LU86002A1 - AMINOPHENOL COMPOUNDS - Google Patents

Description

The present invention relates to aminopheno derivatives! having a stimulating action on BZ-adrenoceptors. processes for their preparation, pharmaceutical compositions containing them and their application in medicine.

5 Aminophenol derivatives having a suironituid or ureidD substitute in the phenol nucleus have previously been described as bronchodilators having a stimulating activity on ô-adrenoceptors.

Thus the British patent \ ° 99358 ** describes compounds of general structure

IjiHSO 2R 1

It H-ZÇHNR3RIt

JkV R2 A · 10 where R1 represents lower alkyl, phenyl or tolyl: X represents inter alia hydroxy; Z represents inter alia -CH (OH) -; R2 and P3 each represent, inter alia, hydrogen; and R ** represents a hydrogen. lower alkyl or aralkoyl or aryioxyalkyl in which the aryl nucleus may optionally be substituted by hydroxy, methoxy or methylatedioxy.

15 British patent Ι \! ° 1 286 225 describes compounds this general structure * f

RNHCON

\ "- · // V.

HO— · '-ÇH-ÇHNÎHR1 * \ _ H i 1.

- =. OH R3 where Ri represents a hydrogen, an aicoy.E e ~ Z 'è 15. jo pn ~ n .. =, A cimethyl-t aminoétnyle or a diethylaminopropyie; P2 and R3 each represent, inter alia, hydrogen; and R4 represents C3 to C5 alkyl. a C3 to C6 cycloaicoyl, a Zl è ZS cycioacoyiméthyie or the group /; l u 2% '• ί R5 -ch <ch3) ch2- ^ R6 where R5 and R6 each represent hydrogen, hydroxy or methoxy.

Dn has now found a new group of aminophenol derivatives, which differ in their structure from those described in the British patents Nos. 993 58 ^ and 1 286 225, and which have a desirable and useful activity profile.

Thus, the invention provides compounds of general formula (I)

QNH

\, • - · R 1

// \\ I

H0— \ fHCH2NH ^ (CH2) B0 (CHa) nAr (I) · = · OH R2 where m is an integer ranging from 2 to 8 and n is an integer ranging from 1 to 7 with the precision that the sum of m + n is from k to 12; Ar represents a phenyl group optionally substituted by one or more substituents chosen from halogen atoms, C1 to C6 alkyl or C1 to C6 alkoxy groups, or an alkylenedioxy group of formula -0 (CH2) dD-, where p represents 1 or 2; RI and R2 each represent a hydrogen atom or an aicoyl group C1 to C3 with the precision that the total these carbon atoms in R1 and R2 is not greater than U \ Q represents a group R3CO-, R3MHCO- , R3RA \ SC2 - or R5SC ^ -, where R3 and R4 each represents a hydrogen atom or an a: C1-coyl group C3 and R5 represents a C1-acyll group at CU \ and their salts and solvates (e.g. hydrates) physiologically acceptable.

It will be appreciated that the compounds of general formula (I) have f or 0Q2UX asymmetric carbon atoms, ie the carbon atom / / / a> 3> *

of the group -CH- and, when R1 and R2 are different groups, the atom Î. OH

of carbon to which they are attached.

The compounds according to the invention therefore include all their enantiomers, diastereoisomers and mixtures, including the racemates. Preferred are 5 compounds where the carbon atom in the group -CH- is in the configuration R. OH

In one aspect, the invention provides compounds of formula (I) where m, n, R1 and R2 are as defined above, Ar represents a phenyl group optionally substituted by one or two substituents chosen between the atoms of halogen, C1 to C3 alkyl or C1 to C3 alkoxy, or an alkylenedioxy group of formula -0 (CH?) 0- where p is 1 or 2.

and Q represents the group R3C0-, R3NHCD- or R5S0.2. - where R3 and R1 "are as defined in formula (I), and R5 represents a C1 to C3 alkyl group.

- In the general formula (I), the chain - (CH_) - can be p. ex.

Z m - (CH2) 2 -, - (CH2) 3 -, - (CH2) 4 -, - (Cl · ^) 5 -, - (CK,) 6 - or - (CH2) 7 and the .. chain - (CH2) cannot be eg · "(CH, ^ -, - (CH ^).“ · - (CH) - or - (CH) -.

LJ LO

Preferably, the total number of carbon atoms in the chains 20 - (CH2) m ~ and - (CH2) - is from 6 to 12 inclusive and can be p. ex. 7, B, 9 or 10. Particularly preferred are the compounds where the total of m + n is 7, 8 or 9,

The preferred compounds of general formula (I) are those where m is 2 or 3 and n is 6, or m is 4 and n is 3, 4 or 5, or m is 5 and n is 2, 3 or 4. preferably m is 5 and n is 4.

In the compounds of formula (I), R1 and R2 can be each, e.g. ex ,, methyl, ethyl, propyl or isopropyl bag? only if one of the radicals R1 and R2 is a propyl or isopropyl group. the other is a hydrogen atom or a methyl group. So p. ex. R 'Can be an atom. 3Q of hydrogen or a methyl, ethyl or propyl group. R2 can be, p. eg, a hydrogen atom or a methyl group. R1 and R2 each preferably represent a hydrogen atom or a methyl group.

a preferred group of compounds is that where Ri st R2 are all L-

U

-AT

two of the hydrogen atoms, or RI is a hydrogen atom and R2 is t a C1 to C3 alkyl group, in particular a methyl group.

In group Q, R3 and R4 can each be p. ex. a hydrogen atom or a methyl, ethyl, propyl or isopropyl group, and R5 may be p. ex. a methyl, ethyl, propyl, isopropyl or butyl group. Preferably R3 represents a hydrogen or a methyl, RU represents a hydrogen or a methyl, and R5 represents a C1 to C3 alkyl. Preferred meanings for group Q are HDD- CH ^ CD-, \ h CD-, (CH ^^ MSO ^ -, and R5SC ^ where R5 is C1 to C3 alkyl, more particularly methyl or n- A preferred group of compounds is that where Q is the group HCD-, MH ,, CO- or, preferably, CH ^ SO ,, -.

Examples of the optional substituents which may be present on the phenyl group represented by Ar include bromine, iodine or, in particular, chlorine or fluorine atoms, or a C1-C3 alkyl group (e.g. methyl or ethyl), or a C1 to C3 aicoxy group (e.g.

- methoxv or ethoxy). The pheny group represented by Ar can p. ex. contain one or two substituents, which may be present in positions 2, 3, 4, 5 or 6 on the phenyl ring. Ar is preferably a phenyl group optionally substituted with a substituent, in particular a methyl group or a fluorine atom, preferably Ar represents an unsubstituted pnenyl group.

A preferred group of compounds is made up of those of formula (Ia)

QNH

»1 • - · R i // \\! HO - / .— ipHCH 2NHSjl (CH2) m0 (CH 2) nAr (ia) · == OH R2 where 25 m is an integer ranging from 2 to 5; n is an integer ranging from 2 to 6, and the total of m + n is 7, 6 or 9: - R 'represents a hydrogen and R2 represents a hyarogen atom or a methyl group; / / 4 5%

Ar represents a phenyl group optionally substituted by a methyl group or a fluorine atom; and Q represents HCD-, CH3CQ-, CO-, (CH ^ NSO ^ - or R5SO2 - where R5 is C1-C3 alkyl; and their physiologically acceptable salts and solvates.

A particularly preferred group of compounds of formula (la) is that where m is 5 and n is U.

Another particularly preferred group of compounds of formula (Ia) is that where Q is R5SO - and R5 is a methyl group.

In another particularly preferred group of compounds of formula (Ia), Ar is a phenyl group substituted by a fluorine atom or. preferably, an unsubstituted phenyl group.

As particularly important compounds of the invention, there may be mentioned: I 15 N- [2-hydroxy-5- [1-hydroxy-2 - [[6- (4-phenylbutoxy) hexyl] umino] ethyl] phinyl] methanesulfonamide ; N- [2-hydroxy-5- [1-hydroxy-2 - [[6- [4- (4-fluorophenvl) butoxy] hexyl] amino] ethyl] phenyl] methanesulf onamide; N- [2-hydroxy-5- [1-hydroxy-2- [[1 -methy1-6- (2-phenylethoxy) hexy1] amino] ethyl] phenyl] methanesulfonamide; N- [2-hydroxy-5- [1-hydroxy-2 - [[6- (3-phenylpropoxy) hexyi] amino] ethyl] phenyl] formamide; N- [2-hydroxy-5- [1-hydroxy-2 - [[6- (4-phenyibutoxy) hexyl] amino] ethyl] phenyl] urea; 25 N- [2-hydroxy-5- [1-hydroxy-2- [[3 - [(6-phe'nylhexyl) oxy] propyl] amino] e ^ thyl] phenyl] meVr.sr.esul f onamide; ^ N- [2-hydroxy-5- [1-hydroxy-2 - [[6- (3-phenylpropoxy) hexyl] amino] ethyl] phenyl] urea; Î 6 »N- [2-hydroxy-5- [1-hydroxy-2 - [[6- (3-phenylpropoxy) hexyl] amino] ethyl] phenyl] methanesul f onamide; N- [2-hydroxy-5- [1-hydroxy-2 - [[6- [4- (4-methylphenyl) butoxy] hexyl] amino] ethyl] phenyl] methanesulf onamide: 5 and their salts and physiologically solvates acceptable.

Suitable physiologically acceptable salts of the compounds of general formula (I) include the addition salts of acids derived from inorganic and organic acids, such as hydrochlorides, hydrobromides, sulfates, phosphates, maleates, tartrates, citrates, benzoates, 4- methoxy- ^ benzoates, 2- or t-hydroxybenzoates, i * -chlorobenzoates, p-toluenesulfonates, methanesulfonates, sufamates, ascorbates, saiicylates, acetates, fumarates, succinates, lactates, glutarates, gluconates, tricarballylates, hydroxy-naphtaates, hydroxy-naphtaates . ex. 1-hydroxy- or 3-hydroxy-2-naphthalenecarboxylates, or oleates. The compounds can also form salts with suitable bases. Examples of such salts include the alkali metal salts (eg, sodium and potassium), and the alkaline earth metal salts (eg, calcium or magnesium).

The compounds according to the invention have a selective stimulating action on BZ-adrenoreceptors. which furthermore is of a particularly aia ^ ia-20 gous profile. The stimulating action has been demonstrated on the trachea or isolated coding, where it has been shown that the compounds produce relaxation of these PtsF-induced contractions. your compounds according to the invention have a particularly long duration of action in this experiment.

The compounds according to the invention can be used in the treatment of diseases associated with reversible obstruction of the airways such as asthma and chronic bronchitis.

The compounds according to the invention can also be used for the treatment of premature birth, depression and congestive heart failure, and are also indicated as useful for the treatment of inflammatory and allergic dermatological diseases, glaucoma, and without the treatment of the conditions in which you have the advantage of gastric acidity, in particular in gastric and gastro-duodenal ulceration.

"The invention therefore further provides the compounds of formula (I) and their physiologically acceptable salts and solvates for application in the treatment or prophylaxis of diseases associated with reversible obstruction of the airways in human or animal subjects .

The compounds of the invention can be formulated for administration in any convenient manner. The invention therefore includes within its scope pharmaceutical compositions comprising at least one compound of formula (I) or one of its physiologically acceptable salts or solvates formulated for application in human or veterinary medicine. These compositions can be presented for application with physiologically acceptable carriers or excipients, optionally with additional medicinal agents.

The compounds can be formulated in a form suitable for administration by inhalation or insufflation, or for oral, buccal, parenteral, local (including nasal) or rectal administration. Gn prefers administration by inhalation or insufflation.

For administration by inhalation, the compounds according to the invention are conveniently delivered in the form of a presentation of aerosol spray liquids from pressurized containers, using a suitable carrier, such as dichlorodifluoromethane. trichlorofluoromethane. aichiorotétrafiuoroéthane. carbon dioxide or another suitable gas, or from a neoulizer. In the case of a pressurized aerosol, the dosage unit can be determined by providing a source to deliver a measured amount.

Another solution, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, e.g. ex. a powdery mixture of the compound and a suitable powder base such as lactose. amioc.n. _e powder composition can be presented in unit dosage form without p. ex. capsules or cartridges, p. ex. gelatin, or oes biisters from which you can - administer the powder using an inhaler or insuffiator. v Deur - administrative administration the pharmaceutical composition can take the form, e.g. eg, tablets, capsules, powders, solutions, siroDs / l \ _ 8 or suspensions prepared by conventional means with acceptable excipients.

For oral administration, the composition may take the form of tablets, drops or lozenges formulated in a conventional manner.

The compounds of the invention can be formulated for parenteral administration. The injectable formulations can be presented in unit dosage form in ampoules, or in multi-dose containers with the addition of a preservative. The compositions can take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient can be in powder form for reconstitution with an appropriate vehicle, e.g. ex. sterile pyrogen-free water, before use.

For local administration, the pharmaceutical composition can take the form of ointments, lotions or creams formulated in a conventional manner, with p. ex. an aqueous or oily base, generally with the addition of suitable thickening agents and / or solvents. For nasal application, the composition may take the form of a spray liquid, formulated p. ex. in the form of an aqueous solution or suspension or in the form of an aerosol using a suitable blower.

The compounds of the invention can also be formulated in rectal compositions such as suppositories or enemas to keep, p. ex. containing bases for conventional suppositories such as cocoa butter or another glyceride.

When pharmaceutical compositions are described above for oral, buccal, rectal or local administration, they can be presented in a conventional manner in combination with controlled release forms.

A proposed daily dose of active compound for the treatment of humans from 0.005 µm to 100 mg, which can be conveniently administered in one or two doses. The precise dose used naturally depends on the age and condition of the patient and the route of administration. Years. an oose suitable for administration by inhalatic: 1 is oe G, 005 mg to 20 mg, for K oral administration from 0.02 mg to 100 mg. and for parenteral administration, 35 from 0.01 mg to 2 mg for administration by injection and *

V

9

The compounds according to the invention can be prepared by a number of methods, as described below where Q, m, n, Ar, RI and R2 are as defined for the general formula (I) unless otherwise indicated .

It will be appreciated that some of the reactions described below are capable of affecting other groups in the starting material which are desired in the final product; this applies in particular in the reduction processes described, in particular when a hydride reducing agent is used and when final products are required where Q represents the group R3CO-, and where hydrogen and a metal catalyst in the preparation of intermediates containing an ethylene or acetylene bond. Care must therefore be taken according to conventional practice, either to use reagents which do not affect such groups, or to carry out the reaction as part of a sequence which avoids their use when such groups are present in the product. of departure. In the general methods described below, the final step in the reaction may be the removal of a protecting group. The appropriate protecting groups and their removal are described in the general method (2) below.

According to a general process (1), a compound of general formula (I) can be prepared by alkylation. Conventional methods of alkylation can be used.

Thus, for example, in a process (a), a compound of general formula (I) can be prepared where R1 is a hydrogen atom by alkylation of an amine of general formula (II)

QN'H

\ __ 6 / \, c R 60—. . — CH CH oNR 'R ε (II} \ / i

OH

(where each of these radicals R6 and R7 is an inkcrogen atom or a protecting group and R8 is a hydrogen atom) followed by the removal of any protecting group when there is one.

We can conduct alkylation (a) using an alkalinizing agent! of general formula (III): f i '10 "s * LCH (CH2) m0 (CH2) nAr (III) R2 where L represents an leaving group, p. ex. a halogen atom such as chlorine, bromine or iodine, or a nhydrocarbylsulfonyloxy group such as methane-sulfonyloxy or p-toluenesulfonyloxy.

The alkylation is preferably carried out in the presence of an appropriate acid fixative, e.g. ex. inorganic bases such as sodium or potassium carbonate, organic bases such as triethyliamine, diisopropylethylamine or pyridine, or alkylene oxides such as ethylenoxide or propylene oxide. The reaction is conveniently carried out in a solvent such as acetonitrile or an ether, e.g. ex. tetrahydrofuran (THF) or dioxane, a ketone, e.g. ex. butanone or methyl isobutyl ketone, a substituted amide, e.g. ex. dimethylformamide (DMF) or a chlorinated hydrocarbon, e.g. ex. chloroform, at a temperature between room temperature (TA) and the reflux temperature of the solvent.

According to another example (b) of an alkylation process, a compound of general formula (I) can be prepared in which R1 represents a hydrogen atom by alkylation of an amine of general formula (IV): QNH ^ · _- · R60 __ / \ —x1 CH, NR7R8, \ _ / 2 (IV) • ........ · where R6 and R7 are as defined above, R8 represents a hydrogen atom or a group convertible into a hyorogen atom under the reaction conditions, and X1 res °

^ -CH (OH) - or ^ C = G

t i> _ 11 with a compound of general formula CV): R2C0 (CH2) m0 (CH2) nAr (V) in the presence of a reducing agent, followed if necessary by the removal of any protective groups.

Examples of suitable R8 groups convertible into a hydrogen atom include arylmethyl groups such as benzyl, 6 (-methylbenzyl and benzhydryl).

Suitable reducing agents include hydrogen in the presence of a catalyst such as platinum, platinum oxide, palladium, palladium oxide, Raney nickel or rhodium, on a support such as charcoal , using alcohol, p. ex. ethanol, or an ester, e.g. ex. ethyl acetate, or an ether, e.g. ex. THF, or water, as the reaction solvent, or a mixture of solvents, e.g. ex. a mixture of 2 or more of those just mentioned, at normal or increased temperature and pressure, e.g. ex. from 20 to 100 ° C and from 1 to 1G atmospheres.

Alternatively, when one or both of the radicals R7 and R8 are hydrogen atoms, the reducing agent may be a hydride such as diborane or a metal hydride such as sodium borohydride, sodium cyanborohydride or lithium aluminum hydride. Solvents suitable for the reaction with these reducing agents depend on the particular hydride used, but include alcohols such as methanol or ethanol, or ethers such as diethl ether or tert-butyl methyl ether. or TH-.

When using a compound of formula (Ilj where R7 and R8 each represent a hydrogen atom, the intermediate imine of formula 25 (VI) can be formed:

QNH

\ · - · // \ r60— · χ —ipHCH 2N = (p (CH2) m0 (CH2) nAr (VI) · = · OH R2 * / ► '«12 (where R6 is as defined for formula ( II)).

The reduction of imine using the conditions described above, followed, if necessary, by the removal of any protective groups, gives a compound of general formula (i).

- * When it is desired to use a protected intermediate of general formula (II) or (IV) it is particularly convenient to use hydrogen and a catalyst as it is said above with the protecting groups R6 and R7 which are capable to be transformed into a hydrogen atom under these reducing conditions, thus avoiding the need for a separate deprotection step.

Suitable protective groups of this type include arylmethyl groups such as benzyl, benzhydryl and and-methylbenzyl.

In another general process (2), a compound of general formula (I) can be obtained by deprotection of a protected intermediate of general formula (VII):

QNH

--- R1 R6Ü— · CHCH2NR7C (CH2) m0 (CH2) nAr (VII) "\ = / i) HR 2 15 (where R6 and R7 are as defined above except that at least one of the radicals R6 and R7 is a protecting group).

The protecting group can be any conventional protecting group, e.g. ex. as described in "Protective Groups in Drganic Chemistry", dir. publ. J.F.iiJ. ^ cOmie (Plenum Press. 1973). As examples of suitable hydroxyl protecting groups 2> q represented by R6, mention may be made of aralkyl groups such as benzyl, diphenyimethyl or triphenyimethyl and tetrahydropyranyl. As examples of suitable amino protecting groups represented by R7, there may be mentioned aralkyl groups such as benzyl, C <-methylbenzyl, diphenyimethyl or tripnyimetyl. And acyl groups such as trichioracetyl or trifluoroacetyl.

Deprotection to give a compound of general formula (Γ, · can be carried out using conventional techniques. Thus, eg, iorscue i R6 and / or R7 is an aralkyl group, it can be cleaved by hydrogenation u 13 in the presence of a metal catalyst (eg palladium on charcoal). When R6 is tetrahydropyranyl, it can be cleaved by hydrolysis under acidic conditions. The acyl groups represented by R7 can be removed by hydrolysis, eg with a base such as sodium hydroxide, or a group such as trichioracetyl can be removed by reouction with, for example, zinc and acetic acid. The choice of the acyl group R7 and its removal process depend however, the nature of the Q group.

In another general process (3), a compound of general formula (I) can be prepared by reduction. Thus, p. for example, a 1Π compound of general formula (î) can be prepared by reducing an intermediate of general formula (\ / III):

QNH

• - · R60—. X1-X2-X3-CH;, QCH9Xlt-Ar (VIII) \ _ / * (where R6 is as defined for the general formula (II) and at least one of the radicals X1, X2, X3 and XU represents one reducible group and the other (s) take the appropriate meaning as follows, i.e. XI is 15 -CH (GH) -, X2 is -CH! \! R7, X3 is -CR1R2 (CH ) - and XU is 2 ^ 2 m-1 - (CH ^) ^ _ ^ -) then if necessary by removing any protective grouoes.

Suitable reducible groups include those where XI is a group) .C = 0, X2 is a group -CH MY- (where Y represents a group convertible into hydrogen by catalytic hydrogenation, e.g. a group 2 arylmethyie like benzyl, benzhydryl or c (-methylDenzyle), or an imine group (-CH =! \ i-) or a group -COMH-, X3 is a group -CD (CH 1 - or 2 "mi a group -CR1R2X5- where X5 is a C2 to C7 alkenylene or a C2 to C7 alkynyene, or -X2-X3- is a group -CH ^ \ = CR2Ch '- or X4 is "a 2' 2 m-1 aicenylene C2 has a a. Cynyisne in C du. In a ssp ~~~ ^ '"^ mo1 ^ - · 25 of the reduction process, the group R5 can be a group convertible into hydrogen under the reducing conditions employed and can be p.

ex. an arylmetny group such as benzyl, benzhydryl or Of-metncloenZs-e.

Reduction can be achieved by using these reducing agents conveniently used for reduction of ketones. imines, amid ° = l! Ï i ^ 14 protected, alkenes and alkynes. Thus, p. eg, when XI in the general formula ^ (VIII) represents a group ^ C = 0 this can be reduced to a group -CH (OH) - by using hydrogen in the presence of a catalyst as described above - above for the process (1) part (b). Alternatively, the reducing agent 5 may be. p. e.g., a hydride such as diborane or a metal hydride such as lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, sodium borohydride or aluminum hydride. The reaction can be carried out in a solvent, optionally an alcohol, e.g. ex. methane or ethanol, or an ether such as THF, or a halogenated hydrocarbon such as dichloromethane.

When X2 in the general formula (VIII) represents a group -CH NY- or the group -CH = N-, or X2-X3 represents -CH N = CR2 (CH) 2 2 2 m-1 this can be reduced to a -CH, NH- or -CH0 NHCHR2 group (CH A - ci 2 mi using hydrogen in the presence of a catalyst as described above for process (1) part (b). Other solution , when X2 or -X2-X3 is the group -CH = N- or -CH OCR 2 (CH) - this can be reduced 2 2 m-1 * to a group -CK, \ H- or -CH_ NHCHR2 (CH „). - using an agent ci 2m-.

„Reducer and the conditions which have just been described for the reduction of XI when this represents a group ^ C = 0.

^ When X2 or X3 in the general formula (tlll) represents a group -CGNH- or -CD (CH j. - this can be reduced to jn group -O Nh- or Z m-1 2 -CH (CH> „- using a hydride such as diborane or a complex metallic nvoru ^ s 2 2 m i such as lithium aluminum hydride or sodium-bis (2-methoxyethoxy) aluminum hydride in a solvent such as an ether, e.g.

25 ex. TH- or diethyl ether.

When X3 in the general formula (VIiç represents a group -CR1R2X5- this can be reduced to a group -CR1R2 (Ch} - by using 2 m-1 of 1 hydrogen in the presence of a catalyst as it is said previously for the process ( 1) part (b).

When X6 is a C2 to C6 alkenyiene o, an acynyniene g-C? t to C6 this can be reduced to - (CH) - using this Cnvc-og-ne ~ 2 n-1 "... a catalyst as described above. In this aspeco process ς is reduced. The products oe appropriate start this ~ onr.ule <\ l ", includes · * * j those where CR1R2X5 and / or X4 each contain a bond -OC- or -OC- - 15

When both contain unsaturated bonds, these can be similar or different.

The specific examples of the reduction process are those in which a compound of general formula (I) is prepared where - (CH) - represents 2 m 5 "(CH) - from a corresponding compound where - (CH) - represents 2 5 2 m -CH = CH (CH2) 3-, -CsC (CH2) 3 -, - (Cl · ^) 2 CH = CHCH2 - or - (CH 2) 2OCCH2 -

In other examples, a compound of general formula (I) can be prepared where - (CH 2) n - represents - (O ^) ^ - or - (CH 2) 3 - by reduction of a corresponding compound of general formula ( ï) where - (CH2) - represents 10 -CH CH = CH-CH -, -CH C = CCH -, -CH CH CH = CH-, -CH CH CM>, 2 2 2222 22 -CH CH = CH- or -CH2C = C-.

In the general methods described above, the compound of formula (I) obtained can be in the form of a salt, conveniently in the form of a physiologically acceptable salt. If desired, these salts can be converted to the corresponding free acids using conventional methods.

- The physiologically acceptable salts of the compounds of general formula (I) can be prepared by reacting a compound of general formula (I) with an appropriate acid or base (el in the presence of an appropriate solvent such as 1 acetonitrile. 1 acetone , chloroform, ethyl acetate, or an alcohol, e.g. methanol, etnanol or isopropanol.

Physiologically acceptable salts can also be prepared from other salts, including other physiologically acceptable salts, of compounds of general formula (I), using conventional methods When a specific enantiomer of a compound of general formula "' 0 'X1 is required, one can obtain 1 By resolution of a racemate corresponda' "· * d a compound of general formula d; year using conventional methods-

Thus, in an example, it is possible to use an optically active acid suitable for forming seis with is rscemats G jp compound of general format c (I). It is possible to separate 10 mixture of isomeric salts resulting p.

ex. by fractional crystallization, er diastereoisomenic salts with ρ8—; τ, from which one can isolate 1 required enantiomer of a compound oe formula genô ^ a’0 * - (I) by transformation into the required free base.

Alternatively, the enantiomers of an account of general formula (I) can be synthesized from the optically active intermediates 30 "-prayed using any of the general methods described herein.

AT

ï, 16

The specific diastereoisomers of a compound of formula (I) can be obtained by conventional methods, e.g. ex. by synthesis from a suitable asymmetric starting material using any of the methods described here, or by transformation of a mixture of isomers of a compound of general formula (I) into suitable diastereoisomeric derivatives, p. ex. salts which can be separated by conventional means, e.g. ex. by fractional crystallization.

Suitable methods for preparing the intermediate compounds used in the above general methods are described below. In the following discussion, Ar, RI, R2. R6, R7, R8, Q, X1, X2, X3, X6, X5, V and L

are as defined above unless otherwise indicated. "Hai" represents a halogen atom. When an intermediate with a protected hydroxy and / or amino group is desired, it can be obtained using conventional protection methods, e.g. ex. those described by ^ cOmie (see process (2) 15 above).

Dn can prepare the intermediate compounds of general formula (VIII) for application in the general process (3) by a number of processes.

So p. ex. the intermediates of general formula (VIII) where XI is a group ^ .C = 0 can be prepared from a haioketone of formula (IX): QNH ^ r6q— / \ —cocH2Hal (IX) "-—-" by reaction with an amine of general formula fxi: R 1 R7NHÇ (CH2) m0 (CH2) nAr (X) R2 - 'c3 “' - ^ tÎ of hydrogen ο ^ u ~ grcjoe rsns ^ ormaole 9" ar such tern / 1 by catalytic hyorogenation.

/ 1 / V._> '17

The reaction can be carried out in a cold or hot solvent, e.g. ex. THF, tert-butyl-methyl-ether, dioxane, chloroform, dimethylformamide (DMF). acetonitrile or a ketone such as butanone or methyl isobutyl ketone, or an ester., p. ex. ethyl acetate, preferably in the presence of a base such as diisopropylethylamine. sodium carbonate or another acid scavenger such as propylene oxide.

The intermediates of formulas (II) and (IX) are known compounds or can be prepared according to the methods described by Kaiser et al. in J. Med. Chem., 1974, 17, 49 and Larsen et al, in J. Med. Chem. 1967, 10.

10,462.

The intermediates of general formula (VIII) where X1 is a group> C = 0 can be reduced by the corresponding intermediate where xi is a group -CH (OH) - using p. ex. a metal hydride such as sodium borohydride in a solvent, e.g. ex. ethanol.

The iminoketones of general formula (VIII), that is to say where X2 is a group -CH = ^ - can be obtained from a phenylglyoxal derivative of formula (XI):

QNH

\ R60— / \ —C0CH0 (XI) · - · by reaction with an amine of formula (X) where Y represents a hydrogen atom in a solvent like benzene, THF or an alcohol, p. ex. etbano. at temperatures up to reflux. The onenv.-glyoxai derivatives of formula (XI) can be obtained from a hslocetone, this formula · ΊΧ '· uar the action of a dialkyl sulfoxide such as dimethyl sulfoxide.

We can prepare the intermediaries of general formula Γν · τττ c. ^ X3 is a group -CO (CH_), - oar acviatio- of one year · -no, · .Ρ i /! '18 m

QNH

\ * - · r «0_ / XkHjNHR7 (ΧΠ) using an activated ester or derivative of an acid of formula (ΧΙΠ):

Ar (CH2) n0 (CH2) mC02H (XIII)

Suitable activated derivatives include acid chloride, an anhydride or imidazolide. The reaction can optionally be carried out in a solvent such as THF, benzene or chloroform, optionally in the presence of a base such as pyridine or triethylamine. The acids (XIII) can be used directly if a coupling agent T is added. like dicyclohexylcarbodiimide.

The acids of formula (ΧΙΙΓ>) can be obtained by treatment of an alcohol of general formula (XIV):

Ar (CH2) n0 (CH2) mCH20H (XIV) 10 with an appropriate oxidizing agent, e.g. e.g., pyridinium dicnromate in a solvent such as DV.F.

We can obtain the intermediaries ae formal (VIII; cù -X2-X3- represents "'rr-"' Dar reaction of an amine this eormüie · '> ::: where R? Is a hydrogen atom with a compound ce formula O cans ur solvent romme Ί5 acetonitrile.

One can prepare the intermediaries as ^ crm ^ ie · ΥΙΟ · cl «, r es * -COMH- by reaction c an amine ae formula <x :. ol R? is ir. - erogenous with an acid of formula (XV): - /

II

ij 19

QNH

• - · »R60— / \ —X 1C0 2H (XV) \ _ / 2 • - · in the presence of a coupling agent such as dlcyclohexylcarbodiimide. The acids of formula (XV) can be prepared by methods analogous to the conventional methods for the preparation of Qi-keto and o (-hydroxy-carboxylic acids).

5 Gn can prepare the intermediates of formula (VIII) where X3 is -CR1R2X5- and / or XU is a C2 to C6 alkenylene or a C2 to C6 alkynylene by methods analogous to those described here for the preparation of compounds of formula (I).

Qn can prepare the intermediaries of formulas (III), (V), (X) and 10 (XIV) as it is said in the British patent! \ J ° 2 UO 800 A or by? processes analogous to those described here.

The following examples illustrate the invention. The temperatures are in ° C. "Drying" refers to drying using magnesium sulfate unless otherwise indicated. Thin layer chromatography (TLC) is carried out on · Si02. The column chromatography! Z ‘and the instant chromatography / FCS / are both carried out on silica (Merck 9385).

The following abbreviations are used: EA ethyl acetate; from ER diétnyiêther; RT ambient temperature 20 Ca cyciohexane: CT compound or title ΆΕ methanoi; TH'- tetrahydrofuran; 1 toluene: ET ethanol; 25 A 0.88 DN1F dimethylformamide / li ammonia solution ...

Λ 20

Intermediate 1 N- [2- (Phenylmethoxy) -5 - [[(phenylmethyl) [6- (3-phenylpropoxy) hexyl] âmino] acetyl1phenyl] formamide

A solution is maintained at 23 ° for 18 h ae solution JW5-ibromoacétyi) -5 2- (phenylmethoxy) phenyl / formamide (0.53 g), hydrobromide V.'6- (3-phenyl-propoxy) hexyl / benzene methanamine (0, 68 g) (Compound A) and \, \ - ciisopropyi-étnylamine (0,65 g) in dichlorométhane (10 mi). The mixture is diluted with water (20 ml), extracted with ER (30 ml) and the organic phase is washed with water (20 ml), brine (20 ml), dried and evaporates 10 to give an oil. Purification by / FCS / eluting with ER-CX (3: 2) gives the product as a pale yellow oil (0.72 g). CC ^ i (ER-CX 3: 2) Rf 0.28.

Likewise we prepare:

Intermediate 2 = 15 N- [2- (Phenylmethoxy) -5 - [[(phenylmethvl) [6- (3- 7 phenylpropoxylhexyllaminoüace'tyljphe'nvllure'fi. (1> 01g) CCD '! Silica deactivated with Et ^ iV ( EA-CX 4: 1) from a- / 5- (Dromoacetyl) - 2- (phenylmethoxy) phenyl / urea (0.8 g) and compound A (0.91 g).

Intermediate 3 2o N- [2- (Phenylme, 'thoxy) -5 ~ [[(phenylme / thyl) [6- (3-phenylpropoxy) hexyl] amino] acetyl] phenyll methanesulf onamide (0.5g) CL · i ( CX-ER 3.2) 0.36 from ^ - / 5 - <. Bromoacetyl) -2- (phenylmethoxy) phenyl / - methanesulfonamide (0.45 g) and of compound A (0.46 g '.

25 Intermediate a N- [5- [1-Hydroxy-2 - [[6- (4-phenvlbutoxv) hexvl] (phenvImethv1) aminn] ethyl] -2- (phenvlmethoxy) phenvl] tTiethanesul-P-onamide A solütion ae \ - / 5- (bromoacétyi) -2- (Dnénylmétnoxy) phenén / - methanesulf onamide (1,9 g) and de ^ - / 6- (4-phenylbutoxy) hexyl / benZènemétn3namne - 30 (* '' s2 Q) Gaas * e THr 'Ί0 ~ mK * stirred under nitrogen, Wdiisaorcp is added. - ^ ethyiamme (1.23 g) and the mixture is stirred under nitrogen at RT for 4: - 21

The solution is diluted with ER (50 ml), filtered and evaporated in vacuo to give a brown oil (4.2 g) which is dissolved in ME (50 ml) and which is treated with borohydride sodium (0.74 g). The mixture is stirred under nitrogen

for 1 h, diluted with water (150 ml) and extracted with ER

5 (2 x 150 ml). The organic phase is washed with water (2 x 100 ml), dried and evaporated in vacuo to give a brown oil. Purification by / FCS / eluting with CX-EA (2: 1) gives the CT as a yellow oil (1.92 g). TLC (CX-EA 2: 1) Rf 0.23.

Found C 69.8 H 7.8 h 4.2 10 C H! \ I O N / A, 75H O requires C 70, C H 7.7 \ 4.2%.

39 50 2 5 2

Intermediate 5 [5- [1 - Hydroxy-2- [[6- (4-phenvlbutoxy) hexyl] (phenylmethy1) ami no] ethyl] -2- (phenylmethoxy) pheny 1] uree.

A solution of \ - / 5-bromoacetyl) -2- (phenylmethoxy) -15 phenyl / urea (2 g) and Î \ - / 6- (4-phenylbutoxy) hexy! / Benzenemethane (1.87 g) is treated in THF (100 ml) stirred under nitrogen with I \ l, I \ i-diisopropyl-ethylamine (1.42 g). The mixture is stirred at RT under nitrogen for 19 h, ^ diluted with ER (50 ml), filtered and the filtrate is evaporated in vacuo.

A result of the resulting orange oil (4.4 g) in ME (100 ml) is treated with sodium borohydride (1.2 g) and stirred under nitrogen for 19 h. The mixture is diluted with water (200 ml), extracted with ER (2 x 150 ml) and the organic phase is washed with water (100 ml / day, dried and evaporated in vacuo to give a orange oil Purification by / FCS / eluting with EA-CX (2: 1) gives the CT as a yellow oil (1.72 g) TLC (EA-ME 3: 1) Rf 0 , 7.

Intermediate 6

(E) -4- (4-Fluorophenyl) -3-buten-1-oI

□ n is added dropwise n-butyliithium (1.6 M in hexane, 100 ml) to a stirred suspension of ce bromide, '3-h'icroxyprop.v, i) triphenyl-30 pnosphonium (32.1 g) aans ie dry THF (200 ml) re-roiled at 0 ° C under nitrogen. A solution of 4-fiuorobenzaldéhyoe (9.93 g) is added dropwise to dry THF (100 ml), and the mixture is stirred under nitrogen at 0 ° C for 30 minutes and at RT for another 1 h 1 / 2. Carefully dilute the melanae with / 22

water (25 ml), the solvent is evaporated under vacuum at 40 ° and the residue is divided between EA (200 ml) and water (200 ml). The aqueous phase is re-extracted with EA (200 ml), the organic phases are combined, dried and evaporated in vacuo to give a brown oil. Purification by / FCS / eluting with CX-ER (1: 1) gives the CT as a colorless oil (6.33 g). CCM

(CX-ER 1: 1) Rf 0.13.

Intermediate 7 (E) -1 - [[4- (6-Bromohexyl) oxy] -2-butenyl] -4-fluorobenzene is stirred for 18 h a mixture of intermediate 6 (5.73 g), 1.6- 10 dibromohexane (25.2 g), tetrabutylammonium bisulfate (1.5 g) and 40% sodium hydroxide solution (45 ml), diluted with water (200 ml) and extracted with EA ( 2 x 150 ml). The organic phase is washed with water (100 ml), brine (100 ml), dried and evaporated in vacuo to give a yellow oil. Purification by / FCS / eluting with CX-EA 15 (10: 0-> 9: 1) gives a yellow oil (8.49 g). TLC (CX-EA 9: 1) Rf 0.34.

Intermediate 8 (E) -N- [2-Hydroxy-5- [1-hydroxy-2 - [[6 - [[4- (4-fluorophenyl) -3-butenyl] oxy] hexyl] amino] ethyl] phenyl] methanesulE onamide 20 Intermediate 7 (1.34 g) is added to a stirred solution of / 5- / (2-amino-1-hydroxyethyl) / - 2-hydroxyphenyl / methanesulfonamide (1.50 g) and i \., \ -tiiisopropylethylamine (0.57 g) in DM F (25 ml) at 70 ° under nitrogen.

The solution is stirred at 70 ° for 5 h, diluted with water (1GC ml) and extracted with EA (2 x 100 ml). The organic phase is washed with water (100 ml), dried (\ a SD) and evaporated in vacuo to give a brown oil which is purified by / FCS / on silica deactivated with triethylamine (Merck 9385, 100 g) eluting with EA-ME (9: 1) to give a brown foam (0.5 g). Trituration with ER gives C 'as a white solid (0.47 g) Mp 79-80 ° (dec.).

- / / // t * "23

Intermediate 9 N- [5-Acetyl-2- (phenylmethoxy) phenyl] propanesulf onamide Propanesulfonyl chloride (2.8 g) is added to a stirred solution of 1- / 3-amino-A- (phenylmethoxy) phenyl / ethanone (3.95 g) and tri-ethylamine (3.58 g) in dry dichioromethane (80 ml) at 0 ° C. The solution is stirred at 0 ° C for 2 h, diluted with ER (20G ml), washed successively with 2N HCl (100 ml) and an 8¾ sodium bicarbonate solution (100 ml), dried and evaporated in vacuo to give a solid cream.

This is diluted in CX to give a solid which is stirred in 1 M sodium hydroxide (10 ml) and separated by filtration. The filtrate is acidified with 2N hydrochloric acid extracted with EA (2 x 150 ml). The combined dried organic extracts are evaporated in vacuo to give a cream solid which is recrystallized from EA to give a white solid (3, AG g). Mp 130-130.5 °.

- 15 Intermediate 10: N - [5-nromoacetyl-2- (phenylmethoxy) pheViyl] propane- null £ onamide

A solution of bromine (1.52 g) in chloroform (25 ml) is added dropwise for 1 h 1/2 to a stirred solution of intermediate 2o 9 (3 g) in chloroform (25 ml) at YOUR. The solution is washed with water (30 ml), an 8¾ sodium bicarbonate solution (30 ml ... or dry (Na ^ SO ^), and evaporated in vacuo to give a product which it is recrystallized from EA to give a product which is recrystallized from EA which gives the CT in the form of a pale orange solid (2.75 g), 25 Pf 99.5-100.5 °.

Intermediate 11 N- [2- (Phenylmethoxy) “5- [2 - [[6 ~ (3-phe / r.vIoroooxv) hexylj (phenylmethyl) aminol-l-oxoethyljDnénvlj propanesul £ onamide

30 The mixture is stirred together under nitrogen for 2 1/2 hours 1D

(0.65 g), ^ - / 6- (3-phenyiproooxy) hexyl / benzenememethanamine (0.5 g) And / M.iSi-diisopropylethylamine (0.22 g) in DW.F (10 ml). The solution is diluted to 24 with water (50 ml), extracted with EA (2 x 50 ml) and the organic phase is washed with HCl 2! \! (30 ml), 8% sodium bicarbonate solution (30 ml), then dry (Ma0 SO,). Evaporation under vacuum gives a yellow oil which L μ is purified by / FCS / eluting with T-EA (9: 1) to give the CT in the form of a colorless oil (0.77 g). TLC (T-EA 9: 1) Rf 0.15.

I ntermediajre 12 1- [4 - [(6-Bromohexyl) oxy] butyl] -4-methvlbenzene

A mixture of 4-methylbenzenebutanol (6.5 g) is stirred at RT for 20 h. 1,6-dibromohexane (24.4 g), aqueous sodium hydroxide (50¾ w / v; 10 25 ml), and tetrabutylammonium bisulfate (0.5 g), diluted with water (50 ml), and extracted with ER (2 x 100 ml). The dried extract is evaporated and the residue is purified by / C / eluting with CX and then with CX-ER (93: 7) to give the CT in the form of a colorless oil (9.8 g). CCM (CX-ER 9: 1)

Rf 0.5.

15 Intermediate 13 Hydrochloride? N- [6- [4- (ft-Methylphenyl) butoxy] hexyl3benzëneme * thanamine

Intermediate 12 (5.0 g) is added dropwise to oenzylamine (25 ml) at 110 °. The solution is heated to 110-120 ° for 2 h. cooled, poured into HCl (2 M; 250 ml), and filtered to give the CT as a white solid (5.3 g), mp 119-121 °.

Intermediate added 1 4 3 - [(6-Phenylhexyl) oxy] -1-propanol

Sodium (0.95 gi) is dissolved in hot 1.3-uropanediol (9.47 g) and then added dropwise or (5-Dromonexyl) benzene (10 g). The mixture is stirred under nitrogen at 100 ° for 3 h, pour it into water (200 ml) and 2 M HCl (30 ml) and extract with ER (2 x 150 ml), dry and evaporate under vacuum to give a yellow void, your purification by / FCS / eluting with CX-ER (3: 1 -> 0: 1; give the CT as a colorless oil (5.46 g). CCvi (CX-ER 3: 1) Rf 0.08.

: / * / ~ / Γ 25

Intermediate 15 [6- (3-Bromopropoxy) hexy1] benzene

Triphenylphosphine (7.50 g) in dry dichioromethane (50 ml) is added dropwise over 10 minutes to a stirred solution of intermediate 5A 1A (5.2 g) and carbon tetrabromide (9 , A9 g) in dry dichloromethane (90 ml) at 0 ° C under nitrogen. The solution is stirred at RT pendan | 2 h, absorbed on silica (AO g) and purified by / FCS /. Elution with! CX-ER (8: 1) gives a colorless oil which is distilled to give the CT as a colorless oil (5.58 g). CCM (ER) Rf 0.63.

10 Intermediate 16 IN, N-Dimethyl-Nl- [5- [2 - [[6- (A-phe, nylbutoxy) hexyl] I (phenylmethy1) amino3-1-oxoethyl1-2- (phenylmethoxy) phenyl] 'sul- P amide

Dn stirred together at RT under nitrogen for U h 1/2 of the bromoacetyl-2- (phenylmethoxy) phenyl / -N, i \ i, -dirnétnysuIfamide (0.8 g), of the | ’V / 6- (A-phenylbutoxy) hexyl / benzenemethane (C.6A g) · and \. \ - diisopropylethylamine (0.27 g) in DMF (10 ml). Go evaporates the solvent in vacuo and the residue is dissolved in EA (10D ml) and washed with water (75 ml).

The aqueous phase is re-extracted with EA (2 x 5G ml) and the combined organic phases are dried and evaporated in vacuo to give a yellow oil. Purification by / FCS / eluting with T-EA (10: 1) gives the CT in the form of a yellow oil (0.66 g). CCM (T-EA 5: 1) Rf 0.35.

Intermediate 17 N_ [5_ (4- Phinvlbutoxv) pentvl] benzenemethanamine 25 / A - / (5-Dramopentyl) oxy / butyl / Denzene (A, 0 g) is added dropwise to benzylamine (20 ml) è 110 °. Dnauf ^ e solution at 11G-1200 for 90 min and cooled, ün added HCl (2 v: '25 ml 'and the mixture is extracted with EA (2 x 100 ml). Gn washed the organic extract a. eo eu aqueous sodium carbonate (100 ml) and brine (100 ml, dried, and made 3o - evaporate. The residue is distilled to give the CT as a colorless oil! (3.3 g) Peb 190-19570.1 mm Hg. CCM (CX-ER 1: 1) Rf 0.25

‘L

* 26 ",. ^ Example 1 I "N- [2-Hydroxy-5- [1-hydroxy-2 - [[6- (3-phenylpropoxy) hexyl]! Amino] ethyl] phenyl] formamide | Intermediate solution 1 is hydrogenated ( 0.25 g) in ethanol .5 (20 ml) at RT and atmospheric pressure on 10 pall palladium catalyst on carbon (0.15 g) and 10% platinum on carbon (0.15 g). The mixture is filtered through Hyflo and evaporated in vacuo. The residue is triturated with ER and cooled to give the product in the form of a white solid (0.092 g), mp 85-86 ° (dec TLC silica deactivated 10 with Et ^ N (EA-ME 7: 3) Rf 0.68.

Likewise we prepare:

Example 2 M_ [2-Hydroxy-5- [1-hydroxv-2 - [[6- (3-phenylpropoxy) hexyl] amino] ethyl] phenyl] uréc, 15 Pf 78-80 °. TLC silica deactivated with Etj \ (EA-ME 7: 3) Rf 0.62 (0.26 g) from intermediate 2 (0.6 g).

Example 3 N- [2-Hydroxy-5- [1-hydroxy-2 - [[6- (3-phenylpropoxy) hexylj aminoléthyljphenyllmethanesulE'onaroide, 20 Pf 130-134 ° (decj. TLC silica deactivated with Et7 \ (EA- ME 7: 3) Rf C. 62 (0.13 g) from intermediate 3 (0.3 g).

EXÇjnpIe h N- [2-Hydroxy-5- [1-hydroxy-2 - [[6- (4-phgnvlbutoxv) hexvl] amino3ethyl] phe / nyl] methanesul, P onamide

25 Intermediate 4 (0.98 g) is hydrogenated in absolute ethanol (2C

(20 ml) on catalysts with palladium on lün on cnsrnon "e must '50 mg and platinum at 5% on charcoal (53 rrg). 3n filter the mixture through "Hyflo and evaporate in vacuo. The residual oil hrune (G.72 g) solidifies when triturated with ER to give the CT (0.34 g). 89-91 °.

£ 30 Found c £ 1.8 H 7.7 \ 5.55 C25h38 ^ 2% S.Q.25h? D requires C 62.1 H 8.G N 5.8%.

/ / / 27 "~ Example 5 - N- [2-Hydroxy-5- [1-hydroxy-2 - [[6- (4-phenylbutoxy) hexyl] amino] ethyl] phenyl] ure £

Hydrogenate a solution of intermediate 5 (G, 7 g) in ethanol 5 (15 ml) on 10¾ palladium catalysts on charcoal (50 mg) and 5% platinum on charcoal (50 mg ). We filter the mixture through

Hyflo and evaporated in vacuo to give a yellow oil which is triturated with ER to give an off-white solid (0.32 g), mp 87-89 °. TLC (EA-ME 1: 1) Rf 0.18.

Example 6 N- [2-Hydroxy-5- [1-hydroxy-2 - [[1-methyl-6- (2-phenylethoxy) hexy1] amino] ethvl] phenyl] methanesul ^ onamide

Hydrogenate a solution of / 7- / 2-phenylethoxy / heptan-2-one (0.70 g) and ^ - / 5- / 2 - / ^ 5 ^ 60 ^ 101916 ^ 1) 8 ^ 1 ^ 0-1 -oxoethyl / -2- (phenylmethoxy) -15 phenyl / methanesulfonamide (1.54 g) in absolute ethanol (50 ml) on a mixture of 5¾ pitin catalysts pre-reduced on charcoal (253 me; and of 10% palladium on charcoal (250 mg) cans i'étnanGi (25 ml; Gr. filter the mixture through Hyflo and evaporate in vacuo to give a white solid (1.3 g). by / FCS / on silica deactivated with triethylamine (Merck 9385, 50 g) eluting with EA-ME (9: 2) followed by trituration with ER gives the CT in the form of a white solid (C.88 g>, 122.5-123.5 °.

Found C 60.3 H 7.7 \ 5.9 ^ 6 ^ 2¾ S 0.75H O requires Z 63.3 H 7.9 \ 5.9%.

Example 7 N- [2-Hydroxy-5- [1-hydroxy-2- [Γ 6- [to- (4-fluorophenvl) butoxv] hexvl] amino] ethvl] phenvljmethsnesul -f cnar.ide

A solution of intermediate E (C. 25 c) is hydrogenated in absolute ethanol (10 ml) over a pre-reaction mixture of 10% palladium catalysts. on charcoal (40 mg) and platinum at 5% on charcoal (40 mg) □ ethanol (5 m%. 19 mixture is filtered through Hvflo and gold. does e-sn "1"? - under vacuum to pour a brown oil to: when grinding with EE cane / a 28 the CT in the form of an off-white solid (0.15 g) mp 84-85 ° (dec.).

Found C 56.5 H 7.4 N 5.4

Cl · H FJNL Oc S.2H O requires C 56.4 H 7.8 M 5.3¾.

CD 47 Z D c txe.mple 8 5 N- [2-Hydroxy-5- [1-hvdroxv-2-E [6- (3-phenylpropoxy) hexyl].

amino] ethyl3phenyl3propanesul-P onamide

Gn hydrogen an intermediate solution 11 (0.65 g) in absolute ethanol (40 ml) on a mixture of catalysts pre-reduced to palladium at 10¾ on charcoal (150 mg) and platinum at 5% on charcoal wood (150 mg) 10 in ethanol (10 ml). The mixture is filtered through Hyflo and evaporated under vacuum to give a yellow oil which when triturated with ER gives the CT in the form of a white solid (170 mg), mp 82-83.5 ° ( Dec.).

Found c 62.3 H 7.9 N 5.5 C26H4G Γν2 ° 5S-0.5H 2 ° necessary C ό2 · 2 H 8’2 N 5.6%.

'T5 Example 9 N- [2-Hydroxy-5- [1-hydroxy-2 - [[3 - [(6-phenylhexyl) oxy3 propyl3 amino3 ethylj phenvl3methanesulP onamide, benzoate (salt)

Dn adds intermediate 15 (0.69 g) dropwise to D ^ f 2i; (2 mi) to a solution of j \ / / 5 - / (2-amino-1-n \, Sroxyethyl) .'- 2-hycroxyphenyi. - methanesulfonamide (0.85 g) and iv.M-diisopropylethylarmne (0.33 g) in D ^ IF (20 ml) at 80 ° under nitrogen. Dn stir the mixture at 80 ° for 3 h, and evaporate in vacuo. The residual oil is dissolved in EA (50 ml) and washed with water (100 ml). The aqueous phase is re-extracted with EA (75 ml), the combined organic phases are dried (\ a2 SO ^) and evaporated in vacuo to give an oil. Purification by / FCS / eluting with t-and-a (39: 10: 1) gives a brown oil which is cissout cane v £ (10 ml · and treated with benzoic acid (0.08 g) The solvent is evaporated in vacuo and the residue is triturated with ER to give the CT as an ivory solid (30 mg (140 mg). mp 133-133.5 °).

Found C 62.75 H 7.27 \ 4.77 C ,. π N_CL S.C, H, α .0.5H O required C 62.50 H 7.28 \ 4.70¾.

24 3b Z u / b z 2 / / t "* 29 β"

Example 10 N- [2-Hydroxy-5- [1-hydroxy-2 - [[5-U-phenylbutoxy) pentyl] amino] ethyl] phenyl] acetamide

A solution of 5-bromoacetyl-2- (phenylmethoxy) phenyl / acetamide (1.00 g), intermediate 17 (0.9 g) and M, \ - diisopropylethylamine is stirred under nitrogen for 6 h. (0.46 g) in DMF (50 ml). The solution is diluted with water (50 ml) and extracted with EA (2 x 100 ml) and washed with HCl 2 \ i; (50 ml), 2 M sodium bicarbonate (50 ml), dried (Ma SD) and evaporated in vacuo to give a yellow oil which crystallizes when allowed to stand. The resulting cream solid (1.67 g) is dissolved in ethanol; (90 ml) and hydrogenated on a mixture of catalysts pre-reduced with 10% palladium oxide 1 on charcoal (300 mg) and 5% platinum oxide on charcoal (300 mg) in ethanol (25 ml). The mixture is filtered through Hyflo and evaporated in vacuo to give an oil which after trituration with ER gives a brown foam. Purification by / FCS / | eluting with T-ET-A (39: 10: 1) gives an oil which after trituration with ER gives the CT in the form of a brown foam (0.31 g). CCS t. J U i “; A 39: 10: 1) Rf 0.26.

j: Found C 68.66 H 8.53 M 6.39 i 20 ç, c H ,, Ο, 0.5H 0 requires C 68.62 H 8.52 M 6.40%.

| 2b 5b 2 4 c! Example 11! - AM- [2-Hydroxy-5- [1-hydroxy-2 - [[6- (4-phenvlbutoxy) hexvl] amino] ethyl] phenyl3-N, N-dimethylsul- amide! Hydrogenate a solution of intermediate '6 (0.61 g) in ethanol i 25 absolute (30 ml) on a mixture of catalysts pre-rewetted with this z'.azirs i "; at 5% on carbon of wood (150 mg) and 12% Palladium oxyce on charcoal (150 mg) in ethanol (10 ml). The mixture is filtered through and evaporated in vacuo to give a ^ ' Ιε The purification by / FCS / by eluting with T-ET-A (39: 1G: 1; gives a null D: i ^ e had... ^ ^ Er er 30 the grinding with ER gives a solioe cream (0.2G gi . ^ 75-77% - Found C 60.96 H 8.12 M 8.16 C ,. Η, „N OL S requires C 61.5 * η S.'4 M 6.28%.

: /! Π / u 30 F x ejn piei 2 N- [2-Hvdroxy-5- [1-hydroxy-2 - [[6- [4- (4-methylphenyl) butoxy] hexyl] amino] ethyl] phenvl] methanesul-f onamide □ n leaves at RT for 18 h a solution of N- / 5- (bromoacetyl) -5 2- (phenylmethoxy) phenyl / methanesulf onamide (1.0 g), the amine (0.9 g) obtained by basification of intermediate 13, and the \, t \; - diisopropylethylamine (0.4 g) in THF (20 ml), filtered and evaporated. The residue is purified by / C / eluting with CX-ER (1: 1) to give a yellow oil (1.0 g). The oil is hydrogenated in ethanol (50 ml) and THF (30 ml) on 1050 l palladium on charcoal (0.4 g) and 5% platinum on charcoal or wood (0.3 g) for 5 h, filter and evaporate. The residue is purified by / 0 / eluting with T-ET-A (80: 20: 1) to give a yellow gum, which is triturated with ER (40 ml) to give the CT in the form of a solid yellow (0.2 g), mp 65-67 °.

TLC (T-ET-A 80: 20: 1) Rf 0.2.

Example 13 N- [2-Hvdroxy-5- [1-hydroxv-2 - [[6- (4-phenylbutoxy) hexvlj amino] ethyl] phenvljméthanesulf onamide, acétste (sçl)

A solution of N- / 2-hydroxy-5- * i-nydroxy-2 - // 6-4-phenyl-butoxy) hexyl / amino / ethyl / phenyl / methanesulfonamide (4.0 g) in chloro-form is treated (50 ml) with acetic acid (0.8 g) and the chlo roform is evaporated. The residue is triturated with ER ^ 50 ml) to leave a yellow solid which is recrystallized from EA- ^ E to give the CT scus in the form of a white sample (3.7 g), mp 121-123 °.

Found C 59.3 H? .C \ 5 A

25 C25H38r'2C5 S‘C2 -C-5h2 G necess * c 55 <2 '"7-c' * 5

Examples of suitable formulations of the compounds of the invention are found below. The term "ingréc.snt act; '" is. = É; t. rwT represent a compound ce l'irventior. and may be, p εν ..: r ~ pcsé ce exemple 4.

/ Λ% 31

TABLETS

They can be prepared by normal processes such as wet granulation or direct compression.

A. Direct compression 5 mg / tablet

Active ingredient 2.0

Microcrystalline cellulose USP 196.5

Magnesium stearate BP 1.5

Compression weight 200.0 10 The active ingredient is sieved through an appropriate sieve, mixed with the excipients and compressed using punches 7 mm in diameter.

Tablets of other strengths can be prepared by changing the ratio of the active ingredient to microcrystalline cellulose or the compression weight and using appropriate punches.

.V

B. Wet granulation mg. compressed

Active ingredient 2.C

Lactose 3P 151.5

20 Starch BP 30, G

BP '15.0 pregelatinized corn starch

Magnesium stearate BP 1.5

2ZZ.Z compression peaks

The active ingredient is sieved through a suitable sieve and mixed with lactose, amioon and starch, but frozen. C ~ eichte appropriate volumes of purified water and the powders are granulated. Dry acnes are sorted granules and mixed with stearate this magnesium, sure: then compresses the granules into tablets using these punches of, 7 mm in diameter.

/ / 32 ί "* ......- T.

",

Tablets of other strengths can be made by changing the ratio of active ingredient to lactose or poios to compression and using appropriate punches.

C. For oral administration 5 mg / tablet

Active ingredient 2.0

Lactose BP 94.8

Sucrose BP 86.7

Hydroxypropylmethylcellulose 15.0 Ί0 Magnesium stearate BP 1.5

Compression weight 200.0

The active ingredient is sieved through an appropriate sieve and mixed with lactose, sucrose and hydroxypropyimethylcellulose.

Appropriate volumes of purified water are added and the powders are granulated, li · 15 After drying, the granules are sorted and mixed with magnesium stearate. Gn then compresses the granules into tablets using appropriate punches.

The tablets can be coated with a film with suitable film-forming materials, such as hydroxypropyl methylcellulose, using standard techniques. Another solution is to coat the sugar tablets.

CAPSULES

mg csDsule

Active ingredient 2.0 * Starch 1500 97, -

25 Magnesium stearate BP

Filling weight 1DC, 0 * Forms this directly compressible starch.

P

fi * \ \ # 33

The active ingredient is screened and mixed with the excipients.

The mixture is poured into hard gelatin capsules \ ° 2 using suitable equipment. Dn can prepare other doses by changing the filling weight and if necessary by changing the size of the capsule as appropriate.

SYRUP

It can be a presentation with or without sucrose.

mg / 5 ml dose

Active ingredient 2.0 1Π

Sucrose BP 275Q.0

Glycerin BP 500.0

Buffer )

Aroma)

Dye) as required 15.

Preservative) - Purified water BP qs 5.0 ml

The active ingredient, the buffer, the flavor, the color and the preservative are dissolved in part of the water and the glycerin is added.

Heat the rest of the water to dissolve the sucrose and then cool. 2G

The two solutions are combined, the volume is adjusted and mixed. The syrup produced is clarified by filtration.

B. Without sucrose mg- dese of 5 ml active ingredient 2.C mo

OC

Hydroxypropyi-méthyiceliulose USP

(viscosity type 4000) 22.5 mg

Buffer

Coloring flavor ^ Preservative according to oesoms

Softener

Purified water B = qs 5.2 / d \ ___ Ȏ 3 h

Ja?

The hydroxypropyl methylcellulose is dispersed in hot water, cooled and then mixed with an aqueous solution containing the active ingredient and the other components of the formulation. The resulting solution is adjusted to volume and mixed. The syrup is clarified by filtration.

5 MEASURED DOSE PRESSURE AEROBOL A. Aerosol in suspension.

mg / dose measured per container

Active ingredient micronized 0.100 26, AO mg

Oleic acid BP 0.100 2.6A mg 10 Trichlorofluoromethane BP 23.6A 5.67 g

Dichlorodifluoromethane BP 61.25 1A, 70

The active ingredient is micronized in a liquid energy mill to an interval of fine particulate size. The oleic acid is mixed with the trichiorofluoromethane at a temperature of 10-15 ° C. and the micronized drug N 15 is mixed in the solution with a mixer with high shear power. The suspension is measured in aluminum aerosol containers, embossed to the containers are suitable measurement valves delivering 85 mg of suspension, and pressure dichlorodifluoromethane is poured into the containers through the valves.

20 B. Aerosol in solution.

mg / dose measured per container

Active ingredient Q.C55 13.20 mg

Ethanol BP 11,100 2.66 g; Dichiorotétrafiuoroéthane BP 25,15 / ό, ΟΑ g | Dichlorodifluoromethane BP 37.7AG 9.06 g; It is also possible to include oe ± acts cté.que 3-, cu "· agent censit- [suitable active, eg Snan 85 (trioleate oe sorDitan;

*. · I dissolve the active ingredient in ethanol with olêiQuS acid

j or 1 tensiu-ac ^ x ’· if used. Qn measures the sc u'im '"'" og 'Pue i ·. 30 in suitable aerosol cans, pj.s we put the trionlcro - '. ^ Or: - methane. Valves are fixed by embossing appropriate measures on the receptacles and dichlorodifluoromethane is poured therein under pressure through the valves.

Λ 35

w SUPPOSITORIES

Active ingredient 2.0 mg * üJitepsol H15 qs 1.0 g * Registered quality of Adeps Solidus Ph. Eur.

A suspension of the active ingredient is prepared in the molten liiitep and poured, using suitable apparatus, into mo. for suppositories with a size of 1 g.

INJECTION FOR AD "ü1I \ ISTRATIO \ i \ travei \ euse mg / ml 10 Active ingredient 0.5 mg

Sodium chloride BP as required

Water injectable BP qs 1.0 ml - Sodium chloride can be added to adjust the tone and the pH can be adjusted, using an acid or a base, to that of optimal stability and / or to facilitate the dissolution of the ingredient in

Alternatively, suitable buffer salts can be used.

The solution is prepared, clarified and poured into ampo ,. of appropriate size sealed by melting the glass. The iniect is sterilized, .. by heating in an autoclave using one of the aopropra 20 cycles. Another solution, the solution can be sterilized by filtration and the back, in sterile ampoules under aseptic conditions. The solution can be co., Under an inert atmosphere of nitrogen or other suitable gas. IMHAL CARTRIDGES / JI j, \ mg.- · cartridge 25 Micronized active ingredient r.

Lactose BP qs 25.0

We micronized the active ingredient cans ur moul · - · è 0 - / = - = n ^ ·. at a fine particle size interval before mixing: with normal quality for compression in a blender · at other times 32 The powder mixture is poured into cansules of gelatin cure. '! in a suitable wrapper. The contents of csw'r / are administered with a powder inhaler like Rotahaier from Glaxo.

Claims (12)

3. Compounds according to claim 2, where m is 2 or 3 and n is 6, or m is U and n is 3, z, or 5, or m is 5 and n is 2, 3 or k. 5 a.m. Compounds according to claim 3, where m is 5 and n is 4. 5. Compounds according to any one of claims 1 to 6, in which R 1 and R 2 independently represent a hydrogen atom or a methyl group. ί 6. Compounds according to claim 5, in which R1 is a hydrogen atom and R2 is a hydrogen atom or a methyl group. i 7. Compounds according to any one of claims 1 to G where Q is HCÜ- I CH ^ CD-, NH ^ CO-, (CH ^ NSO ^ -, or RSSO ^ - where R5 is C1 to C3 alkyl J. t 8. Compounds according to claim 7 where Q is R5SO ^ - where R5 is methyl. 9. Compounds according to any one of claims 1 to 8 where Ar is an unsubstituted phenyl group or is a phenyl group substituted by a substituent which is a methyl group or a fluorine atom. 10. Comnnqps of general formula (la ', QNH * - R1 H0 - χ / - ^ HCH2NHÇ (CR2) œ0 (CH2) nAr (la) · = · OH R2. Y- WHERE i 20 m is a whole number going this 2 to 5; n is an integer ranging from 2 to 6, and the total of m * n is 7, B or 9; R1 represents a hydrogen and R2 represents a hydrogen atom or a / methyl group; / Γ "τ · 'ν m £ - Λ' 38 4? * Ar represents a phenyl group optionally substituted by a methyl group or a fluorine atom; and Q represents HCO-, CH ^ CO-, NH2 CO-, (CH ^ NS02 ~ or R5SÜ2 - where R5 is C1 to C3 alkyl; and their physiologically acceptable salts and solvates. 11. Compounds of general formula (la) according to claim 10 where m is 5 and n is 4, Q is CH SO - and Ar is a phenyl group or a phenyl group substituted by a fluorine atom. 12. The compound N- / 2-hydroxy-5- / 1-hydroxy-2 // 6- (i »-phenylbutoxy) hexyl / amino / ethyl / phenyl / methanesulfonamide and its physiologically acceptable salts and solvates. % 13. The compounds * N- [2-hydroxy-5- [1-hydroxy-2 - [[6- (4-phenyibutoxy) hexyl3 amina) £ .thyl] phenyl) methanesul f onamide; N- [2-hydroxy-5- [1-hydroxy-2 - [[6- [4- (4-fluorophenyl) butoxy] hexy1) amino] ethyl] phenyl] methanesulf onamide; N “[2-hydroxy-5- [1-hydroxy-2 - [[1-methyl-6- (2-phenylethoxy) hexyl] amino] ethyl3phenyl3me, thanesulf onamide; N- [2-hydroxy-5- [1-hydroxy-2-C [6- O-phe'nylpropoxy) hexyl] amino] e / thyl3 phenyl] form friend of; N- [2-hydroxy-5- [1-hydroxy-2r [[6- (4-phenyIbutoxy) hexyl3 amino.3 ethyl3phenyl3'uree; -Q H- [2-hydroxy-5- [1-hydroxy-2- [[3-C (e-phe ^ nylhexyl) oxy 3 propyl3 amino] ethyl] phenyl3me'tHanesul f onamide; 'Τ' "kJ N- [2-hydroxy-5- [l-hydroxy-2 - [[é- (3-phenylpropoxy) hexyl3 /. Amino.3éthyl3phenyl3uré e; fl '' '¥ m £ Ir 39 & 91 H .% N- [2-hydroxy-5- [1-hydroxy-2- [[6- (3-phcnylpropoxy) hexyl] amiho] ethyl] phcnyl] methanesu1 f onamide; N- [2-hydroxy-5- [1 -hydroxy-2 - [[6- [û-U-methylphenyl) butoxy] hexyl] amino] ethyl] phcnyl] methancsulf onamide: 5 and their physiologically acceptable salts and solvates H. Compounds of formula (I) such as defined in claim 1. where m. n, R1 and R2 are as defined in claim 1, Ar represents a phenyl group optionally substituted by one or two substituents chosen from halogen atoms, C1 to C3 alkyl groups or C1 to C3 alkoxy, or an alkylenedioxy group of formula -0 (CH O- where p is 1 or 2, and Q represents the group R3C0-, R3NHC0- or RSSÜ ^ - where R3 and R ^ are as defined in claim 1, and R5 is C1 to C3 alkyl.% 15. Process for the preparation of compounds according to any one as claims 1 to or one of their physiologically acceptable salts and solvates, wherein: (la) for the preparation of a compound of formula (I) where R1 is a hydrogen atom, alkyl an amine of general formula (II) QNH Π60— / \ —ÇI-ICH 2NR 7R 8 (II) · = · OH 20. each of the radicals R6 and R7 is a hydrogen atom or a protecting group and R8 is a hydrogen atom) 'W / j ^ ci s V ___' "• λ ·" '' "'* *' m · * f Λ 40 awsc an alkylating agent of general formula (III) S 'fi * 5 '. ! v! LCH (Cll2) njO (Cll 2) πΛγ (III) i I Π2 (^ 0 L represents an outgoing group) then, if necessary, remove any group | protector possibly present; or t Ob) for the preparation of a compound of formula (I) where R1 is a hydro-9ene atom. an amine of general formula (IV) QNH ^ R60— · \ —X1 — CH, NR7R8 \ _ / 2 (IV) • '· is alkylated (where each of the radicals R6 and R-7 is a hydrogen atom or a protective group% „f ·, RB represents a hydrogen atom or a transformable group <to? in such an atom under the reaction conditions, and X1 represents -CH (OH) - or y C = 0) with a compound of general formula (V) R2C0 (CH2) m0 (CH2) nAr (V) 10 in the presence of a reducing agent then, if necessary, any protective group which may be present is removed; or (2) a protected intermediate of general formula (VII) QNH) is deprotected - * Rl R "0-- --CftCH2NR7j: (CH2) m0 <CH2) nAr (VII) * '. = / ÔH k2" y " / 5 a- ✓ * * £ Λ f 4ΐ imf _% Where each of the radicals R6 and R7 is a hydrogen atom or a protecting group J? · Y, save that at least one of the radicals R6 and R7 is a protecting group); or (3) an intermediate of general formula (VIII) QNH is reduced "- · r6q— / \ —xl-X ^ X ^ CHjOCHjX ^ -Ar (VIII) •" · 5 (where R6 is a hydrogen atom or a protective group, X1 is -CH (OH) or a group convertible into such a group by reduction, X2 is -CH2 NR7 or a group convertible into such a group by reduction, X3 is -CRlR2 (CH2) m_1 or a transformable group into such a group by reduction, and 10 x * i is - (CH) or a group transformable into such a group by reduction, ÿ 1 2 n-1 ^ at least one of the radicals X1, X2, Χ3 and XU representing a reducible group), .. * 4¾ then, if necessary, any protective group which may be present is removed; y and if desired, the resulting compound of general formula (I) or a salt thereof is transformed into a physiologically acceptable salt or solvate. / U / * & rs bs * r 42 Λ * ζ · 16. Pharmaceutical composition comprising at least one compound of general formula% (I) as defined in any one of Claims 1 to 14 or one of its salts or products physiologically acceptable solvation, with a physiologically acceptable carrier or excipient. Woji, $ 3 --- r -------- .t \ '^ y