FI114474B - Process for the preparation of therapeutically useful basic quaternary amides - Google Patents

Abstract

The invention relates to basic quaternary amides of formula <IMAGE> in which - Ar represents an optionally substituted mono-, di- or tricyclic heteroaromatic or aromatic group; - T represents a direct bond, a hydroxymethylene group, an alkoxymethylene group in which the alkoxy group is C1-C4 or a C1-C5 alkylene group; - Ar' represents a phenyl which is unsubstituted or substituted one or a number of times, a thienyl, a benzothienyl, a naphthyl or an indolyl; - R represents hydrogen, a C1-C4 alkyl, an omega -(C1-C4)alkoxy(C2-C4)alkyl or an omega -(C1-C4)alkanoyloxy(C2-C 4)alkyl, - Q represents hydrogen; - or else Q and R, together, form a 1,2-ethylene, 1,3-propylene or 1,4-butylene group; - Am<(+)> represents the radical <IMAGE> in which X1, X2 and X3, together and with the nitrogen atom to which they are bonded, form an azabicyclic or azatricyclic system optionally substituted by a phenyl group; - A<(-)> is a pharmaceutically acceptable anion. These compounds are useful in the preparation of medicaments intended for the treatment of pathologies involving the tachykinin system.

Description

114474

The present invention relates to a process for the preparation of novel basic quaternary amides.

In particular, the present invention relates to a new class of basic quaternary amides for therapeutic use in pathological conditions resulting from the tachykinin system such as, without limitation or exclusion: pain (D. Regoli et al., 1987, Life Sciences, 40, 109-117). , Allergy and Inflammation (JE Morlay et al., Life Sciences, 1987, 4_1, 527-544), Poor circulation (J. Losey et al., 1977, Substance P, Von Euler, US and Pernow ed., 287-293) , Raven Press, New York), Gastro-15 intestinal disorders, (D. Regoli et al., Trends Pharmacol. Sci., 1985, 6, 481-484), difficulty breathing (J. Mizrahi et al., Pharmacology, 1982). 25, 39-50).

Endogenous ligands for tachykinin receptors have been described, such as substance P (SP), neurokinin A 20 (NKa) (SJ Bailey et al., 1983, Substance P, P. Skrabanck ed., 16-17 Boole Press, Dublin). and neurokinin B (NKb) (SP Watson, Life Sciences 25, 797-808 (1983)).

The present invention relates to a process for the preparation of a therapeutically effective amount of a basic quaternary amide which is an antagonist of the substance P NK1 receptor.

The amide of formula I

E R Q

Ar-T-CO-N-CH9-C-CH9-CH9-Am®, Αθ '! | (i) αγ · * ,, where '' y '30 -Ar is phenyl which is mono- or disubstituted with a substituent selected from the group consisting of halogen, hydroxy,

C 1 -C 4 alkoxy and trifluoromethyl, wherein said substituents are the same or different; or Ar is a naphthyl group monosubstituted with halogen; - T is a direct bond or a -CH 2 group; - Ar 'is phenyl disubstituted with a halogen atom 5 or Ar' is naphthyl; -R is hydrogen or C 1 -C 4 -alkyl, or (C 1 -C 4) -alkoxy- (C 2 -C 4) -alkyl or - (C 2 -C 4) -alkanoyloxy- (C 1 -C 4) -alkyl; - Q is hydrogen; - or Q and R together form a 1,2-ethylene, 1,3-propyl-10 -ene or 1,4-butylene group; -Am + is a radical selected from the group consisting of 1-azonia bicyclo [2.2.2] oct-1-yl, 4-phenyl-1-azonia bicyclo [2.2.2] oct-1-yl, 4-benzyl-1-azonia bicyclo [2.2.2] oct-1-yl, 1-azonia bicyclo [2.2.1] hept-1-yl, 4-phenyl-1-azonia bicyclo [2.2.1] hept-1-yl, and 4-benzyl- 1-azonia-bicyclo [2.2.1] hept-1-yl; and - "A is a pharmaceutically acceptable anion.

Pharmaceutically acceptable anions are those normally used to convert quaternary ammonium ions of products intended for pharmaceutical use into salts, preferably chloride, bromide,: * · *: iodide, hydrogen sulfate, methanesulfonate, paratoluene · * ·. sulfonate, acetate and benzenesulfonate anions.

. ·. : When Ar is a phenyl group, this may preferably be mono- or disubstituted especially at position 2,4, but also, for example, at position 2,3, 4,5, 3,4 or 3,5. The substituents on the phenyl group may be: F; Cl; br; I; CF 3; hydroxy, '' alkoxy containing from 1 to 4 carbon atoms, preferably isopropoxy or ethoxy, and, for example, n-propoxy, methoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy.

• · · ϊ ,,.: The radical Ar may also represent a bicyclic aromatic; a group which is 1- or 2-naphthyl which may contain • · * optionally one halogen substituent.

Particularly good are those compounds of formula (I) wherein Ar is a phenyl group substituted with an iso- t: propoxy group preferably at the 3-position.

3 1 1 4474

In formula (I), T preferably represents a methylene group. The substituents R and Q are preferably a radical and hydrogen, respectively; A 2-methoxyethyl group and hydrogen; The 2-acetoxyethyl group and hydrogen or R and Q together form a 1,3-propylene group.

The substituent Ar 'is preferably a phenyl group preferably substituted with two chlorine atoms, especially at the 3- and 4-positions.

The radical X 11 © X 7 - N - 10 represented by Am + in formula (I) is preferably a residue of the azabicyclic system selected from the group consisting of: 15 (a) 1-Azonic bicyclo [2.2.1] heptane (b) ) 1-azoniabicyclo [2.2.2] octane ... (c) 4-phenyl-1-azonia bicyclo [2.2.2] octane; *, * groups (b) and (c) are particularly good.

Particularly good basic quaternary amides of the invention are those compounds of formula (I) wherein: - Ar is a 3-isopropoxyphenyl group; : - T is a methylene group; - R and Q are respectively a methyl group and hydrogen; The 2-acetoxy-25 ethyl group and hydrogen or taken together form a 1,3-propyl, ···, lene group; - Ar 1 is 3,4-dichlorophenyl; : "- Am + is a radical (b) or (c) as defined above; A - is a pharmaceutically acceptable anion, preferably chloride, methanesulfonate or benzenesulfonate.

114474 4 These compounds represented by the formula: jgi. rr "iPr-0 CH2-CO-N-CH2'C-CH2-CH2-N '/' ^^ - R a, A <- * a where iPr represents isopropyl, R1 and Q 'represent respectively a methyl group and hydrogen ; The 2-acetoxyethyl group and hydrogen or together form a 1,3-propylene group, R "is hydrogen or a phenyl group and A ~ is the same as above, in particular the methanesulfonate or chloride ion, are potent antagonists of substance P.

Compounds of formula (I1) wherein R 'and Q' together form a 1,3-propylene group are extremely potent and have a greater affinity for the neurokinin I receptor than the substance P itself. They therefore form a specific subject of the present invention.

Among these compounds are those compounds of formula (I ") · · ·: ch2 <: h2®P" W (^ »a0

r? (QL

a wherein A 'is a pharmaceutically acceptable anion, especially methanesulfonate, chloride and benzenesulfonate, are of most interest.

The process for the preparation of the compounds of formula (I) according to the invention is characterized in that t> '. reacting a sulfonate derivative of formula (II) • 114474 5

R Q

I I (II)

Ar - T-CO-N-CH2-C-CH2-CH2-OY

Ar 'wherein Ar, T, R, Q and Ar' have the same meaning as above and OY is a leaving group, preferably a methanesulfonate or 5-benzenesulfonate group, with a tertiary cyclic amine Am wherein Am is 1-azabicyclo [2.2.2] octane, 4-phenyl-1-azabicyclo [2.2.2] octane, 4-benzyl-1-azabicyclo [2.2.2] octane, 1-azabicyclo [2.2.1] heptane, 4-phenyl-1-azabicyclo-10 lo [2.2.1] heptane or 4-benzyl-1-azabicyclo [2.2.1] heptane, in an aprotic polar solvent at a temperature between room temperature and 120 ° C, and then the anion of the quaternary salt thus obtained. is exchanged for another pharmaceutically acceptable anion.

The organic solvent is preferably a polar aprotic solvent, for example acetonitrile, N, N-dimethylformamide, N, N-dimethylphenylacetamide, but also an ether, for example tetrahydro. {rofuran, dioxane, methyl t-butyl ether or ketone, for example methylethylketone, with acetonitrile being particularly preferred.

'.1 Within the temperature range set forth above, the best temperature range is from 70 to 90 ° C. When acetonitrile is used as a solvent, it is preferable to use the boiling point of the reaction mixture.

The compound thus obtained is isolated by washing with conventional techniques, for example by concentrating the solvents. slurry the residue with water, then purify by conventional tech- niques, such as chromatography or crystallization.

"· The methanesulfonate anion resulting from the reaction of the cyclic" · amine Am with the methanesulfonyloxy derivative of formula (II) may be exchanged in situ after isolation of a compound of formula (I) wherein A "is a methanesulfonate ion, to the second anion by conventional methods, for example, by exchange in solution, such as hydrochloric acid, when A 5 represents the chloride anion, or by converting the anion to another anion by eluting a compound of formula (I) from an ion exchange resin such as Amberlite IRA68

The methanesulfonyloxy derivatives of formula (II) used as starting material for the process of this invention may be prepared according to Scheme 1 below, wherein the following formulas:

In route A: Q = H; R = H, C 1 -C 4 -alkyl In Route B: R + Q = - (CH 2) n -, where n = 2,3,4 In Scheme 1, the reactions of the various steps are shown to indicate the type of said reactions without giving any procedure for their execution, who are well known.

Thus, for example, in route A in step 2 and in route B in step 6, "H2" means that the starting nitrile is reduced, for example, by catalytic hydrogenation (Raney nickel in ethanol in the presence of ammonia to give primary amine IV).

·. In step 2, on route A, the term "alkylation" ». : means that, after reduction, the primary amine 25 is alkylated either directly with the halide or alkylsulfate or indirectly by acylation and reduction of the carbonyl group. Thus, for example, reaction of the primary amine of formula (IV) with ethyl chloroformate and reduction of the ethoxycarbonyl group yields a compound of formula (IV) wherein R is methyl, as disclosed in EP-A: Nos. 0, 428, 434, and 0, 474, 561. Substitute the ethyl chloroformate C2-C4 alkanoyl acid with chloride (or other functional derivative) and reduce the carbonyl group of the N-acylated derivative thus obtained. Compounds of formula (IV) having C2-C4 alkyl are prepared by substituting ethyl oxalyl chloride, ethyl hememalonate or ethyl hemisuccinate for the ethyl N-acylated derivatives. -C 4) alkyl derivative which is O-acylated or O-alkylated to give the w-alkanoyl of formula IV oxyalkylated or w-alkoxyalkylated derivatives wherein R is w- (C2-C4) -alkanoyloxy- (C2-C4) -alkyl or w- (C1-C4) -alkoxy- (C2-C4) -alkyl.

Similarly, substitution of the alkyl chloroformates with w- (C 1 -C 4) alkoxy- (C 2 -C 4) alkanoic acid chloride and reduction as described above directly yields w-alkoxyalkylated derivatives of formula IV wherein R is w - (C 1 -C 4) alkoxy- (C 2) -C 4) alkyl.

The ethyl chloroformate may be replaced by di-t-butyl carbonate (Boc-Boc) in the preparation of a compound of formula IV (R = methyl).

Similarly, for example, in step A of step A, "H +" means that the tetrahydropyranyloxy group is subjected to acid hydrolysis under conditions well known in the literature.

t · * · * I t · • · »» »· · • t i * · * t« *> · 11 »·.

• · I

• t 1 · • · • · * »» »• · 114474 8

Route A Chart 1 Route B

/) —OCH2-CH2-Br + Ar'-CH2-CH

'O

/ \ —O- ch2-ch2- ch-cn

Ar '\\\\ / \ Br-ccHj ^ cOjEi (where m = X Possible _i \ A 2 or 3) alkylation. ^ - R (CH 2) m -CO 2 Et

^^ - 0-CH2-CH2-CH-CHrNH ^^^ 0-CH2-CH2-C-CN

° Ar 'av) Ar' 6 ^ »2

HO-CO-T-Ar V

v - / ~ \ / (CH2) fflVP

V_> - ° -CHrcH2-C | '-O / y-O-CH 2 -CH 2 -CH-CH 2 -N-CO-T-Ar? li / j H ^^ -O ',

[.Alpha.] D @ 20 -CH2

l * 'N. A1' (V) \ -— / ^ HO-CO-T-Ar t) ···: '* Q R ^ H + 2) * * ·' j (where Q and R are

Ha-CH, -CH, -C-CH 2 -N-CO-T-Ar same as ka::: | vassa i)

Ar 'VI

YC1. ·! · *? Γ Y -O-CHn-CH-j-C-CH? -N-CO-T-Ar i | i (LI) Γ. Ar '.

: ·· (] in section Y is outgoing, ···. Group) t t i 114474 9

The significance of the substituent Ar depends on the choice of one of its acids H-C-T-Ar as its functional derivative in steps 3 and 8. All of these acids are well known in the literature, can be readily prepared according to the literature or are commercially available.

The meaning of the substituent Ar 'depends on the choice of the nitrile Ar' -CH 2 -CN which yields the amine by reaction with 2-tetrahydropyranyloxy-1-bromoethane, hydrogenation of the compound so obtained and optionally N-alkyl 10 (step 2).

Route A of Scheme 1, wherein R = H, alkyl and Q = H, is described in the literature in EP-A-0 428 434 and A-0 474 561.

Route B of Scheme A undergoes sequential reactions well known to those skilled in the art, such as alkylation of a nitrile with a brominated derivative in the presence of lithium thiisopropylamide (LDA) (step 5) followed by reduction of a nitrile in the presence of a catalyst to afford the corresponding amine. (step j5) after reduction of the intermediate amide (step j), for example AV El'tsov et al. i According to Biol. Soedin., Akad. Nauk SSSR 1965, 109-12 {CA

1965, 63, 16299).

. ·. A: The reaction conditions for certain steps 25 are the same for both routes in Scheme 1. Thus, the reduction in steps 2 (route A) and 6 (route B) is carried out under the same conditions.

«· * - t * *.,! Similarly, Step 1 (route B) and the reduction of the N-acylated derivative or 'ethoxycarbonyl in the indirect alkylation reaction of Step 2 (route B) occur under the same conditions.

Finally, acylation in steps .3 (route A) and 8 ^ (route B) is performed under the same conditions.

; ·. In the process of the invention for the preparation of compounds of formula (I), a derivative (II) prepared by the reaction of an alcohol (IV) with a Y-Cl derivative, for example mesyl chloride or benzenesulfonyl chloride (step 9), is reacted with a tertiary amine (? -cyclic amine?) of formula (III) according to Scheme 2 below.

Figure 2 5

Q R

I I

CH 3 -SO 2 -O-CH 2 -CH 2 -C-CH 2 -N-CO-t -At '(H)

At * Xl X “J (ΙΠ) X3 (I)

Separation of racemic mixtures yields the enantiomers (I *) which are also part of the invention.

However, it is desirable to carry out the rearrangement of racemic mixtures with the intermediate amino alcohols which readily form salts with optically active acids. The amino alcohols correspond to the compounds (IV) and • i »h '(V) obtained according to Scheme 1, Step 2 (Route A) and Step 1 ~ (Route B) after deprotection of the protecting groups by acid hydrolysis: · * T # * / \ I / - \ / (cH2> nx \ ^ Ln h ° -CH2-CH2-CH-CHrNH and} -0-CH2-CHr <j: l · av) 0 at · m • * · * * '··' where Ar 'and R are the same as in formula (I) and m 20 is 1,2 or 3.

The enantiomers are then separated by classical methods. such as crystallization or preparative chiral high pressure chromatography.

•> • »11 114474

The preparation of optically pure compounds is illustrated in Scheme 3 below, where "*" means that the carbon atom so designated is in a particular (+) or (-) configuration.

In Scheme 3, the last step is illustrated for the operation with the free free acid. However, it can be carried out with a functional derivative thereof which can simultaneously react with the hydroxyl and amino groups of the molecule.

In this case, it is desirable to carry out the re-protection of the hydroxyl group, for example, with dihydropyran to form tetrahydropyranyl ether.

The preparation of compounds (VI *) according to Scheme 3 wherein R is hydrogen or a C 1 -C 4 alkyl group and Q is hydrogen is described in EP-A-0 428 434 and A-0 474 561.

Scheme 3 / - \ 1 / - \ / (C * 2Vh (V-O-CH, -CH 7 -CH-CH 7 -NH (γ-O-CH 2 -CH 2 -C Γ "VV 1., W 1> ^ · ΝΗ

Ar '^ (IV) T (V) H +: ·' v Q k. li: m ho-ch2-ch2-c-ch2-nh cm ί *; Separation of enantiomers

A: I do

l «

·; * HO-CH2-CH2-ciCH2-NH

Ar '(VIP) HO-CO-T-Ar

T

»· (VI *)» 12 114474

The preparation of optically pure compounds of formula (VI *) wherein Q and R are bonded and represent 1,2-ethylene, 1,3-propylene or 1,4-butylene is carried out in the same manner.

In particular, compound (VII *), which is prepared by separation of enantiomers (VII), is conjugated to an acid of formula Ar-T-CH in the presence of a conjugating agent by conventional methods. As described above, a functional derivative of this acid, such as it-10, may be used, suitably activated with, for example, cyclohexylcarbodiimide or benzotriazolyl-N-oxytris-dimethylaminophosphonium hexafluorophosphate (BP) or a functional derivative, e.g. anhydride, mixed anhydride, acid chloride, or an activated ester such as paranitrophenyl ester.

The compound thus obtained having the formula:

Q R

I. I.

HO-CH 2 -CH 2 -C -CH 2 -N-CO-T-Ar 1 (VI *): V at '* · * * *, then reacting with derivative YC1 according to Scheme 9, Scheme 9, yielding an optically pure derivative of formula (II).

The reaction of the tertiary amine (III) (= cyclic amine Am) V 'allows the preparation of compound (I) of the invention in optically pure form.

The amines of formula (III) are those described in the literature.

Among these amines, the most preferred are those with cyclic systems containing from 5 to 9 carbon atoms and one nitrogen atom, as mentioned below: · · · 30 (a ') 1-azabicyclo [2.2.1] heptane, prepared according to Gassman et al., J. Am. Chem. Soc., (90), 5, 1355-6 (1968).

I * 13 114474

Gn (fc *) 1-azabicyclo [2.2.2] octane or quinuclidine.

? 5 (c ') 4-phenyl-1-azabicyclo [2.2.2] octane or 4-phenylquinuclidine prepared according to J. Perrin, J. Rg. Chem. , 1957, 2_2, 1484 - 1489.

10

The above compounds of formula (I) also include those in which one or more hydrogen or carbon atoms have been replaced by their radioactive isotope, for example, tritium or carbon-14. Such compounds * ··, teas are useful in research, metabolism, or pharmaceutical • »f. in kinetic work, in biochemical experiments, the reseote as a <1 * ligand.

1 * * ”* · The compounds of the invention have been subjected to biochemical tests.

V * Compounds (I) have shown antagonistic effects on substance P binding in experiments performed on IM9 membranes of rat brain cortex and lymphoblastic cells in M.A. Cascierin et al. mu-25 can, J. Biol. Chem. 1983, 258, 5158-5164, and D.D. Paya ♦ · eta ai. J. Immunol. 133: 3260-3265 (1984).

* ··· 'Among the compounds studied, (+) -1- [2- [3- (3,4- (3'-dichlorophenyl) -1 - [(3-isopropoxyphenyl) acetyl] -3-piperidinyl] ethyl] -4-phenyl-l-azoniabicyclo [2.2.2] octane

> I J

114474 14 (Compound 4) has been shown to be a potent antagonist of the substance P at the NK 1 receptor: it inhibits the binding of substance P to its receptor, with an inhibition constant (Ki) of 10 to 20 µM in various biochemical experiments.

In particular, the compounds of the present invention are active ingredients in pharmaceutical preparations which are suitable for use as medicaments in view of their toxicity.

The above compounds of formula (I) may be used in daily doses of 0.01 to 100 mg / kg body weight of the mammal to be treated, preferably at daily doses of 0.1 to 50 mg / kg. In humans, the dosage may preferably vary from 0.5 to 4000 mg per day, particularly 2.5 to 1000 mg per day, depending on the age and type of treatment being treated: 15 preventive or curative treatments.

To be used as medicaments, the compounds of formula (I) are generally administered in single doses. Said single doses are preferably included in pharmaceutical formulations in which the active ingredient is mixed with a pharmaceutical excipient.

In pharmaceutical preparations, their effective, · ** '; the substances can be administered in single doses and mixed ♦ · I *. the classic pharmaceutical carriers in humans and in animals ·.,: R, when the dosage is oral, sublingual, subcutaneous * 25 subcutaneously, intramuscularly, intravenously, transdermally, topically, or rectally.. Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, powders, granules and oral solutions or suspensions, oral or sublingual dosage forms, subcutaneous, intramuscular, intravenous, nasal or oral administration. forms and rectally administrable forms;

• * »

When preparing a solid preparation in the form of tablets, the active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, acacia or the like. Tablets 114474 15 may be coated with sucrose or other suitable agents, or may be further processed to prolong or delay their action and to provide a sustained release of the active ingredient.

The gelatin capsule preparation is prepared by mixing the active ingredient in a diluent and pouring the resulting mixture into soft or hard gelatin capsules.

The preparation in the form of a syrup or a drug syrup may contain the active ingredient, preferably with a caloric-free sweetener, in the presence of methylparaben and propylparaben as antiseptics, and a flavoring and coloring agent.

Water dispersible powders or granules may contain the active ingredient in admixture with dispersants or foaming agents or substances which form suspensions, such as polyvinylpyrrolidone, and sweetening or flavoring agents.

For rectal administration, recourse supposito transducers, which are prepared with binders that melt 20, the VAT at the rectal temperature, for example cocoa butter or with acid-glycol.

, for parenteral, nasal or ocular administration; ·, aqueous suspensions, isotonic saline or. sterile and injectable solutions containing dispersants and / or pharmacologically compatible foaming agents, for example propylene glycol or butylene glycol.

* (·! · ') For inhalation dosing, an aerosol containing V · sorbitan trioleate or oleic acid and trichlorofluoromethane, dichlorofluoromethane, dichlorotethan · rafluoroethane or other biocompatible propellant is used.

The active ingredient may also be incorporated into microcapsules, optionally with one or more carriers or additives.

* 2 (2

»I

In each individual dose, "· 1 · 35 active ingredient is present in an amount such that a suitable dose of 16,114,774 is suitably adjusted to the desired dosage type and dose, e.g., tablets, gelatin capsules, and the like, bags, ampoules, so that one such unit dose contains 0.5 to 1000 mg of active ingredient, preferably 2.5 to 250 mg, to be administered once to four times daily.

The present invention also relates to the use of compounds of formula (I) in the manufacture of a medicament for the treatment of psychological disorders involving excess of tachykinins, particularly substance P, and all respiratory, gastrointestinal, urinary, immune and cardiac vascular system and central nervous system] for the treatment of tachykinin-dependent disorders, pain and migraine.

Non-limiting examples of these include: - acute and chronic pains associated with, for example, migraine, cancer pain and chest pain, or chronic inflammatory conditions such as osteoarthritis and rheumatism, - inflammations such as chronic respiratory disease, asthma. , allergies, rhinitis, hypersensitivity eg to pollen and mites, rheumatism, osteoarthritis, psoriasis. : ulcerative colitis, Crohn's disease, inflammatory bowel disease (irritable colon), prostatitis, neurological disease - '. V'. diseases such as rheumatism, psoriasis, Crohn's disease, diabetes, and central nervous system disorders, such as rheumatism, psoriasis, Crohn's disease, diabetes, and central nervous system disorders; , such as depression, depression, depression, psychosis, schizophrenia, mania, dementia, epilepsy, Parkinson's disease, Alzheimer's disease, narcotic addiction, Down's syndrome and Huntington's disease, and 35 neurodegenerative diseases, i · 114474 17 - gastrointestinal disorders such as nausea, irritable colon, gastric and duodenal ulcer, diarrhea and hyper secretion, - cardiovascular disorders such as migraine-5-related cardiovascular disorders, edema, thrombosis, coronary heart disease.

The following examples illustrate the invention without limiting it in any way.

The melting points, m.p., of the compounds are measured on a Koffle-10 heating bench.

Preparations A. Amino Alcohols (VII) and (VII *).

Preparation I: Scheme 1 - Route A.

(a) α- (2-Tetrahydropyranyloxyethyl) -3,4-dichloro-15-ribenzeneacetonitrile.

16.5 g of 80% sodium hydride in oil are suspended in 200 dry tetrahydrofuran. A solution of 100 g of 3,4-dichlorophenylacetonitrile in 500 ml of tetrahydrofuran is added dropwise at 20 ° C over a period of 30 minutes, then the reaction mixture is stirred at room temperature for 2 hours. The mixture is cooled to -20 ° C and a solution of 118 g of 1-bromo-2-tetrahydropyranyloxyethane 100 is added. of tetrahydrofuran, allow the mixture to warm to room temperature and after 2 hours add a solution of 50 g of ammonium chloride in 3 liters of water. Extract with 1.5 liters of ether, wash with saturated NaCl solution: Decant, dry over MgSO 4 and concentrate under vacuum. The residue is chromatographed on silica gel, eluting with CH 2 Cl 2, then ethyl acetate 95-5 (v / v). The fractions of the pure compound are concentrated in vacuo to give : 118 g of oil.

· = '(B) 2- (2-Tetrahydropyranyloxyethyl) -3,4-dichloro-1,1'-ribenzene-ethanamine * * * 118 g of the above nitrile are suspended in 35 700 ml of absolute ethanol. Add 300 ml of concentrated ammonia, then add Raney nickel 114474 18 (10% of the amount of nitrile starting material) under a stream of nitrogen. It is then hydrated under a hydrogen atmosphere at room temperature and normal pressure.

16 liters are absorbed in 4 hours. The catalyst 5 is separated by filtration over celite, the filtrate is concentrated to dryness in vacuo, the residue is dissolved in saturated NaCl solution. After extraction with ether and drying over MgSO4, 112 g of an oil are obtained.

(c) 2- (2-Hydroxyethyl) -3,4-dichlorobenzene-ethanamine 81 g of the compound obtained in (b) above are dissolved in 38 ml of methanol.

Add 80 ml of ethereal solution saturated with hydrochloric acid and maintain the temperature between 20 and 25 ° C.

Stir for 30 minutes at room temperature, then concentrate to dryness. The residue is dissolved in 250 ml of water, washed twice with ether, made basic with NaH solution, extracted with CH2Cl2. After drying over MgSO4, concentrate to dryness, dissolve in 20 800 ml of isopropyl ether, filter off the insoluble matter by Celite, concentrate in vacuo to about 300 ml, triturate with the amino alcohol crystals,. stir overnight.

; * ·, {Filter, rinse with isopropyl ether, then n-pentane. This gives 30.2 g of the desired compound, 'v. freezing. Mp = 90-91 ° C.

(d) (+) - 2- (2-Hydroxyethyl) - (3,4-dichlorobenzene * n -ethanamine) To 29 g of boiling D (-) tartaric acid in 800 ml of methanol is added a solution, containing 44.7 g of the compound prepared according to the preceding step · ... '(c) in 300 ml of methanol.

···, Allow to cool to room temperature and stir for 4 hours. Filter, rinse with ethanol, then with ether. This gives 34.1 g of tartrate.

114474 19

Recrystallization of 1.75 list of methanol gives 26.6 g of tartrate.

[α] ϋ5 = - 4.2 ° (c = 1, in H2)

The tartrate is dissolved in 120 ml of water. Make alkaline with NaH solution, extract twice with CH 2 Cl 2, dry over MgSO 4, concentrate to dryness. Dissolve in a small amount of isopropyl ether, add n-pentane, filter to give 15.4 g of the compound.

Mp = 79-80 ° C.

[Α] d5 = + 9.4 ° (c = 1, in CH3H) (e) (+) - N-Methyl-2- (2-hydroxyethyl) -3,4-dichlorobenzene-ethanamine hydrochloride (el) N- (4- (2-hydroxyethyl) -2- (3,4-dichlorophenyl) butyl] ethylcarbamate 15 g of the compound obtained in the preceding step (d) are dissolved in 200 ml of CH 2 Cl 2 9.9 ml of triethylamine are added. .

Cool to 0 ° C and add a solution of 6.3 ml of ethyl chloroformate in 30 ml of CH 2 Cl 2 dropwise at this temperature. After 15 minutes, wash with water, then dilute HCl solution, then saturated; Aqueous NaHC3. After drying over MgSO4, it is concentrated to dryness to give 20 g of compound as an oil.

(E2) Reduction of the ethoxycarbonyl group to methyl · group * In 5.1 g of lithium / aluminum hydride suspended in 60 ml of anhydrous THF, a solution of 20 g of the compound obtained in the preceding step is added. In 150 ml of 30 anhydrous THF. Heat under reflux for 1 hour. Hydrolyze with 20 ml water, inorganic material F, filter, concentrate to dryness. The oil obtained is dissolved, ·· *, in 100 ml of acetone. Add ether saturated with hydrochloric acid until pH = 1, then ether until solution '**' · 35 is cloudy. After stirring for 1 hour, the crystals are filtered, rinsed with a little acetone, then ether to give 11 g of N-methyl-2- (2-hydroxyethyl) -3,4-dichlorobenzenethanamine hydrochloride. Mp = 129 ° C.

[α] D 25 = + 8.4 ° (c = 1, in CH 3 H) (f) N-Methyl-2- (2-hydroxyethyl) -3,4-dichloro-benzenethanamine hydrochloride (-)

By proceeding, as above, starting with L - (+) - tartaric acid, the enantiomer - (-) is obtained. Mp = 129 ° C.

[.Alpha.] D @ 20 = -8.4 DEG (c = 1 in CH3H)

Preparation II: Scheme 1 - Route B, m = 1.

10 (a) 3,4-Dichloro-α- (2-tetrahydropyranyloxyethyl) benzeneacetonitrile 20 g of 55-60% sodium hydride in oil are suspended in 200 ml of dry tetrahydrofuran. A solution of 85 g of 3,4-dichlorophenylacetonitrile in 500 ml of tetrahydrofuran is added dropwise at 20 ° C over a period of 30 minutes, then the reaction mixture is stirred at room temperature for 2 hours. To the resulting mixture, cooled to -20 ° C, is added a solution of 98 g of 2-bromoethoxytetrahydropyran in 100 ml of tetrahydrofuran, the mixture is allowed to warm to room temperature and after 2 hours, a solution of 50 g of ammonium chloride in 3 liters of water is added. Uu- * * *; Is taken up in 1.5 liters of ethyl ether, washed with saturated sodium chloride solution, decanted, dried over MgSO4 and concentrated in vacuo.

The residue is chromatographed on silica gel: eluent: r, dichloromethane. The pure compound fractions are concentrated / in vacuo to give 83.6 g of an oil.

(b) B-Tetrahydropyranyloxyethyl B-cyano-B- (3,4-dichlorophenyl) ethyl propionate 21 g of the nitrile prepared according to the above (a) are suspended in 100 ml of tetrahydrofuran, then added dropwise and at room temperature, a solution of 0.067 moles of lithium diisopropylamide in 100 µl of tetrahydrofuran and the reaction mixture is stirred for about 35 minutes at room temperature. 12 g of ethyl bromoacetate are then added and the mixture is heated at 50 ° C for two hours 114474 21. The mixture is cooled and poured into a saturated ammonium chloride solution and extracted with ethyl ether, washed with water, the ethereal phases are separated by decantation, dried over Na2S4 and concentrated in vacuo. The residue is purified by silica gel chromatography, eluting with dichloromethane / ethyl acetate 100/1 (v / v). Concentration of the pure fractions gives 13 g of the desired compound.

(c) 4- (2-Tetrahydropyranyloxyethyl) -4- (3,4-dichlorophenyl) -2-pyrrolidone 10 g of the compound prepared above are dissolved in 250 ml of ethanol and 40 ml of ammonia and hydrogenated at room temperature. and at normal pressure in the presence of Raney nickel. After the theoretical volume of hydrogen has been absorbed, the mixture is filtered with celite and the filtrate is concentrated in vacuo. The residue is dissolved in water, extracted with ethyl ether, then the ether phase is washed with water, dried over MgSO4 and concentrated to dryness, m = 8.6 g.

(d) 3- (2-Tetrahydropyranyloxyethyl) -3- (3,4-dichlorophenyl) pyrrolidine 3.9 g of the above 4- (2-tetrahydropyranyloxyethyl) -4- (3,4-dichlorophenyl) - 2-pyrrolidone solvent; to 50 ml of tetrahydrofuran and add the solution to a suspension of 0.9 g of lithium aluminum hydride in 5 ml of tet. : Rahydrofuran heated to 60 ° C. The reaction mixture is heated for 1 hour at 60 ° C, then cooled. Add 1 mL of water, 1 mL of 4N sodium hydroxide and 3 x # mL of water. The inorganic material is filtered off and the filtrate is concentrated. The residue is dissolved in ethyl ether, dried over MgSO4 and concentrated in vacuo to give 3.4 g of the desired compound.

(e) 3- (2-hydroxyethyl) -3- (3,4-dichlorophenyl) -. Pyrrolidine ♦ * To 3.4 g of 3-tetrahydropyranyloxyethyl-3- (3,4-dichlorophenyl) pyrrolidine dissolved in 20 ml of methanol: 35% is added hydrochloric acid ethyl ether,

• t I

:; nes pH = 1. Stir for half an hour at room temperature, concentrate 114474 22, dissolve the residue in water, basify with sodium hydroxide solution, extract with dichloromethane, wash with saturated NaCl solution, dry over Na2S4 and evaporate to dryness. Oil is obtained.

Dissolve in 20 ml of a 50/50 (v / v) isopropyl ether / ether mixture. Stir, wash with ether and dry under vacuum over P2 2, m = 2.6 g.

Preparation III: Scheme 1 - Route B, m = 2.

(a) Gamma (2-tetrahydropyranyloxyethyl) gamma-cyano-gamma (3,4-dichlorophenyl) ethyl butanoate 21 g of the nitrile prepared in the above step (a) are dissolved in 100 ml of tetrahydrofuran, then added dropwise at room temperature, of 0.067 mol of lithium diisopropylamide dissolved in 100 ml of tetrahydrofuran and the reaction mixture is stirred for one hour at room temperature. 12 g of bromoethyl propionate are then added and heated at 50 ° C for two hours. The mixture is cooled and poured into a saturated ammonium chloride solution and extracted with ether, washed with water, the ether-20 phase is separated by decantation, dried over Na 2 SO 4 and concentrated in vacuo. The residue is purified on silica gel; by chromatography, eluting with dichloromethane / ethyl acetate 100/1 (v / v).

Concentration of the pure fractions gives 13 g · h of the desired compound.

(b) 5- (2-Tetrahydropyranyloxyethyl) -5- (3,4-dichlorophenyl) -2-piperidinone 13 g of the compound prepared above are dissolved in 250 ml of ethanol and 40 ml of ammonia and hydrogenated. at room temperature and normal pressure Raney nickel * * *

In the presence of Iin. After the theoretical volume of hydrogen has been absorbed, the mixture is filtered through celite and the filtrate is concentrated. in vacuo. The residue is dissolved in water, extracted with ether, then the ether phase is washed with water, dried over MgSO4 and concentrated to dryness, m = 9 g.

114474 23 (c) 3- (2-Tetrahydropyranyloxyethyl) -3- (3,4-dichlorophenyl) piperidine; 3.9 g of 5- (2-tetrahydropyranyloxyethyl) -5- (3,4-dichlorophenyl) piperidinone prepared above are dissolved in 50 ml of tetrahydrofuran and added to a suspension of 0.9 g of lithium aluminum hydride in 5 ml of: in tetrahydrofuran heated to 60 ° C. The reaction mixture is heated for one hour at 60 ° C, then cooled. Add 1 ml of water, 1 ml of 4N sodium hydroxide and 3 10 ml of water. The inorganic material is filtered off and the filtrate is concentrated. The residue is dissolved in ethyl ether, dried over MgSO4 and concentrated in vacuo to give 3.4 g of the desired compound.

(d) 3- (2-hydroxyethyl) -3- (3,4-dichlorophenyl) -piperidine. Compound (V) To 55 g of 3- (2-tetrahydropyranyloxyethyl) -3- (3,4-dichlorophenyl) piperidine dissolved in 200 ml of methanol is added ethereal hydrochloric acid until pH = 1. Stir for half an hour. at room temperature, concentrate to dryness, dissolve the residue in water, basify with NaH, extract with * CH2Cl2, wash with saturated NaCl solution, dry over Na2S2 and evaporate to dryness. This gives oil.

The oil is dissolved in 200 ml of a 50/50 (v / v) mixture of isopropyl ether / ether. Stir, filter, wash with E / ethyl ether and dry under vacuum over P2 2 to give 45 g of the desired compound. Mp = 122 ° C. t; (e) 3- (2-Hydroxyethyl) -3- (3,4-dichlorophenyl) -30 piperidine (+). Compound (V *) · To 43 g of the compound obtained above, which is solubilized · Under a reflux condenser, add 23.54 g of L (+) - tartaric acid, which is dissolved in 250 ml of 100% ethanol. dissolved in 750 ml of 100% ethanol. The reaction mixture is heated to reflux for 1.5 hours, allowed to warm to room temperature, the resulting crystals are filtered, washed with 100% ethyl acetate. and dried under vacuum at 50 ° C over P2C> 5 to give 31 g of tartrate which is recrystallized by dissolving it in 540 ml of ethanol at 100 ° C, filtering, washing with ethyl ether and drying in vacuo On P205 to give 25 g of tartrate.

[α] ϋ ° = + 8.5 ° (c = 1, in H2)

The tartrate is then dissolved in water, neutralized with NaH solution, extracted with CH2Cl2, washed with water, dried over Na2S4 and evaporated to dryness. The oil is dissolved in ether / isopropyl ether, the crystals are filtered off, washed with ethyl ether and dried in vacuo at 50 ° C to give 13.5 g of base. Mp = 138 ° C.

[α] D 20 = + 8.2 ° (c = 1, in CH 3 H) (f) 3- (2-hydroxyethyl) -3- (3,4-dichlorophenyl) -piperidine (-)

By proceeding as above, starting with (D) - tartaric acid, the (-) enantiomer is obtained. Mp = 139 ° C.

[α] D = -8.4 ° (c = 1, CH 3 H)

Preparation IV: Scheme 1 - Route B, m = 3.

20 (a) δ- (2-Tetrahydropyranyloxyethyl) -5-cyano-5- (3,4-dichlorophenyl) ethyl pentanoate: · 36 g of the 3,4-dichloro-α - [(2-tetra- • · Hydropyranyloxy) ethyl] benzeneacetonitrile (Prepared according to Preparation II (a)) Dissolved in · 100 ml of dimethylformamide, 4.6 g of 60% NaH are added in small portions. . The reaction mixture is stirred for 3 hours at room temperature, cooled to 0 ° C, then 22.4 g of 4-bromoethyl butyrate in 40 ml of dimethylformamide are added. The reaction mixture is stirred for 3 hours at room temperature. The reaction mixture is poured into water, extracted with ether, washed with saturated NaCl solution, dried over Na2SO4 and concentrated in vacuo. The residue is purified by chromatography on silica gel in toluene as eluent. This gives 24 g of the desired product.

35 114474 25! (b) 6- (2-Tetrahydropyranyloxyethyl) -6- (3,4-dichlorophenyl) perihydro-2-azepinone 8 g of the compound obtained above are hydrogenated at normal pressure and room temperature in the presence of Raney nickel, dissolved in 120 ml of ethanol.

After the theoretical volume of hydrogen has been consumed, the catalyst is filtered off and the solution is concentrated in vacuo.

The resulting oil is then dissolved in 20 ml of xylene and the reaction mixture is heated under reflux for 48 hours. The resulting residue is purified by silica gel chromatography, eluting with dichloromethane / methanol 100/1 (v / v). This gives 4 g of the desired product in the form of an oil.

(c) 3- (2-Tetrahydropyranyloxyethyl) -3- (3,4-dichlorophenyl) perihydroazepine Using 2 g of the compound obtained above, 0.49 g of lithium aluminum hydride and following the above preparation in step (d), 1 7 g of the desired compound in the form of an oil.

(d) 3- (2-Hydroxyethyl) -3- (3,4-dichlorophenyl) -20-azepine I Using 1.7 g of the above compound starting material and following the above preparation in step '· (e), 1 , 3 g of the desired compound.

: _ '. I B. Substituted Phenylacetic Acids 25 B1. 3-isopropoksifenyylietikkahappo

Preparation V. 13 3-Isopropoxyphenylacetic acid is not known in the literature, but can be prepared using known alkoxy. methods for the preparation of siphenylacetic acids.

3Q

(a) 3-Hydroxyphenylethyl acetate 55 g of 3-hydroxyphenylacetic acid dissolved in 400 ml of 100% ethanol are heated under reflux overnight with a few drops of concentrated H2S4.

Evaporate to dryness, dissolve in ethyl ether, wash with water, then with a saturated aqueous solution of NaHC3.

f »114474 26

After drying over MgSO4, then evaporation, 58 g of an oil are obtained.

(b) 3-Isopropoxyphenylethyl acetate 58 g of the above compound, 88 g of K2C3 and 108 g of 5-iodopropane dissolved in 300 ml of DMF are heated at 80-100 ° C for 8 hours. The DMF is evaporated in vacuo, the ethyl acetate is dissolved and washed with 10% aqueous K 2 Cl 3. After drying over MgSO4 and evaporation, the residue is purified by silica gel chromatography, eluting with CH2Cl2. This gives 61 g of an oil.

(c) 3-Isopropoxyphenylacetic acid 31 g of the compound obtained above and 20 g of NaH dissolved in 400 ml of ethanol are heated under reflux for 2 hours. Evaporate to dryness, dissolve in water 15 and basify with concentrated HCl. Extract with ethyl ether, wash with water, dry over MgSO4 and concentrate to dryness to give 27 g of the desired compound. Mp = 33-35 ° C.

B2. 2-iodo-5-isopropoksifenyylietikkahappo.

Preparation V.2.

2-Iodo-5-isopropoxyphenylacetic acid is not known in the literature, but can be prepared by example. Therefore, the methods described by R. E. Counsel et.

: al., J. Med. Chem. , 1973, 16, 6, 684-687 by replacing benzyl chloride with 2-iodopropane.

15 g of the thus prepared 2-iodo-5-isopropoxyphenylacetonitrile are dissolved in 160 ml of ethanol in the presence of 18 g of KOH, and then the mixture is heated under reflux for 2 hours. Concentrate in vacuo, treat the residue with water, then wash sequentially with ethyl ether, acidify the aqueous phase by adding HCl to pH 1, extract with ethyl ether, wash with water, dry over Na2SO4: Concentrate in vacuo and purify the residue by chromatography on ***** 35 silica gel using CH2Cl2-CH3OH (100/2, v / v) as eluent. The pure fractions are concentrated to give 8 g. the desired acid in the form of an oil NMR spectrum (200 MHz): 1.2 ppm - 20¾; 3.5 ppm - 10¾; 4.6 ppm - 1CH; 6.6 ppm - 1H (aromatic); 6.9 ppm - 1h (aromatic); 7.6 ppm-1H (aromatic).

5 C. Acyl derivatives (VI) and sulfonyloxy derivatives (II)

Preparation VI: Scheme 1 - Route B, m = 1.

(a) 3- (2-Hydroxyethyl) -3- (3,4-dichlorophenyl) -1- (3-isopropoxyphenyl) acetylpyrrolidine 10 in 1.9 g of 3-isopropoxyphenylacetic acid dissolved in 50 ml of CH2Cl2 , 2.25 ml of triethylamine, then 2.6 g of 3- (2-hydroxyethyl) -3- (3,4-dichlorophenyl) pyrrolidine prepared above. The mixture is cooled to 0 ° C, then 4.42 g of BP are added and the reaction mixture is allowed to warm to room temperature. After 30 minutes, the mixture is concentrated in vacuo, the residue is dissolved in ethyl ether and washed successively with water, dilute

NaH solution, saturated NaCl solution, dilute HCl solution, saturated NaCl solution and NaHC3 ~ 20 solution. The ethereal phase is dried over MgSyn, filtered and concentrated in vacuo to give 3.6 g of the desired compound.

(b) 3- (2-Methanesulfonyloxyethyl) -3- (3,4-dichlorophenyl) -1- (3-isopropoxyphenyl) acetylpyr. j. Rolidine; 2.2 g of the compound prepared above are dissolved in 50 ml of CH 2 Cl 2 and cooled to 0 ° C. 1.5 g • t 1 of triethylamine are added followed by dropwise addition of 0.57 g of methanesulfonyl chloride. The reaction mixture is allowed to stand for 15 minutes at 30 ° C, then concentrated in vacuo, the residue is taken up in ether, washed with water, the ether phase is dried over MgSO 4, filtered and concentrated in vacuo.

The residue is chromatographed on silica gel, eluting with heptane / ethyl acetate 50/50 (v / v) to pure: * 35 ethyl acetate.

I »» · taa 114474 28

The pure compound fractions are concentrated in vacuo, then the residue is taken up in ethyl ether / isopropyl ether to give 2.5 g of the desired compound.

Preparation VII: Scheme 1 - Route B, m = 2.

(a) Optically pure 3- (2-hydroxyethyl) -3- (3,4-dichlorophenyl) -1 - [(3-isopropoxyphenyl) acetyl] piperidine in 16 g of 3-isopropoxyphenylacetic acid dissolved in 500 ml CH2Cl2. 22.5 ml of triethylamine, then 22 g of (-) 3- (2-hydroxyethyl) -3- (3,4-dichlorophenyl) piperidine prepared according to Preparation III (f) above are added. The mixture is cooled to 0 ° C, then 42.6 g of BP are added and the reaction mixture is allowed to warm to room temperature. After 30 minutes, the mixture is concentrated in vacuo, the residue is dissolved in ether and washed successively with water, diluted with NaH solution, saturated NaCl solution, dilute HCl solution, saturated NaCl solution and NaHC3-20 solution. The ether phase is dried over MgSO4, filtered and concentrated in vacuo to give 36 g of optically pure compound.

(b) (+) - 3- (2-Methanesulfonyloxyethyl) -3- (3,4-dichlorophenyl) -1 - [(3-isopropoxyphenyl) acetyl] piperidine 22 36 g of the compound prepared above are dissolved in 500 ml of CH2Cl2 and cooled to 0 ° C. I '' '11.5 ml of triethylamine are added, followed by 6.3 ml of methanesulfonyl chloride dropwise. The reaction mixture is allowed to stand for 15 mi-30 nuts at 0 ° C, then concentrated in vacuo, the residue is dissolved in ether, washed with water, ether phase, dried over MgSO 4, filtered and concentrated in vacuo. <· Hot. The residue is chromatographed on silica gel, eluting with a 50/50 (v / v) mixture of heptane / ethyl acetate to pure ethyl acetate.

• »29 114474

The pure compound fractions are concentrated in vacuo, then the residue is taken up in ethyl ether / isopropyl ether to give 37.5 g of the desired compound. Mp = 72 ° C.

[Α] D 20 = + 25.7 ° (c = 1, in CHCl 3)

Preparation VIII: Scheme 1 - Route B, m = 3.

(a) 3- (2-Hydroxyethyl) -3- (3,4-dichlorophenyl) -1 - [(3-isopropoxyphenyl) acetyl] perihydroazepine in 0.76 g of 3-isopropoxyphenylacetic acid dissolved in 50 ml CH 2 Cl 2, 1.2 g triethylamine, then 1.15 g of 3- (2-hydroxyethyl) -3- (3,4-dichlorophenyl) azepine prepared above. The mixture is cooled to 0 ° C, then 1.77 g of BP is added and the reaction mixture is allowed to warm to room temperature. After 30 minutes, the mixture is concentrated in vacuo, the residue is dissolved in ethyl ether and washed successively with water, dilute NaH solution, saturated NaCl solution, dilute HCl solution, saturated NaCl solution and NaHC3 solution. The ether phase is dried over MgSO4, filtered and concentrated in vacuo to give 1.8 g.

(b) 3- (2-Methanesulfonyloxy-ethyl-3- (3,4-dichloro) -phenyl) -1 - [(3-isopropoxyphenyl) -acetyl] -peridine-hydrazazine; The compound prepared is dissolved in 50 ml of CH2Cl2 and cooled to 0. 0.38 g of triethylamine is added, followed by the dropwise addition of 0.44 g of methanesulfonyl chloride The reaction mixture is allowed to stand for 15 minutes at 0 concentrate in vacuo, dissolve the residue in ethyl ether, wash with water, dry the ether phase 30 over MgSO 4, filter and concentrate in vacuo, chromatograph the residue on silica gel, eluting with 50/50 (v / v) heptane / ethyl acetate. to pure ethyl acetate.

The pure compound fractions are concentrated in vacuo, then the residue is taken up in ether / isopropyl ether to give 2 g of the desired compound.

(11) 114474 (c) 3- (2-Benzenesulfonyloxyethyl) -3- (3,4-dichlorophenyl) -1 - [(3-isopropoxyphenyl) acetyl] -piperidine.

To 11.3 g of the product obtained in Preparation VII (a) above, in a solution of 160 ml of CH 2 Cl 2 and cooled to 0 ° C, are added 4.6 ml of triethylamine followed by dropwise addition of 4.3 ml benzenesulfonyl chloride. The reaction mixture is kept at ambient temperature for 18 hours and then treated sequentially with 100 mL HCl, 100 mL 10% Na 2 CO 3, and 100 mL water. The organic phase is poured off, dried over Na 2 SO 4 and concentrated in vacuo. The residue is chromatographed on silica gel using cyclohexane / AcOEt (80/20, v / v) as eluent. The pure product fractions are concentrated to give 8.4 g of the desired product.

Example 1 (I) '' M = ~ ^ 0): T = "CH 2 *: R = -CH 3; Q = H; Ό-iPr; Am® = 'aq = ci ©:" a% I »;; * 0.75 g of 4-phenylquinuclidine, synthesized according to T. Perrin, J. Rg. Chem., 1957, 22, 1484-1489, and i * V * 1 g of N- [2- (3) , 4-Dichlorophenyl) -4-methanesulfonyloxybutyl] -N-methyl- (3-isopropoxyphenyl) carboxamide prepared according to EP-A-428 434 is dissolved in 5 ml of acetonitrile. The residue is dissolved in CH2Cl2, then washed successively with 2N HCl, washed with saturated NaCl solution, the organic phase is dried over MgS4, filtered The residue is taken up in ethyl ether to give 0.39 g of 1- [3- (3,4-dichlorophenyl) -4- (N-methyl-3-isopropoxyphenylacetylamino) butyl). ] -4-phenyl-l-azoniabicyclo [2.2.2] glycero (Compound 1) mp 98-100 ° C.

Example 2 (OrAr? - ^): t.-CH2-; R..CH3; q.h; o— iPr

Cl

By proceeding as in Example 1 and starting from 10 optically pure (-) - N- [2- (3,4-dichlorophenyl) -4-methanesulfonyloxybutyl] -N-methyl- (3-isopropoxyphenyl) carboxamide EP-A-428434 provides (-) - 1- [3- (3,4-dichlorophenyl) -4- (N-methyl-3-isopropoxyphenylacetylamino) butyl] -4-phenyl-1-azonia bicyclo [2.2.2] octane chloride (Compound 2), optically pure. Mp = 97-99 ° C.

: · [Α] D 20 = - 47.2 ° (c = 1, in CH 3 H) • I Example 3 • Ϊ: (I): Ar = ~ (^^: t = 'CH 2 -; CH3; Q = H; O— iPr t;; Ar '= - ^^; Am® = \' A ° = a ° i '1 20 σ •% * I 1

By proceeding as in Example 1 and using quinucleic acid as the tertiary amine, 1- [3- (3,4-dichlorophenyl) -4- (N-methyl-3-isopropoxyphenylacetylamino) - 114474 32 butyl] -1 -azonium bicyclo [2.2.2] octane chloride (Compound 3). Mp = 68-70 ° C.

Example 4 (I): Ar =: T = -CH 2 -; R + Q = - (CH 2) 3 -O-iPr; Α · β · 0 → »: »β.αθ 5 ° 2.25 g of 4-phenylquinuclidine and 3.17 g of mesylate prepared according to Preparation VII (b). is dissolved in 30 ml of acetonitrile and the reaction mixture is heated under 10 reflux for 10 hours. The mixture is concentrated in vacuo, the residue is dissolved in CH 2 Cl 2 and washed successively; with 3N HCl solution, then with saturated NaCl solution, the organic phase is dried over MgSO 4, filtered, and concentrated in vacuo. The residue precipitates from acetone / 15 n / ether to give 2.8 g of (+) - 1- [2- [3- (1,3-dichlorophenyl) -1 - [(3-isopropoxyphenyl) acetyl] - 3- [piperidinyl] ethyl] -4-phenyl-1-azonia bicyclo [2.2.2] octane chloride as optically pure (Compound 4). Mp = 132 ° C.

[α] D 20 = + 16.3 ° (c = 1, in CH 3 H) Example 5 (I): Ar = - <Q> T a -ch 2 -; R + Q = - <ch2) 3- ;; o - ί Pr b; »E.

* Cl t <1 1 4474 33 2.65 g of 4-phenylquinuclidine and 8.3 g of benzenesulfonate prepared according to Preparation VII (c) are dissolved | 40 ml of acetonitrile, and the reaction mixture is heated under reflux for 6 hours. The mixture is concentrated in vacuo, the residue is treated with CH 2 Cl 2 and washed successively with 1% aqueous benzenesulfonic acid and then with water. The organic phase is dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue precipitates in isopropyl ether to give 8 g of optically pure (+) - 1- [2- [3- (3,4-dichlorophenyl) -1 - [(3-isopropoxyphenyl) acetyl] -3-piperidinyl] ethyl] -4-phenyl-1-azonia bicyclo [2.2.2] octane-benzenesulfonate (Compound 5). Sp. 195.5 ° C. [α] D = -50.7 ° (c = 1, in CH 3 OH).

In a manner analogous to Examples 1-5, compounds 6-12 of Tables I and II are prepared.

j t $, * t 114474 34 i i

Table I

R

- {CHo) o-CH-CHT-N-CO-T-Ar \ py \ _ / © ""

Ar '

Cl 0

Pre-Sp. ° C

character / Ϊγο Ar 'R T Ar [<I] D * 6 fel ch3 - ρϋΐ 150 -gPl' 57'9 *

Cl F

7 1 (^) CH 3 - OQ) F ^

ΓΓ31 ch3 -ch3- O

: · 'XpP ^ / ^ OiPr

Ί F

:? 01,? - OCH3 9? (1 (1H - (OT I04-10? * 1 'xp ooch3 *)) The rotations, pp, were measured at 20 (c = 1, CH2).

114474 35

Table II

CH2) 2 4 ^ .N-CO-CH2-Ar Αθ to ^ Y Cl __ Cl__

Ex .__ Ar__ΑΘ_Sp. ° C and / orMp 10 Υ Cl® 125; -16.0 * O i Pr n £ Q] Br © 196-198 '"oh Λ .1 12 [" (ij "Cl © 156-160' f +12" (0 = 1; MeOH),

j__OiPr___Y

Example 13; (I): Ar = (jQ ^; T = -CH 2 -; Q = H).

: '-: R = -CH 2 -CH 2 -O CO CH 3. Ar '= [(3

Cl

Am + =; Aö = Cf © \ W / \ _ / © 114474 36! t

Step 1 8.2 g of ethyl oxalyl chloride are added dropwise to a solution of 19 g of 2- (2-tetrahydropyranyloxyethyl) -3,4-dichlorobenzene-ethanamine (obtained according to Preparation 5 (I), step (b)) and 7 g of triethylamine. The reaction mixture is stirred for one hour at ambient temperature and concentrated in vacuo. The residue is taken up in ethyl ether, then washed successively with water, dried over Na 2 SO 4 and concentrated in vacuo. The residue Kro-10 is chromatographed on silica gel using CH 2 Cl 2 / CH 3 OH (100/1, v / v) as eluent to give 16 g of N-ethyl-oxalyl-2- (2-tetrahydropyranyloxyethyl) -3,4-dichloro-benzene-ethanamine.

Step 2 16 g of the product obtained above are dissolved in 40 ml of THF and the solution is added dropwise to a suspension of 1.7 g of LiAlH 2 in 5 ml of THF at 50 ° C. The reaction mixture is refluxed for 4 hours, then cooled, hydrolysed, filtered and concentrated in vacuo. The residue is chromatographed on silica gel using CH 2 Cl 2 / CH 3 OH (100/5, v / v) as eluent. 14 g of N- (2-hydroxyethyl) -2- (2-tetrahydropyranyloxyethyl) -: 3,4-dichlorobenzenethanamine are obtained in the form of an oil.

•, * Step 3 '. ** 25 3, 55 g of BOP are added at 0 ° C to a solution of 2.4 g of the product prepared above, 1.1 g of triethylamine and 1.3 g of 3-isopropoxyphenylacetic acid in 60 ml. in CH 2 Cl 2. The reaction mixture is stirred for 1 hour at 0 ° C and subsequently concentrated in vacuo, treated with AcO-Et, washed with water, dried over Na 2 SO 4 and concentrated in vacuo. The residue is chromatographed on silica gel with CH2Cl2 / CH3OH (100/3, v / v) as eluent to give 2.2 g of N- (2-hydroxyethyl) -N-3-isopropoxy- '. phenylacetyl-2- (2-tetrahydropyranyloxyethyl) -3,4-35-dichlorobenzene-ethanamine in the form of an oil.

114474 37

Step 4 0.41 g of acetyl chloride is added to a solution of 2.2 g of the product obtained above in 10 ml of CH 2 Cl 2 in the presence of 56 g of triethylamine in CH 2 Cl 2. The reaction mixture 5 is stirred for 1 hour and then concentrated in vacuo, washed with ethyl ether, water, dried over Na 2 SO 4 and concentrated in vacuo to give 2 g of N- (2-acetoxyethyl) -N-3-isopropoxyphenylacetyl-2- (2- tetrahydropyranyloxyethyl) -3,4-dichlorobenzene-10-ethanamine in the form of an oil.

Step 5 2 g of the oil obtained above are dissolved in 20 ml of methanol saturated with HCl and the mixture is stirred for one hour at ambient temperature. Concentrate in vacuo, treat the residue with AcOEt, wash with water, dry over Na 2 SO 4 and chromatograph the residue on silica gel using CH 2 Cl 2 / CH 3 OH (100/3, v / v) as the eluent. 1.2 g of N- (2-acetoxyethyl) -N- (3-isopropoxyphenylacetyl) -2-hydroxyethyl-3,4-dichlorobenzene-ethanamine are obtained in the form of an oil.

Step 6: 0.5 g of the product obtained above is dissolved in 10 ml of CH 2 Cl 2 in the presence of 0.11 g of triethylamine. 0.125 g of mesyl chloride is added and the reaction mixture is stirred for 30 minutes at ambient temperature. After concentration in vacuo, the residue is successively treated with AcOEt (washed with water, dried over Na 2 SO 4 and concentrated * in vacuo to give 0.5 g of N- (2-acetoxyethyl) -N- (3-isopropoxyphenylacetyl)). -2-mesyloxyethyl-3,4-dichloro-30-ribenzene-ethanamine in the form of an oil.

Step 5 Dissolve 0.50 g of the product prepared above and 0.25 g of β-4-phenylquinuclidine in 1 ml of dimethylformamide and heat the reaction mixture at 80 ° C for 10 hours.

The reaction mixture is poured into water and then extracted successively with aq. AcOEt, washed with water, saturated NaCl-114474 (38 µl), concentrated in vacuo and the residue chromatographed on silica gel using a mixture as eluent; CH 2 Cl 2 / CH 3 OH (100/5, v / v). The pure fractions are concentrated in vacuo, the residue is treated with CH 2 Cl 2 and precipitated by addition of ethyl ether to give 0.45 g of 1- [3- (3,4-dichlorophenyl) -4- (N- (2-acetoxyethyl) -3-isopropoxy) siphenylacetylamino) butyl] -1-azonia bicyclo [2.2.2] octane chloride (Compound 13). Sp. 90-92 ° C.

Example 14 A tablet containing:

250 mg of compound 4

Lactose 80 mg

Polymerized polyvidone 20 mg

Methylhydroxypropylcellulose 10mg Hydrogenated castor oil 40mg

Example 15

Enteric tablet containing: i Tablet:

250 mg of compound 4 6 mg of hydroxypropyl cellulose

Lactose 62 mg: · ': Microcrystalline cellulose 60 mg

Carboxymethyl starch 12 mg: Polyethylene glycol 6000 10 mg 25 Coating:

Endraget L 100 1 mg t *

Dibutyl phthalate 1 mg • t · '·' 'Isopropyl alcohol (evaporated) 28 mg

Example 16 Drinking Solution Containing: 100 mg of Compound 4

Ethyl Alcohol 100 mg \ .. t Propylene Glycol 50 mg • ·

Polyvidone filler 20 mg 35 Glycerin 50 mg:: Artificial flavor 2.5 mg 39 114474

Required amount of purified water ad. 1.0 mg! Example 17

Suspension for injection containing:

50 mg of compound 4 1.5 mg of polysorbate 80

Polyoxyethylene glycol 20 mg

Methyl and ethyl parahydroxybenzoate 1.5 mg

Sorbitol 30 mg 10 Polyvidone filler 10 mg

The amount of water needed to inject the preparation ad. 1 mg

Example 18

Gelatin capsule containing: 2.5 to 250 mg of Compound 4

Modified Corn Starch 50 mg j Talc 25 mg

Anhydrous colloidal silica 1 mg

Stearic Acid 10 mg 20 Lactose Amount Ad. 100 mg!

Gelatin Example 19, '* · Suppositories containing:; 150 mg of compound 4 * 25 Amount required for semi-synthetic glycerides.

t *

»I

Claims (2)

40, 114474 A process for the preparation of a therapeutically useful basic quaternary amide, which is an antagonist of the substance P NK 1 5 receptor, having the formula IF f Ar -T-CO -N-CH-C-CH 2 -CH 2 -Am φ, Αθ 2 | 2 2 (I) Ar 'where 10. Ar is phenyl mono- or disubstituted with a substituent selected from the group consisting of halogen, hydroxy, C 1 -C 4 alkoxy and trifluoromethyl, wherein said substituents are the same or different; or Ar is a naphthyl group monosubstituted with halogen; 15. T is a direct bond or a -CH 2 group; - Ar 'is phenyl disubstituted with a halogen atom, or Ar' is naphthyl; R 1 is hydrogen or C 1 -C 4 alkyl, or o- (C 1 -C 4) alkoxy (C 2 -C 4) alkyl or to- (C 2 -C 4) alkanoyloxy (C 1 -C 4) alkyl; . . - Q is hydrogen; - or Q and R together form a 1,2-ethylene, 1,3-propyl-1-ethylene or 1,4-butylene group; : · * -Am + is a radical selected from the group 1-azoniabicyclo [2.2.2] oct-1-yl, 4-phenyl-1-azonia bicyclo [2.2.2] -25 oct-1-yl, 4 benzyl-1-azonia bicyclo [2.2.2] oct-1-yl, 1-azonia bicyclo [2.2.1] hept-1-yl, 4-phenyl-1-azonia bicyclo [2.2.1] hept-1- yl and 4-benzyl-1-azonia bicyclo; [2.2.1] hept-1-yl; and - A 'is a pharmaceutically acceptable anion, characterized in that a sulfonate derivative of formula II 1 »114474 is introduced! 41! RQ 11 (ID Ar -T-CO-N-CH 2 -C-CH, -CH, -OY I 2 2 Ar 1 wherein Ar, T, R, Q and Ar are as defined above and OY is a leaving group, preferably methanesulfonate - or a benzenesulfonate group, with a tertiary cyclic amine Am, wherein Am is 1-azabicyclo [2.2.2] octane, 4-phenyl-1-azabicyclo [2.2.2] octane, 4-benzyl-1-azabicyclo [2.2 .2] -octane, 1-azabicyclo [2.2.1] heptane, 4-phenyl-1-azabicyclo [2.2.1] heptane or 4-benzyl-1-azabicyclo [2.2.1] heptane in aprotic, in a polar solvent at a temperature between room temperature and 120 ° C, and then the optional anion 15 of the quaternary salt thus obtained is exchanged for another pharmaceutically acceptable anion. Process according to claim 1, characterized in that a compound is prepared wherein Am is 1-azabicyclo [2.2.2] octane or 4-phenyl-1-azabicyclo [2.2.2] octane. I 42 114474