AU592396B2 - Novel phenylnaphthyridines carrying functional groups in the 3-position the process for their preparation and drugs especially ulcer-inhibiting drugs in which they are present - Google Patents

Abstract

Phenylnaphthyridines functionalised in position 3, of formula: <IMAGE> in which: X and Y denote the hydrogen atom, a halogen, a lower alkyl group containing 1 to 5 carbon atoms, trifluoromethyl, an alkoxy, methylthio, nitro or cyano and may be in an ortho, meta or para position in the aromatic ring, preferably in a meta or para position Z is a functional group which may contain: - an unsaturation - an alkylthio functional group substituted or otherwise by guanidine, urea or nitrodiaminoethene derivatives - an alkylsulphinyl functional group - an ether functional group - an alcohol functional group, esterified or otherwise - a ketone functional group - an acidic functional group, esterified or otherwise - a halogen - a cyano functional group - an amine functional group - an aminoacid or amidoacid functional group - a phosphorylated functional group - an aromatic or heteroaromatic nucleus and medications containing one of these derivatives or optionally one of their nontoxic addition salts with acids.

Description

1~ t 4 C 592396 COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 Form COMPLETE SPECIFICATION FOR OFFICE USE Short Title: Int. Cl: Application Number: Lodged: 0 C r' .4 I I' Complete Specification-Lodged: Accepted: Lapsed: Published: Priority: fl* 4$.

q a.

*0 S 40I 5 Related Art: TO BE COMPLETED BY APPLICANT Name of Applicant: Address of Applicant: Actual Inventor: Address for Service:

CARPIBEM

128, rue Danton, 92500

FRANCE

RUEIL MALMAISON, JEAN-MARIE TEULON $4 GRIFFITH HASSEL FRAZER 71 YORK STREET SYDNEY NSW 2000

AUSTRALIA

Complete Specification for the invention entitled: NOVEL PHENYLNAPHTYRIDINES CARRYING FUNCTIONAL GROUPS IN THE 3-POSITION THE PROCESS FOR THEIR PREPARATION AND DRUGS ESPECIALLY ULCRR-INHIBITING DRUGS IN WHICH THEY ARE PRESENT The following statement is a full description of this invention, including the best method of performing it known to us:- 1638A/bm f 1f- NMrvel phenyinaphthyridines Garry4-: -uhctart Gfroups n in the 3-position, the re- ss for their preparation and drugs, espec;Ty ulcer-inhibiting drugs, in The present invention relates to novel phenylnaphthyridines carrying functional groups in the 3position, of the formula It also relates to the process for the preparation of the said products and their applications, especially in therapy.

The novel compounds according to the invention are selected from the group comprising thoe compAund of the goenerA-l: frmua- 0 z N 0 o in which: X and Y represent the hydrogen atom, a halogen, a lower alkyl group containing 1 to 5 carbon toms, a trifluoromethyl, an alkoxy, a methylthio, a nit o or a cyano and can be in the ortho, meta or para p ition on the aromatic ring, preferably in the meta or ara position, and Z is a functional group which can contain: a unit of unsaturation, an alkylthio functional group which is unsubs ituted S 'V -2a phenylnaphthyridine compound of the formula N N

-X

x *r 0 9* 9 0a 0r 09 0 0 0r 0000 0 0 *0 I 0*

S

p.

and non-toxic acid addition salts thereof, in which X and Y independently represent the hydrogen atom, a halogen, a lower alkyl group having from 1 to 5 carbon atoms, a trifluoromethyl, alkoxy, methylthio, nitro or cyano and Z is propenyl or propynyl

-(CH

2 )n-S-(CH 2 )mR or (CH 2 )n-SO-(CH 2 )mR wherein n and m are the same or are different and are numbers ranging between 0 and 5 inclusive and R is methyl, SC 3 NIl C

N-CH

3 N -CN NH C 1411-CH 3 CH-NO2 or NH C

NH-CH

orrJR~ *0 *n 0 009

-(CH

2 )n-0-(CH 2 )m-CH 3 wherein n and m are the same or different and are numbers ranging between 0 and 5 inclusive

(CH

2 )n-OH or an ester thereof selected from the group consisting of acetate, propionate, nicotinate, furan-2-carboxylate, and phenylacetate, wherein n is a number ranging from 0 to inclusive

-(CH

2 )n-CHOH-(CH 2 )mR' or an ester thereof selected from the group consisting of acetate, propionate, nicotinate, furan-2-carboxylate, and phenylacetate, wherein n and m are the same or are different and are numbers ranging between 0 to inclusive and R' is methyl or an aromatic or heteroaromatic nucleus S selected from the group consisting of phenyl or pyridyl S-3-

-(CH

2 )n-CO-(CH 2 )m-CH 3 wherein n and m are the same or are different and are numbers ranging between 0 to 5 inclusive

-(CH

2 )n-COOH wherein n is a number ranging from 3 to inclusive

-(CH

2 )nHal, wherein n is a number ranging from 0 to inclusive and Hal is halogen

-(CH

2 )n CN, wherein n is a number ranging from 0 to inclusive

-(CH

2 )n-NRIR 2 wherein n is a number ranging from 0 to 5 inclusive and NR 1

R

2 forms a piperazine ring substituted by a lower alkyl, phenyl or phenyl substituted by methoxy or NRIR 2 forms an imidazole ring

NH-R

3 t c 15 -(CH2 -CH wherein n is a number between 0

COOH

and 5 inclusive and R 3 is hydrogen or a para-chlorobenzoyl group -(CH2) P wherein n is a number between 0 and 5 inclusive and R 5 and Rg are ethyl and .5 25 phenyl, pyridyl, thiophene or furan.

The compounds of the formula according to :the invention can be synthesized by classic methods z 0 L^j so 1 1 r-i.

r 1 4 involving a Stobbe, Perkin, Claisen or Knoevenagel condensation reaction with an aldehyde of the formula

(II):

,CHO

(II)

*4 4 44 4 4** i if 4* Uif 4.

44* i? In the formula X and Y are defined as above.

In general, the aldehydes of the formula (II) can be obtained by the oxidation of an alcohol of the formula (III) with a mild oxidizing agent such as MnO 2 in an organic solvent such as methylene 10 chloride or chloroform, at a temperature of between 20 and 50 0

C.

CH OH

S(III)

;T:

~f In the formula (III), X and Y are defined as above.

The alcohols of the formula (III) are obtained by the reduction of an acid or one of its esters of the formula (IV) with a classic reducing agent such XICl~i t 5 as lithium aluminum hydride, in an organic solvent such as tetrahydrofuran or ethyl ether; in the case where the phenyl nucleus carries a substituent which is sensitive to certain reducing agents, for example a nitro or cyano substituent, the reducing agent for reducing the ester will be chosen so as not to affect this substituent, an example being lithium borohydride prepared "in situ" from potassium borohydride and lithium chloride.

CO OR *r 4 att e.

S *1II.

4 4 4 *r 4 S .41.1( 3 9

V)

>1 In the formula X and Y are defined as above and R is the hydrogen atom or an alkyl.

The processes for synthesizing the products of the formula therefore consist in reacting the 15 aldehydes of the formula (II) with: Sacid anhydrides of the formula: Z-CH -C 2 Z-CH2-C 0 Z being defined as above, in the presence of the sodium salt of the acid Z-CH 2

COOH;

acid anhydrides of the formula: T i 1 t 6 CH2C- 0

(CH

2 )n- 1

CH

2 CH2COC1 or its chloride

(CH

2 n- CH COC1 2 in the presence of the sodium salt of the corresponding acid, n being defined as above; acid esters of the formula: Z-CH -COOR" Z being defined as above and R" being an alkyl, in the presence of a sodium or potassium alcoholate, sodium hydride or sodium metal; or lactones of the formula: 4, 9t ai 9, o *4 9 99rt 49 i *499 9.

'49* a 9i 99 4 oJ 9i (CH2) n-CH CH C 4 n being defined as above and R' being a methyl or an aromatic or heteroaromatic nucleus, in the presence of a sodium or potassium alcoholate, sodium hydride or sodium metal.

15 These reactions can be carried out without a solvent or advantageously in an organic solvent such as an alcohol, benz toluene or N-methylpyrrolidone, at a temperature between about 20 and 200 0

C.

The S--O derivatives are obtained by oxidizing the compounds, for example with a peracid, it being possible to use metachloroperbenzoic acid, in a solvent such as chloroform or methylene chloride.

I The ester derivatives of alcohols will be obtained in the conventional manner by esterifying the 0 b c ii ~r i:r I- ~r 4 -7- *4 j: C 4 T~ 4 r 4 rrr

IC

corresponding alcohols with an acid chloride or an acid anhydride.

The ketone derivatives are synthesized by oxidizing the secondary alcohols with known oxidizing agents such as Jones' reagent or Sarett's reagent, in an organic solvent such as acetone, chloroform or methylene chloride.

The halogen derivatives are prepared by reacting thionyl chloride or hydrobromic acid with the corresponding primary alcohols; these derivatives can be used in particular to synthesize amino derivatives by reaction with the corresponding amine, or imidazolyl derivatives by reaction with metallated imidazole, or to prepare certain cyano, alkoxy or alkylthio derivatives by reaction with the sodium or potassium salt of the corresponding compound, or certain amino and amido acids via malonic synthesis by condensation with the previously metallated dialkyl acetamidomalonate, or alternatively via the synthesis of phosphorus compounds by reaction with trialkyl phosphites.

Addition salts of certain compounds of the formula can be obtained by reacting these compounds with a mineral or organic acid by a method known per se. Hydrochloric, hydrobromic, sulfuric, phosphoric, toluene-4-sulfonic, methanesulfonic, cyclohexylsulfonic, oxalic, succinic, formic, fumaric, maleic, citric, aspartic, cinnamic, lactic, glutamic, N-acetylaspartic, N-acetylglutamic, ascorbic, malic, benzoic and acetic acids may be mentioned among the acids which can be used for this purpose.

According to the invention, therapeutic compositions are proposed with are useful in particular for the treatment of gastrointestinal ulcers, the said compositions containing at least one compound of the formula in association with a physiologically ::aa a i. 1- 00 Q0 0 0 a 06*0 090 *9 @e9 ,b@ 04 aa 0 Do 0* 9) @0 9a Do a q 0@ O 4'9 o p.

8acceptable excipient.

Further characteristics and advantages of the invention will be understood more clearly from the following description of a few preparative examples which in no way imply a limitation but are given by way of illustration.

Table I below shows the structural formulae of some of the products.

Example 1 2-(3-Trifluoromethylphenyl)amino-3-hydroxymethylpyridine Formula III: X 3-CF3; Y H A solution of 200 g of 2-(3-trifluoromethylphenyl)aminonicotinic acid in 500 ml of anhydrous tetrahydrofuran is added dropwise to a suspension of 52 g of lithium aluminum hydride in 1000 ml of anhydrous ethyl ether. After the addition has ended, the reaction mixture is heated under reflux for 3 h. After cooling, the excess hydride is destroyed by adding ethyl acetate and then a saturated aqueous solution of sodium 20 sulfate. The precipitate formed is filtered off and washed with ether. The combined filtrates are evaporated in vacuo and 185.2 g of 2-(3-trifluoromethylphenyl)amino-3-hydroxymethylpyridine are recovered in the form of crystals melting at 103-105 0

C.

25 The following derivatives are prepared by this method: 2-aminophenyl-3-hydroxymethylpyridine Formula III: X Y H Oil; yield: 2-(4-fluorophenyl)amino-3-hydroxymethylpyridine Formula III: X 4-F; Y H Crystals; m.p. 89-90°C; yield: 88% 2-(3-methylthiophenyl)amino-3-hydroxymethylpyridine Formula III: X 3-SCH 3 Y H r ii 1 1

II

*6i *r I ts 0 -9 Oil; yield: 2-(2,5-difluoropheyl)amino-3-hydroxymethylpyridine Formula III: X 2-F; Y Crystals; m.p. 71-4 0 C; yield: 98% 2-(3-methoxyphenyl)amino-3-hydroxymethylpyridine Formula III: X 3-OCH 3 Y H Crystals; m.p. 94-95 0 C; yield: 98% 2-(3-chlorophenyl)amino-3-hydroxymethylpyridine Formula III: X 3-C1; Y H Crystals; m.p. 114-5 0 C; yield: 94% 2-(4-chlorophenyl)amino-3-hydroxymethylpyridine Formula III: X 4-C1; Y H Crystals; m.p. 124-126 0 C; yield: Example 2 15 2-(3-Cyanophenyl)amino-3-hydroxymethylpyridine Formula III: X 3-CN; Y H 8 g of lithium chloride are added in small amounts, with stirring, to a solution of 3S'.3 g of methyl 2-(3-cyanophenyl)aminonicotinate in 600 ml of tetrahydrofuran containing 10 g of potassium borohydride. After the addition has ended, the mixture is heated under reflux for 4 h and then concentrated in vacuo. After water and ice have been added to the resulting residue, extraction is carried out with 25 ether and the ether phase is washed with water and then dried over sodium sulfate. After evaporation of the ether, 31.6 g of 2-(3-cyanophenyl)amino-3-hydroxymethylpyridine are obtained in the form of crystals melting at 126 0

C.

The following derivatives are prepared by this process: 2-(3-nitrophenyl)amino-3-hydroxymethylpyridine Formula III: X 3-NO2; Y H Crystals; m.p. 150-5 0 C; yield: 84% O 00 04 *000 O 5 S t I V 1.6

ID

A

t f I t t I, *1 a. a.

a *9 a ~a 1*4 41 4 Vt t i ~t VV V V V 4

('V

C

C.

C

I

V

I V V

IC

4 V C IV 10 2-(3-cyano-4-chlorophenyl)amino-3-hydroxymiethylpyridine Formula III: X =3-CN; Y =4-Cl Crystals; m.p. 147*C; yield: 2-(3-cyano-4-fluoroplhenyl)amino-3-hydroxymethylpyridine Formula III: X 3-CN; Y 4-F Crystals; m.p. =126 0 C; yield: Example 3 2- (3-Trifluoromethylphenyl )aminonicotinaldehyde Formula II: X 3-CF 3 Y H 690 g of Mn0 2 are added in small portions to a solution of 185 g of 2-(3-trifluoromethylphenyl)amino- 3 hydroxymethylpyridine, prepared in Example 1, in 15 2300 ml of chloroform. After the addition has ended, the mixture is stirred at room temperature for 6 h.

The reaction medium is then filtered on celite and the filtrate is evaporated to dryness. The crystals thus obtained, weighing 175 Qi, are recrystallized from 20 heptane. 160 g of 2-(3-trifluoromethylphenyl)aminonicotinaldehyde are thus recovered in the form of crystals melting at 80-1 0

C.

The following derivatives are prepared by this method: 25 2-phenylaminonicotinaldehyde Formula II: X Y H Crystals (isopropyl ether); m.p. =77-8 0 C; yield: 2- (3-cyariophenyl )aminonicotinaldehyde Formula II: X 3-CN; Y =H 30 C-lstals (acetonitrile); mn.p. 153-4'C; yield: 2-(4-fluorophenyl )aminonicotinaldehyde Formula II: X Y H Crystals; m.p. 67-8*C; yield: 71% 2- (3-meth~'lthiophenyl )aminonicotinaldehyde

V

I I 11 ~s L

I

I

I

4**t *4* It U t

I

II

I' e

C

lIt 4 Formula II: X 3-SCH 3 Y H Crystals; m.p. =63-4'C; yield: 2-(2 Formula II: X 2-F; Y Crystals (isopropanol); m.p. 129-i30 0 C; yield: 76% 2- (3-methoxyphenyl )aminonicotinaldehyde Formula II: X 3-0CH 3 Y H Crystals (isopropyl ether); m.p. 65-66'C; yield: 2-C 3-chlorophenyl )aminonicotinaldehyde Formula II: X 3-Cl; Y H Crystals; m.p. =99-100'C; yield: 78% 2- (3-nitrophenyl )aminonicotinaldehyde Formula II: X 3-NO 2 Y =H Crystals (acetonitrile); m.p. 160-2'C; yield: 2-C 3-cyano-4-chlorophenyl )aminonicotinaldehyde Formula II: X 3-CN; Y 4-Cl Crystals (acetonitrile); m.p. 203 0 C; yield: 2-(3-cyano-4-fluorophenyl )amninonicotinaldehyde Formula II: X 3-CN; Y 4-F 20 Crystals (acetonitrile); m.p. 193 0 C; yield: 2-C 4-chiorophenyl )aminonicotinaldehyde Formula II: X 4-Cl; Y H Crystals (isopropyl acetate); m.p. =101-2'C; yield: Example 4 [1-(3-Trifluoromethylphelyl)-1 ,2-dihydro-2-oxo-1 ,8naphthyridin-3-yl]-1 ,2-propene and 2,3-propene Formula I: X 3-CF 3 Y Z 1,2-propenyl and 2, 3-propenyl 30 A mixture of 31 g of 2-(3-trifluoromethylphenyl)aminonicotiflaidehyde, prepared in Example 3, 14 g of the sodium salt of 4-pentenoic acid and 31 g of 4-pentenoic anhydride in 40 ml of N-methylpyrrolidone is heated at 170-80*C for 1 h 15 min.

i I:

A:-

t oc *r t *r .4.I r 14*

A,

r 4 A t

A

A~it

A

~a 4* 12 The reaction mixture is then cooled, water and Ice are added and extraction is carried out with methylene chloride.

The organic phase is washed with water, with a 10% solution of sodium hydroxide and then again with water and dried over sodium sulfate. The methylene chloride is evaporated off and the residue obtained is filtered on silica gel. By elution with isopropyl ether, crystals are recovered which, when recrystallized from isopropanol, give 8 g of a mixture consisting of [1-(3-trifluoromethylphenyl)-1,2-dihydro-2-oxo-1,8naphthyridin-3-yll-1,2-propene and 2,3-propene in the form of crystals melting at 151-4 0

C.

Example 15 1-(3-Trifluoromethylphenyl)-1,2-dihydro-2-oxo-3-methylthio-1,8-naphthyridine Formula I: X 3-CF3; Y H; Z SCH 3 A mixture of 9.7 g of 2-(3-trifluoromethylphenyl)aminonicotinaldehyde, prepared in Example 3, 6.5 g of sodium methylthioacetate and 14.5 g of methylthioacetic anhydride in 10 ml of N-methylpyrrolidone is heated at 110-120 0 C for 1 h 15 min.

The reaction mixture is then cooled, water and ice are added and extraction is carried out with 25 methylene chloride. The organic phase is washed with water, with a 10% solution of sodium hydroxide and then again with water and dried over sodium sulfate.

The methylene chloride is evaporated off to give a residue which crystallizes from ether. After recrystallization from ethanol, 2.6 g of 1-(3-trifluoromethylphenyl)-1,2-dihydro-2-oxo-3-methylthio-1,8-naphthyridine are obtained in the form of crystals melting at 202- 203 0

C.

0 66 i r I 13 Example 6 1-(3-Trifluoromethylphenyl)-1,2-dihydro-2-oxo-3-methylthiomethyl-1,8-naphthyridine Formula I: X 3-CF 3 Y H; Z CH 2

-S-CH

Prepared by the procedure of Example Crystals (isopropanol); m.p. 144-7 0 C; yield: Example 7 [1-(3-Trifluoromethylphenyl)-1,2-dihydro-2-oxo-1,8naphthyridin-3-yl]ethan-2-ol Formula I: X 3-CF 3 Y H; Z CH 2

-CH

2

-OH

A solution of 30 g of 2-(3-trifluoromethylphenyl)aminonicotinaldehyde, prepared in Example 3, and 30 g of butyrolactone in 150 ml of benzene is added dropwise to a suspension of 8.2 g of sodium hydride in S' 15 150 ml of benzene. The reaction is initiated with a few drops of ethanol and the reaction mixture is then 9A.. ,stirred for 3 hours. After water has been added, chloroform is added and the organic phase is separated off, washed with water and then dried over sodium 20 sulfate. The solvent is evaporated off and the residue obtained crystallizes from a mixture of iso- Spropyl ether and acetone. The crystals obtained are filtered off, washed with ether and dried. The 24 g of product thus obtained are recrystallized from acetonitrile to give 17 g of [1-(3-trifluoromethylphenyl)- 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]ethan-2-ol in the form of crystals melting at 179-180 0

C.

Example 8 S1-(3-Trifluoromethylphenyl)-1,2-dihydro-2-oxo-3-methylsulfinyl-1,8-naphthyridine Formula I: X 3-CF 3 Y H; Z SOCH 3 2.8 g of 80-90% metachloroperbenzoic acid are added in small portions, with thorough stirring, to a i y a f t s W i v i w 14 solution of 5 g of 1-(3-trifluoromethylphenyl)-1,2dihydro-2-oxo-3-methylthio-1 ,8-naphthyridine, prepared in Example 5, in 500 ml of chloroform cooled to 0 0

C.

The mixture is subsequently allowed to reach room temperature and then left to stand overnight.

The chloroform phase is subsequently washed with water, with an aqueous solution of ammonia and then again with water and dried over sodium sulfate.

After evaporation of the solvent, the crystals obtained are recrystallized from isopropanol to give 3.3 g of 1-(3-trifluoromethylphenyl)-1,2-dihydro-2oxo-3--methylsulfinyl-1 ,8-naphthyridine in the form of crystals melting at 227-8 0

C.

Example 9 15 1-(3-Trifluoromethylphenyl)-1,2-dihydro-2-oxo-3metl hylsulfinylmethyl-1 ,8-naphthyridine Formula I: X 3-CF; Y H; Z CH -SO-CR 43' 2 3 Prepared by the procedure of Example 8 Crystals (isopropanol); m.p. =194-5'C; yield: 66% 4*1 Example [1-(3-Trifluaoromethylphenyl)-1 ,2-dihydro-2-oxo-1 ,8naphthyridin-3-yl Jpropan-3-ol Formula I: X 3-CF; Y H; Z =CH -CH CR -OH 3 2- 2- 2 Prepared by the procedure of Example 7 using S-valerolactone aCrystals (Cd 4 m.p. =121-2'C; yield: Example 11

IL

o~ Acetate of [1-(3-trifluoromethylphenyl)-1 ,2-dihydro- 2-oxo-1 ,8-naphthyridin-3-yl ]propan-3-ol Formula I: X 3-CF 3 Y H; Z CR 2-CH 2-CR A solution of 7 g of [1-(trifluoromethylphenyl)- 1 ,2-dihydro-2-oxo-1 ,8-naphthyridin-3-yllpropan-3-ol, r 15 ii 4 t 4 t t 4 1* 1 1 It *t f t t c ttt I. t I t tt

I

4t t re 11 4 4 141 S :r t{t t t ri: 4444 14 4 4 prepared in Example 10, in 20 ml of acetic anhydride is heated under reflux for three hours. After evaporation of the acetic anhydride, the residue obtained as crystals is carefully washed with pentane and then dried to give 7 g of the acetate of (1-(3-trifluoromethylphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3yl]propan-3-ol in the form of crystals melting at 93- Example 12 (1-Phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)propan- 3-ol Formula I: X Y H; Z CH 2

-CH

2

-CH

2

-OH

Prepared by the procedure of Example Crystals (toluene/isopropanol); m.p. 166-8 0

C;

15 yield: Example 13 Acetate of (1-phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin- 3-yl)propan-3-ol Formula I: X Y H; Z CH -CH -CH -0-CO-CH Prepared by the procedure of Example 11 Crystals; m.p. 156-8 0 C; yield: 93% Example 14 (1-Phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)ethan- 2-ol 25 Formula I: X Y H; Z CH 2

-CH

2

-OH

Prepared by the procedure of Example 7 Crystals (ethanol); m.p. 216-7 C; yield: 51% Example Acetate of (1-phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin- 3-yl)ethan-2-ol Formula I: X =Y H; Z CH -CH -O-CO-CH 2 2 3 1 11~ lC1 11111119 rB~B ar~-mnn~41CI~----- 16 Prepared by the procedure of Example 11 Crystals; m.p. 190-1 0 C; yield: I. t r t tt C c

C

C

C

t c Example 16 Acetate of [1-(3-trifluoromethylphenyl)-1,2-dihydro- 2-oxo-1,8-naphthyridin-3-yl]ethan-2-ol Formula I: X 3-CF 3 Y H; Z CH -CH -O-CO-CH Prepared by the procedure of Example 11 Crystals; m.p. 100-2 0 C; yield: 93% Example 17 (1-Phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)butan- 4-ol Formula I: X Y H; Z CH-CH 2-CH2-CH2-OH Prepared by the procedure of Example 7 using E-caprolactone 15 Crystals (acetonitrile); m.p. 176-7 0 C; yield: 42% Example 18 3-[1-(3-Trifluoromethylphenyl)-1,2-dihydro-2-oxo-1,8naphthyridin-3-yl]pyridine Formula I: X 3-CF 3 Y H; Z 3-pyridyl A solution of 10.6 g of 2-(3-trifluoromethylphenyl)aminonicotinaldehyde, prepared in Example 3, and 10 g of the acetate of 3-ethylpyridine in 75 ml of toluene is added dropwise to a suspension of 2.9 g of sodium hydride in 50 ml of toluene. The reaction is 25 initiated with a few drops of ethanol and the reaction mixture is then stirred for one hour at room temperature and 20 min at 80 0 C. After cooling, the mixture is poured into a mixture of water and ice, and chloroform is added. The organic phase is separated off, washed with water and then dried over sodium sulfate.

The solvent is evaporated off and the residue crystallizes from an isopropyl ether/acetone mixture.

Z

I

FCC

C c 17 The crystals obtained are filtered off, washed with ether and dried. 5.5 g of 3-II1-(3-triflucromethylphenyl)-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin-3-yl]pyridine are thus recovered in the form of crystals melting at 208-9'C.

Example 19 [1-(3-Trifluoromethylphenyl)-1 ,2-dihydro-2-oxo-1 ,8naphthyridin-3-yl ]butan-4-ol Formula I: X 3-CF; Y Z CH CH CH CH -OH 32 2 2 2 Prepared by the procedure of Example 7 using E-caprolactone Crystals (CC1) m.p. =117-8'C; yield: Example [1-(3-Trifluoromethylphenyl)-1 ,2-dihydro--2-oxo-1 ,8naphthyridin-3-yllpropan-2-ol &Formula I: X 3-CF 3 Y H; Z CH 2 -CHOH-CH 3 Prepared by the procedure of Example 7 using Y-valerolactone *Crystals; m.p. 121-2'C; yield: 22% Example 21 'r Acetate of (1-phenyl-1,2-dihydro-2-oxo-.1,8-naphthyridin- 3*l *1n- -o Formula I: X Y Z =CH -CH -CH -CH -0-CO-CH 2- 2 2 2- 3 t Prepared by the procedure of Example 11 Crystals (isopropanol); m.p. =148-150 0 C; yield: 92%

C

Example 22 0 C,(1 -Phenyl-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin-3-yl)propan- 2 -ol Formula I: X Y Z CH 2

CHOH-CH

3 Prepared by the procedure of Example 7 using Y-valerolactone Crystals (xylene); m.p. 165'C; yield: 34% Example 23 (1-Phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)propan- 2-one Formula I: X Y H; Z CH -CO-CH 2 3 ml of Jones' reagent are added dropwise, with thorough stirring, to a solution of 8.5 g of (1-phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)propan- 2-ol, prepared in Example 22, in 300 ml of acetone.

4 44 t~ A Vr 4) SAfter thne addition nas ended, stirring is continued for 10 min, 50 ml of water are then added and stirring is continued for 15 min. A further quantity of water is added, extraction is carried out with chloroform and the extract is washed with water, with a dilute solution of sodium hydroxide and then again with water and dried over sodium sulfate. After evaporation of the solvent, the residue obtained is filtered on silica gel and the crystals formed are recrystallized from acetonitrile to give 3.8 g of (1-phenyl-1,2-dihydro- 20 2-oxo-1,8-naphthyridin-3-yl)propan-2-one in the form of crystals melting at 218-9 0

C.

Example 24 1,3-Diphenyl-1,2-dihydro-2-oxo-1,8-naphthyridine Formula I: X Y H; Z phenyl 25 Prepared by the procedure of Example 18 using ethyl phenylacetate Crystals (isopropanol); m.p. 197-8 0 C; yield: Example 3-(1-Phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)pyridine Formula I: X Y H; Z 3-pyridyl Prepared by the procedure of Example 18 t

C

I a 144 14~c *i 14 I:c I 14 141 -r~n.----s4sr't--n-~r~s4-A-444-ttflt,44,4- 'i r. r I- 1 -i

L

*I @4 1*.

4 *r 3' 0L )i li

I

4 04 19 Crystals (acetonitrile); m.p. 236-8 0 C; yield: Example 26 4-(1-Phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)pyridine Formula I: X Y H; Z 4-pyridyl Prepared by the procedure of Example 18 using the acetate of 4-ethylpyridine Crystals (methanol); m.p. 280-3 0 C; yield: Example 27 3-[1-(3-trifluoromethylphenyl)-1,2-dihydro-2-oxo-1,8naphthyridin-3-yl]thiophene Formula I: X 3-CF3; Y H; Z 3-thiophenyl Prepared by the procedure of Example 18 using the acetate of 3-ethylthiophene 15 Crystals; m.p. 205-6 0 C; yield: 41% Example 28 1-Phenyl-1,2-dihydro-2-oxo-3-methoxy-1,8-naphthyridine Formula I: X Y H; Z OCH 3 A mixture of 9.9 g of 2-phenylaminonicotin- 20 aldehyde, prepared previously, 16 g of methoxyacetic anhydride and 7.8 g of sodium methoxyacetate is heated at between 150 and 160 C for 1 hour.

The reaction mixture is then cooled, water and ice are added and extraction is carried out with 25 chloroform. The chloroform phase is washed with water, with a dilute solution of sodium hydroxide and then again with water and dried over sodium sulfate. The solvent is evaporated off and the residue crystallizes from ether. After recrystallization from dimethyl- 30 formamide, 4 g of 1-phenyl-1,2-dihydro-2-oxo-3-methoxy- 1,8-naphthyridine are obtained in the form of crystals melting at 272-4°C.

A

L I~ ;r

I

1 1 Example 29 1-(3-Trifluoromethylphenyl)-1,2-dihydro-2-oxo-3-methoxy- 1,8-naphthyridine Formula I: X 3-CF 3 Y H; Z OCH3 Prepared by the procedure of Example 28 Crystals (ethyl acetate); m.p. 221-3 0 C; yield: Example 2 -[1-(3-trifluoromethylphenyl)-1,2-dihydro-2-oxo-1,8naphthyridin-3-yl]furan Formula I: X 3-CF 3 Y H; Z 2-furanyl Prepared by the procedure of Example 18 using the acetate of 2-ethylfuran Crystals (isopropanol); m.p. 205-6 0 C; yield: Example 31 15 [1-(3-Cyanophenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin- 3-yl]ethan-2-ol Formula T: X 3-CN; Y H; Z CH 2-CH -OH Prepared by the procedure of Example 7 Crystals; m.p. 189 0 C; yield: 57% 20 Example 32 Acetate of [1-(3-cyanophenyl)-1,2-dihydro-2-oxo-1,8naphthyridin-3-yl]ethan-2-ol Formula I: X 3-CN; Y H; Z CH 2-CH 2-O-CO-CH3 Prepared by the procedure of Example 11 Crystals (ethanol); m.p. 176-7 0 C; yield: ct c tt r t .r *r I t tt

ILC

Ic tc C I t C I I. 1 _I-il ~B Example 33 [1-(3-Cyanophenyl)-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin- 3-yl]propan-2-ol Formula I: X 3-CN; Y H; Z CH 2

CHOH-CH

3 Prepared by the procedure of Example 7 using Y-valerolactone i i i.

r~ a

C

C C C C C Cc

C

Ct C Vt 4

C

C C

C

C

C C I- *C C

C

C

'C

21 Crystals; m.p. 124-7'C; yield: 44% Example 34 [1-(3-Cyanophenyl)-1 ,2-dihydro-2--oxo-1 ,8-naphthyridi- 3-yl ]propan-2-one Formula I: X 3-CN; Y H; Z CM -CO-CM Prepared by the procedure of Example 23 Crystals; m.p. 184-6'C; yield: 62% Example 1-(3--Cyanophenyl)-1 ,2-dihydro-2-oxo-3-methylthiomethyl- 1 ,8-naphthyridine Formula I: X 3-CN; Y H; Z CM 2-S-CH3 Prepared by the procedure of Example Crystals (acetonitrile); m.p. 204-5 0 C; yield: Example 36 15 1-(3-Cyanophenyl)-1 ,2-dihydro-2-oxo-3-methylsulfinylmethyl-i ,8-naphthyridine Formula I: X 3-CN; Y Z CH 2-SO-CM Prepared by the procedure of Example 8 Crystals; m.p. 217-8'C; yield: 20 Example 37 [1-(4-Fluorophenyl)-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin- 3-yl IIethan-2-ol Formula I: X Y H; Z CM 2-CM 2-OH Prepared by the procedure of Example 7 Crystals (methanol); m.p. 199-200*C; yield: 48% Example 38 1-(3-Methylthiophenyl)-1 ,2-dihydro-2-oxo-3-methylthiomethyl-i ,8-naphthyridine Formula I: X 3-SCM 3 Y M; Z CM 2-S-CM A solution of sodium ethylate prepared from 4 17i; 3 :I _11 ft it *i 4

I

*i 0p

S:C

#44,4 .4 ft 44C 22 ml of ethanol and 1.2 g of sodium is added dropwise to a solution of 9.8 g of 2-(3-methylthiophenyl)aminonicotinaldehyde, prepared previously, and 7.4 g of ethyl (-methylthiopropionate in 30 ml of ethanol.

After the addition has ended, the mixture is heated for 10 min at 50 0 -60 0 C, with stirring. The solids are seen to pass completely into solution and then the formation of a precipitate is observed. The mixture is then allowed to return to room temperature and stirring is continued for 30 min. The precipitate is filtered off, washed with a small quantity of ethanol, water and then ether and dried. Recrystallization from methanol gives 3.8 g of 1-(3-methylthiophenyl)-1,2dihydro-2-oxo-3-methylthiomethyl-1,8-naphthyridine in the form of crystals melting at 132-3 0

C.

Example 39 [1-(3-Trifluoromethylphenyl)-1,2-dihydro-2-oxo-1,8naphthyridin-3-yl]propan-2-one Formula I: X 3-CF3; Y H; Z CH2-CO-CH 20 Prepared by the procedure of Example 23 Crystals; m.p. 124-5 0 C; yield: Example [1-(3-Methylthiophenyl)-1,2-dihydro-2-oxo-1,8naphthyridin-3-yl]propan-2-ol Formula I: X 3-SCH 3 Y H; Z CH 2

-CHOH-CH

3 A solution of sodium ethylate prepared from 1.5 g of sodium in 50 ml of ethanol is added dropwise, at a temperature of 40 0 C, with thorough stirring, to a solution of 12 g of 2-(3-methylthiophenyl)aminonicotinaldehyde, prepared previously, and 6.4 g of Y-valerolactone in 50 ml of ethanol. After the addition has ended, the reaction mixture is allowed to return to room temperature and then stirred for 3 hours. The 9 4t

'V

t

T-

I

23 precipitate formed is filtered off, washed with water and then with a small quantity of ethanol and dried.

After recrystallization from ethyl acetate, 7 g of [1-(3-methylthiophenyl)-1,2-dihydro-2-oxo-1,8naphthyridin-3-yl]propan-2-ol are obtained in the form of crystals melting at 116-7 0

C.

Example 41 [1-(2,5-Difluorophenyl)-1,2-dihydro-2-oxo-1,8naphthyridin-3-yl]propan-2-ol Formula I: X 2-F; Y 5-F; Z CH2-CHOH-CH Prepared by the procedure of Example Crystals (isopropyl ether); m.p. 111-2 0 C; yield: 52% Example 42 15 [1-(2,5-Difluorophenyl)-1,2-dihydro-2-oxo-1,8naphthyridin-3-yllpropan-2-one Formula I: X 2-F; Y 5-F; Z CH2-CO-CH 10 g of Sarett's reagent are added in small amounts, with thorough stirring, to a solution of 5 g 20 of [1-(2,5-difluorophenyl)-1,2-dihydro-2-oxo-1,8naphthyridin-3-yl]propan-2-ol, prepared in Example 41, in 50 ml of methylene chloride. After the addition has ended, stirring is continued for 4 hours, a further 10 g of Sarett's reagent are then added and the mixture S. 25 is heated under reflux for 5 hours, with stirring.

After standing overnight at room temperature, the 7 °7 mixture is filtered on celite and the methylene chloride phase is washed carefully with water and o. dried. After evaporation of the solvent, the residue S' 30 obtained is filtered on silica gel. Crystals are obtained from an isopropanol/isopropyl ether mixture and these are filtered off, washed with isopropyl ether tt t I 4 rCL tL~ t I I A ~C

I

II

*1 I~ I~ 14 4~t~ c' £0

I

4,

IL

*1 24 and then dried to give 2.5 g of E1-(2,5-difluorophenyl)-1 ,2-dihydro-2-oxo-1,8-naphthyridin-3-yllpropan- 2-one in the form of crystals melting at 141-2'C.

Example 43 1-(4-Fluorophenyl)-1 ,2-dihydro-2-oxo-3-methylthiomethyl-i ,8-naphthyridine Formula I: X Y H; Z CH 2-S-CR Prepared by the procedure of Example 38 Crystals (dimethylformamide); m.p. 225-6'C; yield: Example 44 1 (3-Chlorophenyl) -1 ,2-dihydro-2-oxo-3-methylthiomethyl-i ,8-naphthyridine Formula I: X 3-Cl; Y H; Z =CR 2-S-CH3 Prepared by the procedure of Example 38 Crystals (ethyl acetate); m.p. 167-8 0 C; yield: Example 1-(3-Methoxyphenyl)-1 ,2-dihydro-2-oxo-3-methylthiomethyl-i ,8-naphthyridine Formula I: 3-OCR 3 Y Z CR 2-S-CR Prepared by the procedure of Example 38 Crystals (methanol); m.p. =181-2'C; yield: Example 46 [1-(3-Chlorophenyl)-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin- 25 3-yl~lpropan-2-ol Formula I: X 3-Cl; Y H; Z =CR 2 -CROH-CR 3 Prepared by the procedure of Example Crystals; m.p. 132 0 C; yield: Example 47 [1 -(3-Chlorophenyl ,2-dihydro-2-oxo-1 ,8-naphthyridin-

A

r I

F

I

I

LI

I

ii 25 3-yl ]propan-2-one Formula I: X 3-Cl; Y H; Z CH 2-CO-CH3 Prepared by the procedure of Example 42 Crystals; m.p. 166'C; yield: Example 48 [1-(3-Cyanophenyl)-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin- 3-yl Ipropan-3-ol Formula I: X 3-CN; Y H; Z CH 2 CH 2-CH 2-OH Prepared by the procedure of Example 40 using J -valero- 10 lactone Crystals (ethanol); m.p. =166-7'C; yield: 37% Example 49 [1-(3-Chlorophenyl)-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin- 3-yl ]ethan-2-ol Formula I: X 3-Cl; Y H; Z CH 2'CH 2-OH Prepared by the procedure of Example 7 Crystals (acetonitrile); m.p. 175*C; yield: Example Acetate of [1-(3-chlorophenyl)-1 ,2-dihydro-2-oxo-1 ,8naphithyridin-3-yl ]ethan-2-ol Formula I: X 3-Cl; Y H; Z =CH 2-CH 2-0-CO-CH3 Prepared by the procedure of Example 11 Crystals (isopropanol); m.p. 138-9 0 C; yield: Example 51 25 1- (3-Cyanophenyl)-1 ,2-dihydro-2-oxo-3-methoxymethyl- 1 ,8-naphthyridine Formula I: X 3-CN; Y H; Z CH 2-OCH3 Prepared by the procedure of Example 38 using ethyl f -methoxypropionate Crystals (methanol); m.p. 192-3 0 Cp yield: 27% A: P

A:

t t re A:

A:

A:

a a:

C

~C

a ~4 A: A:

A:

44~ ~t A: C A: t tA: ~X:a L i_ 1.

I

\t n I 1 26

'I

OF Ir 0 -9 1 It S I 0> 0 *941 u 01 *e 0 1 6a r Example 52 1-(3-Cyanophenyl)-1,2-dihydro-2-oxo-3-methoxy-1,8naphthrit Lne Formuie I: X 3-CN; Y H; Z =OCH 3 Prepared by the procedure of Example 38 using ethyl methoxyaceLate Crystals (dimethylformamide); m.p. 284'C; yield: 29% Example 53 [1-(3--Methoxyphenyl)-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin- 3-yl propan-2-ol Formula I: X 3-OCH 3 Y H; Z CH 2-CHOH-CH3 Prepared by the procedure of Example Crystals; m.p. 171'C; yield: 53% 15 Example 54 [l-(3-Methoxyphenyl)-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin- 3-yl]propan-2-one Formula I: X =3-OCH 3 Y=H; Z CH 2 O-CH3 Prepared by the procedure of Example 23 20 Crystals (ethyl acetate); m.p. 161-4 0 C; yield: 43% Example 1-(3-Nitrophenyl)-1,2-dihydro-2-oxo-3-methylthiomethyl- 1,8-naphthyridine Formula I: X 3-NO 2 Y H; Z CH -S-CH 25 Prepared by the procedure of Example 38 Crystals (dimethylformamide); m.p. 190-1 0

C;

.yield: 22% Example 56 [1-(3-Methylthiophenyl)-1,2-dihydro-2-oxo-1,8naphthyridin-3-yl propan-2-one Formula I: X- 3-SCH 3 Y H; Z CH 2

-CO-CH

3 .!1 >4 l-l

CI

.4 0@ -r~m n:; I L Mb h III i v i -2er, J 'I J 27 Prepared by the procedure of Example 23 Crystals (filtration on silica gel, eluent: chloride/ether m.p. 146 0 C; yield: methylene 0* .9 0 0 Os so 0 0:**4 a..

9 *40 p S0 09 9* 000 99 9 9 '9 9 90 0 5* Example 57 [1-(4-Fluorophenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin- 3-yllpropan-2-ol Formula I: X 4-F; Y H; Z CH 2-CHOH-CH3 Prepared by the procedure of Example Crystals; m.p. 171-2 0 C; yield: 41% Example 58 [1-(4-Fluorophenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin- 3-yl]propan-2-one Formula I: X 4-F; Y H; Z CH2-CO-CH3 Prepared by the procedure of Example 23 15 Crystals (ethyl acetate); m.p. 203 0 C; yield: Example 59 [1-(3-Nitrophenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin- 3-yl]propan-3-ol Formula I: X 3-NO 2 Y H; 2 CH 2 -CH 2-CH 2-OH 20 Prepared by the procedure of Example 40 using dvalerolactone Crystals (toluene); m.p. 160-2 0 C; yield: Example 1-Phenyl-1,2-dihydro-2-oxo-3-methoxymethyl-1,8- 25 naphthyridine Formula I: X Y H; Z CH -OCH 2 3 Prepared by the procedure of Example 38 using methyl P-methoxypropionate Crystals (acetonitrile); m.p. 206-207 0 C; yield: p il-: 7~Tr, -4 28 Example 61 1-Phenyl-1 ,2-dihydro-2-oxo-3-methylthiomethyl1,8naphthyridine Formula 1E: X Y H; Z CH 2-SCH3 Prepared by the procedure of Example'38 Crystals (acetonitrile); m.p. 207-208'C; yield: 61% Example 62 1-(3-Cyano-4-chlorophenyl)-1 ,2-dihydro--2-oxo-3-methylthiomethyl-1 ,8-naphthyridine Formula I: X 3-CN; Y 4-Cl; Z CH 2-SCH3 Prepared by the procedure of Example 38 Crystals (acetonitrile); m.p. 218-9*C; yield: I, if a *5 *9*9 4~ ''at '9 9.

S.C

S 5

S

*t S C I 5.

St S S

~C

5* 4 I I *5

V

944O9~ .5.

50 0 S S *5 Example 63 [1-(3-Cyano--4-chlorophenyl)-1 ,2-dihydro-2-oxo-1 ,8- 15 naphthyridin-3-yllpropan-2-ol Formula I: X =3-CN; Y =4-Cl; Z CH 2-CH0H--CH3 Prepared by the procedure of Example Crystals (acetonitrile); m.p. 201-2*C; yield: Example 64 20 11-(3-Cyano-4-chlorophenyl)-i ,2-dihydro-2-oxo-1 ,8naphthyridin-3-yl ]propan-2-one Formula I: X 3-CN; Y 4-Cl; Z CH-I CO-CH3 Prepared by the procedure of Example 23 Crystals (acetonitrile); m.p. 202-4'C; yield: 52% 43% 25 Example (1-Phenyl-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin-3-yl]-1 ,2propene Formula I: X Y H; Z CH=CH-CH 3 Prepared by the procedure of Example 38 using ethyl 4-pentenoate Crystals after filtration on silica gel and recrystal-

A

I

I

-29 lization from isopropanol; m.p. =201-202'C; yield: Example 66 1 -Phenyl-1 ,2-dihydro-2-oxo-3-cyano-l', 8-naphthiyridine Formula I: X Y Z CN A solution of 10 g of 2-phenylaminonicotinaldehyde, prepared previously, and 6.8 g of ethyl cyanoacetate in 100 ml of toluene containing 1 ml of piperidine and 0.8 ml of acetic acid is heated under reflux for 3 hours. After the reaction mixture has been allowed to return to room temperature, the crystals formed are filtered off, washed with water and then with a small quantity of ethanol and dried. After recrystallization from acetonitrile, 4.8 g of 1-phenyl- 1 ,2-dihydro-2--oxo-3-cyano-1 ,8-naphthyridine are recovered in the form of crystals melting at 289'C.

Example 67 1-(3-Cyano-4-fluorophenyl)-1 ,2-dihydro-2-oxo-3-methylthiomethyl-1 ,8-naphthyridine 20 Formula I: X 3-CN; Y 4-F; Z CH 2 SCH 3 Prepared by the procedure of Example 38 Crystals after separation by preparative HPLC; m.p.= 223'C; yield: 17% Example 68 25 t1-(3-Cyano-4--ethoxyphenyl)-1 ,2-dihydro-2-oxo-1 ,8naphthyridin-3-yl ]propan-2-one Formula I: X 3-CN; Y 4-OCH;5 Z =CH 2-CO--CH3 Using the procedure of Example 40 to react valerolactone with 2-(3-cyano-4-fluorophenyl)amino-- 30 nicotinaldehyde, the condensation reaction is found to be accompanied by replacemient of the F atom with the ethoxy group, the sodium ethylate having reacted with .4 $4 ft ft

I

4 *1, ft ft 4.

ft ft I *t ft $7 ft4ft ft.

4 $7 'ft.' ~ft ft 4 ft 4.

4. ft ft ft $7 ft $7$ ~4*fl4$7 9 ft *tftft ft *44* 44 C a ft.

ft~.

A

.1 30 this halogen activated by the nitrile group. Preparative HPLC therefore makes it possible to isolate cyano-4-ethoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin- 3-yl]propan-2-ol in the form of crystals melting at 145'C, which are oxidized with Jones' reagent by the procedure of Example 23 to give [1-(3-cyano-4-ethoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]propan- 2-one in the form of crystals melting at 188-9 0 C, with an overall yield of 5% for both reactions.

Example 69 Acetate of [1-(3-cyanophenyl)-1,2-dihydro-2-oxo-1,8naphthyridin-3-yl]propan-2-ol Formula I: X 3-CN; Y H; Z CH2-CH(O-CO-CH )-CH Prepared by the procedure of Example 11 Crystals (ethanol); m.p. 160-2 0 C; yield: Example Nicotinate of [1-(3-cyanophenyl)-1,2-dihydro-2-oxo- 1,8-naphthyridin-3-yl]propan-2-ol Formula I: X 3-CN; Y H; Z CH 2 -CH(O-CO-

)-CH

3 A solution of 5 g of [1-(3-cyanophenyl)-1,2dihydro-2-oxo-1,8-naphthyridin-3-yl]propan-2-ol, prepared in Example 33, and 4 g of nicotinoyl chloride in 150 ml of tetrahydrofuran containing 2.5 ml of triethylamine is heated under reflux for 5 hours. After 25 the mixture has been allowed to return to room temperature, it is left to stand overnight, water treated with sodium hydroxide is then added and extraction is carried out with chloroform. The organic phase is washed with water and then dried over sodium sulfate, the chloroform is evaporated off and the residue obtained crystallizes from ether. After recrystallization from acetonitrile, 3.8 g of the nicotinate of 41 Cl It Sr I rr vc

C

SC C CIr I O *r 4 4 4;

,W

31 [1-(3-cyanophenyl)-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin- 3-yllpropan-2-ol are recovered in the form of crystals i melting at 179-180'C.

Example 71 Nicotinate of (1-phenyl-1 ,2-dihydro-2-oxo-1 ,8naplithyridin-3-yl )propan-2-ol

-N

Formula I: X Y H; Z CH 2 -CH(O-CO-\ )-CH 2 3 Prepared by the procedure of Example Crystals (acetonitrile); m.p. 154-5'C; yield: Example 72 Acetate of [1-(3-cyanophenyl)-1 ,2-dihydro-2-oxo-1 ,8naphthyridin-3-yl ]propan-3-ol Formula I: X 3-CN; Y Z CH CR CH -0O-CO-CR 2 2 2 3 Prepared by the procedure of Example 11 Crystals (ethanol); m.p. =151-3'C; yield: tiff Example 73 B- Acetate of (1-phenyl-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin- 3-yl)propan-2-ol *SS-rFormula I: X =Y Z CH -H(0-CO-CR )-CH 2 3 3 Prepared by the procedure of Example 11 Crystals (isopropanol); m.p. 114-6 0 C; yield: **'Example 74 Acetate of [1-(3-methylthiophenyl)-1,2-dihydro-2-oxo- 1 ,8-naphthyridin-3-41]propan-2-o1 Formula I: X 3 i3; Y H; Z CH 2 -CR(0-CO-CRJ)-CH 3 Prepared by the procedure of Example 11 Crystals; m.p. 138'C; yield: 88% Example Acetate of [1-(3-chlorophenyl)-1 ,2-dihydro-2-oxo-1 ,8- 330 naphthyridin-3-yl ]propan-2-ol 32 t t t 4 t St 4 S t 4 14 S S. S S

S

1455 414 44 4 C 4444 4 5? S S 4554 4 J~ 4. 4 45 5.5 C S S 44CC C~ S V 45 C 4 L~ 4 45 Formula I: X 3-Cl; Y Z CH 2-CH(0-CO-CH 3)-CH3 Prepared by the procedure of Example 11 Crystals; m.p. 119-120'C; yield: Example 76 Nicotinate of [1-(3-chlorophenyl)-1 ,2-dihydro-2--oxo- 1 ,8-naphthyridin-3-yllpropan-2-ol

-N

Formula I: X 3-Cl; Y H; Z =CH 2-CH(O--CO-O )-CH3 Prepared by the procedure of Example Crystals (isopropanol/isopropyl ether); m.p. =130'C; yield: 62% Example 77 Propionate of (1 -phenyl-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin- 3-yl )propan-2-ol Formula I: X Y H; Z CH 2-CH(O-CO-C 2H 5)-CH3 15 Prepared by the procedure of Example 11 using propionic anhydr ide Crystals (isopropyl ether); m.p. =90-2'C; yield: 68% Example 78 Acetate of [1i-(3--trifluoromethylphenyl)-1 ,2-dihydro-2- 20 oxo-1 ,8-naphthyridin-3-yllpropan-2-ol Formula I: X =3-CF 3 Y H; Z CH 2 CH(0-C0-CH 3 )-CH 3 Prepared by the procedure of Exalnple 11 Crystals (isopropanol); m.p. 142-3'C; yield: Example 79 25 [1-(3-Methylthiophenyl)-1 ,2-dihydro-2-oxo-1 ,8naphthyridin-3-yl ]propan-3-ol Formula I: X 3-SCH 3 Y Z CH 2-CH 2-CH 2-OH' Prepared by the procedure of Example 40 using 4 -valerolactone Crystals (acetonitrile) with one molecule of water of jy r e C z-~VrW~ a a ai a..

33 hydration; m.p. 114-6 0 C; yield: 44% Example Maleate of S-methyl-N-methyl-N'-{2-[ (1-phenyl-1, 2dihydro-2-oxo-1 ,8-naphthyridin-3-yl)methylthioethyl3isothiourea Formula I: X Y H; Z CH 2 SCH -CH--NH-C=N-CH

S-CH

3 This is prepared by following the procedure of Example 38 using ethyl S-methyl-N-methylisothiourea- N'-ethylthiopropionate. The addition of maleic acid in an acetone/ether mixture to the crystals obtained, m.p. 164'C, gives the maleate in the form of crystals melting at 181-183 0 C; yield: Example 81 [1-(4-Chlorophenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin- 3-ylllpropan-2--ol Formula I: X 4-Cl; Y H; Z CH 2 -CH0H-CH 3 Prepared by the procedure of Example Crystals (xylene); m.p. 166'C; yield: 41% Example 82 20 Acetate of [1-(4-chlorophenyl)-1,2-dihydro-2-oxo-1,8naphthyridin-3-yl]propan-2-ol Formula I: X 4-Cl; Y H; Z CH -CH(0-C0-CH3

)-CH

Prepared by the procedure of Example 11 Crystals; m.p. 167*C; yield: 92% Example 83 Acetate of [1-(3-methylthiophenyl)-1 ,2-dihydro-2-oxo- 1 ,8-naphthyridin-3-yl propan-3-ol Formula I: X 3-SCH 3 Y H; Z CH 2

-CH

2

-CH

2 -0-CO-CH 3 Prepared by the procedure of Example 11

I.

a a 44** a a a a aJ a a a.

A

I

-34 {Crystals (isopropanol); m.p. =93-4'C; yield: 76% Example 84 [1-(4-Fluorophenyl)-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin- 3 -yll]propan-3-ol Formula I: X Y Z =CH-CH -CH -OH 2 2 2 Prepared by the procedure of Example 40 using d'-valerolactone {Crystals (ethanol); m.p. =168-9'C; yield: Example [1 -(4-Chlorophenyl)-1,2-dihydro-2-oxo-1 ,8-naphthyridin- 3 -yl Ipropan-3-ol Formula I: X 4-Cl; Y Z =CH -CH -CH -OH 2 2 2 cc r Prepared by the procedure of Example 40 using 6 -valero-

C

lactone Crystals (isopropanol); m.p. =165*C; yield: 42% Example 86 Acetate of [1-(4-chlorophenyl)-1 ,2-dihydro-2-oxo-1,8naphthyridin-3,-yl Jpropan-3-ol Formula I: X 4-Cl; Y H; Z =CHi CH -CH -0-CO-CH Prepared by the procedure of Example 21 221 Crystals; m.p. =143-5 0 C; yield: Example 87 [1-(4-Chlorophenyl)-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin- 3-yllpropan-2-one Formula 1: X 4-Cl; Y Z CH -CO-CH 3 4Prepared by the procedure of Example 23 Crystals (isopropanol); m.p. 192-3*C; yield: Example 88 2-(l-Phenyl-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin-3-yl)-1- .phenylethanol I x .4

I

I

4 4 4 4 i 4 4 I I PP I It

I,.

35 Formula I: X Y H; Z CH 2

-CH(OH)

Prepared by the procedure of Example 40 using butyrolactone Crystals (isopropanol); m.p. 149-151 0 C; yield: 32% Example 89 Furan-2-carboxylate of (1-phenyl-1,2-dihydro-2-oxo-1,8naphthyridin-3-yl)propan-2-ol Formula I: X Y H; Z CH2-CH(O-CO-7

)-CH

3 Prepared by the procedure of Example 70 using the chloride 10 of furan-2-carboxylic acid Crystals (isopropanol); m.p. 140-2 0 C; yield: Example Phenylacetate of (1-phenyl-1,2-dihydro-2-oxo-1,8naphthyridin-3-yl)propan-2-ol Formula I: X Y H; Z CH 2

-CH(O-CO-CH

2 -0 )-CH 2 2 3 Prepared by the procedure of Example 70 using phenylacetyl chloride Crystals (isopropanol); m.p. =102-4 0 C; yield: Example 91 [1-(3-Cyanophenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin- 3-yl ]butan-4-ol Formula I: X 3-CN; Y H; Z CH -CH -CH -CH -OH 2 2 2 2 Prepared by the procedure of Example 7 using E-caprolactone Crystals (acetone); m.p. 160-2 0 C; yield: 22% VA~AAttX>AVA~rAt A~r~tr~ 7-7 i~ -Q4 pp- 36 Example 92 Acetate of 2-(1--phenyl-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin- 3-yl -phenylethanol Formula I: X Y H; Z CH 2- CH(0-CO-CH3 Prepared by the procedure of Example 11 Crystals (acetone); m.p. =190-2'C; yield: 0. 04 1 0 0 0* 0 4 *0 0Wee 0 0* 00 a

II.

0t o 0 0 0000 0 4*00 .4 S I

I,

I

04I(.

0 Example 93 Acetate of [1-(4-fluorophenyl)-1 ,2-dihydro-2-oxo-1 18naphthyridin-3-yl jpropan-3-ol Formula I: X Y H; Z CH 2-CH 2-CH 2-0-CO-CH 3 Prepared by the procedure of Example 11 Crystals (xylene); m.p. =154-5 0 C; yield: Example 94 Acetate of f1-(3-methylthiophienyl)-i ,2-dihydro-2-oxo- 15 1 ,8-naphthyridin-3-ylllethan-2-ol Formula I: X 3-SCH 3 Y H; Z CH 2-CH 2-0--CO-CH 3 Prepared by the procedure of Example 11 Crystals; m.p. 118-121 0 C; yield: 92% Example (1-Phenyl-1,2-dihydro-2-oxo-1 ,8-naphthyridin-3-yl)butan- 3 -ol Formula I: X Y H; Z CH 2-CH 2-CHOH-CH3 Prepared by the procedure of Example 40 using c&-caprolactone 25 Crystals (toluene); m.p. 132-5 0 C; yield: Example 96 Acetate of (1 -phenyl-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin- '4-yl )butan-3-ol Formula I: X Y H; Z CH 2-CH 2-CH-(0-CO-CH 3)-CH3 0t 0 .11* 000 0 0

I.

.1 37 Prepared by the procedure of Example 11 Crystals; m.p. 140-1°C; yield: 82% Example 97 (1-Phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)butan- 3-one Formula I: X Y H; Z CH2-CH2-CO-CH 3 Prepared by the procedure of Example 23 Crystals (acetone); m.p. 157 0 C; yield: Example 98 2-(1-Phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)- 1-(pyridin-3-yl)ethanol

=N

Formula I: X Y H; Z CH2-CH(OH) Prepared by the procedure of Example 40 using 3-yl)butyrolactone Crystals (acetone/ether); m.p. 155-7 0 C; yield: 36% Examples 99 and 100 A solution of 15 g of 2-(3-cyano-4-fluorophenyl)aminonicotinaldehyde, prepared previously, and 7.5 g of r-valerolactone in 500 ml of tetrahydrofuran containing 20 a solution of sodium methylate, prepared from 1.7 g of sodium in 50 ml of methanol, is stirred for 7 hours at room temperature. After the reaction mixture has been standing overnight, water and ice are added, extraction is carried out with chloroform and the extract is washed 25 with water, dried over sodium sulfate and evaporated to give a mixture of 11 g of two derivatives. With the condensation reaction, it is found that part of the fluorine derivative has reacted with the sodium methylate to give a methoxy group. The following two derivatives are recovered by filtration using preparative HPLC: 4 CI Ife r Ci 4- C 4 44IO 44 r.

4 C -y -38 Example 99 [1-(3--Cyano-4-fluorophenyl)-1 ,2-dihydro-2-oxo-1,8naphthyridin-3-yl lpropan-2-ol Formula I: X Y Z CH C1CHOH-CH 3 Crystals; m.p. =208 0 C; guantity: -3.2 g r Example 100 11-(3-Cyano-4-methoxyphenyl)-1 ,2-dihydro-2-oxo-1 ,8naphthyridin-3-yl Ipropan-2-ol Formula I: X 3-CN; Y 4-OCR 3 Z =CR CHOH-CH 32 3 Crystals; m.p. =191-2'C; quantity: 4.3 g Example 101 V 1-Phenyl-1 ,2-dihydro-2-oxo-3-ethoxymethyl-1 ,8-naphthyridine Formula I: X =Y=RH; Z =CH -0-CRH 2 2 Prepared by the procedure of Example 38 using ethyl S 15 P-ethoxypropionate Crystals (methanol); m.p. =182'C; yield: ffc~ Example 102 N-Cyano-N'--(2-[ (l-phenyl-1 ,2-dihydro-2-oxo-1 ,8naphthyridin-3-yl )methylthio]ethy1l -methylguanidine N- CN Formula I: X Y Z CH 2 -S-CH CH -H/ cx 2c NH-CH 3 V Prepared by the procedure of Example 38 using methyl N-cyano-N"-methylguanidine-N' -ethyithiopropionate in methanol with sodium methylate cccoCrystals (acetonitrile); m.p. =196-7 0 C; yield: 24% Example 103 N-Cyano-N'-(2-[ (1-(3-methylthiophenyl)-1 ,2-dihydro-2oxo-1 ,8-naphthyridin-3-yl)methylthiolethyl] -N"--methylguanidine

A

p 1 I 39 on o 0n 0 *0 *0

S

a S S 0 o *0 C

N---CN

Formula I: X 3-SCH Y H; Z CH -S-CH -CH -NH-C 3 2 2 2 N H \NH-CH 3 Prepared by the procedure of Example 38 using methyl N-cyano-N"-methylguanidine-N'-ethylthiopropionate in methanol with sodium methylate Crystals (methanol); m.p. 176°C; yield: Example 104 (1-Phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)-3bromopropane Formula I: X Y H; Z CH2-CH2-CH2-Br 30.7 g of (1-phenyl-1,2-dihydro-2-oxo-1,8naphthyridin-3-yl)propan-3-ol, prepared in Example 12, in 614 ml of 47% hydrobromic acid are stirred at room temperature for one hour. The reaction mixture is subsequently heated at 90 0 C for 6 hours and then con- 15 centrated in vacuo, the concentrate is taken up with water, extraction is carried out with methylene chloride and the extract is washed with water and dried over sodium sulfate. The methylene chloride is evaporated off and 37 g of (1-phenyl-1,2-dihydro-2-oxo-1,8- 20 naphthyridin-3-yl)-3-bromopropane are recovered in the form of crystals melting at 162 0

C.

Example 105 (1-Phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)-3methoxypropane 25 Formula I: X Y H; Z CH -CH -CH -O-CH 3 g of (1-phenyl-1,2-dihydro-2-oxo-1,8naphthyridin-3-yl)-3-bromopropane in a solution of sodium methylate, prepared by reacting 1 g of sodium with 100 ml of methanol, are heated under reflux for 3 hours. The reaction mixture is subsequently concentrated in vacuo, the residue is then taken up with t-- I i T Z-N

I:

i s #5~ S S" 40 water and extracted with methylene chloride and the extract is washed with water, dried over sodium sulfate and evaporated.

After recrystallization of the resulting crystals from isopropanol, 4.2 g of (1-phenyl-1,2dihydro-2-oxo-1,8-naphthyridin-3-yl)-3-methoxypropane are recovered in the form of crystals melting at 136- 7 0

C.

Example 106 10 (1-Phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)-3methylthiopropane Formula I: X Y H; Z CH2-CH2-CH2-S-CH 3 A solution of 10 g of (1-phenyl-1,2-dihydro- 2-oxo-1,8-naphthyridin-3-yl)-3-bromopropane in 50 ml of dimethyl sulfoxide containing 2.5 g of the sodium salt of methylmercaptan is stirred for 3 hours. At the start of the reaction, an exothermic effect is observed and the solids are seen to pass totally into solution, and then, when the reaction mixture has returned to room temperature, the formation of a precipitate is observed. Water and ice are then added to the reaction mixture and the precipitate formed is filtered off, washed carefully with water and then dried.

By recrystallization from isopropanol, 7 g of (1-phenyl- 25 1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)-3-methylthiopropane are recovered in the form of crystals melting at 135-6 0

C.

Example 107 (1-Phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)-3cyanopropane Formula I: X Y H; Z CH 2 -CH2-CH2-CN A solution of 10 g of (1-phenyl-1,2-dihydro-2oxo-1,8-naphthyridin-3-yl)-3-bromopropane in 50 ml of S 5* *c S

SO

S

5555E ar *841c ea 1i I i 41 *r 4 *9 t £r I P IlL *1 t i 9 4 e *r n' 9 4 dimethyl sulfoxide containing 1.5 g of sodium cyanide is stirred at room temperature for 3 hours. Water and ice are then added to the reaction mixture., and the precipitate formed is filtered off, washed carefully with water and dried. By recrystallization from acetonitrile, 4.3 g of (1-phenyl-1,2-dihydro-2-oxo-1,8naphthyridin-3-yl)-3-cyanopropane are recovered in the form of crystals melting at 210-1 0

C.

Example 108 N-(2-[(1-phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3yl)methylthio]ethyl)-N'-methyl-2-nitro-1,1-diaminoethene

CH-NO

Formula I: X Y H; Z CH2-S-CH2-CH2-NH-C

\NH-CH

3 Prepared by the procedure of Example 38 using methyl N'-methyl-2-nitro-1,1-diaminoethene-N'-ethylthiopropionate in methanol with sodium methylate Crystals (dimethylformamide/water) hydrated with 1/3 m.p. 207-9 0 C; yield: 12% Example 109 5-[1-(3-Trifluoromethylphenyl)-1,2-dihydro-2-oxo-1,8naphthyridin-3-yl]pentanoic acid Formula I: X 3-CF3; Y H; Z CH2-CH2-CH -CH2-COOH A mixture of 18.3 g of 2-(3-trifluoromethylphenyl)aminonicotinaldehyde, synthesized previously, 16 g of sodium pimelate and 20 g of pimelic anhydride in 40 ml of N-methylpyrrolidone is heated at 170-180 0

C

for 1 h 15 min.

The reaction mixture is subsequently cooled, water and ice are added and the resulting mixture is then rendered basic with a 10% solution of sodium hydroxide. The neutral products are extracted with ethyl acetate. The aqueous phase is then acidified in -X ll~~ i: ^i -I

-U

42 Cr C CC C C CZ tCC O C', COC c ~aa

CICC

S C the cold with acetic acid and extracted with methylene chloride and the extract is washed with water and dried over sodium sulfate. After evaporation of the methylene chloride, the residue obtained is chromatographed on silica gel. Elution with a 99.5/0.5 mixture of methylene chloride and acetic acid gives a residue which crystallizes from isopropyl ether. The crystals obtained are filtered off, washed with isopropyl ether and dried to give 6.3 g of 5-[1-(3-trifluoromethylphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]pentanoic acid in the form of crystals melting at 136- 8 0

C.

Example 110 4-[1-(3-Trifluoromethylphenyl)-1,2-dihydro-2-oxo-1,8- 15 naphthyridin-3-yl]butanoic acid Formula I: X 3-CF 3 Y H; Z CH -CH2-CH -COOH A mixture of 10 g of 2-(3-trifluoromethylphenyl)aminonicotinaldehyde, synthesized previously, 24 g of sodium adipate and 11.2 ml of adipoyl chloride in 60 ml of N-methylpyrrolidone is heated at 170-180 0 C for 1 h min.

The reaction mixture is subsequently cooled, water and ice are added and the resulting mixture is then rendered basic with a 10% solution of sodium hydroxide. The neutral products are extracted with ether. The aqueous phase is then acidified in the cold with acetic acid and extracted with ether and the extract is washed with water and dried over sodium sulfate.

After evaporation of the solvent, the residue obtained is chromatographed on silica gel. Elution with a 99.5/ mixture of methylene chloride and acetic acid gives a residue which crystallizes from isopropyl ether.

After the crystals have been filtered off, washed and recrystallized from acetonitrile, 4.5 g of 4-[1-(3-tri-

I/

I 1 43 fluoromethyiphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin- 3-yllbutanoic acid are obtained in the form of crystals melting at 165-6'C.

Example 111 5-(1-Phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)pentanoic acid Formula I: X Y H; Z CH 2 CH 2 -CH 2 -CH -COOH Prepared by the procedure of Example 109 Crystals (acetonitrile); m.p. 187-8 0 C; yield: 23% Example 112 4-(1-Phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)butanoic acid Formula I: X Y H; Z CH -CH -COOH the 2 2 C2C O Prepared by the procedure of Example 110 0 Crystals (acetonitrile); m.p. 178-9 0 C; yield: The following Examples 113 to 119 were also synthesized by the procedure of Example 109: Example 113 6-[1-(3-Trifluoromethylphenyl)-1,2-dihydro-2-oxo-1,8- 20 naphthyridin-3-yljhexanoic acid g Formula I: X 3-CF 3 Y H; Z CH -CH -CH -CH -CR -COOH 32 2 2 2 2 Crystals; m.p. 126-7 0 C; yield: 28% 0* Example 114 6-(1-Phenyl-1 ,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)hexanoic acid Formula I: X Y H; Z CH 2

-CH

2

CH-CH

2

-C

2

-COOH

Crystals (acetonitrile); m.p. 157-8 0 C; yield: 28% Example 115 5-[1-(3-Chlorophenyl)-1,2-dihydro-2-oxo-1,8-naphthyridi- 3-yl]pentanoic acid 44

I

Formula I: X 3-Cl; Y H; Z CH CR -CH 2-CR -CR 2-COOR Crystals (acetonitrile); m.p. =160-1*C; yield: Example 116 5-[l-(3-Methylthiophenyl)-1 ,2-dihydro-2-oxo-1 ,8naphthyridin-3-yl Ipentanoic acid Formula I: X 3-SCH 3 Y Z =CH 2-CHR -CH 2-CR -COOH Crystals (methanol); m.p. =158-160'C; yield: Example 117 5-[l-(3-Nitrophenyl)-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin- 3-ylllpentanoic acid Formula I: X 3-NO 2 Y H; Z CR 2-CH 2-CH 2-CH 2-COOR Crystals (ethanol); m.p. 183-5'C; yield: Example 118 5-II1-(4-Fluorophenyl)-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin- 15 3-yllpentanoic acid Formula I: X 4-F; Y Z =CR 2-CR 2-CH 2-CR 2-COOR Crystals (acetonitrile/acetone); m.p. 200-2 0

C;

yield: 21% Example 119 20 5-[1-(3-Cyanophenyl)-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin- 3 -yl Ipentanoic acid Formula I: X 3-CN; Y Z =CR 2-CH 2-CR 2-CR 2-COOR Crystals (dimethylformamide); m.p. 193-4 0 C; yield: tI t It C 4 1 t: 4 4 4 t :t 4 t: t 4 PAP:4 4 Example 120 1-(1-Phenyl-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin-3-yl)- 3-[4-(2-methoxyphenyl)piperazin-1-yllpropane Formula I: X =Y Z A solution of 7 g of (1-phenyl-1,2-dihydro-2oxo-1,8-naphthyridin-3-yl)-3-bromopropane, prepared in Example 104, and 3.9 g of 1-(2-methoxyphenyl)piperazine in 100 ml of xylene containing 2.8 ml of triethylamine is heated under reflux for 3 hours. The reaction mixture is then cooled, water and ice are added and extraction is carried out with chloroform. The chloroform phase is then extracted with a 10% solution of hydrochloric acid. The acid aqueous phase is subsequer. 'y rendered basic in the cold with a 10% solution of sodium hydroxide and then extracted with methylene chloride and the extract is washed with water, dried over sodium sulfate and evaporated. The residue obtained crystallizes and, after recrystallization from 15 isopropanol, 4.8 g of 1-(1-phenyl-1,2-dihydro-2-oxo- 1,8-naphthyridin-3-yl)-3-[4-(2-methoxyphenyl)piperazin- 1-yl]propane are recovered in the form of crystals melting at 112-3 0

C.

Example 121 (1-Phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)-2bromoethane Formula I: X Y H; Z CH2-CH2-Br Prepared by the procedure of Example 104 Crystals; m.p. 206 0 C; yield: 25 Example 122 1-(1-Phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)- 2-[4-(2-methoxyphenyl)piperazin-1-yl]ethane 0 o- CH 0 Formula I: X Y H; Z CH2CHH2-N U Prepared by the procedure of Example 120 Crystals (isopropanol); m.p. 129-131 0 C; yield: 30 Crsta1 -,Ii i:-I r 1 I 46 e4 4:1 4: 4: 4:4 4: 4 4: I'1 4:44 4: eC 4: C.

*4 4 4: 9 9.~ 4( 4, 4 Example 123 1-(1-Phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)- 2-(imidazol-1-yl)ethane Formula I: X Y H; Z CH -CH -N N 2.4 g of imidazole are added in small amounts to a suspension of 0.8 g of sodium hydride in 550 ml of dimethylformamide. After the addition has ended, the mixture is heated for 1 hour at 90 0 C and then allowed to return to room temperature and a solution of 10.7 g of (1-phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)- 2-bromoethane,prepared in Example 121, in 100 ml of dimethylformamide is added. After the addition has ended, the mixture is heated for one hour at 90°C and then concentrated in vacuo. The residue is taken up 15 in water and crystallizes and the crystals obtained are filtered off, washed with water and dissolved in a solution of hydrochloric acid.

The aqueous phase is washed with ethyl acetate and then rendered basic in the cold with a 10% solution of sodium hydroxide. The crystals formed are filtered off, washed with water containing a small quantity of acetone and dried. After recrystallization from acetonitrile, 3.8 g of 1-(1-phenyl-1,2-dihydro-2-oxo- 1,8-naphthyridin-3-yl)-2-(imidazol-1-yl)ethane are 25 recovered in the form of crystals melting at 208-9 0

C.

Example 124 (1-Phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)[4methylpiperazin-1-yl]methane Formula I: X Y H; Z CH 2 -Nc -CH 3 Prepared by the procedure of Example 38 using ethyl (4-methylpiperazin-i-yl)propionate 4.

Jl 47 Crystals (isopropanol) crystallized with 1 mol of water; m.p. 145-6 0 C; yield: 8% Example 125 3-(1-Phenyl-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin-3-yl)-2- (4 -chlorobenzoyl )aminopropionic acid Formula I: X =Y Z =CH 2-CH ZC 2 "NH-C0 O Cl Prepared by the procedure of Example 7,using dimethyl N-i 4-chlorobenzoyl )glutamate Crystals (acetonitrile); m.p. 197-9'C; yield: 8%

C

C

C

C (C C( (C

C

C C 4-f

C'

V cC CLf C C 1

C

Example 126 2-(1-Phenyl-1 ,2-dihydro-2-oxo-1 ,8-naphthyridin-3-yl)- 2- (4-chlorobenzoyl )aminoacetic acid

,ZCOOH

Formula I: X =Y H; Z CH N COl Prepared by the procedure of Example 7 'hng dimethyl 1 5 N- (4 -chlorobenzoyl )aspartate Crystals (acetic acid); m.p. 236-237'C; yield: 7% Example 127 Ethyl 5-(1-phenyl-1 ,2-dihydro-2-oxo-1 ,8-naphthyridii- 3-yl )-2-acetamido-2-ethoxycarbonylpentanoate pOOC 2

H

Formula I: X Y H; Z CH 2 -CH 2

CH

2 cKNH-COCH 3 COOC 8.1 g of (1-phenyl-1,2-dihydro-2-oxo-1,8naphthyridin-3-yl )-3-bromopropane, prepared in Example 104, are added in small amounts to a refluxing solution of 5.7 g of diethyl acetarnidomalonate, metallated beforehand with 0.7 g of sodium, in 70 ml of ethanol.

C r i; 9: 48 0 0 (C 0 0 *0 *0*0 0 0 04 0 a' o *I ~9a 04 0 0o After the addition has ended, reflux is continued for 2 h, the reaction mixture is then concentrated in vacuo, the residue is taken up with a mixture of water and ice and extracted with ethyl acetate and the extract is washed with water and then dried over sodium sulfate. After evaporation of the ethyl acetate, the residue obtained crystallizes from ether. The crystals are filtered off and recrystallized from ethanol to give 4.7 g of ethyl 5-(1-phenyl-1,2-dihydro- 2-oxo-1,8-naphthyridin-3-yl)-2-acetamido-2-ethoxycarbonylpentanoate in the form of crystals melting at 1800C.

Example 128 5-(1-Phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)- 15 2-aminopentanoic acid hydrochloride /NH2 Formula I: X Y H; Z CH2-CH2-CH -CH

COOH

A solution of 4.7 g of ethyl 5-(1-phenyl-1,2dihydro-2-oxo-1,8-naphthyridin-3-yl)-2-acetamido-2ethoxycarbonylpentanoate, prepared in Example 127, in 110 ml of 20% hydrochloric acid is heated under reflux for 9 hours. The reaction mixture is then concentrated in vacuo, the residue obtained is taken up with ether and the crystals thus formed are filtered off and then dried. After recrystallization from an 8/2 aceto- 25 nitrile/water mixture, 2.4 g of 5-(1-phenyl-1,2-dihydro- 2-oxo-1,8-naphthyridin-3-yl)-2-aminopentanoic acid hydrochloride are recovered in the form of crystals melting at 203-5 0

C.

Example 129 3-(1-Phenyl-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)diethylphosphonopropane r: i :Si-i-ui-i-- -9 ~L I; iii;i- i I .r 49 OC2H A mixture of 7.3 g of (1-phenyl-1,2-dihydro-2oxo-1,8-naphthyridin-3-yl)-3-bromopropane, prepared in Example 104, and 28 ml of triethyl phosphite is heated at 120-130 0 C for 6 hours. The reaction mixture is then evaporated to dryness in vacuo. The residue obtained crystallizes from isopropyl ether. The crystals are filtered off, washed with isopropyl ether and dried to give 8 g of a derivative which are filtered on silica gel. With a 9/1 methylene chloride/methanol eluting mixture, 7 g of 3-(1-phenyl-1,2-dihydro-2-oxo-1,8naphthyridin-3-yl)diethylphosphonopropane are recovered in the form of crystals melting at 119-121 0

C.

C C C C Ct c

C,

ct t C CL C t Cr C t k 7 I r 50 TABLE I N 0 51 45-1 8 Example 4 51 45-1 9 Example -I H-S-CH3 r4 2i 3 t cc M z 0 I r"ct 5145-20 Example 6 51 45-23 Ii t I~ 4 1

CII~

Cc

C

I

C

'V

4 *~It II C

I

H-CH-OH

N N 0

C

3 SOCH3 Example 7 Example 8 5145-24 51 45-25 cCFSO-CH3 N

N

CF3 Example 9 51 51 45-39 CH -CH -CH -OH 2 2 2 N N 0 N.

CF

3 23 N N 0 ICF 3 Example 5145-40 Example 11 .CH -CHi-CH-OH 222 51 45-41 Example 12 Ar t

I

t L 51 45-42 I] 1,CH CHi-CH-O- CO-CH3 N 0 Example 13 V. L 5145-43 a I C-

OH

N N Example 14 5145-44 NI N CH7CHF CO-CH 3 Nn N 0 Example 52 -C1+2CHT O- CO-CR 5145-46 Example 16 CRFCR 2CH 2CH7OH 51 45-47 Example 17 5145-49 Example 18 4* 9* 9 9 9 9* I 9 4 9999 9.

9 9 99 1 9 99" 9 9't 99 9 9 ~C N CF 3 5145-50 Example 19 7I 9 c e C; V.c 5145-51 CHF-CH(OH)-CH3 N 0 CF 3 Example 9999

C

9 9 9 CC 5145-52 C- CR-CR- CR 0-CO-CR 3 0 Example 21 -r ,-r~rrr'rrZrtrW~r---r- 53 CHF OCR 5145-54 51 45-58 51 45-55 51 45-6 1 51 45-62 Example 23

I

CN IN7 ~t t t t v o 9 00 w0 Example 24 Example Example 26 Example 27 N N 0 N CF 3 c ZOCH 3 450 4Eape2 5145-64 Example 28 54 5145-65 OCH3 N N 0 Example 29 5145-66 N N 0

-CF

3 Example Cs C

'C

CC

C'i t CE r Ce C C PC i C C frC C C 5145-70 H CHF- O-CO-CH 3

CN

'NCHTC0-CH 3 rN 0

OCN

Example 32 Example 34 5145-71 CHF

S-CH

5145-72 Example 5145-74 CHF SO-CH3 N N

OCN

Example 36 i i-1 I 55 51 45-7 6 C I C H0 FNn Example 37 CH-7S-CH3 5145-77 >Ji 51 45-78 e i: CHi-CO-CH 3 CF 3

'H-CH-CH

OH

Example 38 Example 39 Example 51 45-79

C

51 45-81 Example 41 5145-0 CHCO-CH3 514 -8 Example

F

42 56 5145-82 5145-83 51 45-84 5145-85 99 99 9 9 9 9. 9 C 9 99 .9 9 9 4.

S

*44 44 99 9999 9 14 S C 9444 4.4 1 4 44 44 C 4 4 C 44 44~ 0 .J44 400 4 0 4440 4 9 144 4£ 4 CC S-C9 N N 0 2 1 N N 0 C OS-C 3 C 2 3 "N N 0 03 CHFC7CFO N 2I 2 C N ON0 Example 43 Example 44 Example Example 47 Example 48 5145-87 Example :7, 57 5145-88 5145-89 5145-90 5145-91 5145-92 4, .4 *s 4 4* 4 4 *604 .4.

4 00 4 CH2- O-CH3 IN MIN

NN

0 CH3 3 N N 0

N

CO-CH 3 N N 0 0CH 3 M HT SH3 N N N NO 2 N H7

CO-CH

3

SCH

3 H CHOH)-CH3 2 3 N :N Example 51 Example 52 Example 54 Example Example 56 Example 57 q.44 09 4p 5145-93 r r w. -58 5145-94 ICHT-

CO-CH

F

Example 58 CHF CHT CH7 OH 5145-95 Example 59 5145-96 -0-CH 3 99

I

r* a

I

rq n I +e ,r i i re *ar

I

re r re r c r c* a 5145-97 Hi- S-CH3 HrS-CeH3 r4 I NJ

C

Example Example 61 Example 62 5145-99 r,,r c 5145-100 2 3M6,'H

CN

Example 63 2 t 5145-1 f 5145- 59 01 7-COCH3

N!C

CN

Example 64 Example 102 SCcc t~ c Otte 5145-103 51 45-105 5145-106 Example 66 Example 33 CH-S-CH3 Example 67 5145-107 CHF CO-CH 3 N N 0 Example 68 00C 5145-108 -i -i, 60 CH CH--CO-CH 1 3 CH 3

O

5145-109 5145-110 5145-111 5145-112 4

S~

tf e tL tC c r Ir *f o *i C o *I

CH-CH-OH

II

r I CH

~C

HF -0-CO-O

N.I

NI CH 3 CH CHF CHT 0-CO-CH (-NnN 03 Example 69 Example Example 22 Example 71 Example 72 Example 73 1 5145-113 CHF'

H--COCH

3

CH

MNN 0 A

A

61 51 45-11 4 5145-115 5145-116 .9 4 4 9 4 4 4 i S 4, :t~ 4.

4 *1~ n I *"'CH5-CH(OH)-CH 3 N 0 CH-CH-0-CO-CH N SCH 'rCH-CH--CO-CH3 N NO C 3 N CHg-CH-0-CO CH-CH-O- CO-C2 HS 101 OH-CH-0-CO-CH

N

Example 46 Example Example 74 5145-117 Example 76

S

I

~Z

~j 1 1~< I I 9 4' 4 1

I

51 45-118 Example 77 51 45-11 9 Example 78 -62 51 45-121 51 45-122 CH-CHTCH0OH N N 0 ISCH 3 Example 79 CH- S- CH-CH NH C N -CH 3 IN0 Example (OH)-CH 3 51 45-123 Example 81 r C 4C t tft 51 45-124 51 45-1 Example 82 Example 83 M ~CHrCHf-CHf-O-CO-CH3

N

L "3 51 45-1 26 CH2 2 2rCrO 0 Example 84 1 63 5145-127 51 45-1 28 5145-129 5145-130 5145-131 (er LE rL E L rb C L Er Er E I M C CH7CH-CHOH 2 2 2 N 0 ci "0'CH-CH-CH-O-CO-CH3 N N2 2 ci [e CHCO -CH3 2I 3I N N0

C'

ci f"I -H

CHC(OH)

N 0 o' N CHFCH0-Co-JJ

CH-CH-O-CO-C

;0 Example Example 86 Example 87 Example 88 Example 89 Erc Err 9 0 Err 5145-132 Example 64 51 45-133 M

H-CH-CH-CHOH

NO0 Example 91 51 45-1 34 ft ft ft f t t ft t f t r ft C r C ff0 f Ct' V C C C C C? C C C Cf C C C V V 0 C C 00

C

CC

V

~ff C C C V C- 5145-135 51 45-1 36 5145-137 51 45-1 39 N..CH5-CHFCH -0-CO-CH- N

F

CH-CH-

O-CO-CHI

N N 0 IN% SCH 3 CH-TCH2-CH(OH)-CH 3 0 C-rCH-O-CO-CH3 CH3 Example 92 Example 93 Example 94 Example Example 96 7 i~ j 65 CH-CH- CO-CH3 5145-140 5145-141 5145-142 n .11 E, it r t If I t I Irs -t

II

II C t I 1l r

'I

It I I I I 5145-143 5145-144 I CH2-CH(OH)-CH3

CN

F

I N CH7 CH(QH)-CH 3 N N

CN

OCH

3 CH-O-CH-CH3 Ct N 0 Example 97 Example 98 Example 99 Example 1 O' Example 101 5145-145 SN- CN C7- S CH- NH-C 2 NH-CH3 Example 102 t -<V I Ir*s CIIII~-~L~ 66 N CN 7i-S-CH-CH NH- C 2 2 2 N-H 5145-146 Example 103 S

CH

3 5145-147 'H-CH- CHf- O-CH3 Example 105 5145-148 CHF-CH-CH-SCH3 N N 0 j Example 106 .e be

C

Ci be C- I t

S

*t t ir r~ C CL c Ci C 4 4 5145-149 Example 107 5145-151 CH-S-CHCHNH-CH- N2 22NH-

CH

3 N O 0Example 108 CH-CH-CH -CH-COOH 2 22 2 5196-05 Example 109

'CF

3

I

416 5196- 5196 T VT 519 67 -06 CN N I N CF 3 x M, 0 rKNY>KsYCH-CHF-CHF-C01- -07 Example 110 Example 11 1 Example 112 -08

I

51 96-09 C~H-Cr s-CH- CH- COOH N N 0 Example 113 xl' S 4 1 4 S:~ tS~ t 2 4 S

I

~54 IP

I

4-LI 11

I

5196-10 H-CHCOOH Example 114 5196-13 ~CH-CHFCH72 27OO CNLo Example 115 ~vJ~ CH- CH-

CH-COOH

4 p 4 11 i~t

I'

68 5196-1 4 51 96-15 51 96-16 2 2- H-H-CgCzC C' IinN 0 Example 116 CH- CHf-CHrC-iCOOH Example 117

CH-CH-CHTCH-COOH

CI t 51 96-17 N.~CHT-CH-C H-CH-COOH N N 0 6CN Example 118 Example 119 Example 120 t 37-1 i( 4 U'

U'

4' 4' 4' 4' 37-3 CH 3 0 Example 122 -81- -69- 37-4 37-5 M I CH- N N CHrN 2 CH N N-H

N.

SCH 3

CHFC!

CO00 QH-CO

H-

'COOH

Example 123 Example 124 Example 125 Example 126 Example 128 63-1

I

*1 i~

I

I

I t

I

I

I I.

I

I~ I (C 63-2 NH-CO -c

COOH

63-3 NH 2 SCHrGH-CH-CH

CO

NO-

0C 2 H INOC2 H5 63-4 63-4 Example 129 I~ I 70

PHARMACOLOGY

ULCER-INHIBITING ACTIVITY 1 Method Groups of 10 to 30 male rats of the OFA strain (originating from IFFA CREDO, France), weighing 160- 180 g, are put on a water-only diet 24 hours before the oral administration of the test product.

Thirty minutes after gavage, an ulcerogenic drug or a necrogenic agent (absolute ethanol) is administered orally at doses which cause the maximum gastric ulceration in the control animals. The stomachs are then removed either 6 hours or 1 hour after the final treatment, depending on the test. The gastric lesions E ,r are then evaluated macroscopically (grading and measurement of the size of the ulcers).

2 Results r The results are expressed in the form of active doses (doses resulting in a 50% inhibition of the lesions caused) determined graphically from the straight line expressing the relationship between the S: percentage inhibition and the dose used.

er r C e i C L 1 71 ACTIVE DOSE mg'kg oral administration) (expressed in ar *T I It I

~I

r ~r C tec0 Example 6 Example 7 Example 9 Example 10 Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Example 19 Example 20 Example 21 Example 22 Example 23 Example 24 Example 25 Example 26 Example 32 Example 33 Example 36 Example 38 Example 39 1) Administration of an ulcerogenic drug 1.4 2.95 0.105 16 3 3.8 1.1 1 4.5 7.5 4.5 0.9 7.2 0.120 0.150 1.9 3.4 1.6 0.9 0.019 0.820 0.240 1 2) Administration of a necrogenic agent 0.09 0.180 0.44 0.35 0.13 0.18 0.09 0.65 0.29 0.22 0.07 0.018 0.8 0.008 0.002 2.4 0.036 0.35 0.015 0.008 0.075 0.016 0.115 c~; 1(c j I t A- cI

C

I I4co 3.

I C 72 ACTIVE DOSE (expressed in mg-kg- oral administration) 1) Administration of an 2) Administration of ulcerogenic drug a necrogenic agent *q 0 0 0 0 0I *4 t~t

V

V.

V'V~t i C V

C,

4CCC t ec 00 4

C

44 Example 40 Example 41 Example 42 Example 43 Example 44 Example 45 Example 47 Example 48 Example 50 Example 51 Example 52 Example 54 Example 56 Example 57 Example 58 Example 59 Example 60 Example 61 Example 62 Example 64 Example 66 Example 67 Example 69 Example 70 0.850 1.4 2 1 .5 0.280 0.940 0.145 1.65 0.550 0.280 0.350 0.900 0.890 0.080 0.045 0.4 0.9 0.190 4 2.8 3.8 0.525 0.125 0.200 0.027 0.070 0.090 0.03 3 0.110 0.035 0.007 0.090 ,.025 0.062 0.080 0.085 0.030 0.005 0.009 0.013 0.115 0.028 2 0.080 0.750 0.016 0.006 0.010

A

i U- 73 ACTIVE DOSE (expressed in mgkg, oral administration) (expressed in mg-kg oral administration) 1) Administration of an ulcerogenic drug 2) Administration of a necrogenic agent *o 9 9, *fs

I

i Ct *0 I

IC*

Co Cr rel Example 71 Example 72 Example 73 Example 46 Example 74 Example 75 Example 76 Example 77 Example 78 Example 79 Example 81 Example 87 Example 90 Example 91 Example 94 Example 95 Example 109 Example 110 Example 111 Example 112 Example 113 Example 116 Example 117 Example 118 0.330 3 0.200 0.024 5.25 0.078 0.061 0.175 1.9 0.600 0.8 4.7 0.600 3.4 4.5 0.34 0.195 2.4 2.5 13 3.6 0.080 0.021 1 0.070 0.090 0.032 0.018 0.225 0.005 0.029 0.017 0.140 0.021 0.150 0.062 0.140 0.140 0.087 0.014 0.250 0.370 2 0.130 0.120 0.100 :4A Wc 1) non-steroidal antiinflammatory agent 2) ethanol -4 I 74 ANTISECRETORY ACTIVITY Li i: 1 Method The pylorus is ligated under ether anesthetic in groups of 5 male rats of the OFA strain (originating from IFFA CREDO, France), weighing 180-200 g.

The test product is administered subcutaneously at the moment of ligation. The animals are sacrificed 4 hours later, the gastric fluid is collected and its acidity is then titrated against 0.1 N sodium hydroxide solution at pH 4 and 7.

t tz t a 1 15 r 5 fo 2 Results The results are expressed as 50% active doses (doses resulting in a 50% inhibition of the total acid secretion) determined graphically from the straight line expressing the percentage inhibition of the total acid secretion as a function of the dose used.

I r C I i .4 r A4- 75 ACTIVE DOSE in m subcutaneous administration) in mg~kg subcutaneous administration) (expressed Ga *o 0

A

ar a1 C t, at r e; a 44? 4rd ft t. 9~ a I~ ea t a% r Example 6 Example 7 Example 9 Example 10 Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Example 19 Example 20 Example 21 Example 23 Example 24 Example 25 Example 26 Example 32 Example 36 Example 38 Example 39 Example 40 Example 41 Example 42 Example 43 0.070 2.6 0.32 1.2 0.09 0.05 0.46 0.35 0.28 0.2 0.17 0.06 0.8 0.013 0.125 0.075 0.130 0.030 0.750 0.170 0.850 0.320 0.04 4 a er V i, r.1 ~1 IC 4 Ii 76 ACTIVE DOSE I1 expressed in mg-kg Example 44 Example 45 Example 47 Example 48 Example 50 Example 51 Example 52 Example 54 Example 56 Example 57 Example 58 Example 59 Example 60 Example 61 Example 62 Example 64 Example 66 Example 33 Example 67 Example 69 Example 70 Example 22 Example 71 Example 72 subcutaneous administration) 0.010 0.095 0.110 2.4 0.06 0.200 0.03 6 1 0.170 0.020 0.170 0.165 1.2 0.052 0.650 0.04 2 0.014 0.033 0.035 0.02 1 0.027 0.150 0. 450 ii ft t

I

I

1<1 r~ *1 I,

I

I

I

II

I

'C

I I t t~

I

I

I

4 Gt o r

A,

77 ACTIVE DOSE in mg-kg- subcutaneous administration) (expressed $1 t ti Example 73 Example 46 Example 74 Example 75 Example 76 Example 77 Example 78 Example 79 Example 81 Example 87 Example 90 Example 91 Example 94 Example 95 Example 109 Example 110 Example 111 Example 112 Example 113 Example 116 Example 117 Example 118 0.100 0.022 u. 300 0.030 0.019 0.200 0.200 0.020 0.490 0.475 0.110 0.170 0.170 0.140 0.090 0.550 0.300 1.2 0.018 0.02 4 0.140 I,

S

t t t C

*C

z rcr C C CC C r r

CC'

C

C' C C CC

C

C C f~C CC C Ci t Cr

CCCI

CC C

C

C

r -rr- It C C

I.I

c t 78

TOXICOLOGY

The first toxicological studies, performed on fasted Sprague Dawley rats after oral administration, made it possible to show that the LD5 values for the majority of the products exemplified are greater than or equal to 300 mg-kg 1 Only the products of Examples 26 and 36 have a 50% lethal dose of between 100 and -1 300 mg.kg

CONCLUSION

The products according to the invention and their non-toxic acid addition salts described in the present Application seem to be of particular value; their ulcer-inhibiting activity and their antisecretory activity are extremely powerful, in particular in the case of the products of Examples 22, 33, 34, 55, 57, 58, 70, 75 and 97. They may be used in the treatment of gastroduodenal ulcers by injection or oral administration in the form of injectable ampoules or gelatin capsules containing doses of 5 to 100 mg.

Claims (16)

1. 4.4 4- o Iu 0441 c Bootk ~L- 'il 44 6 ri -(CH2)n-0-(CH2) -CH3, wherein n and m are the same or different and are numbers ranging between 0 and 5 inclusive 25 (CH 2 )n-OH or an ester thereof selected from the group consisting of acetate, propionate, nicotinate, furan-2-carboxylate, and phenylacetate, wherein n is a number ranging from 0 to inclusive -(CH 2 )n-CHOH-(CH 2 )mR' or an ester thereof selected from the group consisting of acetate, propionate, nicotinate, furan-2-carboxylate, and phenylacetate, wherein n and m are the same or are different and are numbers ranging between 0 to inclusive and R' is methyl or an aromatic or heteroaromatic nucleus S selected from the group consisting of phenyl or pyridyl I 1 -(CH 2 )n-CO-(CH 2 m-CH 3 wherein n and m are the same or are different and are numbers ranging between 0 to 5 inclusive -(CH 2 )n-COOH wherein n is a number ranging from 3 to inclusive -(CH 2 )nHal, wherein n is a number ranging from 0 to inclusive and Hal is halogen -(CH 2 )n CN, wherein n is a number ranging from 0 to inclusive -(CH 2 )n-NRIR 2 wherein n is a number ranging from 0 to 5 inclusive and NR 1 R 2 forms a piperazine ring substituted by a lower alkyl, phenyl or phenyl substituted by methoxy or NR R 2 forms an imidazole ring 4 *4 cr ts a r CEr' Ar; CC C~( NH-R 3 15 (CH) -CH wherein n is a number between 0 2) n COOH and 5 inclusive and R 3 is hydrogen or a para-chlorobenzoyl group 20 (CH P wherein n is a number between 0 0 bR 6 6 and 5 inclusive and R 5 and R 6 are ethyl and 25 phenyl, pyridyl, thiophene or furan. 2. A phenylnaphthyridine compound as claimed in claim 1 wherein X Y H. 3. A phenylnaphthyridine compound as claimed in claim 1 wherein X 3-CN and Y H. 4. A phenylnaphthyridine compound as claimed in claim 1 wherein X 4-F and Y H. A phenylnaphthyridine compound as claimed in claim 1 wherein X 3-NO 2 and Y H.
2. 6. A phenylnaphthryridine compound as claimed in claim 1 wherein X 3-C1 and Y H. P lf -81- 4 I S a S S4 a i5 S. S. .0 S SI 4 44 tt (ft 44 4 t «4 a *4 e r fr 4'
3. 7. The compound according to claim 1, wherein Z is CH 2 SCH 3 CH 2 CHOHCH 3 CH 2 COCH 3 CH 2 CH 2 OH or the acetate ester thereof, or (CH 2 4 COOH.
4. 8. The compound according to claim 1, wherein one of X and Y is hydrogen and the other is hydrogen, 3-CF 3 3-CN, 3-NO 2 3-C1 or 4-F.
5. 9. The compound according to claim 1, wherein X is 4-F and Y is 3-CN. The compound according to claim 1, wherein X and Y are hydrogen and Z is CH 2 CH 2 CH 2 CH 2 OH.
6. 11. The compound according to claim 1, wherein X and Y are hydrogen and Z is CH CH CH CH OC-CH 3 0
7. 12. The compound according to claim 1 wherein X is 4-F and Y 15 is 3-CN and Z is CH 2 SCH 3
8. 13. The compound according to claim 1 wherein X and Y are hydrogen and Z is CH 2 CH 2 CH 2 CH 2 COOH.
9. 14. The phenylnaphthyridine compound as claimed claim 1, which is selected from the following 2O N iN 0 N ft~ Ax A/ .1 AV !j CH -CO-OH 2 3 CH- S-OH 2 3 CH-CHOH -CH CH- CO-OH3 -I N dk 7' -83- c t rt cCcC Ct t r CH CH-CO-CH3 -84- A pharmaceutical composition characterized in that it comprises at least one phenylnaphthyridine compound as claimed in any one of claims 1 to 14, together with a pharmaceutically acceptable vehicle or excipient.
10. 16. A pharmaceutical composition useful for its anti-ulcer activity characterized in that it comprises at least one phenylnaphthyridine of formula as claimed in any one of claims 1 to 14, together with a pharmaceutically acceptable vehicle or excipient.
11. 17. A pharmaceutical composition useful for its anti-secretory activity characterized in that it comprises at least one phenylnaphthyridine compound as claimed in any one of claims 1 to 14, together with a pharmaceutically acceptable vehicle or excipient.
12. 18. A process for the preparation of the compounds of the formula as claimed in any one of claims 1 to 14, which are prepared by a method involving a condensation reaction, selected S.from those of Stobbe, Perkin, Claisen or Knoevenagel, with an aldehyde of the formula (II): 9' i CHO S I. In the formula X and Y are as defined above.
13. 19. The process as claimed in claim 18, wherein the adlehydes of the formula (II) are obtained by the oxidation of an alcohol of the formula (III) with a mild oxidizing agent, for example Mn0 2 in an organic solvent, for example methylene chloride or chloroform, at a temperature of between 20 and 50 0 C. CII 201 (III) Yx S.In the formula (III), X and Y are as defined above. 15 20. The process as claimed in claim 19, wherein the alcohols of .the formula (III) are obtained by the reduction of an acid or one of its esters of the formula (IV) with a classic reducing agent, t for example lithium aluminum hydride, in an organic solvent, for example tetrahydrofuran or ethyl ether; in the case where the phenyl nucleus carries a substituent which is sensitive to certain reducing agents, for example a nitro or cyano substituent, the reducing agent for reducing the ester will be chosen so as not to affect this substituent, an example being lithium borohydride prepared "in situ" from potassium borohydride and lithium chloride. S *i 25 COOR S. (IV) t X y- Y In the formula X and Y are as defined above and R is the hydrogen atom or an alkyl. NT I -86-
14. 21. A process for the preparation of the compounds of the formula as claimed in any one of claims 1 to 14, which comprises reacting the aldehydes of the formula defined in claim 18, with: a) acid anhydrides of the formula: 0 Z-CH -C 0 Z-CH 2 -C 0 Z being defined as above, in the presence of the sodium salt of the acid-Z-CH 2 -COOH; b) acid anhydrides of the formula: CCH 2 COC1 (CH or its chloride (CH )n 2 n-1 2 n-1 CH -CC 2 CH2COC1 in the presence of the sodium salt of the corresponding acid, n being defined as above; c) acid esters of the formula: Z-CH 2 -COOR" Z being defined as above and R" being an alkyl, in the presence of a sodium or potassium alcoholate, sodium hydride or sodium metal; or Sd) lactones of the formula R' (CH n-CH CH--C 7iA, n\ n being defined as above and R' being a methyl or an aromatic or 5 heteroaromatic nucleus, in the presence of a sodium or potassium L alcoholate, sodium hydride or sodium metal, and in the presence of absence of an organic solvent such as an alcohol, benzene, toluene or N-methylpyrrolidone, at atemperature of between about 20 and 2000C.
15. 22. The process as claimed in one of claims 20 or 21, wherein: *0 VtP C CC C CCC Ti a) the S->0 derivatives are obtained by oxidizing the compounds, for example with a peracid, it being possible to use metachloroperbenzoic acid, in a solvent such as chlororform or methylene chloride; b) the ester derivatives of alcohols will be obtained in the conventional manner by esterifying the corresponding alcohols with an acid chloride or an acid anhydride; c) the ketone derivatives are synthesized by oxidizing 15 the secondary alcohols with known oxidizing agents such as Jones' reagent or Sarett's reagent, in an organic solvent such as acetone, chloroform or methylene chloride; and d) the halogen derivatives are prepared by reacting thionyl chloride or hydrobromic acid with the corresponding primary alcohols; the derivatives can be used in particular to synthesize amino derivatives by reaction with the corresponding amine, or imidazolyl derivatives by reaction with metallated imidazole, or to prepare certain cyano, alkoxy or alkylthio derivatives by reaction with the sodium or potassium salt of the corresponding 25 compound, or certain amino and amido acids via malonic synthesis by condensation with the previsously metallated dialkyl acetamidomalonate, or alternatively via the synthesis of phosphorus compounds by reaction with trialkyl phosphites.
16. 23. A phenylnaphthyridine compound of formula (I) according to claim 1 or process of production thereof substantially as disclosed in any of the foregoing Examples. DATED this 26th day of OCTOBER 1989 CARPIBEM sji By their Patent Attorneys GRIFFITH HACK CO. >l t V 2 1 rC~