ITMI932689A1 - SULFONILAMMINO THIOPHENES WITH ANTI-INFLAMMATORY, ANALGESIC AND ANTIPIRETIC ACTIVITIES - Google Patents

Description

Description of the industrial invention having the title: SULFONYLAMINO THIOPHENES WITH ACTIVITY ' INFLAMMATORY, ANALGESIC AND ANTIPYRETIC ARTS?

The present invention relates to 2-sulfcnilanraino thiophenes, to processes for their preparation, to their use of ocher therapeutic agents and to pharmaceutical compositions containing them.

Pi? in particular, the invention relates to compounds of general formula (I)

in which

X? 0, S or -CO-;

? a C1-C4 alkyl optionally substituted with halogen atanes; R2? a hydrogen, C1-C4 alkyl, C1 -C4 alkylsulfcnyl optionally substituted with halogen atoms, or a group of formula -CO-A-R5 where A? an oxygen or a C-C and R5 bond? hydrogen or C1 -C4 alkyl;

R3? selected from the hydrogen group, acyl, cyano, nitro, formyl, carboxy, C1-C4-alkoxycarbonyl, carboxiamide, mono or di C1-C4-alkyl carboxyl do, C1-C4 alkyl sul, fin yl, C1 -C4-alkyl on the source or a group R3a R3b R3c, R3d, R3e having the following structures:

where A and are previously defined canine;

R6? hydrogen, amino or C 1 -C 4 alkyl;

R7? hydroxy, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1 -C4 alkoxycarbonyl-C1-C4-alkoxy;

R8? hydrogen or methyl;

R4? a possibly substituted phenyl with one or more? halogens, cyano, nitro, C1-C4 alkyls, C4-C6 cycloalkyls, C1-C4 haloalkyls, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkoxy, C1-C4 dialkylamino; 2-pyridyl, 3-pyridyl or 4-pyridyl and related dioxides.

Also included in the invention are the non-toxic salts and the optically active forms of the compounds of formula (I), including the raceme and diastereoiscmere mixtures.

Examples of C1-C4 alkyl sinus groups: methyl, ethyl, prcpyl, bufyl, isopropyl, sec-butyl, tert-butyl. Alkyl groups substituted with halogens are for example: chloranethyl, dichloranethyl, fluoranethyl, trifluorcmethyl, 2-fluoroethyl.

Eserpes of C1-C4 alkylsulfene groups: methylsulfenyl, ethylsulfaiyl, propylsulfaiyl, clarcmethylsulfaiyl, trifluorcraethylsulfcnyl.

Examples of C4-C6 cycloalkyl groups are cyclobutyl, cyclopentyl and cyclohexyl.

Examples of C1-C4 alkylsulfinyl groups are: methylsulfinyl, ethylsulfinyl, prcpilsulfinyl, eloremethylsulfinyl, trifluorcmethylsulfinyl.

Examples of COAR5 groups are: carboxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbanyl, tert-butoxycarbonyl.

Examples of groups C1-C4 alkylcarboxyadmide sine methylcarboxyamide, ethylcarboxyamnide, propylcarboxyanide.

Examples of acyl sinus acetyl, prcpicnyl, butyryl, benzoyl, 2-thenoyl, nicotinoyl, cyclohexanoyl groups.

Examples of alkoxy sine groups: methoxy, ethoxy, isoproxy. Examples of C1-C4 alkoxycarbonyl C1-C4 alkoxy groups are: methoxycarboxylethoxy, propoxycarbonylethoxy, iso-butoxycarbanyl-2-methylethoxy.

Examples of substituted phenyl groups are: o-, m-, p-fluorophenyl, 2,4- and 3,5-difluorophenyl; o-, m-, p-chlorophenyl, 2,4-, 3,5-dichlorophenyl, o-, m-, p-trifluoranethylphenyl, 2-, 3-, 4-toluyl, xyl, 3-ethylthiophenyl, o-, m -,? - dimethylanthinophenyl; o-, m-, p-isopropylaraminophenyl, 3,4,5-trimethoxyphenyl, 2,4-dimethoxyphenyl, diethylimvinophenyl, isopropylaimdnof en ile.

When in the poets of formila (I) there is an addo or basic group, this can? be salified respectively with pharmaceutically acceptable addi or bases. The salts ncn toxic cos? obtained as part of the invention.

The basic groups can be salified with both inorganic and organic acids, provided that pharmaceutically acceptable. Examples of inorganic acids such as hydrochloric acid, hydrogen chloride, sulfuric acid, phosphoric acid. Examples of organic acids sin acetic acid, oxalic acid, succinic acid, glutaric acid, lactic acid, citric acid, benzoic acid, p-methoxybenzoic acid, p-anndnobenzoic acid, maleic, fumaric and tartaric acid.

The carboxylic and sulphonic acid groups can be salified with both inorganic and organic bases, provided that pharmaceutically acceptable.

Examples of such salts are those of harmonium, sodium, potassium, calcium, magnesium, aluminum, iron, zinc, copper, alkylanine, tr ane fammi na, cyclic armines, morpholine.

The salts of the compounds of formula (I) with amino acids (for example taurine, lysine) are also provided.

The compost of the invention are endowed with activities? anti-inflammatory, antipyretic and analgesic, and can be considered in the category of non-steroidal anti-inflammatory drugs (NSAIDs).

Sine preferred the following compounds:

5-acetyl-3- {4 1 -f luorophenoxy) -2-methanesulfonylthiinothiophene;

Many NSAIDS (or NSAIDS) have been discovered in recent years and many of them are currently being used in the treatment of analgesic and antipyretic inflammatory and dog conditions. However, many of these compounds have significant side effects that prevent their use in numerous patients. Consequently, the search for new NSAIDs with reduced side effects and a high therapeutic index? more and more? flourishing.

Aromatic sulphonylamines are the subject of numerous patents such as US 3,840,597 (8.10.74), EP 0009554 (16.4.80), EP 0056956 (04.8.82), ffl 2025973 (30.01.80), EP 82101418 (25.02.82 ), JP 61010548 (18.01.86), JP 61010549 (18.01.86); US 4,866,091 (09/12/08); DE 3834204 (20.04.89) and JP 03133975 (06.07.1991).

However, none of these patents contain or refer to

compounds of the present invention n? contains suggestions relating to the particular orientation of the substituents which? specifically aimed at obtaining a high level of activity.

The compounds of formula (I) are prepared starting from 3-bromothiophene, according to the following scheme:

3-brcmothiophene (II), a coranercial product, is subjected to nitration according to conventional techniques, for example nitric acid in acetic anhydride. Compound (III) is then subjected to nucleophilic substitution at position 3- by a compound R4-X-, where and X are as defined above, to give the compound (IV), whose nitro group is reduced to ann? By means of a suitable known method, therefore, after reaction with alkylsulfuryl chloride, compound (V) is obtained, which pu? possibly be substituted for nitrogen with an R2 group. Finally, compound (V) is transformed into compound (I) by Friedel-Crafts acylation with a suitable acyl chloride.

Alternatively, bodies of formula (I) can be prepared according to the following scheme:

By brominating with known methods, for example bromine in chloroform, a thiophene suitably substituted in position 2 (VI), = -CH (OMe) 2 -COCMe, -CN, a body of formula (VII) is obtained which subjected to a reaction of census nitration to synthesize an exposed c of formula (VIII). The latter is then replaced in position 4- by a compound of formula R4-X-, with R4 and X defined above, to give compound (IX), whose nitro group is first reduced to annum according to known methods , then reacted with a suitable alkyl sulphoryl chloride, obtaining again the compounds of formula (I).

When = -CN, from (I) we can? obtaining the corresponding acid by acid hydrolysis, and from this it is then possible to obtain, by means of synthetic methods known in the literature, mono- or di-C1-C4 alkylcarboxamido and C1-C4-alkoxycarbonyl derivatives; again from (I), when R3 = -CN one can? to obtain the corresponding aldehyde by reduction with known agents such as diisobutylaluniniumhydride or H2 / N? Raney. The aldehyde cos? obtained can? be subjected to reaction with suitable triphenylphosphoranilides to synthesize compounds having defined dog in the formulas R3a and R3b, or react with suitable compounds for compounds having R ^ defined dog in the formulas R3 and R3e, or react with hydroxylanmine, haloxycarbine amine and alkoxyl carboxy amine to obtain R3 defined dog in the R3c formula?

The compounds of formula (I), if desired, can be transformed into toxic ncn salts or can be subjected to optical resolution in the case of ehiral compounds by resorting to absolutely conventional methods.

The compounds of the invention have shown advantageous properties. pharmacological. In particular, they carry out significant activities? anti-inflammatory, antipyretic, analgesic without however being accompanied by the typical side effects of NSAIDs.

Pharmacological previews have shown for the compounds of formula (I) an activity? anti-inflammatory superior to that of the compounds described in JP 3133975 confirming the importance of the relative orientation of the substituents on the thiophenic ring for the purposes of this activity.

The results are shown in the following Table, in which compounds A, B correspond to the compounds of the invention according to example 4, respectively 5-acetyl-3- (4 * -fluorophenoxy) -2-methanesulfonylaliminothiophene and 5-acetyl-3 - (21,4'-difluorophenoxy) -2-methanesulfcnylaminothiophene; compound E corresponds to the compound of Example 3, ie 3-phenoxy-2-methanesulfonylaminothiophene; C and D correspond respectively to the compounds of examples 2 and 5 of JP 3133975, namely 5-acetyl-3? Netanesulfcnylaiimino-2- (4'-fluorophenoxy) thiophene and 5-acetyl-3-rretansulfanilairmino-2- (21,4 ' -difluorophenoxy) thiophene; Nim? nimesulide and F? 4-acetyl-2- (4'-fluorophenoxy) methanesulfcnilaniline.

A further object of the invention relates to the use of the compounds of formula (I) as therapeutic algents in particular for the manufacture of medicaments useful in the treatment of inflammatory states, accompanied or not by painful symptoms and hyperpyrexia.

The compounds of the invention can be administered by means of suitable pharmaceutical compositions, optionally comprising other active ingredients.

The compositions, object of the invention, are prepared according to known techniques, for example as described in "Remingtcn's Pharmaceutical Sciences Handxxjk" XVII Ed.Mach Pubi. USA.

According to the invention, the pharmaceutical products can be administered parenterally, for example in the form of a sterile solution or suspension, ready or to be prepared at the time of use, suitable for the venous, intramuscular or subcutaneous route; or enterally in liquid form, for example drinkable solutions or suspensions, syrups, or solid, for example tablets, capsules, granules, also with controlled release, or rectally, in the form of suppositories. Topical formulations are also provided, such as creams, breads, ointments, eye drops, ophthalmic ointments, ear drops, vaginal formulations.

Dosages will be established by the attending physician according to the patient's pathology and status (age, sex, weight, any other clinical indications).

The following examples further illustrate the invention.

Example 1

A 70% HNO3 solution (19 ml, 0.42 mol) in AC2O (40 ml) keeping the temperature below -5 ° C (about 1 hour). At the end of the casting, the temperature is allowed to rise to 25 ° C, then it is diluted with water and after 1 hour under stirring the yellow crystal formed is filtered. It is purified by column chromatography (SiC ^ eluent n-heptane / AcGEt 95/5) obtaining 16 g (77%) of 3-hrcmo-2-nitrothiophene.

Example 2

To a solution of phenol (7.9 g 84.6 rrmol) in dimethoxyethane (160 ml) cooled to 10 ° C, t-BuOK (9.5 g, 84.6 rrmol) are added in portions and left under stirring at that temperature for 20 '. To the opalescent solution 3-hrcmo-2-nitrothiophene (16 g, 76.9 rrmol) and Cidi (380 mg, 3.8 rrmol) are added and after 20 'it is poured into H2O (150 ml). It is extracted with AcCEt (3 x 200 ml), the combined organic phases are washed with H2O, anhydrified on Na2SO4, decolorized with charcoal and concentrated to dryness to obtain 20 g of a brown solid. It crystallizes with i-PrCH (180 ml) obtaining 12.3 g (72%) of 3-phenoxy-2-nitrothiophene with m.p. 119-120? C.

Similarly, the following compounds were prepared:

3- (4-fluoropherhexis) -2-nitrothiophene; m.p. 124-125? C;

3- (2,4-difluorophenoxy) -2-nitrothiophene; m.p. 100-101?

Example 3

AcOH 96% (3.4 ml, 60 mmol) is added to a suspension of Fe powder (4.4 g, 60 mmol) in I ^ O / EtCH 1/2 (14 ml), so as soon as gas development begins, adds 3-phenoxy-2-nitrothiophene (4.4 g, 20 mmol).

After 25 'it is poured into H2O (250 ml), the suspension obtained is filtered on a celite plate and extracted with Et2O (3 x 150 ml). It is concentrated under vacuum, the oon residue is taken up (40 ml), pyridine (8 ml) is added and CH3SC3Cl (3.5 ml, 45 mmol) is dropped in 5 '. After washing with H2O (2 x 20 ml) it is concentrated to dryness and purified by column chromatography (SiO2, eluent hexane / AcOEt 9/1). 2.2 g (42%) of N- [(3-phenoxy) -2-thienyl] methanesulfnarmyide were obtained with m.p. 104-105? C.

Similarly, the following products were prepared:

N- [(4-fluorof erected) -2-thienyl] methanesulfaianmide;

NMR (CDC13, ppm) 3.0 (s-3H); 6.6 (d = 1H); 7.1 (d = 1H)

N- [(2, 4-difluorofeno xsi) -2-tien il] methanesulf cnamnide; m.p. 163-165? C.

Example 4

Acd (2 , 45 g, 31.3 rrmol) and in small portions AlCl ^ (6.9 g, 52 mmol). After 10 'it is poured into H20O / ice, the phases are separated and the aqueous phase is concentrated with CH2Cl (30 ml). The combined organic phases are washed with H2O then brought to pH 9 with NH4CH and extracted with H20 (3 x 50 ml). The combined aqueous phases, washed with CH2CI2 to eliminate the impurities, are stirred and brought to pH 1 with concentrated HC1: a white crystal precipitates which after 20 'under stirring is filtered, washed with H2O and purified on a column of SiO 2 obtaining 2.8 g (55%) of 3- (4 '-fluorophenoxy) -5-acetyl-2-m tansulphene arime notophene with m.p. 149-150? C.

Similarly, the following were obtained:

Example 5

To a solution of 2-thiophencarbonitrile (1.09 g, 10 mnoles) in CHa3 (15 ml) at 25 ° C, 3.4 g (25 mnoles) of AICI3 are added in portions, then, at 25 ° C Br2 is dropped. (0.51 ml, 10 mnoles). It is heated to 40 ° C and after 4 h it is poured into HC12N / ice and extracted with CHZl3 (2-10 ml). The organic phases are washed first with NaHCO3 aq. and then with NaCl aq., anhydrified on Na2SO4 and dry concentrated under toning to obtain 1.4 g (74%) of 4-hrcmo-2-thiophencarbonitrile. NMR (CDCl3, ppm) 7.1 (s-1H); 7.5 (s-1H).

Similarly? been obtained;

4-hrano-2-acetylthiophene

NMR (CDCl3, ppm) 2.5 (s = 3H); 7.51 (d-1H); 7.59 (4.1H).

Example 6

4.3 ml of HNO3390% are added to 4-brcmo-2-thiophenecarbonitrile (0.615 g, 3 mmoles) maintaining the temperature at 10 ° C. Then, cautiously, 0.11 ml of oleum is poured and then heated at 40 ° C for 30 '. The reaction mixture is poured into water / ice and EtQAc (2x5 ml) is extracted; the organic phase is washed with NaHX> 3 aq. (5 ml) and ccn NaCl aq. (5 ml), anhydrified on Na2SO4 and concentrated to dryness under vacuum. They are obtained

0.55 g (73%) of 4-hrcroo ~ 5-nitro-2-thiophen carbonitrile.

NMR (CDC13 / ppm) 7.2 (s = 1H)

Similarly? been obtained:

5-acetyl-3-brcmo-2-nitrothiophene

N4R (CDC13, ppm) 2.5 (s - 3H); 7.4 (s - 1H).

Example 7

To a solution of phenol (7.9 g, 84.6 mmol) in dimethoxyethane (160 ml) cooled to 10 ° C, t-BuOK (9.5 g, 84.6 mmol) is added in portions and left under stirring at that temperature for 20 '. To the opalescent solution obtained, 4-hrcmo-5-nitro-2-thiophencarbcnitrile (21.4 g, 79.6 nmoles) and CuCl (380 mg, 3.8 imoles) are added. After 30 'it is poured into water and extracted with EtQAc (3 x 150 ml). The combined organic phases are washed with H2O, dried over Na2SO4, decoloured with charcoal and concentrated dry to obtain about 20 g (95%), 4-phenoxy-5-nitro-2-thiophenecarbonitrile as a dark solid.

M4R (CDC13, ppm) 6.5 (s-1H)

Similarly, I obtained:

4- (4'fluorophenoxy) -5-nitro-2-thiophencarbcnitrile

NMR (CDCl3, ppm) 6.45 (s-1H)

4- (2,4-difluorophenoxy) -5-nitro-2-thiophencarbonitrile

NMR (CDCl3, ppm) 6.42 (s = 1H)?

Example 8

To a suspension of powdered iron (0.4 g, 6 nmoles) in H2O / EtOH (1.5 ml) 96% AcOH (0.34 ml, 6 ichthyols) is added and when gas evolution begins to be observed, 4-phenoxy-5-nitro-2-thiophencarbonitrile (0.57 g, 2 moles) is added. Dcpo 30 'is poured into water and ccn Et20 is extracted. The solution is concentrated under vacuum then the residue is taken up with CH2CI2 (4 ml), 0.8 ml of pyridine is added and methanesulfcnyl chloride (0.35 ml, 4.5 ml) is added dropwise. It is washed with water, concentrated to dryness and purified by chromatography on a silica gel column, eluting on et. petroleum / EtQAc 1: 9 to obtain 4-phenoxy-5-methanesulfaiylanrrdno-2-thiophenecarbonitrile (0.38 g, 65%).

NMR (CDCI3, ppm) 3.05 (s = 1H)

Similarly, the following were prepared:

4- (4-fluorophenoxy) -5-methanesulfcnylaimino-2-thiofencarbcnitrile

NMR (CDGL31 ppm) 3.05 (s = 3H); 6.75 (s-1H)

4- (2,4-difluorophenoxy) -5-metarLsulfcnylamino-2-thiophencarbonitries NMR (CDC13, ppm) 3.05 (s = 3H); 6.72 (s - 1H).

Example 9

A mixture of 4- (21.41-difluorophenoxy) -5-methanesulfcnilanino-2-thiophenecarbene nitrile (1.5 g, 4.5 mnoles) and Ni Raney (1.5 g) in 70% HUOOH (35 ml) is heated at reflux and after 45 'filtered and concentrated to a small volume. After F.C. 1.28 g (85%) of 4- (2,4-difluorophenoxy) -5-methanesulfcnylanmino-2-thiophencarboxaldehyde are obtained.

NMR (CDC13, ppm) 3.0 (s-3H); 9.8 (s-1H).

Example 10

A mixture of 4- (2 ', 4'-difluorophenoxy) -S-Hietansulfcnilainnino-2-thiophenecarboxaldehyde (2 g, 6 itmoles) and triphenylphosphoranylidene-butyrolactcne in EMSO (10 ml)? kept under stirring at 80 ° C for 1 h. Then the reaction mixture is cooled and diluted with AcQEt (50 ml). Is it washed with H2O and the organic phase? dry concentrated. It is purified by chromatography on silica gel column eluting with petroleum ether / AcCEt 8: 2 to obtain [4- {21,4'-difluorophenoxy) -5- (methanesulfcnylanthin) thienyl-2-methylene] -butyrolactcne (1, 7 g, 70%).

NMR (CDC13, ppm) 3.2 (s = 3H); 8.6 (s-1H)

Similarly we obtain:

[4- (2,4-difluorophenoxy) -5- (methanesulfcnylanmin) thienyl-2-methylene] ethyl acetate

WR (CDC13, ppm) 3.0 (s = 3H); 6.3 (d-1H); 7.3 (d-1H).

Example 11

A mixture of 4- (21.41-difluorophenoxy) -5-methanesulfonylamino -2-thiophenecarbonitrile (1.5 g, 4.5 mmol), hydroxylairmine hydrochloride (0.8 g, 11.5 mmol) and Na2C03 (1, 2 g, 11.6 mmol) in EtCR / H20 2: 3 (50 ml)? held in reflux for a few hours. It is concentrated to a small volume, taken up with water by acidifying with diluted HCl and extracted with AcQEt. The combined extracts dry concentrated and purified on a silica gel column eluting with toluene / AcOEt 1: 1 to give 1 g (60%) of 4- (2,4-difluorophenoxy) -5-methanesulfcnylamino-2-tensionidoxime.

NMR (CDCl3, ppm) 3.0 (s = 3H); 7.4 (s-1H)

Similarly, the following were prepared:

4- (4-fluorophenoxy) -5-methanesulfenylarimino-2-tenanmidoxime (NMR (CDCl3, ppm) 3.0 (s-3H); 7.35 (s-1H)

4-phenoxy-5-methanesulfenilaimdno-2-tenanmidoxime

NMR (CDCl3, ppm) 3.0 (s-3H); 7.3 (s = 1H).

Example 12

4- (2 ', 41-difluorophenoxy) -5-methanesulfcnilanmino-2-thiophencarbanitrile (1.5 g, 4.5 irmel) is dissolved in a 1: 1 glacial H2SO4 / AcOH mixture and kept at 50 ° C for 2h. The mixture of resizicne is poured into H2O / ice, basified with Na2CO3 aq., Washed with Et20 then re-acidified with HC13N and finally extracted with AcQEt. The combined organic phases are dried and concentrated under vacuum to obtain 4- (21,4'-difluorophenoxy) -5-methanesulfcnylanmin-2-thiophenecarboxylic acid.

NMR (CDC13, ppm) 3.0 (s = 3H); 7.7 (s-1H); 12.1 (s = 1H).

Example 13

4- (21,4'-difluorophenoxy) -5-methanesulfcnilanmino-2-thiophenecarboxaldehyde (2 g, 6.1 irmel) and malononitrile (0.38 g, 6.2 irmel) are suspended in i-PrCH (25 ml) , AcCH (0.4 limol) is added and finally benzylaithmine (0.8 irmel) is dropped. After 30 'under stirring, the reaction mixture is concentrated under vacuum to obtain 2 g (90%) of [4- (21,4'-difluorophenoxy) -5- (methanesulfcnylanmin) thienyl-2-methylene-malononitrile.

NMR (CDC13, ppm) 3.05 (s = 3H); 7.4 (s-1H); 8.6 (s = 1H).

Claims (5)

CLAIMS 1. Compounds of general formula (I) in which X? 0, S or -CO-; R1? a C1 -C4 alkyl optionally substituted with halogen atoms; R2? a hydrogen, C1C4 alkyl, C1-C4 alkylsulfonyl optionally substituted with halogen atoms, or a group of formula -CO-A-R5 where A? an oxygen or a C-C and R5 bond? hydrogen or C1-C4 alkyl; R3? selected from the hydrogen group, acyl, cyano, nitro, formyl, carboxy, C1-C4-alkoxycarbonyl, carboxiamido, mono or di C1 -C4-alkyl carboxymide, C1-C4 alkyl on ph inyl, C1-C4-alkyl on phenyl or a group R3a, R3b R3c, R3d R3e having the following structures: where A and R5 are previously defined caries; R6? hydrogen, armine or alkyl; R7? hydroxy, alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkoxycarbonyl-C1-C4-alkoxy; R8? hydrogen or methyl; R4? a phenyl possibly substituted with one or more? halogens, cyano, nitro, C1-C4 alkyls, C4-C6 cycloalkyls, C1-C4 haloalkyls, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkoxy, C1-C4 dialkylarmine; 2-pyridyl, 3-pyridyl or 4-pyridyl and related N-oxides, their non-toxic salts and optically active forms including racemic and diastereoiscmere mixtures. 2- Compounds according to claim 1, in which R4? 4-fluorophenyl or 2,4-difluorophenyl and X? 0. 3. A compound according to claim 1, selected from the group consisting of 4. Process for the preparation of the compounds of claims 1-3, in which R3? acyl according to the following scheme: where the groups are as defined, characterized in that a compound (V) is transformed into a compound (I) by means of the Erledel-Crafts ac ilation reaction, and possible subsequent salification or optical resolution. 5. Process for the preparation of the compounds of claims 1-3, in which R3? as defined above, except acyl, according to the following scheme: