FI59595C - FRAME FOR THE PREPARATION OF THERAPEUTIC ANALYTICAL PRODUCTS 5 ELLER 6-TRIFLUORMETHYL 3- (4-ALKYL-PIPERAS-1-YL) CARBONYLOXY-2- (1,8-NAPHTHYRIDIN-2-YL) ISOINDOLIN-1-ONER - Google Patents

Description

- [B] <11) MOON, LUTUSJULKA, SU 59595 lJ t1 '* utlAggningsskrift dy ° ° 1 C (* 5) rat :::' li My 10 ·:, · Mi w '(51) Kv. «T? /iM.a.3 C 0? D 471/04 // C 07 D 209/48 S U O M I —FI N LAN D (21) P * «* nttih * k * mui - Pittnt * n» eknln | 702699 '(22) HakMiltpllvl - AM & knlnpdac 22.09.76 (23) AlkupUvt — GlMghuttdag 22.09 * 76 (41) Tullut julklMkil - Bllvlt offwtllg 23-03-77

Patent->> Registry Offices (44) Date of publication and publication. - „ratant- och registerstyrelaen '* AmMim utkgd och utijkrift · ** puMkarad 29.05-81 (32) (33) (31) Bjrydstty« uoikaus — Mglrd prlorttuc 22.09-75

France-France (FR) 7528951 (71) Rhöne-Poulenc S.A., 2, avenue Montaigne, 75360 Paris Cedex 08,

France-France (FR) (72) Claude Cotrel, Paris, Cornel Crisan, Sceaux (Hauts-de-Seine),

Claude Jeanmart, Brunoy (Essonne), Mayer Naoum Messer, Bievres (Essonne), France-Frankrike (FR) (7 * 0 Oy Roister Ab (5M Method of ) for the preparation of carbonyloxy-2- (1,8-naphthyridin-2-yl) isoindolin-1-ones - For the preparation of carbamoyl-2- (1,8-naphthyridin-1-yl) carbonyloxy -2- (1,8-Naphthyridin-2-yl) isoindolin-1-one BE Patent 815,019 describes compounds of the general formula:

* · <LS JOO

1 1 / \

0-C0-N N - R

M 1 (O) n wherein A and represent a group CH, n is zero, X (in the 5- and 6-positions) is a group CH, X (in the 7-position) is a group CY, (in the 8-position) is a nitrogen atom.

The present invention relates to compounds of the above formula wherein Z represents the radical -CF 2. More particularly, the invention relates to a process for the preparation of therapeutically useful 5- or 6-trifluoromethyl 3- (U-alkylpiperazin-1-yl) carbonyloxy-2- (1,8-naphthyridin-2-5,59595 yl) isoindolin-1-ones of the formula is 0

O-CO-N N-R

wherein Y is a halogen atom and R is an alkyl group having 1 to 4 carbon atoms, and for the preparation of their acid addition salts.

The invention is characterized in that a) 1-chlorocarbonylpiperazine of formula

Cl-CO-B B-B (II) w wherein R is as defined above is reacted with an isoindoline derivative of the formula

-OCX

OH

wherein Y is as defined above, or h) piperazine of formula / H, NR (VIII) wherein R is as defined above is reacted with a mixed carbonate of formula CF3-F II NL Y (ix) O- CO-O-Ar! 3,59595 wherein Y is as defined above and Ar is a substituted or unsubstituted phenyl group, and that the compound obtained is, if desired, converted into an acid addition salt.

In embodiment a) the compound of general formula (II) is reacted with an early metal salt of the compound of formula (IIi), optionally prepared "in situ", using an organic anhydrous solvent such as dimethylformamide or tetrahydrofuran at a temperature below 60 ° C.

The reaction may also be carried out by reacting a salt of a compound of general formula (II), preferably the hydrochloride, with a compound of general formula (IIi) using pyridine as a solvent and optionally in the presence of a tertiary amine such as triethylamine releasing the compound of formula (II) from its salt.

An isoindoline derivative of formula (IIi) may be prepared by partial reduction of an imide of the general formula: wherein Y is as defined above.

In general, the reduction is carried out with an alkali metal borohydride using an organic solvent or an aqueous-organic solvent mixture such as dioxane-methanol or dioxane-water or ethanol-water as the solvent.

Partial reduction of a compound of formula (IV) may result in isomer products which can be separated from the mixture using physicochemical methods such as fractional crystallization or chromatography.

An imide of formula (IV) can be prepared by reacting an amino-2-naphthyridine of the general formula: wherein Y is as defined above, with an anhydride of the general formula: 11 59595 χνΛ f cf ^ -LN o (VI); o wherein the intermediate is optionally a compound of the general formula: 0 cf3_ (vii) wherein Y is as defined above.

The reaction of an amino-2-naphthyridine of formula (V) with an anhydride of formula (VI) is carried out by heating in an organic solvent such as acetic acid, dimethylformamide, acetonitrile or phenol.

The cyclization of a compound of formula (VII) to a compound of formula (IV) can be carried out either by heating with acetyl chloride in acetic acid or acetic anhydride, or with a condensing reagent such as N, N'-dicyclohexylcarbodiide in dimethylformamide at a temperature below 100 ° C.

The reaction according to embodiment h) takes place in an organic solvent such as acetonitrile at a temperature of about 20 ° C.

The mixed carbonate of formula IX can be prepared by administering chloroformate of the general formula:

Cl-CO-O-Ar (X) wherein Ar is as defined above, react with a compound of formula (III).

The reaction generally takes place in a basic organic solvent such as pyridine at a temperature of 0-20 ° C.

The novel compounds of formula (I) may optionally be purified by physical methods (such as distillation, crystallization, chromatography) or chemical methods (such as salt formation, crystallization and decomposition of this salt under temporal conditions. In this method, the nature of the anionic moiety of the salt is irrelevant; that the salt is clearly defined and easily crystallized).

The new compounds according to the invention can be converted into addition salts with acids.

5,59595

Acid addition salts can be obtained by reacting the new compounds with acids in suitable solvents. For example, alcohols, ethers, ketones or chlorinated solvents are used as organic solvents, the salt precipitates after possible concentration of the solution and is separated by filtration or decantation.

The new compounds and their acid addition salts have interesting pharmacological properties. They have proven to be particularly active as tranquilizers and anticonvulsants.

In animals (rats), they have been shown to be active at doses ranging from 0.1 to 100 mg / kg body weight, in particular in the following experiments: electric shock according to a technique similar to that used by Tedeschi and co-workers. Pharmacol., 125, 28 (1959Tj

- Convulsions induced by pentetrazole according to a technique similar to that used by Everett and Richards / j. Pharmacol., 8l, U02 (19 months) J

- Over-maximum electricity ^ okki 5 According to Svinyard and the technology of the assistants / J. Pharmacol., 106, 319 (1952) J and locomotor activity according to the technique of Courvoisier / Congres des Medecins Alienist es et Neurologistes - Tours - (8/13 June 1959 ^ 7 and Julou (Bulletin de la Soci ^ t ^ de Pharmacie de Lille, n ° 2, January 1967, page 7) ·

The new compounds are only slightly toxic, with a lethal dose of 50% (LD ^ q) generally greater than 300 mg / kg in rats.

Among the novel compounds, mention may be made in particular of 2- (7-chloro-1,8-naphthyridinyl-2) - (4-methyl-1-piperazinyl) -3-carbonyloxy-5-trifluoromethyl isoindolinone-1.

For medical purposes, the new compounds have been used either as bases or as pharmaceutically acceptable acid addition salts. ts- as non-toxic working doses.

Examples of pharmaceutically acceptable acid addition salts include mineral acid salts (such as acid chlorides, sulfates, nitrates, phosphates) or salts of organic acids (such as acetates, propionates, succinates, benzoates, fumarates, maleates, salethylates, theophylline), theophylline -γ-oxynaphthoates) or such acid substitution derivatives.

Pharmaceutical comparative tests

The anticonvulsant effect of the compound prepared according to the invention (Example 1) was compared with the corresponding effect of the compound known from Example 1 of FI 55 559 using the methodology described above, in which convulsion is induced with pentatetrazole. The results are shown in the following table.

6 59595

Compound DA50 mg / kg p.o. DA50 "« / ke Ρ'0 '0 h min 2h h

Example 1 according to the invention 0.6 1 *, 5 FI-55659 from Example 1 ^ 0.1 60 "" - 1

The following examples illustrate the invention.

Example 1

To a suspension of 1 +, 8 g of 2- (7-chloro-1,8-naphthyridin-2-yl) -3-hydroxy-O ...

5-Trifluoromethyl isoindolin-1-one in U80 cm <1> methylene chloride, 10.2 g

O O

(11 +, 2 cin) triethylamine and 66 cm of pyridine, 7.5 g of 1-chlorocarbonyl-1 + -methylpiperazine hydrochloride are added at 20-21 ° C. After 5 h, an additional 7.6 g of 1-chlorocarbonyl-H-methylpiperazine hydrochloride are added. Stirring is continued for 15 h

O

then hydrolyzed with U80 cm of water. The organic phase is separated by decantation. . .

the club and the aqueous phase are extracted with 300 cm of methylene chloride. The organic phases are combined, washed with 150 cm of water and dried over 15 g of anhydrous sodium sulphate.

O

After filtration and evaporation to dryness, the residue (9.5 g) is treated with 100 cm 3 of water. After filtration, the product is washed with 60 cm of water and recrystallized from 3 3 1 * 2 cm of dichloroethane. The dry precipitate is stirred for 1 h in 37 cm of water, filtered, washed and dried. 3.2 g of 2- (7-chloro-1,8-naphthyridin-2-yl) (U-methyl-1-piperazinyl) -3-carbonyloxy-5-trifluoromethyl-isoindolin-1-one are thus obtained, m.p. is 222 ° C.

2- (7-Chloro-1,8-naphthyridin-2-yl) -3-hydroxy-5-trifluoromethyl-isoindolin-1-one and its isomer 2- (7'-chloro-1,8-naphthyridin-2-yl) - 3-Hydroxy-6-trifluoromethyl-isoindolin-1-one can be prepared as follows: to a suspension of 83.6 g of 5N-trifluoromethyl (7-chloro-1,8-naphthyridin-2-yl) phthalimide 1 + 20 cni in methanol and 1 + 20 cm -1 of dioxane, 12 g of potassium borohydride are added at 15-18 ° C. Stir for an additional 2 h, then cool.

O

externally in an ice bath. The precipitate is filtered off, washed with 1 + 0 cm of a mixture of methanol and dioxane (1/1 by volume). The precipitate is filtered off, dried and stirred for 30 minutes in 200 cm of the same mixture, then the precipitate is filtered off, heated to reflux 3. ......

In 200 cm of ethanol. After cooling and filtration of the suspension, 21.9 g of 2- (7-chloro-1,8-naphthyridin-2-yl) -3-hydroxy-5-trifluoromethyl-isoindolin-1-one are obtained, m.p. is 300 ° C.

The solution obtained from the reaction mixture after filtration and the washing of the methanol-dioxane mixture is combined. Add 2500 cm of water. The precipitate formed is filtered off, washed with 600 cm of water and recrystallized twice from methanol-dioxane (1/1 by volume). There are thus obtained 153 g of 2- (7-7,59595 chloro-1,8-naphthyridin-2-yl) -3-hydroxy-6-trifluoromethyl-isoindolin-1-one, m.p. is 265 ° C.

5N-Trifluoromethyl-2- (7-chloro-1,8-naphthyridin-2-yl) phthalimide can be prepared as follows: 73.5 g of trifluoromethylphthalic anhydride, 50.2 g of N-hydroxysuccinimide and 1500 cm -1 of dimethylformamide are heated 18 h at 75-78 ° C. Then 6.1 g of 2-amino-7-chloro-1,8-naphthyridine and 11 + 0 g of N, N-dicyclohexylcarbodiimide are added, followed by heating at the same temperature for 3 h. After cooling, the precipitate 3 3 is filtered off, washed with 100 cm of dimethylformamide and then with 200 cm of isopropyl oxide.

3

Add 1500 cm of water to the reaction mixture. The precipitate that forms is separated. .. 3 ....

by filtration and washed with 1500 cm of methylene chloride. The insoluble matter is filtered off, then the filtrate is evaporated to dryness. 83.6 g of 5N-trifluoromethyl (7-chloro-1,8-naphthyridin-2-yl) phthalimide are thus obtained, m.p. is 265 ° C.

U-trifluoromethylphthalic anhydride can be prepared as follows:

O

106.6 g of U-trifluoromethylphthalic acid and 215 cm -1 of acetic anhydride are heated under reflux for 30 minutes. After concentration at reduced

O

under pressure (30 mm of mercury) »the residue is stirred with k20 cnr of cyclohexane. After filtration and drying, 73.5 g of N-trifluoromethylphthalic anhydride are obtained, melting at 5 ° C.

U-Trifluoromethylphthalic acid can be prepared as follows: 102.3 g of 2-cyano-β-trifluoromethyl methyl benzoate, 108 g of solid • · 3 · 3.

sodium hydroxide, 900 cm of water and 1900 cm of methanol are heated under reflux for 12 h. The solution is decolorized with 0.6 g of activated carbon. filtration

O

then 100 cm of hydrochloric acid (d = 1.19) are added. Extract with 2.25 l of ethyl ether. The organic phase is dried over anhydrous magnesium sulfate. After filtration and concentration, 99.1 g of U-trifluoromethylphthalic acid are obtained, m.p. is 178 ° C.

2-Cyano-U-trifluoromethyl methyl benzoate is suspended in a mixture of

O O

is 1.3 kg of ice, 730 cm of water and 171.5 cm of hydrochloric acid (d = 1.19). The resulting solution

O

A solution of 9.9 g of sodium nitrite in 172 cin of water is added in one portion. Stir for 2 1/2 h at 0-1 ° C. The reaction mixture is filtered and then added dropwise to a solution maintained at U-5 ° C with 226 g of copper sulphate, five g of potassium cyanide in 1320 g of water, a solution prepared according to Gabriel, Ber., 52, 1089 (1919). J> Km of diazo compound addition takes place to maintain the pH

6-7 by adding 10% sodium carbonate solution. Continue stirring, allowing the temperature to rise to 20 ° C. Extract with 3 L of ether. The ether layer is washed with 3,150 cm of water, then dried over 30 kg of anhydrous magnesium sulfate. After filtration and concentration, 9.9 g of 2-cyano-β-trifluoromethylmethyl benzoate with a melting point of 52 [deg.] C. are obtained.

β 59595 2-Amino-U-trifluoromethyl methyl benzoate can be prepared as follows: 1 L, 2 g of 2-amino-U-trifluoromethylbenzoic acid, 1.51 L of methanol and 506 cm 2 of boron trifluoride ether are heated at reflux for 99 h. The solution obtained is added to 350 g of sodium carbonate in 2.8 kg of ice water. Stir for 15 minutes, then extract with 3 l of ethyl ether. The ether layer is washed with 25 cm of water, dried over 30 g of anhydrous magnesium sulfate. After filtration and concentration, 137 g of 2-amino-1-trifluoromethylmethylbenzoate are obtained, m.p. is 6U ° C.

2-Amino-U-trifluoromethylbenzoic acid can be prepared according to Hauptschein and co-workers. J. Amer .Chan.Soc. 76, 1051, (195 * 0.

Example 2

Proceeding as in Example 1, but starting from U, 8 g of 2- (7-chloro-1,8-naphthyridin-2-yl) -3-hydroxy-6-trifluoromethyl-isoindolin-1-one, 15, 1 g of 9-chloro-

O

carbonyl * - »methylpiperazine 1 *, 3 cm (10.2 g) of triethylamine and 3 3 66 cm of pyridine in 250 g of methylene chloride give 7.8 g of crude product, 3 3 which is treated with 50 cm of water. After recrystallization from 2 ** 0 cm of isopropanol, U.7 g of 2- (7-chloro-1,8-naphthyridin-2-yl) -U-methyl-1-piperazin-1-yl-3-carbonyloxy- 6-trifluoromethyl-isoindolin-1-one, m.p. is 219 ° C.

2- (7-Chloro-1,8-naphthyridin-2-yl) -3-hydroxy-6-trifluoromethyl-isoindolin-1-one can be prepared as described in Example 1.

Example 3

To a suspension of 2 g of 2- (7-chloro-1,8-naphthyridin-2-yl) -5-trifluoro-3-methyl-3-phenoxycarbonyloxy-isoindolin-1-one in 280 cm of acetonitrile is added about At 20 ° C 8.5 cm -1 N-methylpiperazine. The reaction mixture is stirred for 3 hours at 20-21 ° C, the reaction mixture is diluted with 1000 cm of water and extracted with 3. ...

With 1100 cm of ethyl ether. The extract is dried over 100 g of anhydrous potassium carbonate, filtered and the solvent is evaporated off under reduced pressure (20 mm Hg) at a temperature in the region of 30 ° C. The residue is recrystallized from 70 sows of boiling acetonitrile. 9.2 g of 2- {7-chloro-1,8-naphthyridin-2-yl-3- (U-methylpiperazinyl) carbonyloxy-5-trifluoromethylisoindolin-1-one are obtained, m.p. 219-221 ° C.

2- (7-Chloro-1,8-naphthyridin-2-yl) -3-phenoxycarbonyloxy-5-trifluoromethyl-isoindolin-1-one can be prepared as follows:

To a suspension of 11.2 g of 2- (7-chloro-1,8-naphthyridin-2-yl-3-hydroxy-5-

O

trifluoromethyl-isoindolin-1-one in 100 cm of pyridine, 10 g of phenyl chloroformate are added over a period of 2 k, keeping the temperature at about 18 ° C. Reaction 3 ......

the mixture is stirred for 30 minutes, then the reaction mixture is poured into 720 cm3 of ice.

3 .....

The precipitate is centrifuged and washed as filter with 250 cm of water. 15 g of 2- (7-chloro-1,8-naphthyridin-2-yl) -3-phenoxycarbonyloxy-5-trifluoromethyl-isoindolin-1-one are obtained, m.p. 2LL * -2l6 ° C.

Claims (2)

59595 Patents: Process for the preparation of therapeutically useful 5- or 6-trifluoromethyl 3- (4-alkylpiperazin-1-yl) -carbonyloxy-2- (1,8-naphthyridin-2-yl) isoindolin-1-ones, of the formula 1 (i> T y - \-O-CO-M ^ ^ KR wherein R is a halogen atom and R is an alkyl group having 1 to 4 carbon atoms, and for the preparation of their acid addition salts, characterized in that a) 1-chlorocarbonylpiperazine of the formula / ~ λ C1-C0-N NR (II) wherein R is as defined above is reacted with an isoindoline derivative of formula I II (m) CP, - N-X and Y where Y is as defined above, or b ) piperazine of the formula m / l -r (viii) v_y wherein R is as defined above is reacted with a mixed carbonate of the formula 10 59595 O CF 3 -Y (IX) O-CO-O-Ar where Y is the same , as above and Ar is a substituted or unsubstituted phenyl group, and that the compound obtained is, if desired, converted into an acid addition salt. and 59595 For the preparation of therapeutically active compounds 5 or 6 trifluoromethyl-3- (k-alkylpeperazin-1-yl) -carbonyloxy-2- (1,1-naphthyridin-2-yl) isoindolin-1-one with the formula CF- - I _I J_Y (I) -Y o-co-t / NR color Y is a halogen atom and R is an alkyl group having 1 to 4 cholaters, and a derivative having the same solvent, with the addition of 1-chlorocarbonylpiperazine with a formulation / - \ C1-C0-H ^ ya-R (II) color R har ovan angiven betydelse, omsättes med ett isoindolinderivat med formeln ° f3 — Ol? —C jC'D— y (m) 1Γ OH color Y heir ονειη angiven betydelse , or b) in piperazine with the formulation / \ HN NR (VIII) V_ / color R is an angular betydelse, omsättes med ett blandcarbonat med formuleln 0 • rOr ^ -XTX 0-CO-O A. R