PT96418A - PROCESS FOR THE PREPARATION OF ANTAGONIST DIPHENYLSULFOXIMINS OF MUSCLE RECEPTORS - Google Patents

Description

CS. This invention relates specifically to derivatives of diprolylsulfoximine N-substituted with pyrolidinyl- (alkyl) 5-piperidinyl (alkyl) and aminoalkyl which are antagonists of selective muscarinic agents gastrointestinal and bladder diseases SB-A-1657 discloses certain N-amino-substituted alkyl-Ss-diphenylsulfoximine derivatives which exhibit broncholytic-antispasmodic activity in mammals and which are useful in the treatment of general conditions associated with bronchial- Chemicals =

The compounds of the present invention are useful for the curative or prophylactic treatment of disease states where the reduction of selective contraction of the gastrointestinal smooth muscles and the acetylcholine mediated bladder could be of benefit, such as in the treatment of disorders of bowel motility in particular as in irritable bowel syndrome, and in the treatment of urinary incontinence, emesis or disease. Irritable bowel syndrome is a disorder of the motility characterized by altered bowel habits and constipation and / or diarrhea), distension and abdominal pain. The muscarinic receptor antagonists of the present invention reduce the motility of the intestine thereby having an antispasmodic effect on the intestine without producing, or significantly reducing, cardiac and cardiac effects.

Thus the present invention provides compounds of the invention

(CH 2) 2 (CH 2)

2 m Q | | R f = 0 h or. C1-6 alkyl is L-L-, or X-? Taken together represent -CH2 > - qu 0 f " is an integer from 2 to 53 '.-. 4 is UlU ίΐηιπ 1 ri Π -Π. : - - - - - - - 1, x. an . 1 ig-direct action, 0 or 8p t

R 4 is a group of the formulas

) in which either R w and K 'are each independently H 5, halo,

(C1 -C6 alkyl), -C (= O) -C (= COCH2), -C (= O) * i 4 '

R 2 taken together represent a group of the formula

2 â € ƒâ € ƒâ € ƒâ € ƒâ € ƒX â € ƒâ € ƒâ € ƒX -X- (C1-U-UA '), wherein X â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒX â € ƒâ € ƒâ € ƒâ € ƒâ € ƒ Or R 1 and R 1 and R 2 are each independently H or C 1 -C 4 alkyl or R 3 is hydrogen and R 2 is -SO 2 R 6, -O-O-O-alkyl, - or

R4,4- 'and R4-4 are each independently hydrogen or C1 -C6 alkyl, Hetn is thienyl, pyridinyl or pyrazinyl m is 1, 2 or 3 n is θ5 1 or 2 = ρ is Θ or 15 and V3, A or. : om as conc

The reaction is carried out in the presence of a compound of formula (I) in which X is a direct bond and Ru is as hereinbefore defined. when π tor Ϊ8ΓΟ, pyrrolidinyl or piperidinyl N '5 is unsubstituted by its 2-position at the β-Oâ,, or β-

However, for alkylated groups,

^ Hw! The compound of formula (I) ΉΞ-0Γ * 1j Br or Iinsin or

J

5

Preferred R5 is hydrogen or a group of the formulas

wherein n is 1 or 2; further preferred are R- is 3- or 4-methoxyphenyl; 4-methylenedioxyphenyl, or 4-methoxybenzoylamino.

Preferably m is 2 =

Preferably n is Θ or 1 =

When X contains a pyrrolidinyl or piperidinyl group which is preferably N-substituted 3-piperidinyl or 2-pyrrolidinylmethyl N-unsubstituted C 1-6 alkyl, wherein the N-unsubstituted C 1-6 alkyl group is as previously defined,

jC. III

The pharmaceutically acceptable salts of the compounds of the

(I) include acid addition salts formed from acids forming non-toxic salts such as hydrochloride, succinate, hydroiodide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, mandelate, bsnazole, salicylate, methanesulfonate, bensenesulfonate and para-toluenesulfonate,

J

The compounds of the formula < I) have at least one asymmetric center and thus will exist as a pair of enantiomers or as diastereomeric pairs of enantiomers. Such enantiomers or diastereomeric pairs of enantiomers may be separated by physical methods, for example by fractional recrystallization, by chromatography or HPLC of a racemic mixture of the parent compound or. of an appropriate salt or derivative thereof. Alternatively an individual enantiomer or a particular diastereomeric pair of enantiomers may be prepared from correspondingly pure, purely pure intermediates. The invention includes both the individual stereoisomers of the compounds of formula (I) together with their mixtures,

A particularly preferred compound provided by the present invention is (3R) -N-C1-4-methoxyphenethyl. piperidin-3-yl 3-diphenylsulfoximine or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) provided by the invention can be prepared by the following methods as illustrated in the following Examples section. All compounds of formula (I) may be prepared as shown in Scheme

Scheme i

R 1) Base, strong, solvent) R 2 (III) 1 1 5

2) Y-CH-C-N - (CH 2 -X-R 213-24m

R R

compounds (D or

(IV)

in which R 1, R 1, R 2, R 3, R 4, R 5, p and X1 is as previously defined reliably the formula (1) and Y is a suitable leaving group; and * g. halo (preferably chloro or bromo), methanesulfonyloxy, trifluoromethanesulfonyl, or p-toluenesulfonyloxy

In a typical procedure, a diphenylsulfokimine derivative of the formula (II) is deprotonated with about one equivalent of a suitable strong base, e.g., sodium hydride, lithium butyllithium or lithium diisopropylamide, and then reacted in. situ

with an alkylating agent of the formula. (III) or < ϊν '> * as required * in an inert organic solvent, eg xylene or toluene

The reaction is preferably carried out by addition of the strong base to a solution of compound (II) at about room temperature and under an inert atmosphere of nitrogen or argon), followed by heating the resulting mixture (II) derivative is then cooled to from about 40 DEG C. until the deprotonation process is complete or substantially complete. The solution containing the anion of the diphenylsulfoximine derivative (II) is then cooled, treated with a solution of the alkylating agent and the reaction is warmed to room temperature to, and preferably at reflux temperature of the mixture. The product of formula (I) is isolated and purified by conventional techniques. it is convenient to deprotonate the diphenylsulfoximin derivative (II) in situ to provide the necessary anion, it is also possible to react the alkylating agent directly with a salt of a compound of the formula (II), and "g" the lithium, sodium, potassium or calcium salt *

One skilled in the art will appreciate that, due to a concurrent rearrangement reaction, the use of an alkylating agent (Iv> of formulas

Wherein R 1, m, X 1 'and Y 2 are as defined previously and a compound of the formula (IV) in this process provides a mixture of products of the formula Cl) wherein X is a group of the formulas

(I.e.

-CHR > (XA) N I i 5 (CH) -X-R3 1 m (XB) • I ετ 1

in which R, R% R '"% X " and m is as defined above with respect to formula (1). Indeed, under certain circumstances, the product of the rearrangement may be the exclusive product of the action,

In many cases the attempted preparation of an alkylating agent of the formula CV > or CV1) results in a mixture of the required product together with the corresponding compound of formula (vi) or (iv) respectively. In certain circumstances the product of the rearrangement is the exclusive product of this reaction of preparation of the intermediate

Such mixtures (V) / (V1) can be used directly in this process and the corresponding mixture of products of formula (I) obtained can be separated by means of conventional crosna-graphic techniques

This effect arises because a compound of formula (V) or CVI) can readily form an aziridinium ion <VIX) during the ous preparation for example? under the conditions of the reaction of alkylation (see the journal article, Miocque and J. P, Duels, Chimie Therapeutique, 1969 (5), 333-3B0, and references therein)

This aziridinium ion is opened to two nucleophilic pathways by the anil derivative of the diphenylsulfoximine derivative (II) in the alkylation reaction thereby justifying the observed product mixture (Scheme 2).

V 7. li M (X)) or i X B

J »3 ... |} h |. . . dl is H u is the anion of the compound and the derivative is prepared by disproportionation of a compound. All compounds of the formula ## STR1 ## Can be p Γ 2? The compound according to any one of claims 1 to 5, wherein R 1 is as defined above. In Scheme 35

Acid acceptor, solvent Compounds (I) Y - (CH) -X2 R5 2 m (X) wherein R4 is hydrogen; n, p and X * sSa as previously defined relative to the formula &lt; I) and Y &quot; is a suitable leaving group, Cferfer "alkoxy, Cferferprealkoxy, Cferferprealkoxy, Cferferprealkoxy, Cferferprealkoxy, phenoxy or p-taluene-sulphonyloxy = -

In a typical procedure a compound of formula (VIII) or (IX), as appropriate, is reacted with a compound of formula (X) in the presence of suitable acid acceptor, e.g. sodium or potassium carbonate, When Y x is chloro or bromo, optionally in the presence of sodium or potassium iodide,

The reaction is washed in a suitable organic solvent, eacetonitrile, at from room temperature to, and preferably, at the reflux temperature of the mixture. The product of the formula I) is then isolated and purified by conventional techniques. O) A compound of the formulas)

_ i o &quot; In which R 1, R 2, R 3, R 4, R 5 and R 4 are independently selected from the group consisting of halogen, halogen, halogen, halogen, halogen, halogen, by reaction of a compound of the formula (VIII) in which K, K%, Râ, ..., Râ, ..., Nâ, ... is as previously defined for formula (I), with a compound of the formula wherein: is as defined in this method. The reaction may be carried out using at least one equivalent. and preferably an excess of the vinylheterocyclol of the formula Het-CH-CH--, and optionally in the presence of suitable organic solvent, the rate can be accelerated by means of the reaction temperature is raised either by addition of a suitable basic acidic catalyst, eg benzyltrimethylammonium hydroxide. The product of formula (XI) or <X11> can be isolated and purified by conventional techniques. 4) A compound of the formula (I) wherein X is a

N

1 x where Ks R ~? X s m and p are as defined for formula (Ϊ) and ΡΓ &quot; is as defined for formula (I) with the exception that when

o r

(I &quot;) can be prepared by reducing a compound of the formulas

) in which R 1, R 2, R 3, X is as previously defined in this method, using a suitable strong reducing agent, lithium aluminum hydride, and in a suitable organic solvent, The reaction is typically carried out by extraction of aluminum hydride in situ by treating an ice-cooled suspension of lithium aluminum hydride in tetrahydrofuran with concentrated sulfuric acid. The compound (XI1) is then added and the resulting mixture is stirred at from 0 ° to the reflux temperature of the mixture, preferably at about room temperature. The product of formula (Cl) is isolated and purified by conventional techniques.

(5) Some of the compounds of the formula (I) wherein R3 is a substituted phenyl group may be prepared from other compounds of formula (I) as follows: (a) A substient C1-6 alkyl, preferably methoxy, in the group phenyl may be converted to hydroxy by treatment with hydrogen bromide. Preferred is concentrated hydrobromic acid at from room temperature to, and preferably, at the reflux temperature of the

This dealkylation can also be achieved by treatment with either C -C-C--thiolic acid in the presence of a strong sodium base, or directly with a C Cu-C--thiolate salt, and the sodium salt, in a suitable organic solvent. The reaction may be heated to accelerate the rate. The preferred thiol is butanethiol.

A substituent is in the phenyl group, wherein R 'and R &quot; R 2 and R 3 are as defined for formula (I> 9 may be reduced to -CH 2 NR 1 R 1 with a suitable reducing agent, and "g" diborane. The reaction is typically carried out in a solvent organic solvent, eg tetrahydrofuran, at from room temperature to the reflux temperature of the mixture

A hydroxy substituent on the phenyl group may be converted to -OCO (C ~-C ~) alkyl by acylation using C -C-C alc alkanoyl chloride or bromide, or a C -C-C «alcan alkanoic anhydride

The presence of an acid acceptor, e.g. sodium bicarbonate or pyridine is preferred. The reaction is typically carried out in a suitable organic solvent at 0 ° C to room temperature and heating is not normally required.

If an acid chloride is used the reaction may be carried out in pyrimidine, the pyridine acting either as solvent or as acid acceptor.

If an acid anhydride is used the reaction may be carried out in the presence of an excess of acid anhydride and in the absence of an additional solvent or a

SC .1. R &gt; The

(d) A substituent of -Cutyl, NH2 in the phenyl group, wherein s is = 1 or 2; can be converted to - CChL ~ &gt; (C1-C4 alkyl) by the addition of a C1-C4 alkanoyl chlorate or bromide or an alkanoic anhydride C. = -CA = The reaction can be carried out in a similar manner to that described above for the 5CcK &lt; e) A substituent - (CHO &gt; s NH 2 on the phenyl group, wherein s is 1, 1 or 2 'can be converted to -CH (CH 2) n NHC 10 C 1-4 alkyl &gt; by reaction with either a C --C -s-sulphonic alkoyl chloride or bromide or with a C -C-C alc-alkanoic anhydride in an appropriate organic solvent, the presence of an acid acceptor, such as such as pyridines, sodium bicarbonate or sodium or potassium carbonate. When a sulfonyl chloride is used the reaction is most conveniently carried out in pyridine, with pyridine as either solvent or acid acceptor. The reaction is usually carried out under nitrogen. cable from øC to room temperature and no heating is required, A substituent on the phenyl group, wherein s is Θ, 1 or 2, may be converted to -C (CH)) by reaction with sulfamide. The reaction is typically carried out at reflux temperature in a suitable organic solvent, "1,4-dioxane"

(g) A hydroxyl substituent on the phenyl group may be converted into C 1 -C 3 alkoxy by first reaction with a suitable strong base, such as sodium hydride, and then by reaction with a C 1 -C 3 alkyl bromide or The reaction is typically carried out at about the temperature

in an N, N-dimethylformamide solvent. (H)

A substituent -CCbU} -NH, .c. s . in the phenyl group, wherein s is 0, 1,4-dichloromethane, or 2, may be converted to - (C 1 -C 6) alkyl by reaction with a C 1 -C 4 alkyl isacyanate. The reaction is typically carried out at about room temperature in an appropriate organic solvent, eg,

Cl) A (C alquil-C substitu) alkyl substituent on the phenyl group, wherein s is 1 or 2, can be hydrolyzed to -C (O) -NH₂ under aqueous conditions using a Ce .g. hydrochloric acid) or base. sodium or potassium hydroxide). The reaction is usually heated to accelerate the rate. -S-O in -CH, -NRR 'Fi', wherein R "and R &quot; , each of which is represented by (i) A -CH2 OH substituent in the phenyl group may be converted, independently, into H or C1 -C4 alkyl, first by reaction with a suitable halogenating agent, eg yionyl chloride, and secondly by reaction with ammonia or with the appropriate amine. Reaction with thionyl chloride is typically carried out with heating, preferably under reflux, and optionally in a suitable organic solvent, e.g. dichloromethane. The reaction with ammonia or the amine is typically carried out in a suitable organic solvent, e.g. ethanol, at room temperature to the reflux temperature of the solvent; conveniently a pump is used as the reaction vessel "

The intermediates used in the preparation of the compounds of formula (I) provided by the invention may be prepared

. 5xXV * O

ALSO

A method of preparation of the invention is disclosed in US Pat.

'. ianos or tòrmu1 poaesn j

ET

Hs acid metabolism

I

(-CH (CH,) CH,, CH 4, CH 4, CH 4, CH 4

- (L-H)

K

M

(XVII) i

f 11 &gt;

Siri ΓΠ; . . The compounds of formula (I) are as defined in formula (I): ## STR4 ## in which R @ ,. 1 _ ?' I have defined for TÒ & f fUUU. I am

Torsnui

V

or (XV) is alkylated with a compound of the formula &lt; X &gt; in the presence of a suitable acid acceptor, and g = sodium or potassium carbonate, and in a suitable organic solvent, the reaction is preferably heated under reflux when Y is chloro or bromo, the reaction is optionally carried out in the presence of sodium or potassium iodide, The secondary amine of formula (XIV) may be methylated in order to provide the tertiary amine (VII), wherein R is methyl) using standard procedures. The methylation may be carried out by means of (XVI) with either an aqueous solution of formaldehyde in formic acid under reflux conditions or by reaction of (XVI) with a solution of formaldehyde in methanol in the presence of sodium cyanoborohydride, the alcohol of formula (VII) may be converted into a compound of formula (II) by conventional techniques, and "g" when Y represents chlorine or. bromo, by reaction with thionyl chloride or bromide respectively? more preferably, when Y is chloro, the compound &lt; III &gt; is formed by reaction with methanesulfonyl chloride in dichloromethane in the presence of triethylamine

Intermediates of the formula (XIv), (XV), (XIV) and (VII) used in the preparation of compounds of the formula &lt; III &gt; The protective groups suitable for this purpose may include those listed in &quot; Protective Broups in Organic Synthesis &quot;, Theodora W = Greene (John Wiley &amp; A protected compound (IX) may then be deprotected by a standard procedure prior to conversion to compound (III) = eg. When the hydroxy group is protected with triphenylmethyl the protecting group may be removed by refluxing in aqueous acetic acid, 3 &gt; Intermediates of formula (IV) may be prepared as illustrated in Scheme 5s

EsguMi ... 5

H (XVIII): Y- (CH 2) -X-R, of acids 2m * (X)

2 m (XIX) (CH) -XX-R 5

N 1 1 s (CH) 2 m (IV) where R '' 5 ms η, ρ? X 1 and Y 2 are as previously defined for the formula (1) and Y 1 is as previously defined for formula (X),

Compounds of the formula (IX), which are either commercially available or are prepared by conventional procedures in taiblography, may be alkylated using a compound (X) in the presence of an acid acceptor by a method similar to that described above with respect to alkylation of compounds (XIV) and (XV) (see method of preparation of intermediates (2) above),

A compound of the formula (XIX) can be converted into a compound (IV) by conventional procedures, Y is preferably chloro and such compounds are prepared by reacting the compound (XIX) either with methanesulfonyl chloride or with thionyl chloride, the reaction being carried out in a suitable organic solvent, eg dichlorophenate, in the presence of an acid acceptor, e.g., tristilamine or pyridine, or with thionyl chloride in chloroform.

As previously discussed in method (1) relative to the preparation of compounds of formula (I) above, an attempt to prepare an intermediate (V) or (VI) may result in a mixture of products of formulas (V) and (V) which is obtained due to the formation of the aziridinium ion (VII) under the preparation conditions used. In fact, in certain circumstances the product of the rearrangement may be the exclusive product of the reaction. Such mixtures of products (V / VI), when formed, are usually used directly in the synthesis of compounds of formula (I) without further purification. 4) Intermediates of formula (VIII) and (IX) can be prepared as illustrated in Scheme 6s

C.BQUEMB-5

1) Solvent, strong base R | -CH 2 -C 1, R 1 (XX) Y - (ch 2) r 2 (G H 2) p Ύ

N I

(XXI) Z

J

(XXII)

Compounds (VIII) or (IX: 1) R 5 is unsubstituted. How they would prefer to define pairs at IC50 is a sapa rre group. y y y y y y y o o "e = q * p &quot; t o 1 u on O "lo> and Z &amp; a suitable protective group? (II) is alkylated with a compound (XX) or (X XI) for the same as disclosed in Method (I) in the preparation of compounds of the above formula (I), wherein instead of an alkylating agent of the formula (III) or (IV) is used, the resulting product, (XXII> du (XXIII), may be deprotected (2-methoxycarbonylamino) hydride in toluene, in order to provide a compound of the formula (VIII) wherein Râ,, is hydrogen, The alkylating agents of the formula and the vinylheterocycles of the formula Het-OH-CH ou or are car-eide compounds which may be commercially available, or are prepared by conventional procedures according to the previous literature. 6) Intermediates of formula (XIII) may be prepared as shown in Scheme 7, (3).

Y (XXIV) C0 (C1 or OH) 1 &quot; (CH, 2p

(XXVI) (XXVI) CONH- (CH) -X1-4 L-Y (XXVI) (CH2) p (CH2)

A compound of formula (XXVI) may be prepared from an amine of formula (XXV) either by acylation with a suitable acid chloride of formula CXXIV, Cl) in a suitable solvent e.g. toluene, and in the presence of a suitable acid acceptor, e.g. pyridines or triethylamine, or by reaction with a carboxylic acid of formula (XXIV, OH) under standard peptide coupling conditions.

A CXXVII amide) may be cyclized to a lactate (a). (IXXVII) under standard conditions, for example when Y &quot; ' ε Y 'are both bromine by stirring the amide (XXVI) with IKA-40 (I) fimberlit resin, dichloroethane and aqueous sodium hydroxide solution at about room temperature. The lactase (XXVIII) can then be reacted with an anion formed from a diphenylsuccinimine derivative (II) to provide a compound (XIII) using an alkylation method similar to that described in method (1) relative to the preparation of compounds of formula (I) above. The starting materials of formulas (XXIV) are (XXV) or are known compounds which may be commercially available, or are prepared by conventional procedures according to the prior literature.

Pharmaceutically acceptable acid addition salts bSd readily prepared by mixing solutions containing the free base of the free base are the desired acid. The salt generally precipitates from the solution, is collected by filtration, or is recovered by evaporation of the solvent. The selectivity of the compounds as phoscarinic receptor antagonists can be measured as follows.

Male guinea pigs are sacrificed and the ileum is removed from the trachea to the bladder and the right atrium which are suspended in physiological saline solution under a resting tension of 1 °; at 32 ° C aerated with 0% to 95% and 5% to 5%. The ileum, bladder and tracheal connexions are recorded using an isotonic transducer (ileum) or isometric (bladder and trachea). The frequency of contraction of the right atrium ds spontaneous beat is derived from contractions recorded isome-tricamanie »

The dose response curves for both acetylcholine (ileum) and carbachol (trachea, bladder and right atrium) are determined using a contact time of 1-5 minutes for each agonist dose until the maximal response is reached The organ bath is removed and the vessel is filled with physiological saline containing the lowest dose of the test compound. The test compound is allowed to equilibrate with the tissue for 2 minutes, and the agonist dose response curve is repeated until the maximal response is obtained. The organ bath is removed and the vessel is filled with physiological saline containing the second concentration of the test compound and the previous procedure. Typically, four concentrations of the test compound are evaluated in each tissue.

The concentration of the test compound causing the doubling of the agonist concentration to produce the initial response is determined by Arunlakshana and Schild (1959), Brii et al., Phanncol. , 1.4, 48-583. Using prior analytical techniques, the tissue's suitability is determined relative to. muscarinic receptor antagonists. Activity against agonist induces bowel or bladder contractility compared to changes in heart rate, is determined in anesthetized dogs. Oral activity is calculated in conscious dogs by determining the effects of the compound, for example, on the heart rate, on the pupil diameter and gut motility. The affinity of the compound for other cholinergic sites is determined in mice after either intravenous or intraperitoneal administration. In this manner the dose causing duplication of pupil size is determined as well as the dose that inhibits the salivation and tremor responses to 5% oxyhemoglobin

For administration to humans in curative or prophylactic treatment of diseases where reduction of selective contraction of gastrointestinal smooth muscle s of the acetylcholine-mediated bladder could bring benefit, such as in the treatment of disorders of bowel motility, particularly as in urinary incontinence, edema or diverticular disease, the crossover dosages of the compounds will be in the range of 3.5 to 35 mg per day for an average adult patient (70 kg). , for a typical adult patient the individual tablets or capsules will typically contain from 1 to 250 mg of active compound in a suitable pharmaceutically acceptable carrier or carrier for administration in single or multiple doses once or several times per day. Dosages for intravenous administration is typically within the range of 0.35 to 35 mg per single dose, as required. In practice, the physician will determine the actual dosage that will be best suited to the individual patient and will vary with the age, weight, and response of the particular patient. The above dosages are exemplary of the average case, but there will, of course, individual situations in 33

that higher or lower dosage ranges are deserved and these stretch within the spirit and the present Smhito invents "

For human use, the compounds of formula (I) may be administered alone but will generally be administered in admixture with a pharmaceutical carrier chosen in view of the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets, containing excipients such as starch or lactose, or in capsules or ova, either alone or in admixture with excipients, or as eluents or suspensions, containing flavoring and coloring agents. »For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example, salts or glucose in an amount sufficient to render the solution isotonic with the blood"

Thus, in a further aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier,

The invention also includes a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament, particularly for use in the treatment of irritable bowel syndrome. The invention further includes a compound of formula (1), or a pharmaceutically acceptable salt thereof. a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of diseases associated with disorders of bowel motility, such as

irritable bowel syndrome and for treatment of emesis, diverticular disease and urinary incontinence. The invention further includes a method of treating a human to cure or prevent either a disease associated with bowel motility disorders such as a syndrome of the irritable bowel * or emesis * diverticular disease and urinary incontinence * which comprises treating said human with an effective amount of a compound of the formula &quot; or, where appropriate, a pharmaceutically acceptable salt or composition thereof The invention also includes any novel intermediates disclosed herein such as those of formulas (VIII) and (XIII).

Drying Examples illustrate the invention;

J

The title compound was prepared from the title compound as a white solid (EXAMPLE 1A) and (2S-Naphthyl) -N- (4-methoxyphenethyl) pyridin-2-yl) methyl] phenylsulphimylimine Example 1B)

Sodium hydride (8.4% dispersion in 0.40 g) was added to a solution of diphenylsulfonimidazole (2.39 g) in ethanol (50%). The mixture was heated under reflux for 15 minutes, and treated with a solution of (3R, 4R) -4-methoxyphenyl) piperidine (250 g) (see Preparation 1) in xylene (25 ml). The reaction was cooled, diluted with ethyl acetate and water and the layers were separated. The organic layer was dried (magnesium sulfate) and concentrated in vacuo. Silica gel column chromatography using ethyl acetate as the eluent provided two distinct products.

The combined fractions contained in the title vacuum (Example 1A) in the less polar material form were to provide the compound of a pale yellow solid (0.45 g, 10%). , 23 '589 Found

Falls; C, 71.5; H, C 3 71.7; H, 7, θ " M, 6.3; 752? N,? 4%.

The fractions containing the more polar material were combined and concentrated in vacuo to provide the title compound (Example 1B) as a pale yellow oil (1.5 g, 34%). cr

Calc'd: 80 DEG-50 DEG (c = Ι, Φ in ethanol).

Found: C, 71.3; Δ, 6.7? N, 6.1; Requires C, 71.7; H, 7.2; hl, or 4%.

EXAMPLES 2f, 2B, 5A, 3BS 4A-4B. 5fl and oB

Examples of the following table are for compounds of the general formula

The Examples were each prepared by means of 37-

•The?

3 &gt; (I.e.

A method similar to that described with respect to Examples 1A and 1B is obtained by reacting diphenylsulfoxinfin with sodium hydride in hexane at reflux and treating the mixture with the appropriate alkylating agent followed by work-up of the The starting material used in the preparation of Examples 4A and 4B was obtained as described in Preparation 4 as the hydrochloride salt. This was converted to the corresponding free base for use in the basification reaction with 2M aqueous sodium hydroxide solution , exhalation of the aqueous mixture with diethyl ether, drying of the organic extract over sodium sulfate followed by concentration in vacuo to provide the required material.

4- (X)

j

J

J

. EXAMPLE 6 N-Π &quot; <4> HetPKxfemethyl. &gt; PiParidin-6-yl Idiphenylsulfoximine

A solution of concentrated sulfolic acid (82 mg) in tetrahydrofuran (2 ml) was added dropwise over 15 minutes to a stirred suspension, cooled by 1x10% lithium aluminum hydride (64 mg) in tetrahydrofuran (2 ml) ml) .The mixture was stirred with ice-cooling for one hour, treated with a solution of 1- (4-methylphenethyl) -2-o-apiperidin-3-ylidiphenylsulfoimimin &lt; (See Preparation 11) in tetrahydrofuran (6 ml) and then further stirred at room temperature for 4 hours. The mixture was quenched by the dropwise addition of a saturated solution of The residue was purified by silica gel chromatography by gradient elution using 0-2% methanol / dichloromethane as the eluant The appropriate fractions were combined and evaporated to a vacuum to afford the title compound as a white solid. of a colorless solid (117 mg, 33%), m.p. 133 - 135Â ° C, which was characterized by 1 H-NMR spectroscopy,

H-1-RfN &lt; CDC1 &gt; S = Cdd, 3-B 7,, 14 <d, d = 8Hz 5 2H) 3 6.82 < (M, 2H) ppm: 8.8 (2H, 2H), 3.86 (m, 2H) (s, 3H), 5H), 2.19 (t, J = 7 Hz, 1H), 7 (5R) -N-Cl- <4-Hydroxyphenethyl) piperidin-5-yl 3-diphenylsulphoximine

A solution of (R) -M-ri-4- [N, N-dimethyl] piperidine-3-yl] (see Example 1A), 48% (8%) bramyric acid) was heated under reflux for 1.5 hours, then cooled and evaporated in vacuo. The residue was made with saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The combined organic extracts were washed with water, dried over sodium sulfate and evaporated in vacuo to give the title compound as a pale brown oil (61 mg, 31%).

J

J

EXAMPLE 6 N-L2 -COR4 -C4 -methoxyphenethyl-N-methyl-amino-2-phenylpropane-1-

Sodium hydride (85% dispersion in oil * 33 mg) was added to a solution of diphenylsulfoximine (217 mg) in toluene (50 ml) and the mixture was heated under reflux for 15 minutes cooled and treated with a solution of The title compound was prepared from the title compound as a white solid (0.25 g) in dichloromethane (5 ml) at 0øC. The mixture was heated under reflux for After cooling to room temperature and diluting with ethyl acetate and water, the layers were separated and the organic layer was washed with water and dried over sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel using a gradient elution using 5% methanol / dichloromethane as eluent The appropriate fractions were combined and evaporated in vacuo to give the title compound (5. mg, 19%) as a white solid. of a colorless foam. • 5 "• 5" Plumbing υ2ώΜ32 * ^ 2υ2 ^ C5 7152H? 7.5? EXAMPLE 9 N-L (2H) -1 - [(4-Methoxyphenethyl) -N-isopropyl] -aminoprop-1-yl] -phenifenylsulfonyl] compound of the formulas

CH 3 was prepared by a method similar to that used in Example 8 employing 1-chloro-2 (S) -L-4-methoxyphenethyl] -N-methylaminopropane (see Preparation 2i) instead of i 2-methylpropane as starting material. The title compound was obtained in the form of an oil. The title compound was obtained as an oil (1: 1). 754§ WPOS5s

The following Preparations illustrate the preparation of starting materials used in Examples 4 /

(ΚΚ) - C1 ο γο- 1 - (4-use to i f in e t i 1) ρ i per x o i i

CH2 Cl2

A mixture of € 30 and € 10 is the same. j. (4-methoxyphenyl) -3-oxo-4-methoxy-4-methylthiophene; β. (1.3 ml) (3: 1) of the title compound was obtained as a white solid (0.8 g). The reaction mixture was cooled to -78 ° C. The reaction mixture was cooled to -78 ° C. O ;; SeC-S SObSi '3L; I T Θ. . The 0 0VS pOr'ad *; to give the title compound a pale brown oil (4, dq), which was obtained by the method of 1 H-NMR spectroscopy and used directly in the preparation of the compounds of formula (I). 1 without erection.

1 H-NMR (300MHz, CDCl3): Î'= (m, 1H); . 2.3? t = 1. d = 8Hz &gt; (D, 1H, J = 14Hz, 1H), 7.43 (d, 1H, J = 8Hz) (4H).

Preparation (5H) -Chloro-1- (3,4-dimethylphenyl) diphenethylpiperidine and (2S) -promos-tyl-1- (5,4-naphthylmethyl) pyrrolidine

(4 ml) was added cautiously to a mixture of &lt; 2S &gt; -C1- (3,4-dimethylenedioxyphanethylethyl) pyrrolidinemethanol (5 g) (see Preparation 7) and pyridine (Θ.2 ml ) was added dichloromethane (70 ml). The resulting mixture was heated under reflux for 3 hours, then cooled and evaporated in vacuo. The residue was triturated with diethyl ether and the resulting solid was collected by filtration, dissolved in water, basified with aqueous sodium hydrogencarbonate solution and extracted with dichloromethane.

The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give a pale brown oil (2.7 g, 51%). which was shown by means of1 H-NMR spectroscopy to be a mixture of the two title compounds. This mixture was used directly in the preparation of Examples 2A and 2B without purification.

Preparation 3 (5R) -Chlor-1- [2- (4-benzothioxan-6-yl) methyl] piperidine and N, N-chloromethyl-

SOCl3, CH3 Cl3, Pyridine

(± 5 ml) was added cautiously to a mixture of (2S, 2R) -1- (1,4-phenyloxymethyl) -6- (2-ethyl) -6- The resulting mixture was heated under reflux for 3 hours, then cooled and evaporated in vacuo, the residue was crystallized from dichloromethane. triturated with diethyl ether and the resulting solid was collected by filtration, dissolved in water, basified with aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate and evaporated in vacuo.

to give a brown oil (&lt; Θ38Θ g; 75%) = which showed by &quot; H-RnN &quot; spectroscopy to be a mixture of the two title compounds. This mixture was used directly in the preparation of Exampples 3A and 3B without further purification, =

Preparation 4

3-chloro-1 - [(5-methoxyphenethyl) piperidine hydrochloride

A solution of 1- (3-methoxyphenyl) -3-piperidinol hydrochloride (72 g) (see Preparation 1) in thionyl chloride (3 ml) in chloroform (5 ml) was heated under reflux for 1.5 hours, , then cooled and evaporated in vacuo, the residue crystallized from 2-propanal / dichloromethane to give the title compound as a colorless solid (1531 g, 44%) =

J

Preparation to (3R) -D-chloro-N- [3- (methylsulfonyl) piperidine

A solution of methanesulfonyl chloride (1.38 g) in dichloromethane (5 ml) was added dropwise over 5 minutes to a stirred solution of &lt; 23 &gt; (3-methoxyphenethyl) pyrrolidinomethanol (2 , 35 g) in Preparation 9) and triethylamine (25 ml) in dichloromethane (25 ml). The mixture was stirred at room temperature for 1.5 hours, diluted with ethyl acetate, washed twice with aqueous The residue was purified by silica gel chromatography on a gradient elution using ~5% ethyl acetate / dichloromethane as eluent. The residue was purified by flash chromatography (silica gel), dried (MgSO4), dried over sodium sulfate, dried over sodium sulfate and evaporated in vacuo. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a pale brown oil (2θ, 6%, 81%) which was crystallized by means of the spectroscopy 1 H-NMR .1 H-NMR (CDCl3): .delta. = 7.2-2.7.35 (m, 1H), -4.12 (m, 1H), 3.21 (s, 3H), 3.1 5 (d, Sr), 2.36 (t, J = 7 Hz, 1 Î', 2.15-2.27 ppm = O = 74-6.88 (m, 3H), 4.0, J = 7 Hz , 1H &gt;, 3.6-3.9 Cm, Cm, 1 &gt; , 1.5-1, (m, 2 H)

PrggaracSo 6S 2S &gt; .7 Q-4 = Metoxifluenzylhydrazide

A mixture of C₂ }Hirro p pyrrolidinemethanol (3.0 g), 4-methoxyphenethyl bromide (7.9 g, 5 g) and sodium iodide (1.0 mg) in acetonitrile (40 ml) The residue was partitioned between ethyl acetate and acetic acid and the organic layer was washed with water and extracted with 2M hydrochloric acid. The acidic extract was washed with ethyl acetate, concentrated with ethyl acetate, and evaporated under reduced pressure. and extracted with ethyl acetate. The organic extract was dried over sodium sulfate and evaporated under reduced pressure to give the title compound as a colorless oil (4.0 g (D, 2H, d = 8Hz), 6.83 (d, 2H, d = 8Hz), 3.81 (s, 3H), 3.59 (dd, 1H, d = 8 and 2Hz), 3.26-3.46 (m, 2H), 2.3-3.1 (m, 7H), 1.6-2.6 (m, 4H &gt; ppm.

. Preparations of the following table are relative to compounds of general formula

These compounds were each prepared by a method similar to that described in Preparation 6 by reacting (2S) -pyrrolidinemethane with the appropriate alkylating agent in the presence of sodium carbonate and using acetonitrile as solvent. In each case the product was obtained in the form of a colorless oil. The product of Preparation 9 was characterized by H-NMR spectroscopy,

Preparation 18

1-Cyclophylexyphenethyl-4-pipsridinpl

This compound was obtained by a similar method to that described in Preparation 6 using 3-pipsridinol instead of (2S) -pyrrolidineecanol and 3-methoxyphenethyl bromide in 2% of 4-methoxyphenethyl bromide as starting materials. The base free obtained after workup, was dissolved in ether and treated with ethereal hydrogen chloride, the resulting precipitate was collected and dried to give the title compound as a colorless solid (17.7 g, 66% ), mp 140-144 ° C =

Found C? 59? B, 2, N, 553 g Cl = HCl 75H2 O requires; (C6 H5) 2 s = m -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH

Sodium hydrate (dispersion in oil, 0.44 g) was added to a solution of diphenylsulfoximine (2.28 g) in Kilane (25 ml), the mixture was heated under reflux for 15 minutes, and then treated with a solution of S-bromo-1- (4-methoxyphenethyl) -2-piperidone (3 = 3 g) in tetrahydrofuran (10 ml) at 0 DEG C. The reaction was heated under reflux for 3 hours. The organic phase was washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel, using a gradient solution using The appropriate fractions were combined and evaporated in vacuo to give the title compound as a pale yellow oil (1.80 g, 38%) as a pale yellow oil. N, 6.2% â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒC1,9,9 H, Î »b C, 69.65 H, 6.3

Found only required

PREPARATION 12 5-Carboxy-1- (4-fluoro-8-methyl) -pyrrolidone OCH.

Ion exchange resin, aq.NaOH, CH2C12

A mixture of 25S-dihromo- M- (4-methylphenethyl) pentane-mide (13.6 g) (Amberlite ion exchange resin &quot; (46 ml) and 5% aqueous sodium hydroxide solution was stirred at ambient temperature for 24 hours and filtered. The filtrate was diluted with dichloromethane and water The organic layer was washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel using dichloromethane as the eluent The appropriate fractions were combined and evaporated in vacuo to provide the title compound as a colorless oil (8.94 g, 86%).

Found: C, 54.73; H, 1.55; N, 4.75; C, 54.17; H, 5.8; N, 4.5%. preparation i-3 2,5-Dibromo-N-4-methoxyphenethylpiperamide

2-Dibromopentanoyl chloride (3 g, g.) (See Chem. Pharm. Bull. Japan, 195, 1982) was added dropwise over 1 minute to a stirred, ice-cooled solution of 4 (11.2 g) in toluene (130 ml) The mixture was stirred at room temperature for 4 hours and then evaporated in vacuo. The residue was partitioned between 5% aqueous hydrochloric acid and dichloromethane the layers were separated. The organic layer was washed with 5% aqueous sodium bicarbonate solution and water was dried over sodium sulfate and evaporated in vacuo to provide the title compound as a colorless solid &lt; , 34.1 g (79%)) mp 84-86 ° C =

A portion of the product was separated from ethyl acetate / hexane to yield analytically pure material, m.p. 86-87 ° C.

Found: C, 42.58; H, 5.38; N, 3.45. C 14 H 9 BrNO 2 Cs? 42.8, H, 4.79; N, 3.6%.

THE

OO

HOOC

liaih4

(4, q) -quinazolin-5 (4-methylphenyl) phenyl] acetamide. acetic acid, J. Org. X in portions over 30 minutes to a suspension 1 vec. w, p Ui Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ. t. (4), (4), (4), (4) and (4). . -u. temperature at two in Γ8.5 r. b. The reaction mixture was extracted with aqueous sodium hydroxide and filtered. The organic layer was washed with 10% aqueous sodium carbonate solution, dried over magnesium sulfate and evaporated in vacuo

J in order to obtain Cu-tipi in 0 ρ X q ra τi =? * 30 o Spraying of oil oil * 1 H, 9.91%). The title compound was obtained as a white solid.1H NMR (300 MHz, CDCl3)? lt; / RTI &gt; (M + H) +. 5.99 (s, r, f, X, Ri i α T, * T 7 7 and z z Η 2H) = 2! s, R f (t 50 = 7H, e 5 2H), 1.44 (s, 1H), 1 = 6H z. IHJ UKF m utávei lus! (1) ppiTj,

Preparation 15

5,4-methylenedioxyphenethyl bromide

HO

Br PBr 3

A solution of phosphorus tribromide (0.1 g) in carbon tetrachloride (50 ml) was added dropwise over 300 minutes to a stirred solution of 3,4-dimethylenedioxyphenyl alcohol (15.0 g) (see Preparation 3) in carbon tetrachloride (250 ml) and the mixture was heated under reflux for 3 hours, washed sequentially with water (twice), 5M aqueous sodium hydroxide solution and water, dried over magnesium sulfate and evaporated. The residue was purified by silica chromatography on silica gel using carbon tetrachloride as the blender. Appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow oil (8.3 g, 40%), which was characterized by spectroscopy

J

-Hydroxistll &gt; 4-bsn ξ od i ο κ -ano

λm

w "i" C5S &quot; Cl X '* - &quot; X

HO vN.

Br

This coroddsto was described as described in. Pr 4 n 16) and instead 354-methylenedioxyethyl alcohol. The title compound was obtained as a pale yellow oil, which was characterized by 1 H-NMR (CDCl3) spectroscopy 8-6.83 (d, J = 8 Hz, 1H &gt; 6.77 & lt 1H), 6.72 (dd, J = 8 and 2 Hz, 1H), 4.28 (s, 4H), 3.59 (t, J = 7 Hz, 2H), 3.1 J = 7 Hz, 2H) ppm.

Preparation 18 1-Chloro-2- (N-E4-deoxy) phenylene-13-N-methyl-1-aza-2-methyl propane

OCH "32 ch2ci2.

CH 2 Cl, N (C 2 H 5) 3,

Methanesulfonyl chloride (0.78 g) was added to a solution of 2-CN- <4-methoxyphenethyl) -M-methylamino-2-methylpropan-1-ol (2.37 g) (see Preparation 19) and tristilamine (1.01 g) in dichloromethane (4 g, ml) the mixture was stirred at room temperature for 2 hours, then evaporated in vacuo.The residue was taken up in ethyl acetate, washed with aqueous solution to 10% sodium carbonate, dried over sodium sulfate and evaporated in vacuo to afford the title compound as a pale yellow oil (2.3% to 9%), which was punctured - used directly in the Exempla a facade & ber-rdaçâo or in addition "

PREPARATION 19 5-Ethyl-4-methoxyphenyl) -N-methylamino-2-methylpropan-1-ol

ch3

Aqueous solution of formaldehyde (25.88 g) was added to a stirred solution of 2- (4-methoxyphenethylamino) -2-methylpropan-1-ol (3.35 g) (see Preparation 20) in formic acid (3.45 g ) and the mixture was heated under reflux for 2.5 hours, acidified with 2M hydrochloric acid, washed with ether, basified with solid sodium hydroxide and extracted into ethyl acetate. The organic extract was dried over sodium sulfate and evaporated in vacuo. The residue was triturated with hexane to give the title compound as a colorless solid (3.times.200 g.). 9%) "iΘΘΘ C C C» »» »» »» »» »» »» »» »» »» »» »» »» »» »» »» »» »» »» »» 9 9 9 9 9 9 9 9 9. C, 70.58; H, 958; N? 559% *

Found C1 requsm

D

Preparation 2C? 2- (4-methoxyphenylamino) -Î ± -methyl-propan-1-ol OCH-

A mixture of 4-methyl-2-phenylethylamine and potassium carbonate (13.88 g) and potassium iodide (8.0 g) in acetonitrile (1 ml) was heated under reflux for 2 hours and evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was separated, stripped over sodium sulfate and evaporated in vacuo. The residual solid was recrystallized from ethyl acetate / hexane to provide the title compound (6.6 g, 61%). m.p. 114-110 ° C. Found: C, 57.5; H, 9.8; N, 6.22; C, 69.9; H5955; N, 6.3%.

Found 0β. ~ Η? ΊΝ0ο requsr;

; 1 \ .,

PREPARATION 21 1-Chloro-2 (3) - (N-C4-methoxyphenethyl-N-methyl) aminopropane

This compound was prepared as described in Preparation 18 using &lt; 2S &gt; - (N "E4-methoxyphenethyl) aminopropan-1-ol (see Preparation 22) instead of 2-N- (4-methyl) &gt; 2-methylpropan-1-ol The title compound was obtained as an oil which was crystallized by spectroscopy from &lt; RTI ID = 0.0 &gt; H- (D, J = 8 Hz, 2H), 6.85 (d, J = 8 Hz, 2H), 4.08 (t, J = 7 Hz, 1 H), 3.8 (s, 3H), 2.56-2.85 (m, 1H), 2.39 (s, 3H); 3 1.48 (d, J = 7 Hz, 3H) ppm

J i

2 (S) -TN-β4-Mstoxyphenethyl) -N-methylpromopropan-1-ol

A solution of C2S> CN (4-methoxyphenethyl) -N-methylamino-N- (triphenylmethyl) propane (1.6 g) (see Preparation 23) in 89% aqueous acetic acid <29 ml) was heated under reflux for 3 hours, cooled and evaporated in vacuo, the residue was taken up in dichloromethane and three wells extracted with 2M chloridric acid. The combined acidic extracts were basified with 2M aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed three times with water, dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography, gradient blotting using 1-2% aqueous ammonia, and 88% ethyl acetate as eluents. Appropriate fractions were combined and evaporated in vacuo. vacuum to give the title compound (9.25 g) as an oil

Found: C, 683.6; H, 9.41, 11.4, 11.4, 12.9, 13.9, 16.9, N, 6.2%,

Preparation 2 (S) - (4-Methoxyphenyl) -N-methyl 13-methane. 1-methyl-1-naphthoic acid

Aqueous solution of formaldehyde (6.6 g) was added to a solution of (2S, 4-methoxyethyl) amino] -N-triphenylmethylpropane (4 mg) (see Preparation 24) in methanol (10 ml) was stirred at room temperature for 5 minutes, treated with sodium cyanoborohydride (40mg) and stirred at room temperature for 21 hours. The reaction was evaporated with 15% aqueous sodium hydroxide solution and evaporated in vacuo. The residue was partitioned between ethyl acetate and water and the organic layer was separated, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography, gradient eluting using 0-2% methanol / dichloromethane as eluant. The appropriate fractions were combined and evaporated in vacuo to provide the title compound as a colorless oil (321 mg, 69%). Found: C, 83.85; H, N 2,8 C72H75ND2 = 0s5H2D Cs, 81, θρ 14, 7.7, N, 3, δ% *

V

V

* &lt; b · &gt; - &lt; 4-methoxyphenyl) amino) -1-t-butoxypropionate

A mixture of (2S) -amino-1-triphenylmethoxypropane &lt; 13.16 g) in preparation 25), 4-methoxyphenethyl bromide (8.6 g), sodium carbonate (2 x g) and sodium iodide (g) in acetonitrile (100 ml) was heated under reflux for 4 hours and allowed to cool to room temperature and diluted with ethyl acetate and water was separated and the organic layer was washed dried over sodium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel, using a gradient solution using 3% methanolic / dichloromethane at rt as the solvent. The appropriate fractions were combined and evaporated in vacuo to provide the desired product (7.9 g, 44%) as a colorless oil.

Found: C, 82.07; H? 7.3 * N * 2.9-s C 31 H 33 N 4 O 2: requires C, 82.5: H, 7.6; N, 3.1% &gt;

C2S- 1-yl] phenoxy] propane

(c6h5) 3c6 (c6h5)

CH 2 NHN "

Triphenylmethyl chloride (5 g) and (2S) -aminopropanol (1.5 g) were mixed until a slurry was obtained and heated at 140 ° C for 25 minutes. The resulting hot syrup was poured into dichloromethane and the solution was evaporated in vacuo, the residue was purified by silica gel chromatography, gradient elution using ~4% methanol / dichloromethane plus 0.1% aqueous ammonia Θ388Θ as eluent. The appropriate fractions were combined and evaporated in vacuo to afford the title compound (mp = 513 g), m.p. 176Â ° C. Found: C, 83.25; H, 7.5; N, 4.4; N, 83535 h5 7 5 3 5 N, 4.4%,

Preparation 26

Diphenylsulfonyl) 1) NCI Acetonyl, (C6u5) 2s or K02cch3) 2) aq. (A) (c6h5) 2s = n-cn (b)

V aq. H2S04 (c6h5) 2S = NH · (a) 4-Cyanodiphenylsulfoximine

A mixture of diphosphilsulfoxide (10.3 gsmol) and cyanamide (4.62 g, v5.1 mmol) in acetone (1 ml) was treated with diisobenzene diacetate (35.4 g) The reaction was diluted with acetone (4 ml) and water (100 ml) at 0 DEG C. The reaction was diluted with acetone (4 ml) and water (100 ml) was added portionwise over 5 minutes with chloroform. then treated with potassium permanganate (19.0 g, 0.012 mol) in portions with stirring for 5 minutes. The mixture was stirred at room temperature for 15 minutes, diluted with water evaporated in vacuo to a half volume with sodium hydrogen sulfite is extracted with chloroform. The combined organic extracts were filtered and the filtrate was evaporated in vacuo. The residue was crystallized from ether to give 2-

crystals ρπ f ο 13 - 11 ° C. C = 6433; H, 4.1; N, 11.6; C, 64 "4 | H, 4.2; N, 11.6%.

Found: C, 65.36;

A solution of the product of part (a) (15 ml, 62 mmol) in water (30 ml) and concentrated sulfuric acid (30 ml) was heated under reflux for 1.5 hours. The reaction was allowed to cool to room temperature, poured carefully into a mixture of concentrated aqueous ammonia (8 ml) and ice (8 g) and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water, followed by brine, dried over potassium carbonate and evaporated in vacuo. The residue was recrystallized from aqueous methanol to give the title compound (9.2 g, g, 68%) as colorless crystals, mp 99-102 ° C. C, 66.5 | H, 5.15; N, 6.7; N, 6.45%.

Found: C, . NOS req u er s 1 11

Claims (1)

A process for the preparation of a compound of the formula (I) s or a pharmaceutically acceptable salt thereof each independently of the formulas acceptable? wherein R1 and R2 are C1-6 alkyl; and X is an X τ OU) fT (CIL) l π Wherein R 1 is H or C 1 -C 4 alkyl and R 'is C 1 -C 6 alkyl; or. R 2 and R 3 taken together represent - (CH 2) wherein r is an integer from 2 to 5; DU is an alkyl 1 X is a direct bond, R is a group of - formulas in which taken or R 1 and R 2 are each independently selected from the group consisting of H, C 1 -C 4 alkyl, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 -alkylcarbonyl, -CH 2 CH 2, -CH 2 CH 2, -CH 2 CH 2, -CH 2 CH 2, -CH 2 CH 2, ; ' are each H or u, and t is an integer of halo, &lt; CH_ &gt; NR 8 R 9, R 2, R 2, R 2, R 2, R 3 and R 8 are independently selected from the group consisting of H, the hydrogen and R 'is -C (O) -alkyl, and R ^ is each independently hydrogen or CΛ-C alquilo alkyl; X * τ * &quot; Het &quot; is thienyl or pyridinyl. pyrazinyl; m is 1, 2 or *. (i.e. (R) -cyclohexylcarbamate. cc S &quot; \ ij Γ \ a R "? m s η? ρ s X BSD C O r r r me me me me me me Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y. (c) reacting a compound of Formula (1) to (1): R 2 and R 3 are as defined above with a compound of the formulas: ## STR1 ## in which R 1 is H or 2 or 4-pyridyl, in one or more of the following groups: of the formula (I) wherein Het is as defined otherwise than R Het &quot; ij d &gt; the reduction of Tormulas have a LIQUIA fortBs network agent been used in an inert organic solvent? of modc). S-t.DS · 0B. Τ Γ ΠΗ ΠΗ ΠΗ Ά Ά Ά Ά Ά ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ ΠΗ Wherein R? K 5 X &quot; = m and p are as defined for formula (u) and R 2 is as defined for formula (I) with the exception that when nor &quot; R &quot; (CH 2) n NHCO (C 1 -C 4 alkyl) or -OCOC (C 1 -C 4) alkyl, Wherein R 1 is as defined for formula &lt; I) p 5 in each of the above (a) through (d) -terms, the optional formation of a pharmaceutically acceptable salt of the product. A process according to claim 1, part (a), characterized in that Y is bromo, methanesulphonyloxy, trifluoromethane-sultonyl, or p-toluene and the diphenylsulfoxime of formula (II) may be reacted with sodium hydride n-butyllithium or lithium diisopropylamine and then reacted in situ with the compound of formula (III) or formula C In an inert organic solvent, the process according to claim 1 (b) is characterized in that Y is chlorine, bromine, bromine, trifluoromethanesulfonyloxy or p-toluene- sulfonyloxy and for the compound ds formula (VIII) or (IX) is reacted with the compound of formula (X). in the presence of sodium or potassium carbonate, in an organic solvent. A process according to claim 1 in part (c), wherein the compound of formula (VIII) or (IX) is reacted with an excess of vinyl-heterocycle of the formula Het-CH 2 - in an organic solvent. is. 3. A process according to claim 1 (d) in which the reducing agent is aluminum hydride and the reaction is carried out in tetrahydrofuran. A process according to claim 13 characterized in that a compound of the formula (I) is obtained wherein Re R is both H and X is a group of the formulas -CH (I.e. &quot; ΐ Λ where rf &quot; A process according to claim 1, characterized in that a compound of formula (I) wherein R1 and R2 are both H and X is a group of the formulas - (CIL) v 2 n A process according to claim 6 or 7, characterized in that in formula (I), X is a direct bond. A process according to claim 1, Claim 6, 7 or 8, characterized in that K is 4-methoxyphenyl, 4-hydroxyphenyl, 3,4-methylenedioxyphenyl or 1,4-benzodioxanedione. The compound according to claim 1, wherein the compound of formula (I) is (3R) -N- N - (4-methoxyphenethyl) piperidin-3-ylphenylsulfamoyl] J. PEREIRA DA CRUZ Ofidal Industrial Property Agent RUA VICTOR CORDON, 10-A 3 «1200 LISBOA