adding a carbonyl.activating agent to form a fourth reaction mixture; 4) adding a primary or secondary amine, (S)-l-phenyl-propylmine, to the fourth reaction mixture to form a fifth reaction mixture; and

S*

5) heating the fifth reaction mixture.

15 In yet another aspect, this invention is in a method for prparing S(-)-(S)-N-(a-ethylbenzyl)-3-hydroxy-2-phenylquinolinecarboxa comprising: reacting an a-hydroxy acid, in a suitable solvent, with a base to form a first reaction mixture, cooling the first reaction mixture, and adding a carbonylactivating agent to form a second reaction mixture; 2) adding a primary or secondary amine to the second reaction mixture to form a third reaction mixture; 3) heating the third reaction mixture; and 4) optionally converting (-)-(S)-N-(a-ethylbenzyl)-3.hydroxy- 2 phenylquinoline-4-carboxamide to a pharmaceuticaly acceptable salt. .*25 In still another aspect, this invention is in a novel intermediate compound of formula (Vii):

O

O -CHCH 3 R4 N Ar Formula

(VII)

wherein Ar and R 3 are as defined above for formula and wherein

R

4 is OH or wherein Ra is Ci- 6 alkyl, aryl, preferably methyl.

In a further aspect, this invention is in a novel intermediate compound of formula

(VIII):

wherein: Formula (ViIa) Ar and R 3 are as defined for a compound Of formula as claimed in claim. I _And n is 1 or 3.

DETA XLED DES CIflN OF TfE INVE "pN In developing the intn netv ehdParticularly whnfor the compound Of formula (MV, R 4 is hydroxy, it was desirable to activate the carboxyl group Of the 4-acid moiety towards addition, while at the same time, and in a single oooeo* operation, topotet the phenol oxygen of R 4 Accordgng Davies, J. Cizem. Soc., 1951, Pp. 1357-1359) coupling of an amine with an activated ot-hydroxy acid provides a compound wherein the addition of the amine .occurs at an undesirable Position, thereby teaching away from producing the desired :0:015 cI-hydroxy aieInaddition, thsPoeuerequires using phosgene (COC1 2 as a *reagent, a very toxic compound, requ irzng specialized equipment for industrial application.

Furthier, it is known that using thionyl chloride, one can couple acids with 0 amines to provide amides. However, usi ng that method to provide amides ftom an -hydrozy acid starting material, one of skill in the art would expect a result of lower yields and undesired side produts.(see Gnaim. J.M. et al., J. Org. CheflL, 1 S1, 4525) Priual due to the (hydroxy moiety.

Without being bound to any Particular mechanistic theory for the instant inventive process, it is believed that in contrast to disclosures in the art, the coupling step between the compound Of formula (WV) and an amine of formula appears to proceed through, inter alia, novel intermediates of formula (VII) and formula (VII), both Of which are converted to desired Product, thus increasing the yield two-fold. Using the instant method therefore, avoids the formation of undesiredi side-products which Must be removed by some form of purification, chromnatogahy.

Indeed, while these novel interMediates, as well as the compound of formula

(VI),

are still Produced in sit~u by the methods of this invention, they are all easily 8

I,

converted to desired product, thus accounting for a more efficient Process (greater than 70% yields are achieved with this process), as well as avoiding the need for a chromatography step.

Thus, the present inlvention provides a process for preparing a compound of formula

MI:

0 N-C -Ar R R N Formula

(I)

or a pharmaceutically acceptable salt form thereof, wherein: Ar is an optionally substituted phenyl group, or a naphthyl or C 5 7 cycloalkdienyl group, or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from S, 0, N; R is linear or branched C 1 -8 alkyl,

C

3 7 cycloalkyl, C4-, 7 cycloalkylalcyl, an optionally substituted phenyl group or a phenyl C 1 6 alkyl group, an optionally substituted five-memberedi heteroaromatic ring comprising up to four heteroatom :selected from 0 and N, hydroxy C 1 6 alkyl, di C 1 6 alkcylaminoalkyl, C 1 6 acylarninoaikyl, C 1 6 alkoxyalicyl, C 1 6 alkylcarbonyl, carboxy, C 1 6 alkoxycarbonyl, C 1 6 alkoxycarbonyl C 1 6 alkyl, amninocarbonyl, C 1 6 20 alkylaminocarbonyl, di C 1 6 alkylaxninocajbonyl; or is a group

-(CH

2 when cyclized onto Ar, where p is 2 or 3;

R

1 I and R 2 which may be the same or different, are independently hydrogen or C 1 6 linear or branched alkyl, or together form a group in which n represents 3, 4, or 5; or R I together with R forms a group in which q is 2, 3, 4or

R

3 and R 4 which may be the same or different, are independently hydrogen, C 1 6 linear or branched ailkyl, C 1 6 alkenyl, aryl, C 1 6 alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxarnido, suiphonanudo, trifluoromethyl, amino, monoand di-C 1 6 aikylanuno, -O(CH2)r-NT 2 in which r is 2, 3, or 4 and T is C 1 6 alkyl or it forms a heterocyclic group

V

1 v or N V

(CH

2 V 'J"(CHOU~ in which V and V 1 I are hydrogen and u is 0, 1 or 2;

-O(CH

2 )s-ow 2 in which s is 2, 3, or 4 and W is C 1 6 aikyl; hydroxyalky 1, mono-or di-alkylanunoalkyl, acylamino, allcylsulphonylarnino, aminoacylanlino, mono- or di-alkylamninoacylaniino; with up to four R 3 substituents being present in the quinoline nucleus; or R 4 is a group -(CH2)t- when cyclized onto R 5 as aryl, in which t is 1, 2, or 3; and

R

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

C

4 7 cYcloalkylalcyl, optionally substituted aryl, wherein the optional substituent is one of hydroxy, halogen, C 1 6 alkoxy or C 1 6 alkyl, or an optionally substituted single or fused ring :heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or eah ring selected from S, 0, N; comprising: 1) adding a compound of formula

(IM:

0

*O

Formula (Jf1) to afou basen racto suitablee, t n orm a sc reaction mixturedn to them fis ecinmxueacompound of formula (rV):

V

0

OH

.R,

R3 N Rs Formula (IV) 2) isolating the compound of formula (IV) and then reacting the compound of formula in a suitable solvent, with a base to form a third reaction mixture cooling the third reaction mixture, and adding a carbonyl activating agent to form a fourth reaction mixture; 3) adding a compound of formula S *N Ar

R,

Formula (V) to the fourth reaction mixture to form a fifth reaction mixture; 4) heating the fifth reaction mixture; and 5) optionally converting the compound of formula to a pharmaceutically acceptable salt, wherein Ar, R, RI, R 2

R

3

R

4 and R 5 as used in a compound of formulae (II) through (VI) are as defined for a compound of formula It will be understood that when R 4 in the compound of formula (IV) is defined as hydroxy, then R 4 in the compound of formula should be a protected alcohol, protected by an acetate group, which is eventually deprotected.

It will also be understood that the fifth reaction mixture comprises the S. compound of formula and a compound of formula

(VI):

Ar N O Formula (VI).

Formula (VI).

li r i r r C l r i~r:~m~rei- l 1 ;:ii-~7c4 Upon heating the fifth reaction mixture, the compound of formula (vI) is Convented to desired product Of formula An example Of Ar as phenyl, is a phenyl optionally substituted by hydroxy, halogen,

C

1 6 alkOxy or C 1 6 alkyl. When Ar is substituted, Preferably, the substituents are independently one or more of halogen or C 1 6 alicyl.

Examples of Ar as a heterocyclic group are thienyl, -pyridyl, and the like.

Examples of Ar as a C 5 7 cycloalkdienyl group is cyclohexadienyl.

A preferred group of compounds is when Ar is phenyl, optionally substituted by C 1 -6 alkyl or halogen; thienyl, furyl, pyrryl, thiazolyl, or a C5- 7 cycloalkdienyl group. A further preferred group is when Ar is phenyl. optionally substituted by C 1 alkyl or halogen; thienyl or a C 5 7 cycloalkdienyl group. A particularly preferred group of compounds is when Ar is phenyl, 2 -chlorophenyl, 2 -thienyl or cyclohexadienyl. Ar is most preferably phenyl.

Examples of R are as follows: methyl, ethyl, Il-propyl, iso-propyl, n-butyl, heptyl, and the like; RhenvI Ci&-Akyl: beuzyl, and the like; hydox-Y CI..6j~k3Lj;

-CH

2 OH, -CH 2

CH

2 OH, -Cf{(Me)OH; di -CJ 6 Aalkvanoal~l

-CH

2 NMe 2

C

1 6 alkoxylatkyl: CHI2OMe; 0 £1.Abkvlcabonyl: -COMe; £1.6 aioyabny -COOMe; f£1-6 lkxlyc ar~nv 00 I- aI v CH2-)COOMe; f 'lvannca1oy: .CONH~e; a6kYIno~arbon l: -CONMe 2 or -CO(I-pyrrolidinyl);

(CH

2 when cyclized onto Ar is as follows: A Preferred group of compounds is when R is C 1 6 alkyl,

C

1 6 alkoxycarbonylC 1 6 alkylcaronylor hydroxy Cj.

6 alkyl. A particularly preferred group of compounds is when R is C 1 -6 alkyl. Most preferably R is ethyl.

An example ofR I and

R

2 as C 1 6 alkyl is methyl, ethyl, fl-propyl, isopropyl, n-butyl, and the like; an example of R I together with R forming a group -(CE12)q.. is spirocyclopentane. Preferably RI and are each hydrogen or C 1 6 alkyl. Most preferably, R I and are each hydrogen.

Examples of R 3 and R 4 are independently hydrogen, methyl, ethyl, n-propyl, n-butyl, methoxy, hydroxy, chlorine, fluorine, bromine, 2 -(dimethylamino)ethoxy, '4,7 n dirnethylaniinopropoxy, dimethylarinoacey1mno, acetylano, dirnethylanunomethyl and phenyl. Preferably

R

3 is hydrogen, hydroxy, halogen,

C

1 6 alkoxy,

C

1 6 alkyl. Preferably

R

4 is hydrogen,

C

1 6 ailcyl,

CI..

6 alkoxy, hydroxy, amino, halogen, aminoalkoxy, mono- or di..alkylarninoalkoxy, mono- or di-alkylaminoalkyl, phthaloylalkoxy, mono- or di-aikylaniinoacyamino and acylanuno. Most Preferably,

R

3 is hydrogen. Most preferably

R

4 is C 1 -6 alkoxy Or hydroxy. Particularly preferable is when R, 4 is hydroxy.

Examples of R 5 are cyclohexyl, phenyl optionally substituted as defined for Ax above; examples of R 5 as a heterocycic group are iyl, thienyl, pyrryl, thiazolyl, benzofuryl and pyridyl. Preferably

R

5 is phenyl, thienyl, fuyl, pyrryl and rthiazolyl. Most preferably

R

5 is phenyl.

Preferred compounds of formula made by the process of the invention are *wherein, Ax is peyotoal usiue by C 1 o6.alyl o halogen; thieyl o a

*C

5 7 cycloalcdienyl group; R is C 1 6 alkyl, C 1 alkoxycarbonyl,

C

1 6 alkylcarbonyl, hydroxy C 1.6 alkyl; R I and R 2 are each hydrogen or C 1 6 ailkyl;

R

3 .is hydrogen, hydroxy, halogen, C 1 6 alkoxy, C 1 ailkyl;

R

4 is hydrogen, C 1 6 soooo: alkyl, C 1 alkoxy, hydroxy, amino, halogen, aminoalikoxy, mono- or dialkylaznznoalkoxy, mono- or di-alkylanunoalkyl, phthaloylalkoxy, mono- or diallcylamrinoacyamno and acylarmno; and R 5 is phenyl, thienyl, furyl, pynryl and 20 thiazolyl.

0 A more preferred compound made by the process of this invention is 00 wherein, Ax is phenyl; R is ethyl; R I and R 2 are each hydrogen;

R

3 is hydrogen;

R

4 is hydroxy; and R 5 is phenyl.

The term "alkyl" as used herein at all occurrences means both straight and 0 25 branche chain radicals of I to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, 0 y ,iw b tl er uy ,an h i e se-uyoiobtl etbtl n h ie 0:900 The term "alkoxy" is used herein at all occurrences to mean a straight or branched chain radical of I to 8 carbon atoms, unless the chain length is limited thereto, bonded to an oxygen atom, including, but not limited to, rnethoxy, ethoxy, n- propoxy, isopropoxy, and the lie.

The term "halogen" is used herein at all occurrences to mean chioro, fluoro, iodo and bromo.

The term "cycloalkyl" is used herein at all occurrences to mean cyclic radicals, preferably of 3 to 7 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.

The terms "aryl" or "heteroaryl" are used herein at all occurrences to mean substituted and unsubstituted aromatic ring(s) or ring systems which may include bi- 13 or tri-cyclic systems and heteroaryl moieties, which may include, but are not limited to, heteroatoms selected from O, N, or S. Representative examples include, but are not limited to, phenyl, benzyl, naphthyl, pyridyl, quinolinyl, thiazinyl, and furanyl.

The term "optionally substituted" is used herein at all occurrences to mean that the moiety may be substituted or not, and if it is substituted, one or more hydrogen on each moiety is replaced with one or more substituents, each substituent being chosen independently from hydroxy, halogen, C 6 alkoxy or C 1 6 alkyl, as defined above.

A particularly preferred compound of formula is ethylbenzyl)-3-hydroxy-2-phenylquinoline-4carboxamide. A preferred pharmaceutically active salt of formula is (-)-(S)-N-(a-ethylbenzyl)-3-hydroxy.-2 phenylquinoline -caroxa ude. hydrochloride.

The compounds described herein may have asymmetric centers. Unless otherwise indicated, all chiral, diasteriomeric and racemic forms are included in the 15 present invention. As is often the case, optimal therapeutic activity is provided only by one configuration of the two chiral centers. It is therefore desirable to produce Sthis material in a form which is highly enriched in only one absolute configuration of the chiral centers. It is well known in the art how to prepare optically active compounds, such as by resolution of the racemic mixture, or by synthesis from 0 optically active starting materials.

Isatin and substituted isatins of formula (II) are commercially available, or .are made by methods known in the art, such as Marvel, et al., Org. Synth. Collect.

Vol. I, 1941, p. 327.

Compounds of formula (II) and related formula are also known, 25 commercially available, or can be made by known methods. See, Normant et al., Synthesis, 1975, pp. 805-807. A particularly useful compound of formula is a-acetoxy acetophenone purchased from Lancaster Synthesis Company.

b Compounds of formula (IV) and related formula (IV) are known or are made by known methods including those disclosed in Marshall et al., Cinchoninic Acid Derivatives, Vol. 95, 1949, pp. 185-190; U.s. Patent Nos. 2,749,347, issued June 1956; and 2,776,290, issued January 1, 1957. The procedure described in Marshall was modified herein by using LiOH as a preferable base over NaOH.

The reactions of the synthetic methods disclosed herein are carried out in a suitable solvent, which is a solvent substantially nonreactive (except where required as a reagents as well) with the reactants, the intermediates or products at the temperatures at which the reactions are performed. Suitable solvents for coupling a compound of formula with a compound of formula (II) are water, 1 i I .I li C -4 alcohols, dimethyl sulfoxide ("DMSO") and dimethylformamide

("DMF")

Water is preferred.

Suitable aqueous bases used in this coupling step are lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and barium hydroxide.

Lithium hydroxide is preferred. Suitably the base is present in an amount between 2 and 6 equivalents, preferably 3 to 5 equivalents, and most preferably 4 equivalents of base is used.

The compound of formula (Il) is added to aqueous base which has been heated to a temperature between about 40 and 70*C, preferably between about and 60 0 C. The ring of the compound of formula (IM) opens upon reaction with aqueous base. The compound of formula is then added, with an exotherm of about 15*C. After the addition of the compound of formula is complete, the temperature of the resulting reaction mixture is raised up to a temperature between about 40C and about I 10°C, preferably up to about 80 0 C, for am appropriate time 15 period (up to about three hours) or until completion of the coupling provides a compound of formula (IV).

The compound of formula (IV) is isolated prior to performing the next step in the process. It is important that the next step be conducted under anhydrous conditions since the carbonyl-activating agent, SOC2, oxalyl chloride,

DCC,

20 POC 3 COC1 2 etc., is hydrolytically unstable and would be destroyed by water.

A

Spreferred carbonyl-activating agent for use in the methods herein is thionyl chloride.

Suitable solvents for use in this step are aprotic solvents, including, but not limited to, polar aprotic organic solvents. More specifically, solvents useful herein include, but are not limited to, ethyl acetate, toluene, tetrahydrofuran. or acetonitrile.

A

preferred solvent for use herein is ethyl acetate.

Suitable bases useful in this step of the process include amine bases, particularly tertiary amine bases. Preferred amine bases are triethyl amine and diisopropylethyl amine. Most preferred is triethyl amine. Suitably, at least 3 equivalents of the amine base are used in the instant reaction process.

After the addition of the base to the compound of formula the reaction mixture is cooled to a temperature below 5*C. Preferably the temperature ranges between about -2 and 2C. The carbonyl-activating agent thionyl chloride,

COCI

2 and POC3) is added and then the reaction mixture is allowed to slowly (about 1 hour) warm to room temperature (about 25*C). at which point a compound of formula or formula shown below, is added. Compounds of formula

(V)

are commercially available from BASF, Celgene, Inc., and Zeeland Chemical Co.. or can be made using methods known in the art, tlusuno. S. et al., I. Chem. Soc., Perkin Trans. 1, 1985, p. 2039; Burk, M.J. et al., J. Am. Chem. Soc., 1996, 118, p.

5142; and Beak, P. et al., J. Am. Chem. Soc., 1996, 118, p. 3757. A particularly preferred compound of formulae or (Va) for use in the method herein is -phenyl propylamine.

Again, without being bound to any particular theory, an investigation of the reaction sequences to determine the actual coupling species revealed, by thin-layer chromatography, three major components in the reaction mixture formed prior to addition of the compound of formula When isolated, the three components were consistent with a compound of formula (VII); a compound of formula (VIII) wherein n is 1; and a compound of formula (VII), wherein n is 3.

Reaction of each of the three components with a compound of formula under conditions as defined herein, each provided the desired compound of formula

(I)

Also isolated was the trimer of the compound- of -formula (VII), however, even under forced conditions, this compound did not provide the desired compound of formula 15 While no spectral evidence exists for formation during the coupling of compound (IV) and compound of the following intermediate: 0 N Ph 20 speculation leads one to predict that the tertiary amine base catalyzes a rapid conversion of the putative intermediate to the coupling species of formula

(VM).

Upon addition of the compound of formula at root temperature, the compound of formula wherein n is 1, reacts to produce a further intermediate of formula which, upon heating to temperatures between 50 and 60*C, reacts with another molecule of the compound of formula ultimately to produce two molecules of the desired compound of formula By pushing the intermediates to react with the compound of formula the yield of desired product increases. In addition, by converting the side-product of formula (VI) to product, the yield increases, and the need for chromatographic removal of this side-product is eliminated.

A preferred sub-group of compounds within the scope of formula are the compounds of formula (Ia): 16 IBf~ ;c.-nPi- ~l~l L Ti N- ~Ar

R

3 H(a) N Ar wherein: Ar is an optionally substituted phenyl. group, or a naphthyl o r C 5 7 cycloalkchenyl group, or an optionally substituted single or fused ring heterocycuic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four betero-atoms in the or each ring selected from S. 0, N; R z is linear or ba c edI 8 alyl

C

3 7 cylakl

C

4 -7 c*cl~ajkylakl an optionally substituted phenyl group or a phenyl C 1 -6 alkyl group, an o ptionally .10 substituted five-memberedJ heteroaromatic ring comprising up to four heteroatom selected from 0 and N, hydroxy C 1 alkyl, di C 1 6 alkylaxninoalkyl c 1 6 aclmnakl '1 -6 alkylcarbonyl, carboxy, C 1 6 alkxycarony1. C 1 6 alkoxycarbonyl C 1 6 ailkyl, aminocarbonyl, C 16 alkylaminocarbony, di C 1 6 alkylaminocarbonyl; or is a group

-(CH

2 when cyclized onto Ar, where p is 2 or 3;

R

2 is hydrogen or C 1 6 linear or branched alkyl; and

R

3 .and. R 4 which may be the samne or different, are independently hydrogen, C 1 -6linear or branched alkyl, C16alkenyl, aryl, C-1 -6 aloy hyry halge, nitro, cyano, carboxy, abxnio suiphonamido, tilomeh 'amino, monoand di-C 1 6 alkylaniino, -O(CH2)rNT 2 in which r is or 4 and T is C 1 6 alkyl it forms a heterocyclic group

NN

or N V)

.(CH

2 )u V J (C H 2 in which V and V 1 I are hydrogen and u isO0, 1 or 2; -0(CH 2 5 0W 2 in which s is 2, 3, or 4 and W is C 1 -6 alkyl; hydroxyalkyl.

mono-or di-alkylaniinoaIkyl, acylanuno, alicylsulphonylamino, aminoacylanuno, mono- or di..alkylaminoacylamino; with up to four R 3 substituents being present in the quinoline nucleus; which can be prepared by a method comprising: 1-7 r' 1) adding a compound Of formula

(MI):

0 Formula (IDI to base in a suitable solvent, to form a first reaction mixture, adding to the first reaction mixture a compound of formula (Ila): 0 Ar)(K.,R4 Formula (Ha) 10 to form a second reaction mixture and heating the second reaction mixture to formn a compound of formula (rVa): 0

OH

Ar Formula (rVa) 2) isolating the compound of formula (Na) and then reacting the compound of formula in a suitable solvent, with a base to form a third reaction, mixture, a 0. cooling te tidraio'mixture, adding a cabn:avatng agent to form a fourth recinMixture; 3) adding a compound of formula (Va): I H

N

H

Formula (Va) to the fourth reaction mixture to form a fifth reaction mixture; 4) heating the fifth reaction m-ixture; and 18 optionally converting the compound of formula (1a) to a pharmaceutically acceptable Salt thereof, wherein Ar, R, R 1

R

2

R

3 R4,, and R 5 as used in a compound of formulae and (rVa) through (Va) are as defined for a compound of formula (1a).

For a compound of formula (1a) preferred embodiments are as follows.

Suitably Ar is phenyl, optionally substituted by C 1 6 alkyl or halogen; thienyl, furyl, pyrryl, thiazolyl, or a C 5 7 cycloalkdienyl group. Preferably Ar is phenyl.

Suitably R is C 1 6 alkcyl,

C

1 6 alcoxycarbonyl,

C

1 6 alkylcarbonyl or hydroxy

C

1 6 alkyl. Prefer 'ably R -is C 1 6 alkyl, most preferably ethyl.

Suitably

R

2 is hydrogen or C 1 6 alkyl. Preferably

R

2 is hydrogen.

Suitably

R

3 is hydrogen, hydroxy, halogen, C 1 6 alkoxy or C 1 6 alkyl.

0.0:.erabl

R

3 is hzydrogen.

Suitably

R

4 is hydrogen,

C

1 6 alkyl, C 1 6 akoxy, hydroxy, amino, halogen, arninoalkoxy, mono- or di..alkylamrinoaucoxy, mono- or di-alkylanlinoalkyl, 0phthaloylalcoxy, mono- or di-alkyanioacylamno and acylamino. Preferably

R

is C 1 -6 alkoxy or hydroxy, most preferably hydroxy.

0 A preferred group of compounds of formula (Ia) made by the process of this invention are wherein, Ar is phenyl, optionally substituted by C 1 6 ailkyl or halogen; 00 020 thienyl, fizzyl, pyrryl, thiazolyl, or a C 5 7 cycloalkdienyl group; R is C 1 6 alkcyl,

C

1

I.

6alkoxabonl C 1.

6 alkylcarbonyl, or hdoyC 1 6 alyl R2 is hyrgnor

C

1 6 alkyl;

R

3 ishydrogen, hydroxy, halogen,

C

1 6 alkoxy,

C

1 6 alkyl; and R4, is hydrogen,

C

1 6 alkyl,

C

1 6 alkoxy, hydroxy, amino, halogen, aminoallcoxy, mono- 000or di..alkylamiinoalkoxy, oo or dialriolyphtwaovlalkoxy, oo or di- 00025 alkylaminoacylniin and acylarnino.

A more preferred group of compoundjs of formula (1a) made by the process of this invention are wherein, Ar is phenyl; R is C 1 6 Aicyl;

R

2 is hydrogen;

R

3 is O 0 hydrogen; and R.

4 is C 1 6 alkoxy or hydroxy.

A very preferred compound of formula (1a) is wherein, Ar is phenyl; R is ethyl;

R

2 is hydrogen;

R

3 is hydrogen; and R 4 is hydroxy.

Optically pure compounds of formula (Va) are commercially available from BASF, Celgene, Inc., and Zeeland Chemical Co., or can be made by methods known in the art, Itsuno, S. et al., J Chem Soc., Perkin Trans. 1. 1985, p. 2039; Burk. M.J. et al., J. Am. Chem. Soc., 1996, 118, p. 5142; and Beak, P. et al.. I. Am.

Chem. Soc., 1996, 118, p. 3757. If the raceruic mixture of formula is used, then the racemate of the final product of formula is made. Separation of the optically active enantiomers is accomplished by known methods,

HPLC.

19* Suitable solvents for coupling a compound of formula with a compound of formula (Ila) are water, C.-4 alcohols, dimethyl sulfoxide ("DMSO") and dimethylformamide Water is preferred.

Suitable aqueous bases used in this coupling step are lithium hydroxide sodium hydroxide, potassium hydroxide, calcium hydroxide and barium hydroxide Lithium hydroxide is preferred. Suitably the base is present in an amount between 2 and 6 equivalents, preferably 3 to 5 equivalents, and most preferably 4 equivalents of base is used.

The compound of formula is added to aqueous base which has been 0 heated to a temperature between about 40 and 70"C, preferably between about and 60*C. The ring of the compound of formula opens upon reaction with aqueous base. The compound of formula (Ha) is then added, with an exothern of about 15*C. After the addition of the compound of formula (Ha) is complete, the Stemperature of the resulting reaction mixture is raised up to a temperature between "-15 about 40 0 C and about 10 0 C, preferably up to about 80°C, for an appropriate time period (up to about three hours) or until completion of the coupling provides a [compound of formula (IVa).

The compound of formula (IVa) is isolated prior to performing the next step in the process. It is important that the next step be conducted under anhydrous .i 20 conditions since the carbonyl-activating agent,

SOCI

2 oxalyl chloride,

DCC,

S POC1 3

COCI

2 etc., is hydrolytically unstable and would be destroyed by water. A preferred carbonyl-activating agent for use in the methods herein is thionyl chloride.

S: Suitable solvents for use in this step are aprotic solvents, including, but not limited to, polar aprotic organic solvents. More specifically, solvents useful herein include, but are not limited to, ethyl acetate, toluene, tetrahydrofuran, or acetonitrile.

A

preferred solvent for use herein is ethyl acetate.

i Suitable bases useful in this step ofthe process include amine bases, particularly tertiary amine bases. Preferred amine bases are triethyl amine and diisopropylethyl amine. Most preferred is triethyl amine. Suitably, at least 3 equivalents of the amine base are used in the instant reaction process.

After the addition of the base to the compound of formula (IVa), the reaction mixture is cooled to a temperature below 5*C. Preferably the temperature ranges between about -2 and 2C. The carbonyl-activating agent is added and then the reaction mixture is allowed to slowly (about I hour) warm to room temperature (about 25C), at which point a compound of formula shown below, is added.

A particularly preferred compound of formula (Va) for use in the method herein is I -phenyl propylanine.

It will be under stood that the fifth reaction mixture comprises the compound of formula and a compound of formula (Via): Ar

H

R Ar 0

NR

2 4 N N0

R

3

N

Ar

R

3 Formula

(VI).

eoo~oeUpon heating the fifth reaction mixture, the compound of formula (VI) is converted to desired product. o ~~This invention also provides a method for preparing()-SN(ethylbenzyl)3hydroxy2phenylquinolin-arboxaa comprising: 00.. 10 1) adding isatin to base in a suitable solvent to form a first reaction mixture, 0 adding to the first reaction mixture an cz-acetoxy ketone to form a second reaction mixture, and heating the second reaction mixture to form an ci-hydroxy acid; 2) reacting the ci-hydroxy acid, in a suitable solvent, with a tertiary amine base to form a third reaction mixture, cooling the third reaction mixture, and adding *000*15 a carbonyl-activating agent to form a fourth reaction mixture; 3) adding a primary or secondary amnine to the fourth reaction miixture to 0 form a fifth reaction mixture; 0000004) heating the fifth reaction mixture; and optionally converting (-)-(S)-N-(aethylezl)3.hydxy- 2 .0 20 hnlunln--ataiet a pharmaceutically acceptable salt.

o Suitably, for step the base is aqueous base, preferably

LOH.

Preferably, the a-acetoxy ketone is a-acetoxy acetophenone.

Preferably, the a-hydroxy acid formed in step is 3-hydroxy-2phenylquinoline4-ar.,oxylic acid.

Preferably, the tertiary amine base of step is triethyl amnine.

Preferably, the cabonyl-activating agent of step is thionyl chloride.

Preferably, the amine of step is I -phenyl propylamine.

The fifth reaction mixture suitably comprises (-)-(S)-N-(a-ethylbenzyly-3 hyrx--hnlunoie-abxrid and (S)-2-Phenyl4 -phenylpropyl)amnocarbony]3qijfliyl 3 -hdoy2peyl4qi carboxylate.

A particularly preferred pharmaceutically acceptable salt is the novel (-)-(S)--aehlezl -hdoy2peyqioln--abxrie hydrochloride salt. The hydrochloride salt is prepared according to the Examples descnibed below.

The product of the above defined reaction may be transformed to other intermediate products which may be active compounds of formula or formula (1a) or which may be useful in producing the compounds of formula and formula (Ia) by well known methods.

The present invention also provides for a method for preparing etybny)3hdoy2penlunln--abxmd comprising: 1) reacting 3-yrx--hnluioie4croyi acid, in a suitable solvent, with triethyl amine to form a first reaction mixture, cooling the first reaction .mixture, and adding thionyl chloride to form a second reaction mixture comprising 6,1 4 2 .3-Tetraphenyl([ 1,5,9,1 3 ]tetraoxahexadecn[ 10, 11l 14,15c~terqunl:e8,6,432ttrn and Ethyl 3aeoy2peyqioie4 carboxylate; 2) ddig ()-1pheylpropylammie to the second reaction mixture to form a *third reaction mixture comprising (-)-(S)N(aethybey)3hyrxy- 2 phnlunlne-abxmd and (S)-2-Phenyl.4 carboxylate; 3) heating the third reaction mixture; and 4) optionally converting (-)(S)N(ahylbenzyl)3hydrxy-..

phnlqioln--croxmd to a pharmaceutically acceptable salt.

It will be understood that reacting 3 -hydroxy-2phenylquinouine-4..caboxylic acid can be made by procedures described above for formula (IV) and formula (IVa).

T1he present invention also provides novel compounds of formula (Vdl): 0 0 -CH 2

CH

3

SR-

4

R

3 N At Formula

(VUI)

wherein: Ar is an optionally substituted phenyl group, or a naphthyl or C 5 7 cycloalkdienyl group, or an optionally substituted single or fused ring heterocyclic 22 group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atomns in the or each ring selected from S, 0, N; and

R

3 is hydrogen, C 1- 6 linear or branched alkcyl, C 1 6 alkenyl, aryl C 1 6 alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamjdo, sulphonarnaido, trifluoromethyl, amino, mono- and di-C 1 6 alkylarnino, 0O(CH2)r-NT 2 in which r is 2, 3, or 4 and T is C 1 6 alicyl or it forms a heterocyclic group or

N

V -t(CH 20 V

:(CH

2 )u in which V and V 1 I are hydrogen and u is 0, 1 or 2; 4: 0.-O(CH)s-OW in which s is 2, 3, or 4 and W is C 1 -6 alkyl; hydroxyaikyl, 10 ~mono-or di-alkylaniinoalkyl, aclmnalkylsulphonylamino, mnayaio 0 0. mono- or diakyaioayanio with up to four R 3 substituents belig present in o.*oo the quinoline nucleus; and 0:0*0: R4is OH or OAc; which are useful as intermediates for the synthesis of pharmaceutically active quinoline compounds of formula or pharmaceutically acceptable salts thereof, *o particularly of (--S--aehlezl--hdoy2peyqioie4 carboxamide and its hydrochloride salt.

For a compound of formula (VEI) preferred embodiments are as follows.

Suitably Ar is phenyl, optionally substituted by hydroxy, halogen,

C

1 6 0 20 alkoxy or C 1 6 ailkyl; Lhienyl or a C5- cycloalkdienyl group: Preferably when Ar is substituted phen yl, the substituents are C 1 -6 alkyl or halogen. Examples of Ar as a heterocyclic group are thienyl and pynidyl. Examples of Ar as a C 5 7 cycloalkdienyl group is cyclohexadienyl.

Most preferably Ar is phenyl.

Examples of R 3 are methyl, ethyl, n-propyl, n-butyl, methoxy, hydroxy, amino, chlorine, fluorine, bromine, 2 -(dimetylamino)ethoxy, dimethylarnunopropoxy, dimethylamnoaceyaino, acetylaxnino, dimethylarninomethyl and phenyl. Suitably

R

3 is hydrogen, hydroxy, halogen, C 1 6 alkoxy, or C 1 6 alkyl.

Preferably

R

3 is hydrogen.

Suitably

R'

4 is acetoxy or hydroxy.

An especially preferred compound is Ethyl 3 acetoxy.2phenylqunoline4 carboxylate, a compound of formula (VII), wherein Ar is phenyl,

R

3 is hydrogen, and R' 4 is QAc.

23 The novel intermediates of formula (VII) are prepared using a preferred subgroup of compounds within the scope of formula formula and formula

(IV),

the compounds of formulae (II) and The method for making intermediates of formula (VII) comprises: 1) adding a compound of formula 0

N

Formula

(II)

10 to at least 2 to 6 equivalents, most preferably 4 equivalents, of aqueous base, preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and barium hydroxide, most preferably lithium hydroxide, in a suitable solvent, water, C-4 alcohols, DMSO and DMF preferably water, to form a first reaction mixture, adding to the first reaction mixture a compound of formula "15 Ar4 Ar R' Formula to form a second reaction mixture, and heating the second reaction mixture to form a compound of formula

O

O H

R-

N Ar Formula (IV) 2) isolating the compound of formula (IV) and then reacting the compound of formula in a suitable solvent, ethyl acetate with a base, suitably at least 3 equivalents of an amine base, triethyl amine and diisopropylethyl amine, to form a third reaction mixture, cooling the third reaction mixture below about 5

*C,

preferably between -2 and 2°C, and adding a carbonyl-activating agent, thionyl cb~loride to form a fourth reaction mixture comprising a compound of formula (Vii), wherein

R

3

R'

4 and Ar are as defined above for formula

(VII).

The present invention further provides novel compounds of formula

(VIMI:

0 Ar For0l Th nemda ffrua(VI)i rpae ytepocs ecie abvefr peang thae asntermedifa mun of formula (VI)exet as olaedo kl inth the same. A preferred intermediate of formula (VIII) is wherein n is 1, i.e., 6, 14-diphenyl-[ I,5Mdoxocino[2, 3 -c: 6 ,7-cldiquinoline8,16-dione. Another preferred intermediate of formula (VIII is wherein n is 3, 6.14.22,30- Tetraphenyl.[1.,9, l 3 ltetraoxahexadecino[2,3..c:6,7-.: 10, 11-c": 14,15c"'ltetraquinoline-8I 6 2 4 3 2-tetrone.

The following examples are intended in no way to limit the scope of this invention. The nomenclature and abbreviations common to the chemocal art are 41 20 used in the examples. Melting points are uncorrected. Liquid chromatograph was conducted on a Zorbax SB C1IS column, 3.5 micron (0.46 X 7.5 cm) with a flow rate of 1.0 mL'min and detection at 360 rum. The solvents were 40:60:0.1 of Acetonitrile:WaterTrifluoroctic acid. The chiral purity of the products were determined by chiral HIPLC conducted on a Chiralpak AD column, 10 micron (0.46 X 25 cm) with a flow rate of 1.0 mL/min and detection at 360 nm. The solvents were 85:15 n-Hexane:Ethanol. All 13 C NMR (carbon magnetic resonance) and 'H NMR (proton magnetic resonance) spectra were obtained using a Bruker Instrument in Dimethyl Sulfoxide-d 6 13 C spectra were run using the GASPE (Gated-Spin Echo) pulse sequence.

EXAMPLES

Example 1: Synthesis of 3-hdroxv -2-henyuinoline-4-carbox li acid SOAc O UOH*O 1) Co-" H NH2 2) HCI A 1 L round-bottomed flask was charged with 360 mL of water and LiOH*HO (34.3 g, 800 mmol) and stirred at 50-60 Isatin(30 g, 200 mmol) was added and the reaction stirred for 30 minutes at 50-60 The c-acetoxy acetophenone (40.95 g, 230 mmol, 1.15 equiv.) was added as a solid in one porion *and the solution heated at 80-85 C until by PAR isatin remains as shown by 10 HPLC (typically 3 hours). The reaction was cooled to room temperature, diluted w ae* and -b m e ,d d *with water (90 mL) and ten-butyl methyl ether ("TBME") (210 mL) and transferred to a separatory funnel. The mixture was shaken well and the aqueous layer drained into an Ehrlenmeyer flask. The aqueous layer was acidified to pH 3.0-3.5 using conc. HCI (-61 mL) and monitored with a pH meter. The suspension of yellow solid was heated to 60-70 C, and held at that temperature for 5-10 minutes and filtered through a Buchner funnel. The flask was rinsed with 90 mL of water at 60-70 *C and the filter cake was washed with this rinse. The solid was suction dried for 10 minutes and charged back to the I L flask. The flask was charged with 600 mL of water, the suspension heated to 60-70 held there for 10 minutes, and **20 filtered through a Buchner funnel. The flask was rinsed with 150 mL of water at 60-70 *C and the filter cake washed with this rinse. The filter cake was dried in a vacuum oven at 80-90 C and <1 mm Hg. After drying to constant weight, the product 3hydroxy-phenylquinoline-4carboxylic acid was obtained as a bright yellow solid: mp 206 IR 3430, 2600, 1634; 'H NMR (300 MHz, DMSO-d) S 8.75 (IH, 6, J 8.2 Hz), 8.01 (3H, min), 7.59 (5H, 3 C NMR MHZ. DMSO..d 8 171.03, 153.98, 151.38, 139.68, 135.62, 129.60, 129.38, 128.27, 127.83, 126.27, 125.22, 124.54, 115.26.

26

I

Example 2: Synthesis of (-)-(S)-N-(a-ethvibenzvl)-3-hvdrox-2-phenyluinolinecarboxamide, hydrochloride NH2 C0OH 1) Et 3 N 1) SEtOAc 65-70 C, 3 h

OH

N 2) SOCI 2) work up

N

S3) HCI

NHCI

A suitable reactor vessel was charged with 265 g (1 Mol) of 3-hydroxy-2phenylquinoline-4-carboxylic acid and ethyl acetate (25 volumes, 5.98 Kg, 6.63 L).

The yellow sluny was heated at 30-40 and the ethyl acetate distilled off under high vacuum until 15 volumes of solvent remained in the still pot. After vacuum distillation, the yellow slurry was cooled to 20-25 Added triethylamine 10 Mol, 0.31 Kg, 0.42 L) to afford a dark orange solution. Cooled the solution to -2 C and slowly added thionyl chloride (1.05 Mol, 0.13 Kg, 0.080 over approx.

30 minutes, keeping the solution temperature less than 2 After complete addition, the tan slurry was stirred at 25 °C for 1 hour. Added -phenyl-n.

propylamine (1.1 Mol, 0.16 Kg, 0.17 L) and heated at 65-70 0 C for about 3 hours.

15 After 3 hours at 65-70 C, cooled the reaction to 20-25 OC. The reactor was charged with ethyl acetate (10 volumes, 2.39 Kg, 2.65 L) and stirred for 5-10 minutes.

Added deionized water (15 volumes, 3.98 Kg. 3.98 Stirred the reactor contents at ambient temperature for 5 minutes and then separated the phases. Washed the organic layer with 0.5 M aq. citric acid (2 x 10 volumes, 2 x 2.8 Kg, 2 x 2.6 L) followed by deionized water (5 volumes, 1.3 Kg, 1.3 At this point, a sample of the organic phase can be removed and assayed by HPLC to determine the presence and content of the freebase form of the desired product. (Note: Typical solution yields range from 80-84% and one can proceed assuming an 80% solution yield).

Added toluene (15 volumes, 3.44 Kg, 3.98 L) and concentrated the solution via vacuum distillation until a final reactor volume of 2.2 L was obtained (this represents 7 volumes of solvent remaining based on freebase available). The reactor was charged with IPA (isopropyl amine) (3 volumes based on freebase available), 0.72 Kg, 0.92 L) and the reactor contents warmed to 70 OC to afford a clear solution.

To the solution, 58.4 g (2 equiv.) of HCI was bubbled in slowly to precipitate the desired product. The precipitate was cooled to 0 *C and held for about I hour. The product was collected by suction filtration. The reaction flask was rinsed with TBME (4 volumes, 0.90 Kg, 1.22 L) and the TBME used as a rinse to wash the filter cake. This washing was repeated with an additional portion of TBME (4 volumes, 0.90 Kg, 1.22 The product was dried to a constant weight in a vacuum oven at mm Hg. The yield of desired product was 301 g, affording a 72% yield of a light beige product: mp 179-180 IR 2450, 1627, 1322; 'H NMR (300MHz, DMSO-dd 6 9.20(1H, d, J 8.2 Hz), 8.19 (1H, d, J 8.4 Hz), 7.96 (2H, 7.71 (1H, 7.60 (5H, 7.44 (2H, 7.37 (2H, 7.27 (1H, 5.02 (1H, q, J 7.5 Hz), 1.81 (2H, 0.94 (3H t, J 7.2 Hz). C NMR (100.625 Mhz) 8 169.8, 151.7, 144.8, 143.3, 139.7, 134.9, 131.3, 129.9, 129.8, 128.3, 128.2, 128.0, 126.8, 126.7, 126.5, 125.7, 123.9, 55.0, 29.3, 11.1.

All publications, including, but not limited to, patents and patent applications cited in this specification, are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

The above description fully discloses the invention including preferred Sembodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration it is believed that one skilled in the art can, given the preceding description, utilize the present invention to its fullest extent. Therefore any examples are to be construed as merely illustrative and not a limitation on the scope of the present invention in any way. The embodiments of the invention in which an 20 exclusive property or privilege is claimed are defined as follows.

o The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

25 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.

28

Claims (8)

1. 2. The method as claimed in claim I, wherein for the compound of formula Ar is phenyl, optionally substituted by C 1 6 alkyl or halogen; thienyl or a C 5 7 cycloalkdienyl group; R is C 1 6 ailkyl, C 1 6 alkoxycarbonyl, C 1 6 allcylcarbonyl, hydroxy C 1- 6 alkyl; R I and R 2 are each hydrogen Or C 1 6 alkyl; R 3 is hydrogen, hydroxy, halogen, C 1 6 alkoxy, C 1 6 alkyl; R 4 is hydrogen, C 1 6 alkyl, C 1 6 alkoxy, hydroxy, amino, halogen, aminoalkoxy, mono- or di-alkylaminoalcoxy, mono- or di-allcylarninoalkyl, phthaloylalkoxy, mono- or di..alkylanioacylarrino and acylamino; and 31 R 5 is phenyl, thienyl, furyl, pyrryl and thiazolyl.
2. 3. The method as claimed in claim 2, wherein for the compound of formula Ar is phenyl; R is ethyl; RI and R 2 are each hydrogen; R 3 is hydrogen; R. 4 is hydroxy; and R 5 is phenyl.
3. 4. A method for preparing ()()N(-tybny)3hdoy2 eyqioie--abxmd comprising: 1) reacting 3-yrx--hnluioie4croyi acid, in a suitable solvent, with trietbyl amine to form a first reaction mixture cooling the fistraio Mixture, and adding thionyl chloride to form a second reaction mixture cors ecin 6, l 4 2 2 ,3O.Tetraphenyl[1,5 9 .l3J troxahexdecno23:67. I0, 11 14,15- c'"Jtetraquinoline-8, l 6 2 4 3 2-tetrone and Ethyl 3 -acetoxy.2-phenylquinoline4 cartboxylate; 2)adn S--hnlpropylamine to the second reaction mixture to forma third reaction mixture comprising (-)-(S)-N-{a..ethylbeI)3hydroxy- 2 phenyquoin-4-ne4oamid and (5)-2-Phenyl4 carboxylate; 3) heating the third reaction mixture; and 4) opinlyconverting (-)-(S)-N-(o-ethybezl).3hyrxy- 2 A compound of formula (YB): 0 -CH 2 CH 2 R 3 N Ar wherein:Formula (VUI) 32 Ar is an Optionally substituted phenyl group, or a naphthyl or C 5 7 cycloalkdienyl group, or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-azorns in the or each ring selected from S, 0, N; and R3is hydrogen, C 1 6 linear or branched alkyl, C 1 6 alkenyl, aryl, C 1 6 alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, suiphonamido. trifluoromethl, amino, mono- and di-C 16 alkylamino, -Q(CH2)r-NT 2 in which r is 2, 3, or 4 and T is C 1 6 alkyl or it forms a heterocyclic group N N or (CH 2 )u V _C 2 in which Vand V 1 I are hydrogen and uisO 0,1or 2; *-O(CH 2 )s-QW 2 in which s is 2, 3, or 4 and W is C 1 alkryl; hydroxyalkyl, mono-or di-aflklaminoaikyi. acylamino, alkylsulpbonylamino, aminoacylamno, mono- or di-alkylaniinoacylamino; with up to four R 3 substitueflts being present in the quinoline nucleus; and R'4is OHor OAc
4. 6. The compound of formula (VUI) according to claim 5, which is *2E.
5. 7. A compound of formula (VII): t ff wherein: Formula (Vm) Ar and R 3 are as defined for a compound Of formula as claimed in claim 1, and n is 1 or 3.
6. 8. The method as claimed in claim 1, wherein the compound of formula (IT) is (-)-(S)-N(a-ethnyI)-3-ydroxy2-pheyquinoin carboxaxnjde.
7. 9. A compound which is (--S--aehleny)3hdoy2 *phenylquinolineaboamde hydrochloride salt.
8. 10. A method for preparing a compound of formula (Ia): .2 Ar -N C 'N N Ar (a wherein: Ar is an optionally substituted phenyl group, or a naphthyl or C 5 7 cycloalkdienyl group, or an optionally substituted single or fused ring heterocyclic group, h avi ng aromatic ch-aracter, containing from 5 to 12 ring atoms and compising up to four hetero-atorns in the or each ring selected from S, 0, N; 34 R is linear or branched C 1 8 alkyl, C 3 7 cycloalkyl, C 4 7 cycloalkylalkyl, an optionally substitutedj phenyl group or a phenyl C 1 6 alkyl group, an optionally substituted five-.memnbered heteroaromatic ring comprising up to four heteroatom selected from 0 and N, hydroxy C 1 6 alkyl, di C 1 6 alkylaminoa.IYl, C 1 6 acylamainoalkyl, C 1 6 alkylcarbonyl, carboxy, C 1 6 alkoxycarbonyl, C 1 6 alkoxycarbonyl C 1 6 alkyl, aminocarbonyl, C 1 6 alkylarninocarbonyl, di C 1 6 alkylamn.inocarbonyl; or is a group -(CH 2 when cyclized onto Ar, where p is 2 or 3;1 R 2 is hydrogen Or C 1 6 linear or branched alkyl; and R 3 and R 4 which may be the same or different, are independently hydrogen, C 1 6 linear or branched alkyl, C 1 6 alkenyl, aryl, C 1 6 alkoxy, hydroxy, halogen, nro, cyano, carboxy, carboxarnido suiphonamido, trifluoromethyl, amino, mono- 9* 9and di-C alkylamino, -C)(CH 2 )r-.NT 2 in which r is 2, 3, or 4 and T is C 1 6 alkyl or it form a heterocyclic group N N V" ACH or V 2 )u in which V and V 1 I are hydrogen and u is 0, 1 or 2; 9999 -O(012)s-0W 2 in which s is 2, 3, or 4 and W is C 1 6 alkl; hydroxyalkyl, mono-or di.afLcylamnoalkyl, acylamino, alkylsulphonylamino, aminoacylamino, mono- or di..alkyainoacyaffino with up to four R 3 substituents being present in 0 0 020 the quinoline nucleus; comprising: 1) adding a compound of formula (EMI: 4 to base in a suitable solvent, to form a first reaction mixture, adding to the first reaction mixture a compound of formula (Ha): Ar 4 Formula (Ua) to form a second reaction mixture, and heating the second reaction Mixture to form a compound of formula ('IVa): Os R4 R 3 N Ar Formula (lVa) 2) isolaing the compound of formula (IVa) and then reacting the compound of formula in a suitable solvent, with a base to form a third reaction Mixture, ca°•..cooling the third reaction mixture, and adding a carbonyl-activating agent to form a ::.fou-,th reaction mxue 3) adding a compound of formula (Va): .21 IH H :Formula (Va) to the fourth reaction mixture to, form a fifth reaction mixture; 4) heating the fifth reaction mixture; and :20 5) optionally converting the compound of formula to a pharmaceutically acceptable salt thereof, wherein hA', R, R 1, R2, R3, R4. and R 5 as used in a compound of formulae and (rVa) through (ViU) are as defined for a compound of formula (1a). DATED this 15th day of January, 2002 SmithKiline Beecham Corporation By DAVIES COLLISON CAVE Patent Attorneys for the Applicants 36