ITMI940238A1 - AZACYCLIC DERIVATIVES - Google Patents

Description

Description of the industrial invention entitled: "AZACYCLIC DERIVATIVES"

The present invention relates to new substituted azacyclocondensated piperazines, to processes for their preparation and to their use in medicine, in particular as diuretics and anti-ischemic agents.

Compounds that are kappa receptor agonists have mostly been studied as analgesics; in this respect, the advantage of kappa receptor agonists over classical mu receptor agonists, such as morphine, lies in their suitability to cause analgesia while lacking morine-like behavioral effects and their ability to induce addiction.

EP-A-343900 and EP-A-398720 (Glaxo Group Ltd.), and EP-A-356247 (Sahkyo Co. Ltd.) describe groups of piperazine derivatives that are said to be endowed with kappa receptor agonism and therefore useful as analgesics, diuretics and in the treatment of cerebral ischemia.

A new structurally related class of azacyclocondensated piperazine derivatives has now been found which exhibit potent kappa receptor agonism and which are particularly useful as diuretics for the treatment of pathological hypcnatremic conditions in mammals and as antiischemic, particularly for the treatment of cerebral ischemia. This new class of derivatives also possess analgesic activity and therefore they are also potentially useful in the treatment of pain, without some of the undesirable behavioral effects of morphine and its analogues. The new class of derivatives is also of potential utility in the treatment of other conditions that respond to the administration of kappa agonists, in particular convulsions, cough, asthma, inflammation (including pain from inflammation), pancreatitis, arrhythmia.

The present invention provides a compound, or a solvate or Scyl thereof, of formula (I):

in which:

each of X and Y is independently CH or N;

RCO is an acyl group in which the R group contains a substituted or unsubstituted carbocyclic or heterocyclic aromatic ring; each of and Rji which can be the same or different, is hydrogen, 1-6 alkyl, optionally substituted with at least one halogen atom (preferably fluorine or chlorine), hydroxy, C - ^ _ g alkoxy (preferably methoxy), acyloxy (preferably acetoxy), thiol, C ^ _g alkylthio (preferably methylthio), acylthio (preferably acetylthio), haloalkoxy (preferably fluoroalkoxy), COR ^, COOR ^, or NHDOR ^, where it is hydrogen or Cj_g alkyl, (preferably methyl or ethyl);

or each of R ^ and R2 is C2_ $ alkenyl, C ^ g cycloalkyl, C4_ ^ cycloalkylalkyl;

O and R2 together form a C2_g alkylene group, or a C2-6 alkenylene group, linear or branched, optionally substituted, the poly-methylene group, linked to the nitrogen atom, preferably having the formula

where Rb, which can be bonded to the same or a different carbon atom where Rc is bonded, is hydrogen, hydroxy, C] _g alkoxy {preferably methoxy) or halogen (preferably fluorine), and is hydrogen, C ^ _g alkyl (preferably methyl) or together with forms a keto group or a cyclic ether containing 1 to 4 carbon atoms, and a is 1 or 2.

Examples of NR ^ I ^ are 1-pyrrolidinyl, 3-hydroxy-1-pyrrolidiniI and 3-fluoro-1-pyrrolidinyl.

When used herein to define the RCO group, the term "aromatic carbocyclic group" includes single or fused rings, having 6 to 12 ring carbon atoms, and the term "heterocyclic aromatic group" includes single or fused rings having 5 to 12 ring atoms, including up to 4 eternatemi in or in each ring, selected from oxygen, nitrogen and sulfur.

When the carbocyclic or heterocyclic group is a bicyclic or fused system, one or both rings may be of the aromatic type.

Conveniently, one of the rings is aromatic and the other is non-aromatic.

The R group preferably has the formula (II):

where n is 0, 1 or 2;

ra is 0, 1 or 2;

m 'is 0, 1 or 2, provided that m m'4: 3;

X is a direct bond or O, S or NRg where

RQ is hydrogen or C ^ _g alkyl,

Ar is a substituted or ncn substituted carbocyclic or heterocyclic group; each of Rg and Rga is Cj, _6 alkyl, C2-6 alkenyl, C2_g alkynyl, C-j_g haloalkyl, C ^ _g haloalkenyl, C2_g haloalkynyl, phenyl or heterocyclyl optionally substituted, phenyl (optionally substituted) C ^ _g alkyl, hydroxy, C ^ _g alkoxy, thiol, Cj_g alkylthio, Cj_g haloalkoxy, C ^ _g haloalkylthio, halogen, NC> 2, CU, CF3, -OCF3, -0CHF2, -OCF2CF2H, -COCl2CF3,, -C0NR10R 2, --S03R S02NR ^ 3R3 ^ ® ~ OCIR ^ ς in which each of the groups Rg to R ^ g is independently hydrogen, C - ^ _ g alkyl, phenyl optionally substituted or phenyl (optionally substituted) C ^ _g alkyl;

or, when m is 2 and m 'is 0, two Rg groups form a C3_g polymethylene group and R ^ is hydrogen or Cj_g alkyl, such as methyl or ethyl.

When Rg or Rga is heterocielyl, it is preferably a system of single rings or aromatic or non-aromatic melts having from 5 to 12 ring atoms, comprising up to 4 heteroatoms in or in each ring, selected from oxygen, nitrogen and sulfur.

Preferred halogens sine F, Cl and Br.

When the two Rg groups are linked they preferably form a

fused cyclopentyl or cyclohexyl ring.

Preferably Ar is phenyl and Rg or Rga is preferably in the meta- and / or para position.

Other examples of Ar are naphthyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothioenyl, indolyl, 2,3-dihydrobenzopyranyl and 2,3-dihydrobenzothiopyranyl.

Preferably Rg or Rga is song, chloro, CF ^, 2-furanyl, 2-pyrryl, 2-thiazolyl, 2-imidazolyl or 2-thienyl, particularly, when

Ar is phenyl, in the meta and / or para position.

X is typically oxygen or a direct bond, and n is typically 0 o

1.

A further preferred R group has the formula (Ila)

C.

where the group - (CHR ^ J ^ -X-, which is defined in formula II, is

in the meta or para position with respect to YR ^ or Ry,

Y is> C = 0,> CHCH,> S = 0 or> 30 ^;

each of and Ry is Cj-6 alkyl, o

Rx and Ry are linked together and RJC represents - (Zm) - <(> ^ <ave> m is O or l and Z is

0, S or NRz where R2 is hydrogen or Cj_g alkyl,

and Ry represents - (CHjlg- where q is an integer from 1 to 4, preferably 2 or 3.

A preferred subgroup of formula (IIa) is a group of formula (IIb

where Y, Z, m, q is the position of -CR ^ - sine as defined in the formula (Ila).

Preferably, q is 2 when Z is oxygen and m is l, and q is 3 when m is 0.

A further preferred subgroup of formula (Ila) is the group of formula (Ile)

wherein Y is C-O or CHOH, each of and Ry is Cj_g alkyl, preferably methyl, and the position of is defined in formula (IIa).

A further preferred group R has the formula (Hd)

where Het is the residue of a single aromatic heterocyclic ring, containing from 5 to 6 ring atoms and comprising up to 3 eternatoms in the ring selected from O, S and N;

and R ^, x, γ, Z, m and q are defined in the formula (Ila).

Particularly preferred examples of R sine 3,4-dichlorobenzyl or 4-trifluoranethylbenzyl.

The compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form we mean, among other things, of a pharmaceutically acceptable level of purity, with the exclusion of the normal pharmaceutical excipients such as diluents and vehicles, and notably material considered toxic at normal dosage levels.

A substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and even more preferably 95% of the compound of formula (I) or its salt or solvate.

A preferred pharmaceutically acceptable form is the crystalline form, including that form in a pharmaceutical body. In the case of salts or solvates, the ionic portions and additional solvents must also be non-toxic.

Examples of pharmaceutically acceptable salts of a compound of formula (I) include the acid addition salts with conventional pharmaceutical acids, for example maleic, hydrochloric, bromidic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric acids. , succinic, benzoic, ascorbic and methanesulfcnic.

Examples of pharmaceutically acceptable solvates of a compound of formula (I) comp yield the hydrates.

The compounds of formula (I) have at least one asymmetric center and therefore exist in more than one stereoisomeric form. The invention extends to all such forms and their mixtures, including racemates.

The present invention also provides a process for the preparation of a caiposto of formula (I) which comprises treating a compound of formula (III)

wherein R ^, Rj, X and Y canine defined in formula (I), with an R30CH compound or an activated derivative thereof, and optionally subsequently forming a salt and / or a solvate of the obtained compound of formula (I).

Suitable activated derivatives of RCOOH are acyl chlorides or acid anhydrides. Another suitable derivative is a mixed anhydride formed between the acid and an alkyl chloroformate.

For example, in conventional methods known to those skilled in the art, the compound of formula (III) can be coupled:

a) with a chloride of an acid in the presence of an organic or inorganic base in an aprotic solvent such as dichlorarethane or dimethylformarmide,

b) with acid in the presence of dicyclohexylcarbodiimide or carbcnyldiimidazole,

c) with a mixed anhydride generated in situ from the acid and an alkyl (for example isobutyl) chloroformate.

The compounds of formula (I) can be activated in their pharmaceutically acceptable acid addition salts by reaction with suitable organic or mineral acids. The solvates of the compounds of formula (I) can be formed by crystallization or recrystallization from an appropriate solvent. For example, hydrates can be formed by crystallization or recrystallization from aqueous solutions, or solutions in organic solvents containing water.

Even salts or solvates of the compounds of formula (I) which are not pharmaceutically acceptable can be useful as intermediates in the production of pharmaceutically acceptable salts or solvates. Consequently, such salts or solvates are also part of this invention.

As mentioned above, the compounds of formula (I) exist in more than one stereoisomeric form and the process of the invention leads to mixtures thereof. The individual isomers can be separated from each other by resolution using an optically active acid such as tartaric acid. Alternatively, an asymmetrical synthesis would offer a way to the individual form.

The compounds of formula (III) can themselves be prepared from known compounds with known methods. For example, compounds in which X and Y enter -CH- (formula (Illa)) can be prepared with the following reaction scheme I:

Scheme I

In this scheme, a compound of formula (VI) is prepared from the compound of formula (VII) known (J. Am. Chem. Soc. 1945, 67, 1711) by reaction with an excess of the suitable amine in the absence or in the presence of solvent , those MeOH.

Compound (VI) is then treated with a haloacetaldehyde, such as chloroacetaldehyde or hromoacetaldehyde, in a dicxane / water mixture at a temperature of 90 ° C for a prolonged tarp period (from 8 to 48 hours), and the resulting compound of formula ( V) is hydrogenated on a suitable catalyst, such as Pt02 or Pt / C 5% in the presence of calcium oxide in a suitable solvent, such as ethanol or 2-methoxyethanol.

The reduction of compound (IV) with diborane or with the borane-methyl sulfide complex in reflux TOF leads to the desired compound of formula (IIa).

The intermediates of formula (VI), (V), (IV) and (Illa) and their salts and solvates are new compounds and, as such, constitute a further object of the invention.

The compounds of formula IH where X is -N- and Y is -CH- (form it inb] can be prepared according to the following reaction scheme II:

Scheme II

(llb)

In this scheme, the compound of formula (VI) is treated with an excess of N, N-dimethylformannu.de dimethyl in reflux toluene to obtain a compound of formula (VIII). The substitution of the N, N-dimethylanthin group with the oxime group in MeCH as solvent gives a compound of formula (IX), which is then cyclized in polyphosphoric acid at a temperature between 80 ° C and 100 ° C.

The resulting compound of formula (X) is hydrogenated on a suitable catalyst, such as Pt02 or Pt / C 5% in the presence of calcium oxide in a suitable solvent, such as ethanol or 2-methoxyethanol to obtain a compound of formula (XI). The reduction of this ccn diborane or the borane-methyl sulphide complex to reflux THF leads to the desired compound of formula (Illb).

The intermediates of formula (VIII), (IX), (X), (XI) and (Illb) and their salts and solvates, are novel compounds, and as such constitute a further aspect of the invention.

The compounds of formula (III) in which X and Y entrants are -N- (formula (IIIc)) can be prepared according to the following reaction scheme ΙΠ:

Scheme m

In this scheme, the known body of formula (XII) (U.S. Pat.

4,578,378) is N-protected with an alkylation process and the resulting compound of formula (XI I) is treated with a selective reducing agent, such as lithium borohydride in reflux THF, to obtain the compound of formula (XIV). This intermediate is activated with methanesulfene or p-toluenesulfene chloride in dichloranethane as solvent and is subsequently treated with the suitable amine. The resulting compound of formula (XV) is transformed into the corresponding imidium chloride by treatment with PCl5 in dichloranethane.

The intermediate (XVI) is subsequently subjected to a 1, 3-dipolar cycloaddition reaction with sodium azide and ammonium chloride in reflux DMF to obtain a compound of general formula (XVII), which can be deprotected using hydrogen on Pd / C 5% as catalyst in a suitable solvent such as ethanol or methanol, giving the desired compound of formula (IIIc).

Alternatively, compounds of formula (XV) can be prepared by intramolecular cyclization, according to scheme IV:

Scheme IV

(XV)

In this scheme, the known compound of formula (XVIII) (CAS [69942-12-7], Angew. Chem., Int. Ed. Engl., 11, 289 (1972)) is activated by treatment with methanesulfonyl chloride or of p-toluenesulfcnyl in a suitable solvent, such as dyestylor, and then it is treated with the suitable antin. The resulting carpox (XIX) is then deprotected using tri-fluoroacetic acid and transformed directly into the dihydrate salt by treatment with H ^ 1 / Eft ^ O.

The compound of formula (XX) is subjected to a reductive anmination process with phthalimido acetaldehyde in the presence of an alkali metal hydride, such as NaBH ^ or NaOffiH ^ in a suitable alcohol solvent.

The resulting compound of formula (XXI) is then cyclized intramolecularly by treatment with hydrazine hydrate in ethanol at room temperature to obtain a compound of formula (XXII).

Direct alkylation with benzyl chloride in the presence of e KI or with ben z al of d in the presence of NaCNBH ^ in MeCH gives rise to the desired compound of formula (XV).

The compounds of formula (III) in those X is -CH- and Y is -N- (formula (Illd)) can be prepared according to the following reaction scheme (V):

Scheme V

In this scheme, a compound of formula (XXIII) is treated with hydrazine in reflux ethanol, and the resulting compound of formula

(XXIV) is then ejected with triethyl orthoform in reflux xylene.

The compound of formula (XXV) obtained is selectively reduced by hydrogenation on PtO 2 in the presence of calcium oxide in a suitable solvent, such as 2-methoxyetharal, to give a compound of formula (XXVI).

The reduction of this with diborane or including methyl borane-sulfide to reflux THF leads to the desired compound of formula (Illd).

The compound of general formula (XXIII) can be obtained from a compound by known methods, for example described in J. Heterocycl. Chem. 1979, 16 (1), 193-4 and in Heterocycles 1984, 22 (2), 299-301.

The activity of the caipostis of formula (I) in the standard tests indicates that they are of potential therapeutic utility in the treatment of hyponatremic pathological conditions, cerebral ischemia, pain, convulsions, cough, asthma, inflammation (including pain from inflammation), pancreatitis and arrhythmia (hereinafter referred to as Dog Conditions).

Consequently, the present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as a therapeutically active substance.

The present invention further provides a pharmaceutical composition which comprises a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (hereinafter referred to as "Compounds"), in the manufacture of a medicament for the treatment of the Conditions.

The present invention also provides a method of treatment and / or prophylaxis of the Conditions in marble, in particular human, which comprises the administration to the martiniferous in need of such treatment and / or prophylaxis of an effective amount of the Corposto.

Such medicaments, and compositions containing the Compounds, can be prepared by mixing a Compound with a suitable carrier, which may contain a diluent, binder, filler, disintegrant, flavoring agent, coloring agent, lubricant or preservative in a conventional manner.

These conventional excipients can be used for example in the preparation of compositions of known agents, for the treatment of the Conditions.

Preferably, a medicament or pharmaceutical exposure of the invention is in unit dosage form and in a form suitable for use in the medical or veterinary field. For example, such preparations may be in concentrated form accompanied by written or printed instructions for use as an agent in the treatment of each of the Conditions.

The suitable dosage range for a Compound depends on the Compound that will be employed, the Condition to be treated and the condition of the patient. It will also depend, among other things, on the relationship between potency and absorbability and on the frequency and route of administration.

The Compound can be formulated for any sleep pathway, and is preferably in unit dosage form or in a form such that a human patient can self-administer it in a single dosage. Advantageously, the carposition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. The preparations can be formulated to give a slow release of the active ingredient.

The compositions can be, for example, in the form of tablets, capsules, sachets, vials, powders, granules, tablets, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.

The compositions, for example those suitable for oral administration, may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; pressing lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylidone, starch, sodium glycolate or microcrystalline cellulose; or pharmaceutically acceptable curing agents such as sodium lauryl sulfate.

The solid compositions can be obtained by conventional methods of mixing, filling, pressing or the like. Repeated mixing operations can be used to distribute the active ingredient in those onpositions that employ large amounts of fillers. When the composition is in tablet, periv or tablet form, any vehicle suitable for formulating solid pharmaceutical compositions can be used, for example magnesium stearate, starch, glucose, lactose, sucrose, rice flour and gypsum. The tablets can be coated according to methods known in normal pharmaceutical practice, in particular with gastroresistant coatings. The carposicines may also be in the form of a capsule to be swallowed, e.g. gelatin containing the compound, if desired with a vehicle or other excipients.

The liquid compositions for oral administration can be in the form, for example, of emulsions, syrups or elixirs, or they can be presented as a dry product to be reconstituted with water or other suitable vehicle before use. Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated co-extractable fats; emulsifying agents, for example lecithin, sorbital monooleate, or acacia skirt; aqueous or aqueous vehicles, which include edible oils, for example, almond oil, fractionated coconut oil, oily esters, for example, glycerin esters, or propylene glycol, or ethyl alcohol, glycerin, water or saline; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and, if desired, conventional flavoring or coloring agents.

The Compounds can also be judged through a non-oral route. According to the usual pharmaceutical procedure, the compositions can be formulated, for example for rectal administration as a suppository or for topical administration of dog cream or lotion. They may also be formulated, for presentation in injectable form, in an aqueous or non-aqueous solution, suspension or emulsion, in a pharmaceutically acceptable liquid, e.g. sterile pyrogenic water or acceptable oil for parenteral administration or a mixture of liquids. The liquid may contain bacteriostatic agents, antioxidants or other preservatives, buffers or solutes to make the isotany solution with blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. Such forms will be presented in unit dosage form such as ampoules or disposable injection devices or in multi-dose forms such as bottles, from which the appropriate dose can be taken, or a solid or concentrated form that can be used to prepare an injectable formulation.

The Compounds can also be administered by inhalation, through the nasal or oral route. This administration can be carried out with a spray formulation comprising a Compound and a suitable carrier, optionally suspended for example in a hydrocarbon propellant.

Preferred spray formulations include a particle micronized Compound in combination with a surfactant, solvent or dispersing agent to prevent sedimentation of the suspended particles. Preferably, the grain size of the Compound is about 2 to 10 μ.

A further modality of administration of the Compounds includes transdermal delivery using a skin patch formulation. A preferred formulation comprises a compound dispersed in a pressure sensitive adhesive which adheres to the skin, thereby allowing the compound to diffuse from the adhesive through the skin to be delivered to the patient. For a constant rate of percutaneous absorption, pressure sensitive adhesives known in the art such as natural skirt or silicone can be used.

The effective dose of Compound depends on the particular Compound used, the Condition to be treated, the patient's condition and the frequency and route of administration. A unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg. The composition can be administered one or more times a day, for example 2, 3 or 4 times a day, and the total daily dose for a 70 kg adult will normally be in the range of 100 to 3000 mg. Alternatively, the unit dose will contain from 2 to 20 mg of active ingredient and will be administered in multiple doses, if desired, to give the above daily dose.

If the compounds are administered according to the invention, unacceptable toxicological effects are not expected.

The affinity to the kappa receptor of the Compounds can be demonstrated in in vitro binding experiments using a selective kappa radioligand {Sbacchi et al., Excerpta Medica, Vol. 914, 211-212, 1990).

The diuretic activity of the Compounds can be evaluated by measuring the urine volume in normally hydrated rats and in water-loaded rats according to the methods of J.D. Leander, J. Pharmaool. Exp. Tber., 1983, Vol. 224, 89 and by A.G. Hayes, J. Pharmaool. Exp., 1987, Vol. 240, 984.

The activity of the compounds in treating cerebral ischemia can be evaluated using the model of ischemic infarction in the dog gerbil described by P. Lysko et al., Stroke, 1992, Vol. 23.

The analgesic activity of the compounds can be demonstrated using the p-phenylchincne-induced abdominal contraction test in mice (Siegmund et al., Proc. Soc. Exp. Biol. 95, 729-, 1957, modified by MiIne and Twoney, Agerrts and Actions, 10, 31-, 1980).

The effects of the compounds in protecting against inflammation pain can be demonstrated using the zanpa pressure test in the dog monoarthritic rat described in Eur. J. Pharmaool. 155, 255-264, 1988. Following subcutaneous administration, the compounds produce an increased analgesic effect in the inflamed paw compared to the non-inflamed paw. The analgesic effect in the inflamed zanpa is strongly counteracted by a low intra-implant dose of the opioid antagonist naloxcne but not by a similar dose of naloxone administered subcutaneously.

Further evidence of the peripheral analgesic action of the Compounds can be obtained from a modification of the abdominal contraction test as described in Br. J. Pharmaool. 73, 325-332, 1981. After administration of PPQ or acetylcholine, intraperitoneal administration of the compounds produces a decrease in the number of abdominal contractions.

The compounds of this invention and their preparation are illustrated in the following Examples, and their sine structures summarized in the Table.

The preparation of the intermediates is illustrated in the Descriptions. Description 1

3-amino -2- (1-pyrrolidinylcarbcnyl) pyrazine

A mixture of 10 g (0.065 moles) of 3-amino-2-pyrazincarboxylic acid methyl ester and 150 ml of pyrrolidine is stirred for 3 days at room temperature. The excess of pyrrolidine is then evaporated under vacuum and the residue crystallized from ethyl acetate / n-hexane to obtain 8.65 g of the desired product.

C9H12N4 °

P.F. s 102-103 ° C

P.M. - 192.218

R.M.N. (80 MHz) OX: i3: & 8.05 (d, IH); 7.80 (d, 1H); 6.60 (s enlarged, 2H); 3.55-3.95 (m, 4H); 1.80-2.05 (m, 4H).

Similarly, 3-amino-2 - [(3-hydroxy-1-pyrrolidinyl carbonylpyrazine is prepared.

Description 2

8- (1-pyrrolidinylcarbcnyl) -imidazo [1,2-aJpyrazine

A mixture of 8.64 g (0.045 mol) of 3-amino ~ 2- (1-pyrrolidinylcarbcnyl) pyrazine and 8.7 ml (0.067 mol) of 50% chloroacetaldehyde in aqueous solution is heated at 100eC for 2 days in the presence of 5.6 g (0.067 moles) of sodium bicarbonate.

The reaction mixture is evaporated under vacuum and the residue, treated with an aqueous solution of potassium carbonate, is repeatedly extracted with methylene chloride. The organic solution is evaporated to dryness under vacuum and the crude product is purified by flash chromatography on silica gel, eluting with a mixture of CHjCl 2 / MeCH / NH ^ CH at 28%, 95: 5: 0.5 respectively.

2.2 g of the desired product are obtained.

<C> 11 <H> 12 <N> 4th

P.F. - 154-156 <e> C

P.M. - 216.238

I.R. (movie): 3130; 2980; 2880; 1635; 1425; 1320 an <-1>

R.M.N. (80 MHz) CDC13: S 8.25 (d, 1H); 7.75-7.95 (m, 3H); 3.80 {t, 2H); 3.35 (t, 2H); 1.80-2.10 (m, 4H).

Similarly, 8- [(3-hydroxy-1-pyrrolidinyl) carbons is prepared! ] -imi dazo [1,2-a] pyrazine.

Description 3.

8- (1 -pirro lidinilcarbcn il) -5, 6, 7, 8- te between hydroimi dazo [1, 2-a Ipirazina 2.05 g (9.48 limol) of 8- (1-pìrrolidin ilcarbcn il) - imi dazo [1,2-a Ipirazine, dissolved in 30 ml of 2-methoxyethanol, are hydrogenated in a Parr apparatus on 190 mg of PtO ^ and in the presence of 580 mg of pulverized calcium oxide.

After absorption of the theoretical quantity of hydrogen, the catalyst is filtered and the filtrate is evaporated to zero under vacuum. 2.1 g of the desired product are obtained in the form of orange oil.

<C> 11 <H> 16 <N> 4th

P.M. = 220.270

R.M.N. (80 MHz) CDC13: £ 6.98 (d, 1H); 6.80 (d, 1H); 5.00 (s, 1H); 3.85-4.35 (m, 3H) 2.70-3.65 (m, 6H) 1.70-2.10 (m, 4H).

Similarly, 8- [(3-hydroxy-1-pyrrolidinyl) carbanyl] -5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine as a someric diasterecd mixture is prepared.

Description 4

8- (l-pyrrolidin ilmet il) -5, 6, 7, 8-tetr aidroimidazo [1,2-a] pyrazine

2.1 g (9.53 irmel) of 8- (1-pyrrolidine the carbon!) -5, 6, 7, 8-tetrahydroimidazof 1,2-a] pyrazine are dissolved in 60 ml of anhydrous 1HF. The solution is heated to 60 ° C and, carefully under a flow of nitrogen e

mechanical stirring add 2.8 ml of a 10 M solution of the borane-dimethylsulfide complex.

The reaction mixture is heated for 6 hours under reflux, cooled

at -10 ° C and then treated with caution with a 6 N acid solution

hydrochloric.

When the addition of the acid is finished, the reaction is heated again for 3 hours at 70 ° C. The residue obtained after evaporation under vacuum V. is treated with an aqueous solution of NaOH at 40%; the dianmina

it is repeatedly extracted with CH2cl2 which is dried on Na2SC> 4 ed

evaporated to dryness under vacuum. 2.0 g of the desired product are obtained with a purity equal to 88% (GC). The product is used without further purification in subsequent reactions.

C11H18N4

P.M. - 206.286

R.M.N. (80 MHz) CDCly ί 7.00 (d, 1H); 6.82 (d, 1H); 2.40-4.20 (m, 12H); 1.65-1.85 (m, 4H).

Similarly, 8- [(3-hydroxy-1-pyrrolidinyl) methyl] -5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine is prepared as a mixture of astereal isomeres a.

Description 5

3-dimethylarmùncmethyleneanmino-2- (1-pyrrolidin ilearben il) pyr azine

A mixture of 4 g (0.021 mol) of 3-amino-2- (1-pyrrolidinylcarbonyl) pyrazine and 3.1 ml (0.023 mol) of Ν, Ν-dimethylformanmide dimethyl acetal is refluxed for 2 hours in 11 ml of toluene .

After evaporation of the solvent under vacuum and subsequent purification of the crude product by flash crcmatography on silica gel (eluent O ^ Cl 2 / J-feCH / NH4 CH at 28%, 94: 2: 0.3 respectively) 2.7 g of the desired product in the form of orange oil.

<C> 12 <H> 17 <N> 5th

P.M. - 247.296

Description 6

3-hydroxyinndrwmethyleneaninino-2- (l-pyrrolidinylcarbonyl jpyrazine

A solution of 1.46 g (0.021 mol) of hydroxylamine hydrochloride in 15 ml of MeCH is dropped under mechanical stirring into a second solution of 5 g (0.020 mol) of 3-dimethylimdncmethyleneamnino-2- (1-pyrrolidinylcarbcnyl) pyrazine in 100 ml of MeCH, containing 1.72 g (0.021 moles) of sodium acetate, maintaining the temperature at 5 ° C.

At the end of the addition, the solution is left to come to temperature and, after 4 hours, the solvent is evaporated to dryness under vacuum. The residue is taken up with Ci ^ C ^; the inorganic salts are filtered off and the filtrate evaporated to dryness under vacuum.

The crude product thus obtained is purified by chromatography

flash on silica gel, eluting with a mixture of C ^ clj / MeCH / Ni ^ CH al

28%; 94: 15: 0.1 respectively.

4.4 g of the desired product are obtained in the form of crystals

Detective stories.

C10H13N5 ° 2

P.F. - 178-180eC

P.M. - 235.244

I.R. (KBr): 3250; 1650; 1580; 1470 cnf1

R.M.N. (80 MHz) CDCl3: is 10.90 (d, 1H); 8.03-8.22 (m, 4H); 3.65-4.00 (m,

4H); 1.80-2.00 (m, 4H).

Description 7

8- (1-pyrrolidinylcarbcnyl) - [1,2,4] triazole [1,5-aIpirazine

A mixture of 1.72 g (0.011 moles) of 3-hydroxyimninanethyleneamino-2- (1-pyrrolidinylcarbones!) Pyrazine and 17 g of polyphosphoric acid

it is heated to 90 ° C for 4 hours. The reaction mixture is then 0 poured into water and ice and the pH of the resulting solution is

brought to 8 by the addition of NaHOO ^. The aqueous phase is extracted

repeatedly with CH2CI2 and the anhydrified organic solution is evaporated to dryness under vacuum.

The crude product is purified by flash chromatography on

silica gel, eluting with a mixture of CI ^ C ^ / MeCH / NH ^ CH at 28%,

94: 3: 0.3 respectively.

1.3 g of the desired product are obtained in the form of white crystals recrystallized from ethyl acetate.

C10H11N5 °

P.F. - 123-12 5 ° C

P.M. = 217.228

I.R. (KBr): 3090; 2885; 1650; 1485; 1310 I was-1

R.M.N. (80 MHz) CDCLj: ^ 8.80 (d, 1H); 8.52 (s, 1H); 8.26 (d, 1H); 3.80 (t, 2H); 3.50 (t, 2H); 1.80-2.05 (m, 4H).

Description 8

8- (1-pyrrolidinylcazbcnyl) -5, 6,7, 8-tetrahydro- [1,2,4] triazole [1,5-a] pyrazine

Prepared following Description no. 3, starting from 3.05 g (0.014 moles) of 8- (1-pyrrolidinylcartxxi yl) - [1, 2, 4] triazole [1, 5-a] pyrazine.

2.9 g of the desired product are obtained which are recrystallized from ethyl acetate.

C103⁄45N5 °

P.F. = 137-139 "C

P.M. - 221.260

I.R. (KBr): 3300; 2980; 1655; 1495; 1440 cnf1

R.M.N. (80 MHz) CDCLj: S 7.85 (s, 1H); 5.00 <s, 1H); 4.00-4.30 (m, 3H); 2.90-3.95 (n, 5H); 2.50 (s anpio, 1H); 1.80-2.05 (m, 4H).

Description 9

8- (1-pyrrolidinylmethyl) -5, 6, 7, 8-tetrahydro- [1,2,4] triazole [1, 5-a] pyraz ina Prepared following Description no. 4, starting from 2.8 g of 8- (lpyrrolidinylcarbonyl) -5, 6, 7, 8-tetrahydro- [1,2,4] triazole [1,5-a] pyrazine.

2.5 g of the desired product are obtained in the form of oil which is used in the subsequent reactions without further purification.

<C> 10 <H> 17 <N> 5

P.M. - 207.276

Example l

7- [(3, 4-dic lorophenyl) acetyl] -8- (1-pyrrolidinylmethyl) -5, 6, 7, 8-tetrahydroimidazo [1, 2-a] pyrazine

I g (4.85 mmol) of the product of Description no. 4 is dissolved in 30 ml of anhydrous methylene chloride. 0.66 g (4.86 mmoles) of anhydrous potassium carbonate are added to the solution and it is cooled to 0 ° C.

1.2 g (5.36 limols) of (3,4-dichlorophenyl) acetyl chloride are then added dropwise, dissolved in 10 ml of CHjCl under magnetic stirring.

After 3 hours it is left to rise to a high temperature and left under stirring all night.

10 ml of water are added, the phases are separated and the organic one dried on Na ^g is evaporated to dryness under vacuum.

The crude product is purified by flash chromatography on silica gel, eluting with a mixture of CH2ci2 / MeCH / NH4CH at 28%, 95: 5: 0.5 respectively.

0.8 g of the desired product are obtained which are crystallized from ethyl acetate / n-hexane.

<C> 19 <H> 22 <C1> 2 <N> 4th

P.F. - 78-80-C

P.M. = 393.312

List analysis: Calculated C, 58.02; H, 5.64; N, 14.25; Cl, 18.03;

Found C, 57.33; H, 5.70; N, 13.95; Cl, 18.16; I.R. (KBr): 2980; 2800; 1635; 1615; 1470 an "1

R.M.N. {80 MHz) CDQ3: 6 6.85-7.45 (m, 5H); 4.50-5.80 (m, 2H); 2.90-4.30 (m, 7H); 2.30-2.80 (m, 4H); 1.65-1.85 (ni, 4H).

Example 2

8- {1-pyrrolidinylmethyl) -7- f (4-trif luorametilfen il) acet il] -5, 6,7, 8-tetrahydroimi dazo [1,2-a] pyrazine

Dog preparation described in Example no. 1, starting from 1 g (4.85 hymns) of the product of Description no. 4 and 1.2 g (5.40 nrools) of (4-trifluorcnetylphenyl) acetyl chloride in 30 ml of anhydrous CH2CI2.

By crystallization from ethyl acetate / n-hexane 0.7 g of the desired product are obtained in the form of white crystals.

C20H23F3N4 °

P.F. - 124-12 5 eC

P.M. - 392.416

Elementary analysis: Calculated C, 61.21; H, 5.91; N, 14.28; F, 14.52;

Found C, 61.22; H, 5.90; N, 14.25; F, 14.44;

I.R. (KBr): 2960; 2790; 1650; 1490; 1415; 1320 cnf1

R.M.N. (80 MHz) CDCI3: 6 7.25-7.60 (m, 4H); 7.05 (d, 1H); 6.82 (d, 1H); 4.50-5.90 (m, 2H); 3.20-4.20 (m, 5H); 3.00-3.15 (m, 2H); 2.20-2.80 (m, 4H); 1.55-1.85 (m, 4H).

Example 3

7- [(3, 4-dichlorophenyl) acetyl] -8 - [(3-hydroxy-1-pyrrolidinyl) methyl] -5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine - mixture of diastereoiscmers Prepared ocite described in Example no. 1, starting from 0.8 g (3.60 limols) of 8- [(3-hydroxy-1-pyrrolidinyl) methyl J-5, 6, 7, 8-tetrahydroimidazo [1, 2-a] pira z ina - mixture of real rods - and 0.96 g (4.32 nmoles) of (3, 4-dic lorophenes 1) acetyl chloride in 20 ml of anhydrous DMF.

The crude product is purified by flash chromatography on silica gel, eluting with a mixture of CHjC ^ / MeCH / NHjOH at 28%, 86: 10: 0.6, respectively.

By recrystallization from ethyl acetate 0.4 g of the desired product are obtained.

<C> 19 <H> 22 <C1> 2 <N> 4 ° 2

P.F. - 160-17 5 * C

P.M. = 409.312

Elementary analysis: Calculated C, 55.75; H, 5.42; N, 13.69; Cl, 17.32;

Found C, 55.09; H, 5.40; N, 13.49; Cl, 18.03 I.R. (KBr): 3250; 2920; 2790; 1650; 1435 cro <-1>

R.M.N. (80 MHz) CDC13: 5 6.75-7.45 (m, 5H); 4.50-5.80 (m, 2H); 3.30-4.40 (m, 5H); 1.50-3.30 (m, 10H).

Bsenpio 4

7- [(3, 4-dic lorophenyl) acetyl] -8- (1-pyrrolidinylmethyl) -5, 6, 7, 8-t and trahydro- [1,2,4] triazole [1, 5-a] pyrazine

Prepared as described in Example no. 1, starting from 1.5 g (7.24 nmoles) of the product of Description no. 9 and 1.86 g (8.32 µmoles) of (3,4-dichlorophenyl) acetyl chloride in 50 ml of anhydrous CHjC ^.

The crude product is purified by flash chromatography on silica gel, eluting with a mixture of CHjC ^ / MeOH / NH ^CH at 28%, 86: 12: 0.6, respectively.

1.0 g of the desired product are obtained, crystallized from ethyl acetate as a free base.

<C> 18 <H> 21 <C1> 2 <N> 5th

P.F. = 113-116 "C

P.M. - 394.302

Elementary analysis: Calaolato C, 54.83; H, 5.37; N, 17.76; Cl, 17.98;

Found C, 54.69; H, 5.34; N, 17.71; Cl, 18.07; I.R. (KBr): 2980; 2790; 1645; 1400 cm <_1>

N.M.R. (80 MHz) CDC13: £ 7.90 (s, 1H); 7.00-7.45 (m, 3H); 4.60-6.10 (m, broad, 1H); 3.40-4.50 (m, 6H); 2.90-3.35 (m, 2H); 2.10-2.90 (m, 4H); 1.40-2.00 (m, 4H).

Example 5

8- (1-pyrrolidinylmethyl) -7- [(4-trifluorcriethylphenyl) acetyl] -5, 6, 7, 8-tetrahydro- [1,2,4] triazole [1,5-a Ipirazìna

Dog preparation described in Example 1, starting from 1.5 g (7.24 thyme) of the product of Description no. 9 and 1.85 g (8.32 irtnols) of (4-trifluoronetylphenyl) acetyl chloride in 50 ml of anhydrous CHjC ^.

The crude product is purified by flash chromatography on silica gel, eluting with a mixture of 28% CI ^ c ^ / MeCH / NH ^ CH, 86: 15: 0.7, respectively.

1.2 g of the desired product are obtained, crystallized from ethyl acetate / acetone as dihydrate.

<C> 19 <H> 22 <F> 3 <N> 5th * <I1:> '<1>

P.F. - 176-177 <e> C

P.M. - 466.336

Elementary analysis: Calculated C, 48.93; H, 5.19; N, 15.02; Cl, 15.21;

F, 12.22;

Troato C, 48.22; H, 5.19; N, 14.69; Cl, 15.09;

F, 11.86

I.R. (KBr): 3420; 2560; 1660; 1330 cnf <1>

N.M.R. (80 MHz) CDCL3 + NaOD: £ 7.90 (s, 1H); 7.25-7.70 (m, 4H); 4.60-6.10 (m, broad, 1H); 3.50-4.50 (m, 6H); 2.90-3.15 (m, 2H); 2.20-2.70 (m, 4H); 1.50-1.90 (ra, 4H).

Similarly, the following compounds were prepared:

7- [(3, 4-dichlorof en il) vinegars! ] -8- (1-pyrrolidinylmethyl) -5, 6, 7, 8-tetr aidro-1,2, 4-triazole [4, 3-a Jpirazine

8- {1-pyrrolidinylmethyl) -7- [(4-trifluoranethylphenyl) vinegars! ] -5, 6, 7, 8-tetr ai dro-1, 2, 4-triazole [4, 3-a Jpirazine

7- [(3, 4 -die lorofenyl) acetyl] -8- (l-pyrrolidinylmethyl) -5, 6, 7, 8- te trai (trout trazole [l, 5-a] pyrazine

8- (1-pyrrolidinylmethyl) -7- [(4-trifluoromethylfenyl) acetyl J-5, 6, 7, 8-tetr aidnotetrazole [1,5-a] pyrazine

TABEL

Claims (29)

CLAIMS I. Compounds of general formula (I) R. N - R, (0 COfl in which: each of X and Y is independently CH or N; ROO is an acyl group in which the R group contains a substituted or unsubstituted carbocyclic or heterocyclic aromatic ring; Q each of R ^ and R2, which can be the same or different, is hydrogen, alkyl, optionally substituted with at least one halogen atom, hydroxy, g alkoxy, acylexy, thiol, C ^ _g alkylthio, acylthio, C ^ _g haloalkoxy, COR ^, COOR ^, CONHR ^ or NKXJR ^, where R ^ is hydrogen or Cj_g alkyl; or each of and R2 is C2_g alkenyl, C3_g cycloalkyl, C cycloalkylalkyl; oRj andR2 together form a C2-8 alkylene group, or a C2-g alkenylene group, linear or branched, optionally substituted; their stereoiscmeric forms, including their mixtures and racemates, their pharmaceutically acceptable salts and solvates. 2. Compounds according to claim 1, wherein each of and Rj, which can be the same or different, is hydrogen, alkyl, optionally substituted by fluorine or chlorine, hydroxy, methoxy, acetoxy, thiol, methylthio, acetylthio, Clg fluoroalkoxy, CGR ^, CCORh, CONHR ^ or NHCOR ^ where is hydrogen, methyl or ethyl, C2-6 alkenyl, C3-g cycloalkyl, 4-12 cycloalkylalkyl; or 3⁄4 and R2 together form a formula group * we which can be bonded to the same or a different carbon layer where Rc is bonded, is hydrogen, hydroxy, Cj_g alkoxy or halogen, and Rc is hydrogen, C ^ _g alkyl or together with 3⁄4 forms a keto group or a cyclic ether containing 1 to 4 carbon atoms, and a is 1 or 2, Compounds according to claims 1-2, wherein R1 and 3⁄4 together form the 1-pyrrolidinyl, 3-hydroxy-1-pyrrolidinyl and 3-fluoro-lpyrrolidinyl groups. 4. Compounds according to claims 1-3, in which: R is a group of fonnula (II) where n is 0, 1 or 2; n is 0, 1 or 2; m <1> is 0, 1 or 2, provided that m m '* 3; X is a direct bond or 0, S or NRg where Rg is hydrogen or C] _g alkyl, Ar is a substituted or black substituted cartoocycly or heterocyclic group; each of Rg and Rga is C ^ _g alkyl, C2_g alkenyl, C2_g alkynyl, Cj_g haloalkyl, Cj_g haloalkenyl, C2_g haloalkynyl, phenyl or ferocies optionally substituted, phenyl (optionally substituted) C ^ _g alkyl, hydroxy, C ^ _g alkoxy , thiol, C ^ _g alkylthio, Cj_g haloalkoxy, C ^ _g haloalkylthio, halogen, N02, CN, CF3, -OCF3, -OCHF2 '-OCP2CF2 <H> »-OOCI2CF3, -CCORg, -cONR10Rn, <-S0> 3 <R> 12 '<_90> 2 <NR> 13 <R> 14 <e> ~ <CCR> 15 ^ which each of the groups Rg to R ^ g is independently hydrogen, Cj_g alkyl, possibly substituted phenyl or phenyl (possibly substituted) Cj_g alkyl; or, when m is 2 and m <1> is 0, two Rg groups form a C ^ _g polymethylene group and R7 is hydrogen or Cj_g alkyl, such as methyl or ethyl. 5. Compounds according to claim 4, in which Rg or Rga is a system of single or melted aromatic or non-aromatic rings having from 5 to 12 ring atoms, yielding up to 4 eternatams in or in each ring, selected from oxygen, nitrogen and sulfur. 6. Compounds according to claim 4, wherein two Rg groups are bonded together to form a fused cyclopentyl or cyclohexyl ring. 7. Compounds according to claims 4-5, in which Ar is phenyl with Rg or Rga in the meta and / or para position, naphthyl, benzothioenyl, benzofuranyl, 2, 3-dihydrobenzof urane, 2, 3-dihydrobenzothioenyl, indolyl, 2 , 3-dihydrobenzothyranyl and 2,3-dihydrobenzothiopyranyl. 8. Compounds according to claims 4, 5 and 7, in which Ar is phenyl and Rg or Rga is bromine, chloro, CF ^, 2-furanyl, 2-pyrryl, 2-thiazolyl, 2-imidazolyl or 2-thienyl, in the goal and / or para position. 9. Compounds according to claims 4-8, in which X is oxygen or a direct bond, and n is 0 or 1. 10. Compounds according to claims 1-2, in which R is a group of formula (IIa) where the group - (CHR ^ -X-, which is defined in formula II, is in the meta or para position with respect to YR ^ 0 Ry, Y is> C-0, XMCH,> S-0 or> S02; each of R3⁄4 and Ry is Cj_g alkyl, o and Ry are bonded together and represents - (3⁄4) - where m is O or l and Z is 0, S or NR3⁄4 where Rj, is hydrogen or Cj_g alkyl, and R ^ represents - (CH2) q- where q is an integer miner from 1 to 4. 11. Compounds according to claims 1-2 and 10, in which R is a group of formula (Ilb) wherein Y, Z, m, q is the position of -CH ^ - sine as defined in claim 10. 12. Compounds according to claims 1-2 and 10, in which R is a group of formula (Ile) wherein Y is C-0 or CHOH, each of and R is C ^ _g alkyl and the position of -CH2- is as defined in claim 10. 13. Compounds according to claims 1-2 and 10, in which R is a group of formula (Ild) must Het is the residue of a single aromatic heterocyclic ring, containing from 5 to 6 ring atoms and comprising up to 3 ether atoms in the ring selected from 0, S and N; and X, Y, Z, m and q canine sine defined in claim 10. 14. Compounds according to claims 1-13, wherein R is 3,4-dichlorobenzyl or 4-trifluoranethylbenzyl. 15. Compound according to claim 1 selected from the group consisting of: 7- [(3, 4 -die lorofenyl) acetyl] -8- (1-pyrrolidinylmethyl) -5, 6, 7, 8-tetrahydroimidazo [1, 2-a] pyrazine 8- (1-pyrrolidinylmethyl) -7- [(4-trifluoromethylphenyl) acetyl] -5, 6, 7, 8-tetxai droimidazo [1, 2-a 3 pyrazine 7- [{3,4-di lorophenyl) acetyl] -8- [(3-hydroxy-1-pyrrolidinyl) methyl] -5,6,7,8-tetra! droimidazo [1, 2-a] pyrazine 7- [(3, 4 -die lorophenyl} acetyl] -8- (1-pyrrolidinylmethyl) -5, 6, 7, 8-tetrahydro- [1,2,4] triazolofl, 5-a] pyrazine 8- (1-pyrrolidinylmethyl) -7- [(4-tr if luorcmet ylf enyl) acetyl] -5, 6, 7, 8-tetrahydro- [1,2,4] triazole [1, 5-a] pyrazine 7- [(3, 4 -die lorophenyl) acetyl] -8- (1-pyrrolidinylmethyl) - 5, 6,7, 8-tetrahydro-1,2, 4 -triazole [4, 3-a] pyrazine 8- (1-pyrrolidinylmethyl) -7- [(4-trifluoromethylphenyl) acetyl] -5, 6,7, 8-tetrahydro-1, 2,4 -thiazole [4, 3-a] pyrazine 7- [{3,4-dichlorophenyl) acetyl] -8- (1-pyrrolidinylmethyl) -5, 6, 7, 8-tetrahydrote trazole [1,5-a] pyrazine 8- (1-pyrrolidinylmethyl) -7- [(4-trifluoranethylphenyl) acetyl] -5, 6,7, 8-tetrazole [1,5-a] pyrazine. 16. Process for the preparation of body of formula (I) of claims 1-15, characterized by the fact that a compound of formula (III) in which Rp t X and Y are defined above, it is treated with a ROOCH compound or its activated derivative, where R is defined above, and eventually a salt and / or a solvate is formed. 17. Process according to claim 16, characterized in that the activated derivative of the RCOOH compound is selected from the group consisting of acyl chloride, acid anhydride or mixed acid anhydride. 18. Intermediate of formula (VI) in which R ^ and R2 are defined above 19. Intermediate of formula (V) in which R ^ and R2 are coma defined above 20. Intermediate of formula (IV) (IV) in which R ^ and R2 are defined above 21. Intermediate formula (IHa) () in which and R2 are the above defined dogs. 22. Intermediate of formula (VIII) in which R ^ and R2 are defined above. 23. Intermediate of formula (IX) wherein R ^ and R2 are as defined above. 24. Intermediate of formula (X) in which and Rj are defined above. 25. Intermediate of formula (XI) in which R ^ and Rj are defined above. 26. Intermediate formula (Illb) in which R ^ and R2 are defined above. 27. Body of claims 1-15 as therapeutic agents. 28. Use of the compounds of claims 1-14 for the preparation of a medicament useful for the treatment of hypcnatremic pathological conditions, cerebral ischemia, pain, convulsions, cough, asthma, inflammation, pancreatitis, arrhythmia. 29. Pharmaceutical compositions containing one or more compounds of claims 1-15 as active principles, in admixture with suitable vehicles.