AP282A

AP282A - Novel derivatives of (p. substituted phenyl) oxybutane amines, their processes of production and the pharmaceutical compositions containing them.

Info

Publication number: AP282A
Application number: APAP/P/1991/000328A
Authority: AP
Inventors: Paule Bonnet; Remi Delansorne; Maurice Faure; Michel Lanquetin; Serge Zunino
Original assignee: Laboratoire Theramex
Priority date: 1990-10-17
Filing date: 1991-10-17
Publication date: 1993-09-08
Also published as: AP9100328A0; BG60680B1; ZA918282B; RO108241B1; FR2670783A1; FR2670783B1; BR9106188A; OA09835A; HU9202176D0; MA22321A1; IL99776A0; CZ182292A3; PL169022B1; FR2668150B1; IE913636A1; WO1992006977A1; HUT61297A; KR927003589A; NO922358D0; EP0505543A1

Abstract

This invention relates to novel derivatives of phenyloxy butanes carrying in position 1 an amino group, processes for their production and pharmaceutical compositions containing them as active ingredients.

Description

NOVEL DERIVATIVES OF (p.SUBSTITUTED PHENYL) OKYBUTANE AMINES, THEIR PROCESSES OF PRODUCTION

AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

This invention relates to novel derivatives of phenyloxy butanes carrying in position 1 an amino group, the processes for their production and the pharmaceutical conqpositions containing them as active ingredients.

The present invention more particularly relates to novel derivatives of phenyl butane, the butane side-chain of them carrying in position 1 an amino cyclic chain.

This invention specifically relates to novel derivatives of

4-(Rj-phenyl) 4-oxy 1-aminobutanes of general formula I (I) wherein R_g is selected from the group consisting of HOH, -0 and

O-tetrahydropyranyl

X is a substituent selected from the group consisting of >N- and >CH-NH and R is a cyclic substituent selected from the group consisting of

a) a Xanthic derivative of the formula wherein and Rj, the same or different, are a hydrogen or a lower alkyl radical having from 1 to 5 carbon atoms in straight or branched chain and Rj is a alkylated derivative selected from the group consisting of a halogenobenzyl group of the formula wherein Z is a halogen atom and an athoxyethyl radical (C^ 0 CjH^)

b) a benzimidazolic derivative of the fonmila

wherein R₄ is a hydrogen or a halogen and R^ is a halogenobenzyl group wherein Z is a halogen or an ethoxyethyl radical.

Among the confounds of general formula I it may be cited the following sub-group :

1. the compounds of general formula I_A wherein R is a Xanthyl group, selected from the group consisting of piperazinyl xanthines of general formula l_A,

AP Ο Ο Ο 2 8 2

wherein R is a Xanthyl group defined as previously and Rg and R? have the above-given definitions and the piperidyl amino xanthines of general formula l_A„

wherein R is a Xanthyl group defined as previously and Rg and R? have the above-given definition.

2. The compounds of general formula I& wherein R is a benzimidazolic group selected from the group consisting of piperazinyl benzimidazoles of general formula Ι_β,

wherein R^, Rg, Rg and R? have the above-given definitions and the piperidylamino benzimidazoles of formula Ι_β„

Among these compounds of formula I the most preferred ones are those for which R? is a terbutyl radical and namely the compounds of general formula wherein R is a benzimidazolic group such as the piperazinyl benzimidazoles of formula I_n, o⁹

wherein R^ and R$ are defined as previously-indicated and the piperazinyl benzimidazoles of formula l_„ o

wherein R^ and Rg have the previously-given definition

Generally-speaking the presently preferred compounds are further those for which Rg is a fluorobenzyl radical and Rg is a hydroxy radical.

This invention also relates to the acid addition salts of a compound of formula I with a mineral or organic acid, preferably a therapeutically-compatible acid.

AP000282

Those which cannot be used in therapy such as the iodates, periodates, reineckates or picrates are utilized as means for isolating, purifying or caracterizing these compound.

Moreover the compounds of general formula I include at least one Η H asymetric carbon when Rg is — or-OH O-tetrahydropyranyl and consequently may be resolved into their optical isomers, namely by salification using a chiral acid such as d-camphosulphonic acid, d-dibenzoyltartaric acid, d-NN-diethyltartramic acid, d-glucose 1-phosphoric acid.

The compounds of general formula I may also-when R_fi is HOH or ^H °

O-tetrahydropyranyl be resolved into their optically-active isomers by acylating first by means of an optically-active acid such as 1-menthoxy acetic acid then with mild saponification. It is further possible to resolve these esters by enzymatic hydrolysis or through chromatography on a column loaded with a chiral carrier.

The present invention further relates to a process for producing the compounds of formula I which consists in that

- for the Xanthic derivatives of formula I, a halogeno xanthine of formula II

Hal :id wherein and R2 are defined as previously given and Hal is a chlorine or bromine is let to react with a halogenated derivative selected from the group consisting of a benzylic halide having the formula III

ΖΛ (ΠΙ) and an ethoxyethyl halide of formula III'

CH₃ CHj 0 CH2 CH₂ Hal (III') wherein Hal means a chlorine or bromine and z is a halogen atom to obtain a Xanthic derivative of general formula IV

wherein R^, Rj and Rg are defined as previously-given then reacts the latter with a 4-(4-R₇~phenyl) 4-oxy 1-aminobutyl derivative of general formula V

wherein X is defined as above-given

R is a Xanthyl group and Rg and R^ have the above-given definitions to produce a compound of formula I_A„ when X is equal to >N- and R to Xanthyl, the compounds of formula

AP Ο Ο Ο 2 8 2

- 7 Ι_Α, may further be produced by condensing a 4-halogeno l-(Ry-phenyl) butyl derivative of general formula VI

Or (VI) (CH₂) 3- Hal wherein Rg and R? have the above-given definitions and Hal is a bromine or chlorine with a N-Xanthyl piperazine of formula VII

(VII) wherein R^, R2, R^ have the above-given definitions.

This reaction is preferably performed in a solvent selected from the cyclic ethers and the alkanols having up to 3 carbon atoms in straight or branched chain, at the reflux temperature of the selected solvent (ether or alkanol) for 2 to 12 hours. A compound of formula I_A, is thus obtained

(I, wherein R^, Rj, R^, Rg and R? have the above-given definitions.

When X is equal to >CH—NH—, the corresponding compound of formula V is prepared by condensing a derivative of general formula VI as (VIII) defined as previously with a 4-oximino piperidine of formula VIII

This reaction preferably is carried out in a solvent selected among the alkanols having up to3 carbon atoms in straight or branched chain, in the presence of an alkaline agent such as an alkali metal carbonate, at the reflux temperature of the selected alkanol for 8 to 12 hours.

A derivative of formula IX is- thus obtained

wherein has the above-given meanings and R_g is a hydroxyl

Ihe oximino derivative IX is further reduced into a primary amine in a medium consisting of an alkanol having up to 3 carbon atoms in straight or branched chain by means of an alkali metal at a temperature selected from 20° and the reflux temperature of the alkanol during from 2 to 12 hours depending on the used temperature.

The aminated derivative of formula X is thus obtained

AP 0OO282 wherein R? has the above-given definition which is condensed with a compound of general formula IV to produce a compound of formula I_A„

R

wherein R^, Rj, Rg and R? have the above-given definitions

This reaction is preferably performed in a solvent selected from the alkanols having from 1 to 5 carbon atoms in straight or branched chain and the polar solvents in the presence of an alkaline agent, an alkali metal carbonate, an earth-alkali metal carbonate, and in the presence of a catalyst such as an alkali-metal iodide. The carbonates may be those of calcium, sodium or potassium. The reaction is carried out at the reflux of the selected solvent, for a set of time which may range from 4 to 30 hours depending on the experimental conditions.

They are thus obtained the derivative of general formula I_Awherein the cyclic amino group is a Xanthyl piperidyl amino or piperazinyl grouping. They may be further converted into the corresponding ketones (Rg - 0) by means of a metallic oxydizing agent.

These new compounds corresponding to the general formula I_A, and I_A„ which have thus been produced may be salified by adding a mineral or organic acid, preferably therapeutically-compatible acids, to obtain the corresponding acid addition salts. These salts also are part of the present invention.

Mainly as acids which may be used for forming the acid addition salts, it may be cited as an example, the hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, propionic, maleic,

- 10 furwric, citric, benzoic and methane sulphonic acids.

These new compounds of general formula I_A are purified, vhen and if necessary, by means of physical or chemical methods such by recrystallisation or by chromatography.

These compounds have been identified and controlled for the purpose of pharmacological studies, by means of known analysis methods such as elementar analysis infra-red spectrophotometry, ultra-violet spectrophotometry, Nuclear Magnetic resonance (NMR), or high performance liquid chromatography (HPLC).

When R is a benzimidazolyl group, the compounds of general formula I in which R is the said benzimidazolyl group and X is an amino >N- group, are produced by condensing an halogenated benzimidazole of general formula XI

wherein R₄ is defined as above-given and Hal means a chlorine or bromine atom with a halogenated derivative selected from the group consisting of benzylic derivatives of formula III

CH2 ~ Hal (III) and ethoxyethyl halides of formula III'

CH₃ CH₂ OCH₂ CH₂ Hal (III')

AP Ο Ο Ο 2 8 2

- 11 wherein Hal means a chlorine or bromine and Z is a halogen atom to produce a halogenated benzimidazole having the general formula XII

wherein R^ and Hal have the above-given definitions and preferably is chlorine or bromine

The compound of formula XII is reacted with piperazine in a medium consisting of a solvent selected among the aromatic hydrocarbons and the substituted aromatic hydrocarbons. The preferred solvents are benzene, toluene and the xylenes. It may be of advantage to perform the reaction at a temperature ranging between 40°C and the boiling point of the solvent for a set ranging from 4 to 24 hours, depending on the used temperature.

I

Λ wherein R^ means hydrogen or a halogen and R^ has the previously-given meanings which is reacted with a 4-halogeno l-(4-R₇-phenyl) butane of formula VI

- 12 wherein Hal means a chlorine or bromine and Rg and have the above-given definitions to produce a compound having the general formula I

B^r

wherein R^, Rg, Rg and R? are defined as above-given.

The benzimidazolic compounds of general formula Ι_βη are produced according to the method which consists in reacting a o.nitroaniline of formula

with a halogenated derivative selected from the group consisting of a halogenated benzylic derivative of formula III d tvQ/ j and ethoxyethyl halides of formula III'

Hal CHj CH₂ OCH₂ CH₃ (III') wherein Z has the above-given meaning and Hal is a chlorine or a bromine to produce an o.nitroaniline of the formula

AP Ο Ο Ο 2 8 2

wherein and Rg have the above-given definitions

- reducing the nitro group by catalytic hydrogenation in the presence of a palladium catalyst to produce the corresponding amine of formula XVI

wherein R₄ and Rg have the above-given definitions

- reacting a compound of formula X with dihydropyran in acidic medium to obtain a tetrahydropyran derivative of formula XIV

CH-/ Vr₇.

(xiv) wherein R^ has the above-given definitions

- reacting the said compound of formula XIV with carbon sulfide in basic medium to obtain the thiocyanate of formula XV

wherein Ry has the above-given definitions

- condensing the o.phenylene diamine of formula XVI with the thiocyanate of formula XV to produce a thiourea of formula XVII

(XVZZ) wherein R₄, Rg and Ry have the above-given definitions

- cyclizing the thus formed thiourea XVII in the presence of a desulphurizing agent in an aromatic hydrocarbon, to produce a benzimidazolic derivative of formula XVIII

wherein R^, Rg and Ry have the above-given definitions

- hydrolyzing in acidic medium the tetrahydropyranyl ether under mild conditions to obtain a benzimidazolic derivative of formula

AP Ο Ο Ο 2 8 2

- 15 Ι_β„ wherein X - >C-NH

wherein R^, R^ and R^ have the above-given definitions which may be oxydized into a ketonic derivative by means of a metallic oxydizing reagent or salified by adding a mineral or organic acid or purified using the same methods as above or identified and controlled for the purpose of pharmacological studies using the same techniques as previously described.

The compounds of formula I are endowed with interesting pharmacological properties namely anti-histaminio and anti-allergic properties. Particularly the compounds of general formula Ig in which R is a benzimidazole ring and their acid addition salts with a mineral or organic therapeutically tolerable acid, show anti-histaminic properties by action on the Hj-receptors which are of the same type than that encountered with ASTEMIZOLE.

Ihe compounds of formula I find hence a use in therapy mainly in the allergic states and in the treatment of asthma in human and animals.

This invention also relates to pharmaceutical compositions including as active ingredient at least one derivative of general formula I or a physiologically tolerable acid addition salt thereof, in admixture or conjunction with suitable pharmaceut ical carrier or vehicle.

The thus defined pharmaceutical compositions are advantageously offered in the various forms suitable for the oral, sublingual,

- 16 parenteral, pemasal, ophtalmic, rectal ways of administration such as the tablets, dragees, capsules, soft gelatine capsules, sprays aerosols, suppositories, injectible solutions or suspensions and the like.

The unit dosology may range from 1 to 20 mg per unit dosage. The daily dosage will vary between 1 and 100 mg in the adult man.

The following examples are given as illustration of the invention and do not limit it.

The melting points -unless the contrary is mentionned- have been determined using a Mettler apparatus. Ihe infra-red spectrums are determined with Perkin Elmer · spectrophotometer 1600 serial FTIR. ihe UV spectrums are measured using a kontron spectrophotometer type UVIKON 860. Ihe determination by HPLC have been performed with a waters apparatus type 600 E filted with an integrator APC 4.

EXAMPLE I

1,3-dimethyl 7-(4-fluorobenzyl) 8-[l-(4-tertbutylphenyl)

4-hydroxybutyl 4-piperidyl amino] Xanthine (I_A>

STEP A : 4-hydroxy iminopiperidine

46,2 g of piperidine 4-one as the hydrochloride are heated at the reflux temperature under stirring with 38,4 g hydroxylamine hydrocloride in 250 ml ethanol in the presence of 100 g sodium carbonate. After 3 hours reflux, the resulting suspension is filtered and the solid is washed four times with 100 ml boiling ethanol. The ethanolic solution is concentrated under vaccuum. The solid residue is taken up in methylene chloride, filtered on clay (Trade mark Celite' ), and concentrated anew to dryness. 34,1 g of a colourless product are obtained which melts at 117,2°C. In TLC it is mono-spot in a system formed with methanol 100/ an monia 2 on plates of silica MERCK and staining with CuCl^ninhydrin.

AP Ο Ο Ο 2 8 2

- 17 Step Β : 1-[(4-tertbutyl phenyl) 4-hydroxy 1-butyl] 4-hydroxy iminopiperidine

A mixture of 11,4 g 4-oximinopiperidine of step A, 24 g of 4-chloro 4-(4-tertbutyl phenyl) 1-butanol and 100 g sodium carbonate in 100 ml ethanol are heated at reflux for 8 hours under stirring. After this set of time the solvent is concentrated under reduced pressure. The dry residue is taken up after cooling with water to eliminate the mineral salts. The product is extracted with methylene chloride and after drying on sodium sulphate and after the solvent is eliminated in vaccuum, the product is recrystallized from isopropyl ether to recover 27 g of pure compound as colourless crystalls. Melting point 128,5-131°C

Step C : 1,3-dimethyl 7-(4-fluorobenzyl) 8-chloroxanthine

A solution of 43 g 1,3-dimethyl 8-chloro Xanthine in 200 ml water and 20 ml sodium hydroxide ION is heated tc 70-80°C to which 27,6 ml 4-f luorobenzyl chloride are portion wise added at this temperature whithin 4 hours. During this addition, 20 ml sodium hydroxide 10N are added by small portions to maintain the pH at an alkaline value. After achievement of this addition, the solution is further leated at 70-80° for 2 hours then let to revert to room temperature under stirring. The precipitate is filtered, dried, washed with water until neutral then dried. Thereafter it is recrystallised from acetone to recover 19 g of pur compound. It melts at

183-184°C.

Step D : 1-4[ (4-tertbutylphenyl) 4-hydroxy] 1-butyl 4-amino piperidine

A solution of 25, 5 g of the oxime of Step A in ethanol previously dried for a nighton a molecular sieve 4A is reduced by means of metallic sodium at the reflux when all the sodium (23,5 g) has disappeared, the reflux is maintained for a further hour then the solution is cooled under nitrogen atmospher. A solution of 57 g hydrochloric acid 4N in 200 ml water is added. Ethanol is evaporated

- 18 off at the maximum posside by destination under reduced pressure. The thus formed amine is extracted with n-butar.ol and after washing with water, concentrated to dryr.ess under vaccuum. It dry residue is taken up in methylene chloride dried cn scdium sulphate, filter and concentrated to dryness. The raw product is recrystallized from a mixture .. (ICO p) -methanol (Ip) —

13,3 g of .. compound are thus obtained. The aminoted derivaoive melts at S5,2’C.

A mixture of 32 1,3—dime thyl Xan thine,

Step Ξ : 1,3-dimethyl 7-(4-fucrccenzyl) 8-[1-(4-tertbutyl phenyl) 4-hydrcxyfcutyl-4 piperidyl) amino] Xabtgine (1,,,)

Λ

8-chloro 7-(4-fluorccenzyl) Ιό g sodium icdice, 30 g

1--( 4-tertbutyl phenyl) 4-hydrcxy]butyl-4 • · * piperidine, 12 g sodium carbonate in 200 ml formamide is heated at the reflux under atmcspher for 24 hours.

After cooling, the suspension is pcwred into 800 ml cold water, the precipitate is filtered and dried then washed until neutral. The raw product is purified by chromatography cn alumina column washing with hexane then writh isccrcpyl ether and finalled with acetone. After having concentrated the acetcnic phase, 17,6 g of solid product are recovered and further recrystallised from a mixture of hexane (3p) and acetone (lp)

Melting point : 95³C dimethyl nitrogen

Analysis

C·,- K,, N, O, F 3j 43 o 3

Theorem!Found

C

67. CS 57.10 c

7.03

7.27

N

14.22

14.03

F%

3.22

3.13

UV Spectrum (MeCH, λ max in nm : 296 and 216.2

IR Spectrum (3rK) in cm^-1 : 1224, 1625, 1640, 1695, 3330, 3400 NMR ^(H] Spectrum in CDCl^ : (internal ref. IMS , i in ppm) :

1,3 (s, 9H of tertbutyl)

3,38 (s, 3H of N-CH₃) ____

_bM3 OfMG^,t)WAP Ο Ο Ο 2 8 2

- 19 3,52 (s, 3Η of N-CH₃)

4,60 (td, 1H CH-O)

- 7,40 (m, 8H aromatics)

Hydrochloride : MP - 167 - 169°

Fumarate : MP - 179°

EXAMPLE 2

1,3-dimethy1 7-(4-fluorobenzyl) 8-[4-(4-tertbutylphenyl)

4-hydroxybuty1) piperazinyl] Xanthine (IA')

Step A : 1-((4-tertbutylphenyl) 4-hydroxy] butyl piperazine

6,36 g piperazine as the anhydrous base are dissolved in 19 ml ethanol at 20°C. When the whole piperazine is dissolved, 8,90 g of 4-chloro 1-(4-(tertbutylphenyl)J

1-butanol are added at once.

The mixture is heated to 80°C for 6 hours then let to revert at 20°C and the reaction mixture is extracted with isopropyl ether. The raw production is thereafter recrystallized from ethyl acetate. 6 g of pur compound are recovered

MP - 114-115’C

Step B : 1,3-dime thyl 7-( 4-fluorobenzyl) 8-(4-(4-tertbutyl phenyl) 4-hydroxy)butyl piperazinyl] Xanthine A mixture of 16,53 g 7-(4-fluorobenzyl) 8-chloro

1,3-dimethylxanthine and 14,86 g of l-(4-(4-tertbutyl phenyl) 4-hydroxy]butyl piperazine in 100 ml dry ethanol is prepared then heated to 80^eC for 9 hours. After termination of the . reaction, ethanol is concentrated under vaccuum and the resulting produit extracted with methylene chloride. After recrystallisation in 1 vol ethanol and 2 vol isopropyl ether, 6 g of pure compound are recovered

MP - 145°C

Analysis ^C32 ^H41 ^N6 °3 ^F

C

Theoretical 66.63 Found 66.24

H	N	F%
7.11	14.57	3.29
7.08	14.33	3.63

UV Spectrum (	dry	ethanol) X max in nm - 291.6	and 205.8
IR Spectrum (	KBr)	: in cm¹ : 1222, 1440, 1510,	1660, 1700, 3180
NMR Spectrum	¹[HJ	(in CDClj, intern. Ref IMS, &	in ppm) :
1,3	(s,	9H of tertbutyl)
3,35	(S,	3H, N-CH₃)
3,52	(s,	3H, N-CH₃)
4,65	(ex	. IH, -CHO)
6,9	- 7,,	40 (m, 8H aromatics)

Hydrochloride : MP - 202 - 204 *C Fumarate : MP - 88 - 89°C

EXAMPLE III

1—(4—FLUQRCBENZYL) 2-(4-( 4 -TER3BOTYLPHENYL) 4—HYDRQXYBUTTXL)

PIPERAZINO] BENZIMIDAZOLE (I®)

Step A : 2-chlorobenzimidazole

A solution of 2-hydroxy benzimidazole (40,2 g) in 93 ml phosphorus oxychloride is heated to reflux under stirring for 6 hours. After achievement the solution is let to revert to -10°C and hydrolysed with 100 g crushed ice 100 ml iced water. They are slowly added 249 ml sodium hydroxide 10N to get a neutral pH value. The precipitated product is filtered, washed with the minimal amount of water. The crystalls are taken up in hot ethanol. After cooling, the alcoholic juices are filtered and concentrated to dryness.

Step B : 2-chloro 1-(4-fluorobenzyl) benzimidazole.

g 2-chlorobenzimidazole are dissolved in 74 ml and 17,35 ml sodium hydroxide at 30%. The mixture is heated to 82°C and to this they are slowly added 23.76 g 4-fluorobenzyl chloride within 5 hours. When the reaction is achieved, the solution is cooled to 20°C and extracted with methylene chloride. The compound is recrystallised from ethyl acetate.

Step C : 1-(4-fluorobenzyl) 2-piperazinyl benzimidazole

In 168 ml xylene 40.8 g anhydrous piperazine and 60 g

AP Ο Ο Ο 2 8 2

- 21 2-chloro (4-fluorobenzyl) benzimidazole are added. The mixture is heated to 80’C for 10 hours. When the reaction is no longer evoluting, the temperature is reverted to 20°C and the pH value is adjusted to 2 with an aqueous solution of hydrochloric acid at 30% the organic solution is washed with water then the pH isincreased to pH 11 with sodium carbonate. The compound is extracted with isopropyl ether. Finally 46 g pure compound are recovered.

Step D : 1-( 4-fluorobenzyl) 2-[4-(4-tertbutylphenyl)

4-hydroxybutyl)piperazino] benzimidazole In 80 ml n-butanol. they are added 28.45 g 2-chloro

1-(4-fluorobenzyl) benzimidazole, 9.7 g sodium carbonate, 13.66 g sodium iodide and 30 g 4-chloro l-(4-tertbutyl phenyl) 1-tetrahydropyranyloxy butane. The solution is heated to 100^eC for 16 hours. When the reaction is achieved the compound is extracted with iospropyl ether ; the organic phase is washed to neutral then concentrated to dryness. The alcoholic function is released by hydrolysis with a solution of by diochloric acid at 0,6% for 45 mn. The compound is anew extracted with ether, neutralized with sodium carbonate and recrystallised from isopropyl ether with a minimal amount of ethanol. They are finally obtained 19.90 g of pure compound melting at 179,2°C.

Analysis Cj₂ Hj₉ 0 F

	c	H	N	F%
Theoretical	74.70	7.58	10.89	3.60
Found	73.57	7.73	10.71	3.66
UV Spectrum	(MeOH) λ max	in nm	: 285,6 -	248,8 - 213
IR Spectrum	(KBr) in cm^-1	: 954,	1080, 1129, 1609, 3222
NMR Spectrum	¹[H] (CDC1,,	IMS as	internal	ref. 6 in ppm)
13	(s, 9H, tertbutyl)

4,65 (td, lH, -CHO-)

5,15 (s, 2H, CHj benzylic)

- 22 6,9 - 7,65 (m, 12H aromatic)

Hydrochloride : MP - 173 - 175,5^eC Fumarate : MP - 196 - 197^eC

EXAMPLE IV

1-( 4—FLUOROBENZYL) 2-[ (TERTBUTYLPHENYL) 4-HYDROXYBOTYL)

4-PIPERIDYL) AMINO] BENZIMIDAZOLE (IB)

Step A : 1-chloro (4-tertbutylphenyl) butanol

200 g 1-chloro (4-tertbutylphenyl) 3-butanone are dissolved in 1680 ml methanol the a solution of 16,78 g sodium borohydride in 151 ml water and 1,31 g sodium hydroxide are added thereto within 30 mn. The temperature of the reaction mixture is Kept between 10 and 20°C during addition of sodium borohydride. It is kept under stirring for 5 hours then the methanolic solution is concentrated under vaccuum. The medium is extracted with isopropyl ether and the compound is recrystallised from 2 vol hexane. 183 g of pure compound are recovered. Its melting point is 50.9 - 51.3°C.

Step B : 1-chloro 1-(4-tertbutylphenyl) 4-tetrahydropyranyloxy butane.

In 8.7 ml dihydropyran they are added 10 mg p.toluene sulphonic acid (APTS). To this mixture they are added within 30 mn at 60^eC, 20 g 1-chloro (4-tertbutylphenyl) butanol. After this addition the mixture is stell heated at between 60 and 65^eC for 30 mn and kept under stirring for further 90 mn. 0.5 g sodium bicarbonate is thereafter added. The mixture is then stirred for 1 hour. The tetrahydropyranylated derivative is directly used without any further purification.

Step C : N-(4-fluorobenzyl) phenylene diamine g N-(4-fluorobenzyl) 2-nitroaniline are reduced in the presence of 34 g of 5% pal1adized charcoal into methanol (560 ml) using a stream of hydrogen at room temperature and normal pression. After achievemed of the reaction, the mixture is washed with nitrogen, filtered on day

AP Ο Ο Ο 2 8 2

- 23 (Trade Mark Celite) and concentrated to dryness. Hie residue is recrystallised from isopropyl ether. The desired N-substituted phenylene diamine is thus obtained recovered Weight : 38.5 g

Ihe starting material N-(4-fluorobenzyl) 2-nitroaniline is prepared by alkylating the 2-nitroaniline by means of 4-f luorobenzyl chloride in the methyl ethyl ketone.

Step D : 1—[ (4-te rttutyl phenyl) 4-tetrahydropyranyl butyl] 4-hydroxyiminopiperidine.

58,4 g of 1-chloro l-(4-tertbutylphenyl)

1-tetrahydropyranyloxy butane in 200 ml ethanol are heated to reflux under stirring with 20g 4-hydroxyimino piperidine and 20 g sodium carbonate. After 20 hours reflux, the solution is concentrated to dryness then take up with water, extracted with dried methylene chloride and concentrated to dryness under vaccuum. 70.5 g of pure compound are thus produced. It is recrystallised from methhanol to recover 40 g of a solid having a melting point of 150 - 151’C.

Step E : 1—[ (4-tertbutylphenyl) 4-tetrahydropyranyloxy butyl] 4-amino piperidine

In a 1 1 reactor a solution of the corresponding oxime (35 g in 235 ml ethanol) is heated to reflux with 25.5 g sodium for reduction during 1 hour. After complete disappearance of the sodium the whole mixture is heated to reflux for b hour then cooled under nitrogen, They is introduced in the medium under stirring a solution of 60 g ammonium chloride in 250 ml water. It is extracted with isopropyl ether, the organic phase is wash with water, dried on sodium sulphate then concentrated to dryness. Hie residue is purified by recrystallisation from methanol to eliminate the starting oxime, not yet reduced optionnaly present. The raw amine after concentration of the methanol, is purified by passing through a column filled with silica dispersed with hexane then eluted with methanol and the eluate is concentrated to dryness. 25 g of a compound are recovered as a thick oil.

- 24 Step F : l-[(4-tertbutylphenyl) 4-tetrahydropyranyl oxybutyl] i sothi ocyanatopipe ridine

In a 250 ml reactor they are put together 10 ml ION sodium hydroxide and 50 ml water then after cooling to 5®C, they are added 6 ml carbon sulphide. A solution of

19.5 g of the amine of the preceding step E in 100 ml water and acetic is intra..duced thereto within 1 hour between O and 10°C and the pH value is adjusted to 7-8. The is stirred for further 2 hours between O and 10°C. The disappearance of the amine is followed through TLC in a mixture of CHCl^/ethanol (7:3). The mixture is warmed to 20°C and to the latter 10 ml ethyl chlorocarbonate are poured dropwise without passing 30*C withing 3/4 hour. The whole mixture is hjeated for 2-3 hours at 50-60’C on the water bath unter termination of the staining into brown of a paper impregnated with lead acetate.

(TLC on SiO2 with cyclohexane 3-ethyl acetate 7). After cooling the solution is extracted with methylene chloride, washed, dried and concentrated to dryness. The product is purified ona column of silica dispersed with hexane and elution by a mixture cyclohexane-5 ethyl acetate 3. 15,3 g of a viscous product are thus obtained.

Step G : N—( 1-(4-tertbutylphenyl) 4-tetrahydropyranyl piperidinyl oxybutyl) N-(2-(4-fluorobenzyl) amino phenyl] Thio Urea In 150 ml methanol they are added 25,4 g

1-(4-tertbutylphenyl) 4-tetrahydropyranyl oxybutyl 4-isocyanatopiperidine and 18,3 g N-(4-fluorobenzyl)

1,2-phenylene diamine and this mixture is for 24 hours. It is thereafter concentrated to dryness under vaccuum and the residue is passed through a column filled with silica dispersed with cyclohexane, to eliminate the excess of aromatic amine.The resulting thiourea is extracted with ethyl acetate. 33 g of on oily compound are thus obtained.

Step H : 1-(4-fluorobenzyl) 2-4-tertbutylphenyl) 4-hydroxybutyl piperidinyl amino] benzimidazole

AP Ο Ο Ο 2 8 2

- 25 They are heatd to reflux into 200 ml benzene, 33 g of the thiourea obtained in the step G, together with 16 g di cyclohexyl carbodiimide for 5 hours. After achievemed of the reaction, it is cooled, washed with water then with an aqueous solution of sodium carbonate and further with water. It is dried and concentrated to dryness under vaccuum, the residue is taken up with 100 ml methanol and 20 ml water then the pH value is adjusted to 1 with concentrated hydrochloric acid. The end of the reaction is followed by TLC on silica plates with chloroform 7 ethanol 3 (revelation UV and Iodoplatinate). It is neutralized after dilution with water using sodium carbonate then sodium hydroxide to reach a pH value of

12. It is extracted with methyle chloride, the organic solution is washed with water, dried, filtered and concentrated to dryness. 37 g of raw product are proced which are washed with isopropyl ethyl and 24 g of the pure compound are obtained. The product is recrystallised from ethyl acetate containing a little methanol.

MP - 164.8 - 165.2°C

Analysis ^C33 ^H41 ^N4 ^{0 F}

C

Theoretical 74.96 FOUND 73.80

H	N	F%
7.82	10.60	3.59
7.80	10.30	3.50

UV Spectrum (MeOH) λ max nm i 286,2 - 249,4 - 218,4 IR Spectrum (KBr) in cm¹ : 1087, 1227, 1570, 1616, 3068, 3227 NMR Spectrum ¹(H) (CDCl^, int.ref IMS, δ in ppm) :

1,3 (s, 9H tertbutyl)

4,02 (td, 1H - CHO)

5,03 (s, 2H, CH₂ benzyl ic)

6,9 - 7,53 (m, 12H aromatics)

Hydrochloride : 204 - 206°C

Fumarate : 177^eC

HAVING ngv.	PAP .
MY. Ol.'G -	\ . ^r '	, ί j L C -A :
TO 6E ΡΕΒΓ0γλ	M10
		- 26 -

CLAIMS:

Claims

CLAIMS:

1°- (4-substitutedphenyl) 4-oxy 1-aminobutane derivatives having the general formula I (I) wherein X is a substituent selected from the group consisting of >N- and >CH - NH

R is a cyclic substituent selected from the group consisting of

a) a Xanthyl group of formula wherein R^ and R2 being the same or different are each a hydrogen in straight or branched cnain or a lower alkyl radical of 1 to 5 carbon atoms and Rg is a halogenobenzyl or an ethoxyethyl group

AP Ο Ο Ο 2 8 2

- 27 wherein R^ is a hydrogen or a halogen and Rg is a halogenobenzyl group or an ethoxyethyl radical R. is a substituent selected from the group consisting of — OH, O-tetrahydropyranyl and -Ό and Ry is a carboxy, a tertbutyl radical or the grouping

CH,

I ³

- C -COOH ι ch₃
2^e- A compound according to claim 1° having the formula I_A wherein R is a Xanthyl group selected from the group consisting of the piperazinyl xanthines of general formula I_A, and the piperidinyl amino xanthines of general formula I_A„ wherein R^ and R2 being the same or different are hydrogen or a lower alkyl radical having from 1 to 5 carbon atoms Rg is a halogenobenzyl group or an ethoxyethyl radical and Rg and R? are as defined in claim 1.
3’- A compound according to claim 1° having the general formula I_ wherein R is a benzimidazolic radical selected from the group consisting of piperazinyl benzimidazoles of formula I_, o and the piperidinylamino benzimidazole of formula Ι_β„ wherein R^, R^, Rg and R?

are as defined in claim 1.
4°- The acid addition salts of a compound of formula I according to claim 1° with a mineral or organic acid
5®- The optically-active isomers of a compound of formula I according to claim 1* or claim 4°
6”- A compound of formula I' according to claim 1® wherein X and R are as defined in claim 1.
7*- A compound according to claim 1* having the formula I'_A

AP η Ο Ο 2 8 2 wherein X, R^, Rj and Rg
8^e- A compound according to claim 1° having the formula Ι'_β αι,-c5¾ wherein X, R^ and Rg are as defined in claim 1.
9^e- A compound according to claim 1° which is 1,3-dimethyl 7-(4-fluorobenzyl) 8-(1-(4-terbutyl phenyl 4-hydroxy)piperidyl-4 amino] xanthine.

1O’-A compound according to claim 1° which is 1,3-dimethyl 7-(4-fluorobenzyl) 8-[4-{4-terbutylphenyl 4-hydroxybutyl] piperazinyl xanthine ll^e- A compound according to claim 1° which is l-(4-fluorobenzyl)

2-[4-(4-terbutylphenyl) 4-hydroxybutyl] piperazino benzimidazole
12*-A compound according to claim 1° which is (1-(4-fluorobenzyl) 2 [ (4-terbutylphenyl) (4-hydroxybutyl )-4 ] piperidyl-4 amino ] benzimidazole.

-sols’- A process for producing the benzimidazolic derivatives of general formula Ι_βΒ according to claim 1’ which consists in reacting a o. nitroanil ine foe formula with a halogenated derivative selected from the group consisting of a halogenated benzylic derivative of formula III and ethoxyethyl halides of formula III'

Hal CK₂ CK₂ och₂ ch₃ (in·) wherein Z is a halogen and Hal is a chlorine or a bromine to produce an o.nitroaniline of the formula

- reducing the nitro group by catalytic hydrogenation in the presence of a palladium catalyst to produce the corresponding amine of formula XVI

AP Ο Ο Ο 2 8 2 are as defined in claim 1 (χνι;

wherein R, and reacting a compound of formula X with dihydropyran in acidic medium to obtain a tetrahydropyran derivative of formula XIV (XIV) wherein R? is as defined in claim 1 reacting the said compound of formula XIV with carbon sulfide in basic medium to obtain the thiocyanate of formula XV wherein R? is as defined in claim 1

7 32 - condensing the o.phenylene diamine of formula XVI with the thiocyanate of formula XV to produce a thiourea of formula XVII wherein R^, R^ and R? are as defined in claim 1 (XVH)

- cyclizing the thus formed thiourea XVII in the presence of a desulphurizing agent in an aromatic hydrocarbon, to produce a benzimidazolic derivative of formula XVIII

- hydrolyzing in acidic medium the tetrahydropyranyl ether under mild conditions to obtain a benzimidazolic derivative of formula wherein R^, R^ and R? are as defined in claim 1 which may be oxidized into a ketonic derivative by means of a metallic oxidizing reagent or salified by adding a mineral or organic acid

AP Ο Ο Ο 2 8 2

- 33 or purified or identified and controlled for the purpose of pharmacological studies.
14°- A process for producing the compounds of formula I according to claim 1° which comprises reacing a halogenated zanthine wherein R^ and are as defined in claim 1 and Hal means a chlorine or a bromine with a halogenated derivative selected from the group consisting of benzylic derivatives of general formula III (III) wherein Z is a halogen and an ethoxyethyl halide of formula III'

C₂ Hg Hal (III') wherein Hal is a chlorine or a bromine to produce a Xanthyl derivative of general formula IV

Hal (IV) wherein R^, Rj and Rg are as defined in claim 1 then suomitting this latter compound to the action 4-(4-phenyl) 4-oxy 1-aminobutane of general formula V of

- 34 ./Τ' (V) wherein X has the above-given definitions and R is a Xanthine group to obtain a compound of formula I_A„
15’- A process for producing a compound of formula I according to claim 1° which consists in reacting a compound of formula VI with a 4-oximino piperidine of formula VIII

- OH (VIII) in a solvent selected from the group consisting of straight or branched chain alkanols having up to.3 carbon atoms in the presence of an alkaline agent at the reflex temperature of the alkanol to produce a piperidino derivative of formula IX

AP C C Ο 2 8 2 wherein Rg is a hydroxy and R? is as defined in claim 1 reducing the oximino derivative into the corresponding primary amine in an alkanolic solvent to produce the aminated derivative of formula X wherein R? is as aefined in claim 1 which is reacted with a compound of formula IV wherein R^, R2 and Rg _{are as} defined in claim 1 to produce a compound of formula 1.,, .4

- 36 vherein R^, Rg and R? are as defined in claim 1 which may, when desired, be oxidised into the ketonic derivative by means of a metallic oxidizing agent or be salifeid by adding a mineral or organic acid.
16’- A process for producing the compounds of formula I_A according to claim 1° which comprises the steps of condensing a 4-halogeno l-fR^-phenyl) butyl derivative of formula VI wherein Rj and Rg are as defined in claim 1 with a substituted piperazine of formula VII in a solvent selected from the group consisting of cyclic ethers and alkanols having up to 3 carbon atoms to obtain a compound of formula I_A,

AP Ο00282

- 37 wherein R^, R^, R^, R_g and R?

are as defined in claim 1
17^e- A process for producing a conpound of general formula I according to claim 1° in which R is a benzimidazolic group and X is the >N- group, which consists in that a halogenated benzimidazole of general formula XI (XI) wherein R^ is as defined in claim 1 and Hal is a chlorine or bromine is reacted with a halogenated derivative selected from the group consisting of the benzyl derivatives of formula III (III) and the ethoxyethyl derivatives of formula III'

CH^ C&2 OCHj C&2 Hal (III') wherein Hal is a chlorine or bromine and Z is a halogen to produce the benzimidazolic derivative of formula XII wherein R, is as defined in claim 1 4 then condensing the compound of formula XII with piperazine to obtain a piperazinyl benzimidazole of formule XIII wherein R^ is hydrogen or chlorine and Rj is as defined in claim 1 submitting the latter to the action of a 4-halogeno

1-(4-R^-phenyl) butane of formula VI •₇ c U_· (CH₂) 3 _ Hal \=J\.

(VI) wherein Had. is a bromine or chlorine and Rg and R? are as defined in claim 1 to produce a compound of formula Ι_β,

AP Ο Ο Ο 2 8 2 <τ
18^β- ^Α pharmaceutical compositions containing as active ingredient at least one compound of formula I according to any of claims 1 to 11° in admixture or conjunction with an inert non toxic pharmaceutically-acceptable carrier.
19®- A pharmaceutical composition according to claim 18® wherein the amount of active ingredient of formula I ranges iron 1 to 20 mg per unit dosage.
20®- A compound of formula I for use in a method for treating allergic diseases and asthma in humans or animals.