JP3135577B2 - Azacyclic derivatives - Google Patents

Description

The present invention relates to novel substituted azacyclic fused piperazines, processes for their preparation, and their use in medicine, especially as diuretics and anti-ischemic agents.

Compounds that are kappa receptor agonists are primarily
It has been studied as an analgesic by interaction with kappa opioid receptors. The advantages of kappa receptor agonists over classic mu receptor agonists, such as morphine, lie in their ability to perform morphine-like behavior and lack an addictive but analgesic effect.

EP-A-343900 and EP-A-398720 (Glaxo Group Ltd) and EP
-A-356247 (Sankyo) is said to exhibit kappa receptor agonism and is therefore useful as an analgesic, diuretic, and is useful in treating cerebral ischemia.

A new class of structurally related azacyclic fused piperazine derivatives has finally been found, which exhibits effective kappa receptor agonism, among others diuretics and anti-diuretics for the treatment of hyponatremia disease states in mammals. It is useful as an ischemic agent, and especially useful for treating cerebral ischemia. Also, this new class of derivatives has analgesic activity,
That indicates that they are not associated with the undesirable behavioral effects of morphine and morphine analogs and are potentially useful in the treatment of pain. In addition, the new class of derivatives are potentially useful in the treatment of other conditions resulting from the administration of kappa agonists, especially convulsions, coughs, asthma, inflammation (including pain from inflammation), pancreatitis, arrhythmias and skin diseases It is.

According to the present invention, formula (I): Wherein X and Y are each independently CH or N; RCO is an acyl group in which the group R contains a substituted or unsubstituted carbocyclic or heteroaromatic ring; R ₁ And R ₂ may be the same or different and, if desired, at least one halogen (preferably fluorine or chlorine), hydroxy, C _1-6 alkoxy (preferably methoxy), acyloxy (preferably acetoxy) ), _{thiol, C 1 to 6} alkylthio (preferably methylthio), acylthio (preferably acetylthio) halo _{-C 1 to 6} alkoxy (preferably Furioro - _{alkoxy), COR h, COOR h,} CONHR h or NHCOR
a _{C 1 to 6} alkyl substituted by _h, wherein the R _h is hydrogen or _{C 1 to 6} alkyl, preferably methyl or ethyl; each or R ₁ and R _{2 hydrogen, C 2 to 6} Alkenyl, C _3-6 cycloalkyl, or C _4-12 cycloalkylalkyl; or R ₁ and R _{2 taken} together are optionally substituted C _2-8 branched or linear polymethylene; Forming a _C2-6 alkylene group, said polymethylene group with a linking nitrogen, preferably of the formula: (Wherein, R _b may be bonded to the same or different carbon atoms and R _c, hydrogen, hydroxy, C _{1 to 6} alkoxy (preferably methoxy) or halogen (and preferably fluorine), R _c Is hydrogen, C _1-6 alkyl (preferably methyl), or together with R _b forms a keto group or a cyclic ether having 1 to 4 carbon atoms, wherein a is 1 or 2 A) or a solvate or salt thereof.

Examples of NR ₁ R ₂ are 1-pyrrolidinyl, 3-hydroxy-1
-Pyrrolidinyl and 3-fluoro-1-pyrrolidinyl.

When used to define an RCO group, the term "carbocyclic aromatic group" includes single or fused rings having from 6 to 12 ring carbon atoms, and the term "heteroaromatic group" Is a single ring or a condensed ring having 5 to 12 ring atoms, and includes a ring consisting of up to 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring or in each ring.

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

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

Preferably, the group R has the formula (II): Wherein n is 0, 1 or 2; m is 0, 1 or 2; m ′ is 0, 1 or 2, provided that m + m ′ ≦ 3 X ₁ is a direct bond or O, S or NR ₈ ; Wherein R ₈ is hydrogen or C _1-6 alkyl; Ar is a substituted or unsubstituted carbocyclic or heterocyclic group; R ₆ and R _6a are each C _1-6 alkyl;
_2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C1-6 haloalkenyl, _C2-6 haloalkynyl, optionally substituted phenyl or heterocyclyl, optionally substituted Phenyl C _1-6 alkyl, hydroxy, C _1-6 alkoxy, thiol, C _1-6 alkylthio, C _1-6 haloalkoxy, C _1-6 haloalkylthio, halogen,
NO ₂ , CN, CF ₃ , -OCF ₃ , -OCHF ₂ , -OCF ₂ CF ₂ H, -OCCl _{2
CF 3, -COOR 9, -CONR 10} R 11, -SO 3 R 12, -SO 2 NR 13 R 14
And -COR ₁₅ wherein each of R ₉ to R ₁₅ is independently hydrogen, C _1-6 alkyl, optionally substituted phenyl or optionally substituted phenyl C _{1 6} alkyl either; or when m is a 2 m 'is 0, 2
One R ₆ forms a C _3-6 polymethylene group, and R ₇ represents hydrogen or C _1-6 alkyl, such as methyl or ethyl.

When R ₆ or R _6a is heterocyclyl, it is preferably an aromatic or non-aromatic single or fused ring system having 5 to 12 atoms, wherein , A ring system consisting of up to four heteroatoms selected from oxygen, nitrogen and sulfur.

 Preferably, the halogen is F, Cl and Br.

When two R ₆ are joined, they preferably form a fused cyclopentyl or cyclohexyl ring.

Preferably, Ar is phenyl, preferably, R ₆ or R _6a is in the meta and / or para position.

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

Preferably, R ₆ or R _6a is bromine, chlorine, CF ₃ , 2-furanyl, 2-pyryl, 2-thiazolyl, 2-imidazolyl or 2-thienyl, in particular when Ar is phenyl In the meta and / or para position.

Typically, X ₁ is oxygen or a direct bond; typically, n is 0 or 1.

More preferred groups R are of the formula (IIa): Wherein the same group — (CHR ₇ ) _n as defined in formula II
-X ₁ -is meta or para to Y ₁ R _x or R _y , where Y ₁ is> C = O,>CHOH,> S = O or> SO ₂ ; each of R _x and R _y Is C _1-6 alkyl, or R _x and R _y are linked together and R _{x is-}
(Z _{m ″} ) —, where m is 0 or 1;
Is O, S or NR _z , where R _z is hydrogen or C
_1-6 alkyl, R _y represents — (CH ₂ ) _q —, wherein q is a number from 1 to 4, preferably 2 or 3.

A preferred subgroup of formula (IIa) is formula (IIb): [Wherein Y ₁ , Z, m ″, q and the position of —CH ₂ — are represented by the formula (I
I the same as the definition of a)]].

Preferably, q is 2 when Z is oxygen and m "is 1, and q is 3 when m is 0.

A further preferred sub-group of formula (IIa) is
c): Wherein Y ₂ is C ＝ O or CHOH, each of R _x and R _y is C _1-6 alkyl, preferably methyl,
The position of —CH ₂ — is the same as defined in formula (IIa)].

More preferred groups R are of the formula (II d): Wherein Het is the remainder of a single aromatic heterocycle, comprising 5 to 6 ring atoms, wherein up to 3 heteroatoms selected from O, S and N R ₇ , X ₁ , Y ₁ , Z, m ″ and q are the same as defined in formula (IIa)].

Particularly preferred examples of R are 3,4-dichlorobenzyl or 4-trifluoromethylbenzyl.

A compound of formula (I) or a salt or solvate thereof,
Preferably, it is in a pharmaceutically acceptable or substantially pure form. Pharmaceutically acceptable forms are substances that are of a pharmaceutically acceptable level of purity, except for common pharmaceutical additives such as diluents and carriers, and are considered toxic at normal dosage levels. Means not included.

Generally, a substantially pure form is at least 50%
It will contain (with the exception of the usual pharmaceutical excipients), preferably 75%, more preferably 90%, even more preferably 95% of a compound of formula (I) or a salt or solvate thereof.

One preferred pharmaceutically acceptable form is the crystalline form, which contains such a form in a pharmaceutical composition. In the case of salts and solvates, the additional ionic and solvent portions must also be non-toxic.

Examples of pharmaceutically acceptable salts of the compounds of formula (I) include conventional pharmaceutically used acids such as maleic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, fumaric acid, salicylic acid, citric acid. Includes acid addition salts with acids, lactic acid, mandelic acid, tartaric acid, succinic acid, benzoic acid, ascorbic acid and methanesulfonic acid.

Examples of pharmaceutically acceptable solvates of the compound of formula (I) include hydrates.

The compounds of formula (I) have at least one asymmetric center and therefore exist as one or more stereoisomers.
The present invention includes all such forms and mixtures thereof, including racemates.

Further, the present invention provides a compound of the formula (III) Wherein R ₁ , R ₂ , X and Y are the same as defined in formula (I), and reacting with a compound of formula RCOOH or an active derivative thereof, There is provided a process for preparing a compound of formula (I), comprising forming a salt and / or solvate of the compound of formula (I).

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

For example, in a standard manner well known to those skilled in the art,
The compound of formula (III) may be coupled with: a) an acid chloride in the presence of an inorganic or organic base in an aprotic solvent such as dichloromethane or dimethylformamide b) dicyclohexylcarbodiimide or carbonyldiamide Acid c) acid and alkyl chloroformate (eg isobutyl) in the presence of imidazole
Anhydrous mixture from in situ from.

The compound of formula (I) may be converted to its pharmaceutically acceptable acid addition salt by reaction with a suitable organic or inorganic acid. Crystallization or recrystallization from a suitable solvent may give a solvate of the compound of formula (I). For example, a hydrate may be obtained by crystallization or recrystallization from an aqueous solution or a water-containing organic solvent.

Non-pharmaceutically acceptable salts or solvates of the compounds of formula (I) may be used as intermediates in the preparation of pharmaceutically acceptable salts or solvates. Thus, such salts or solvates also form part of the invention.

As mentioned above, the compounds of formula (I) exist in one or more stereoisomeric forms, the mixtures of which are obtained by the process according to the invention. The individual isomers may be separated from each other by resolution using an optically active acid such as tartaric acid. Alternatively, individual forms will be obtained by asymmetric synthesis.

The compounds of formula (III) can themselves be synthesized from known compounds by known methods. For example, a compound wherein both X and Y are -CH- (Formula (IIIa)) may be prepared by the reaction of Scheme I below: In this scheme, the known compound (VII) (J. Am. Chem. Soc.) Is reacted with an excess of the appropriate amine in the absence or presence of a solvent such as MeOH, in the presence or absence of a solvent. ), 1945
Year, Vol. 67, p. 1711) to produce the compound of formula (VI).

The compound (VI) is then treated with a haloacetaldehyde such as chloroacetaldehyde or bromoacetaldehyde in a mixture of dioxane / water for an extended period of time (8 to 48 hours), and the resulting compound of formula (V) is
In ethanol or 2-methoxy suitable solvent such as ethanol, it is hydrogenated with a suitable catalyst such as PtO ₂ or 5% Pt / C in the presence of calcium oxide.

Reduction of compound (IV) with diborane or borane methyl sulfide complex in refluxing THF gives the desired compound of formula (IIIa). Formulas (V), (IV) and (III)
The intermediates of a), and their salts and solvates, are novel compounds, so they form a further aspect of the present invention.

Compounds of Formula III where X is -N- and Y is -CH- (Formula (IIIb)) may be prepared according to the following Reaction Scheme II: In this scheme, a compound of formula (VI) is treated with an excess of N, N-dimethylformamide dimethyl acetal in refluxing toluene to give a compound of formula (VIII). solvent
Replacement of the N, N-dimethylamino group with an oxime in MeOH gives a compound of formula (IX), which is then cyclized in polyphosphoric acid at a temperature of 80-100 ° C.

The obtained compound of the formula (X) is converted to ethanol or 2-
In a suitable solvent such as methoxyethanol to give compounds of formula (XI) by hydrogenation using a suitable catalyst such as PtO ₂ or 5% Pt / C in the presence of calcium oxide. Reaction of this compound with diborane or borane methyl sulfide complex in refluxing THF gives the compound of formula (IIIb)
Is obtained.

Formulas (VIII), (IX), (X), (XI) and (III)
b), and their salts and solvates are novel, so they form a further aspect of the invention.

Compounds of formula (III) wherein X and Y are both -N- (formula (IIIc)) may be prepared according to the following Reaction Scheme III: In this scheme, a known compound of formula (XII) (U.S. Pat. No. 4,578,378) is N-protected by an alkylation method and the resulting compound of formula (XIII) is selectively reduced, such as lithium borohydride in refluxing THF. Formulation (XI
The compound of V) is obtained. Treat this intermediate with methanesulfonyl chloride or p-toluenesulfonyl chloride in the solvent dichloromethane and then with the appropriate amine. The resulting compound of formula (XV) is converted to the corresponding imidoyl chloride by treatment with PCl ₅ in dichloromethane.

The intermediate (XVI) is then subjected to a 1,3-dipolar cycloaddition reaction with sodium azide and ammonium chloride in refluxing DMF to give a compound of general formula (XVII), which is reacted with ethanol or 5% in a suitable solvent such as methanol
Deprotection using Pd / C as a catalyst and using hydrogen may give the desired compound of formula (IIIc).

Alternatively, compounds of formula (XV) may be prepared by intramolecular cyclization according to Scheme IV: In this scheme, a known compound of formula (XVIII) (C
AS [69942-12-7], Angew.Chem., Int.Ed.Engl., Vol. 11, p. 289),
Activation by treatment with methanesulfonyl chloride or p-toluenesulfonyl chloride in a suitable solvent such as dichloromethane, then treatment with a suitable amine. Thereafter, the obtained compound (XIX) is deprotected by using trifluoroacetic acid, and then HCl / E
Direct conversion to the dihydrochloride salt by treatment with t ₂ O.

The compound of formula (XX) is treated with Na in a suitable alcoholic solvent.
Subjected to reductive amination with phthalimide acetaldehyde in the presence of an alkali metal hydride such as BH ₄ or NaCNBH _3.

The resulting compound of formula (XXI) is then intramolecularly cyclized by treatment with hydrazine hydrate in ethanol to give the compound of formula (XXII).

Direct alkylation with benzyl chloride in the presence of K ₂ CO ₃ and KI in MeOH or with benzaldehyde in the presence of NaCNBH ₃ in MeOH gives the desired compound of formula (XV).

Compounds of formula (III) wherein X is -CH- and Y is -N- (formula (IIId)) may be prepared according to the following reaction scheme (V): In this scheme, a compound of formula (XXIII) is treated with hydrazine in refluxing ethanol, and then the resulting compound of formula (XXIV) is cyclized with triethyl orthoformate in refluxing xylene.

Suitable solvent such as 2-methoxyethanol, by hydrogenation over PtO ₂ in the presence of calcium oxide, by selectively reducing the resulting compound of formula (XXV) to obtain a compound of formula (XXVI) .

Reduction of this compound with diborane or borane methylsulfide complex in refluxing THF gives the desired compound of formula (IIId).

For example, J. Heterocycl. Chem., 1979, 16 (1), pages 193-194 and Heterocycles (Heterocy)
cles), 1984, Vol. 22, (2), pp. 299-301, and the compound of the general formula (XXIII) can be obtained from the known compound.

The activity of the compounds of formula (I) in standard tests is indicated by pain, cerebral ischemia, hyponatremia disease states, convulsions,
It indicates that they are potentially therapeutically useful in the treatment of cough, asthma, inflammation (including pain from inflammation), pancreatitis, arrhythmias, and skin disorders (hereinafter symptoms).

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

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

The invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof (hereinafter a compound) in the manufacture of a medicament for the treatment of a condition.

The invention also provides a method of treating and / or preventing a condition in a mammal, especially a human, comprising administering to a mammal in need of such treatment and / or prevention an effective amount of a compound. .

Pharmaceuticals containing compounds by mixing the compounds with a suitable amount of a carrier, which may contain diluents, binders, fillers, disintegrants, fragrances, coloring agents, lubricants or preservatives, in a conventional manner And compositions may be manufactured.

These conventional excipients may be used as in the manufacture of compositions of known drugs for the treatment of conditions.

Preferably, the medicament or pharmaceutical composition of the present invention is in a single dose form and in a form suitable for use in the medical or veterinary field. For example, such products may be in pack form with written or printed instructions for use as medicaments for the treatment of each condition.

The appropriate dose of the compound will depend on the compound used, the condition to be treated, and the condition of the patient, and will also depend, inter alia, on the absorbency and frequency of administration, and the route.

The compounds can be formulated for administration by any route, and are preferably in a single dose form or in a form that a human patient can administer to himself once. Advantageously, the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. The product may be designed so that the active ingredient is sustained release.

For example, the composition may be a tablet, capsule, flour, vial,
Powders, granules, sweet tablets, reconstitutable powders, or liquid preparations, such as solutions or suspensions, or suppositories may be used.

For example, compositions suitable for oral administration include conventional excipients such as binders (eg, molasses, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone); fillers (eg, lactose, sugar, corn starch, calcium phosphate). Sorbitol or glycine); tableting lubricants (eg, magnesium stearate); disintegrants (eg, starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose); or pharmaceutically acceptable such as sodium lauryl sulfate. A setting agent may be contained.

Solid compositions may be obtained by conventional methods of mixing, filling, and tableting corn. Repeated mixing operations may be used to disperse the active agent in the composition using large amounts of filler. When the composition is in the form of a tablet, powder or sweetened tablet, all carriers suitable for the formulation of a solid pharmaceutical composition are used, for example, magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. be able to. Tablets may be coated (particularly enteric coated) by methods well known in normal pharmaceutical practice. Also, if it is desired to include a carrier or other excipient, the composition may be in the form of an ingestible capsule, for example, a gelatin containing the compound.

Compositions for oral administration, such as liquids, may be in the form of, for example, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable carrier before use. Such liquid compositions may contain suspending agents such as sorbitol, molasses, methylcellulose, gelatin, hydroxyethylcellulose,
Carboxymethylcellulose, aluminum stearate gel, hydrogenated edible oil); emulsifiers (eg, lecithin, sorbitan monooleate or acacia);
Edible oils (eg, almond oil, fractionated coconut oil), oily esters such as glycerin, propylene glycol, ethyl alcohol, glycerin, aqueous or non-aqueous carriers, including ordinary saline; preservatives (eg, p -Methyl or propyl hydroxybenzoate or sorbic acid); and if desired, conventional additives such as customary fragrances or colorings.

Also, the compounds may be administered by the parenteral route. The compositions may be formulated by routine pharmaceutical methods, for example, as suppositories for rectal administration or creams or lotions for topical administration. The compounds are formulated as injectables, in aqueous or non-aqueous solutions, as suspensions or emulsions in pharmaceutically acceptable liquids (eg, sterile pyrogen-free water or parenterally acceptable mixtures of oils or liquids). May be. The liquid contains bacteriostats, antioxidants or other preservatives, solutes, thickeners, suspending agents or other pharmaceutically acceptable additives to make the buffer or solution isotonic with blood. May be. Such forms may be provided in multi-dose form, such as an ampoule or a disposable device, or in a bottle from which aliquots can be removed, or as a solid form, or as a concentrate that can be used in the manufacture of injectable formulations.

The compounds may also be administered by inhalation via the nasal or buccal route. If desired, such administration may be carried out using, for example, a spray formulation comprising the compound, which may be suspended in a hydrocarbon propellant, and a suitable carrier.

Preferred spray formulations consist of fine compound particles mixed with a surfactant, solvent or dispersant to prevent settling of the suspended particles. Preferably, the compound particle size is about 2 to 10 microns.

A further method of administration of the compound consists of transdermal delivery using a dermal patch formulation. A preferred formulation consists of the compound dispersed in a pressure sensitive adhesive that adheres to the skin, so that the compound is delivered from the adhesive through the skin to the patient. To achieve a constant rate of transdermal absorption, pressure sensitive adhesives known in the art, such as natural rubber or silicone, can be used.

Effective doses of the compounds will depend on the particular compound employed, the condition to be treated, the condition of the patient and the frequency and route of administration. A single dose contains between 20 and 1000 mg, preferably between 30 and 500 mg, in particular 50, 100, 150, 200, 250, 3
It will contain 00, 350, 400, 450 or 500 mg. The composition is administered once or more times a day, for example, two, three or four times a day, and usually comprises one per adult weighing 70 kg.
The total daily dose will be in the range 100 to 3000 mg. Alternatively, a single dose may contain from 2 to 20 mg of the active ingredient, with multiple doses providing the daily dose, if desired.

No unacceptable toxicological effects are expected when the compound is administered in accordance with the present invention.

In vitro binding experiments using kappa-selective radioligands (Sbacchi et al., Excerpta Medica, Vol. 914, 211-212, 1990).
Year) may indicate the kappa receptor affinity of the compound.

JDLeander, Journal of Pharmacology and Experimental Therapeutics (J.Pharmacol.Exp.The
r.), 1983, Vol. 224, p. 89, and HG Haynes, HG Haynes, Journal of Pharmacology and Experimental Therapeutics (J. Pharmacol. Exp.), 1987 240, p. 984, the diuretic activity of a compound may be assessed by measuring urine volume in normally hydrated or water-loaded rats.

P. Lysko et al., Strok
e), as described by Vol. 23 (3), 1992,
The activity of a compound in treating cerebral ischemia may be assessed by using a gerbil model for ischemic stroke.

Abdominal contraction test induced by p-phenylquinone in mice (Siegmund et al., Proceedings of Society for Experimental Biology and Medicine (Proc. S)
Vol. 95, p. 729, 1957, the test is based on Milne and Twomey, Agents and Actions, No.
10, p. 31, 1980) may be used to show the analgesic activity of the compounds.

Protecting against inflammation pain using the paw compression test in monoarthritis rats described in the European Journal of Pharmacology, Eur. J. Pharmacol., Vol. 155, 255-264, 1988. The effect of the compound may be shown. After subcutaneous injection, the compound produces an improved analgesic effect in the inflamed paw as compared to the non-inflamed paw. The analgesic effect in inflamed paws is completely reversed by low dose plantar administration of the opioid antagonist naloxone, but not by a similar amount of naloxone injected subcutaneously.

The modified abdominal contraction test described in the British Journal of Pharmacol., Br. J. Pharmacol. 73: 325-332, 1981 provides further evidence for the analgesic effects of compounds in the periphery. You may get it. Intraperitoneal administration of the compound after administration of PPQ or acetylcholine causes a reduction in the number of abdominal contractions.

The compounds of the present invention and their preparation are described in the following examples, and their structures are tabulated.

 The preparation of the intermediate is illustrated in the description examples.

Description Example 1 3-Amino-2- (1-pyrrolidinylcarbonyl) pyrazine 10 g (0.065 mol) of 3-aminopyrazine-2-carboxylic acid methyl ester and 150 ml of pyrrolidine were stirred at room temperature for 3 days.

Excess pyrrolidine was evaporated under reduced pressure, and the residue was evaporated with EtOAc / n-
Crystallization from hexane gave 8.65 g of the title compound.

C ₉ H ₁₂ N ₄ O Melting point = 102-103 ° C. Molecular weight = 192.218 NMR (80 MHz) CDCl ₃ : δ8.05 (d, 1H), 7.80 (d, 1H),
6.60 (s, broad, 2H), 3.55 to 3.95 (m, 4H), 1.80 to 2.0
5 (m, 4H) Similarly, 3-amino-2-[(3-hydroxy-
1-Pyrrolidinyl) carbonyl] pyrazine was prepared.

Description Example 2 8- (1-Pyrrolidinylcarbonyl) -imidazo [1,2
-A] pyrazine 8.64 g (0.045 mol) of 3-amino-2- (1-pyrrolidinylcarbonyl) pyrazine and 8.7 ml (0.067 mol)
5.6g of a mixture of 50% chloroacetaldehyde (water)
(0.067 mol) in the presence of sodium bicarbonate
Heated at ° C. for 2 days.

The reaction mixture was then evaporated to dryness under reduced pressure and the residue was treated with aqueous potassium carbonate and exhaustively extracted with dichloromethane. The organic solution was evaporated to dryness under reduced pressure and CH ₂ Cl ₂
The crude product was purified by flash column chromatography on silica, eluting with a mixture of / MeOH / 28% NH ₄ OH, 95: 5: 0.5, respectively, to give 2.2 g of the title compound.

C ₁₁ H ₁₂ N ₄ O Melting point = 154-156 ° C. Molecular weight = 216.238 IR (film): 3130; 2980; 2880; 1635; 1425; 1320 cm ^-1 NMR (80 MHz) CDCl ₃ : δ 8.25 (d, 1H), 7.75 to 7.95 (m,
3H), 3.80 (t, 2H), 3.35 (t, 2H), 1.80 to 2.10 (m, 4H) Similarly, 8-[(3-hydroxy-1-pyrrolidinyl) carbonyl] -imidazo [1,2- a] A pyrazine was prepared.

Description Example 3 8- (1-pyrrolidinylcarbonyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine 2.10 g dissolved in 30 ml of 2-methoxyethanol.
(9.58 mmol) of 8- (1-pyrrolidinylcarbonyl) -imidazo [1,2-a] pyrazine was prepared in a Parr apparatus using 190 mg of PtO ₂ in the presence of 580 mg of powdered calcium oxide. For hydrogenation. After the theoretical amount of hydrogen had been consumed, the catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure to give 2.1 g of the title compound as an orange oil.

C ₁₁ H ₁₆ N ₄ O molecular weight = 220.270 NMR (80 MHz) CDCl ₃ : δ6.98 (d, 1H), 6.80 (d, 1H),
5.00 (s, 1H), 3.85 to 4.35 (m, 3H), 2.70 to 3.65 (m, 6
H), 1.70-2.10 (m, 4H) Similarly, 8-[(3-hydroxy-1-pyrrolidinyl) carbonyl] -5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine diastereomer A mer mixture was prepared.

Description Example 4 8- (1-Pyrrolidinylmethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine 2.1 g (9.53 mmol) of 8- (1-pyrrolidinylcarbonyl)- 5,6,7,8-tetrahydroimidazo [1,2-a]
The pyrazine was dissolved in 60 ml of dry THF. The solution was warmed to 60 ° C. and 2.8 ml of a borane dimethylsulfide complex 10M solution was added dropwise while stirring under nitrogen.

The reaction mixture was refluxed for 6 hours, cooled to -10 ° C and 6N
Carefully treated with HCl, then warmed at 70 ° C. for 3 hours.

The solvent was then evaporated to dryness under reduced pressure and the residue was
Treated with aqueous OH. The crude diamine was exhaustively extracted with CH ₂ Cl _2, dried over Na ₂ SO _4, dryness and concentrated under reduced pressure 2.0g
Was obtained with a purity of 88% (GC). The compound was used for the next reaction without further purification.

C ₁₁ H ₁₈ N ₄ molecular weight = 206.286 NMR (80 MHz) CDCl ₃ : δ 7.00 (d, 1H), 6.82 (d, 1H),
2.40 to 4.20 (m, 12H), 1.65 to 1.85 (m, 4H) Similarly, 8-[(3-hydroxy-1-pyrrolidinyl) methyl] -5,6,7,8-tetrahydroimidazo [1,2
-A] Pyrazine diastereomeric mixture was prepared.

Description 5 3-Dimethylaminomethyleneamino-2- (1-pyrrolidinylcarbonyl) pyrazine 4 g (0.021 mol) of 3-amino- in 11 ml of toluene.
2- (1-pyrrolidinylcarbonyl) pyrazine and 3.
A mixture of 1 ml (0.023 mol) of N, N-dimethylformamide dimethyl acetal was refluxed for 2 hours.

The solvent was evaporated under reduced pressure and CH ₂ Cl ₂ / MeOH / 28% NH ₄ OH, respectively
The crude product was purified by flash column chromatography on silica gel eluting with a mixture of 94: 2: 0.3 to give 2.7 g of the title compound as an orange oil.

The C ₁₂ H ₁₇ N ₅ O Molecular weight = 247.296 Description 6 3-hydroxyimino-methylene-2- (1-pyrrolidinylcarbonyl) solution of hydroxylamine hydrochloride 1.46 g (0.021 mol) in MeOH pyrazine 15ml 1.72g, mechanically stirring
100 ml MeOH containing (0.021 mol) sodium acetate
The solution was added dropwise to a solution of 3 g (0.020 mol) of 3-dimethylaminomethyleneamino-2- (1-pyrrolidinylcarbonyl) pyrazine therein, and kept at + 5 ° C.

After 4 hours, the solution was evaporated to dryness under reduced pressure and the residue was washed with CH ₂ Cl ₂
And filtered. The filtrate was evaporated to dryness and CH ₂ Cl ₂ / MeO
The crude product was purified by flash column chromatography on silica gel eluting with a mixture of H / 28% NH ₄ OH, 94: 15: 0.1 respectively to give 4.4 g of the title compound as yellow crystals.

C ₁₀ H ₁₃ N ₅ O ₂ mp = 178-180 ° C. The molecular weight = 235.244 IR (KBr): 3250 ; 1650; 1580; 1470cm -1 NMR (80MHz) CDCl 3: δ10.90 (d, 1H), 8.03~8.22
(M, 4H), 3.65-4.00 (m, 4H), 1.80-2.00 (m, 4H) Description Example 7 8- (1-pyrrolidinylcarbonyl)-[1,2,4] triazolo [1,5- a] Pyrazine 1.72 g (0.011 mol) of 3-hydroxyiminomethyleneamino-2- (1-pyrrolidinylcarbonyl) pyrazine and 17 g of polyphosphoric acid were heated at 90 ° C. for 4 hours. Therefore, the reaction mixture was poured into ice water and brought to pH = 8 with NaHCO ₃ . The aqueous layer was exhaustively extracted with methylene chloride, the organic solution was dried and evaporated to dryness under reduced pressure.

Purify the crude product by flash column chromatography on silica gel, eluting with a mixture of CH ₂ Cl ₂ / MeOH / 28% NH ₄ OH, 94: 3: 0.3, respectively, to give 1.3 g of the title compound as white crystals from ethyl acetate. Was.

C ₁₀ H ₁₁ N ₅ O Melting point = 123-125 ° C. Molecular weight = 217.228 IR (KBr): 3090; 2885; 1650; 1485; 1310 cm ^-1 NMR (80 MHz) CDCl ₃ : δ8.80 (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 Example 8 3.05 g (0.014 mol) of 8- (1-pyrrolidinylcarbonyl) -5,6,7,8-tetrahydro [1,2,4] triazolo [1,5-a] pyrazine Prepared according to Description 3 starting from 8- (1-pyrrolidinylcarbonyl)-[1,2,4] triazolo [1,5-a] pyrazine. 2.9 g of the title compound were obtained and recrystallized from ethyl acetate.

C ₁₀ H ₁₅ N ₅ O Melting point = 137-139 ° C. Molecular weight = 221.260 IR (KBr): 3300; 2980; 1655; 1495; 1440 cm ^-1 NMR (80 MHz) CDCl ₃ : δ 7.85 (s, 1H), 5.00 ( s, 1H),
4.00 to 4.30 (m, 3H), 2.90 to 3.95 (m, 5H), 2.50 (s, broad, 1H), 1.80 to 2.05 (m, 4H) Description Example 9 8- (1-pyrrolidinylmethyl) -5 , 6,7,8-Tetrahydro- [1,2,4] triazolo [1,5-a] pyrazine 2.8 g 8- (1-pyrrolidinylcarbonyl) -5,6,7,
Prepared according to Description 4 starting from 8-tetrahydro- [1,2,4] triazolo [1,5-a] pyrazine.

2.5 g of the title compound were obtained as an oil and used in the next reaction without further purification.

C ₁₀ H ₁₇ N ₅ MW = 207.276 EXAMPLE 1 7 - [(3,4-dichlorophenyl) acetyl] -8-
(1-Pyrrolidinylmethyl) -5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine 1 g (4.85 mmol) of the compound of Description 4 was dissolved in 30 ml of dry methylene chloride and 0.66 g (4.86 mmol) of anhydrous potassium carbonate was added.

1.2 g (5.36 mmol) (3,4-dichlorophenyl) acetyl chloride dissolved in 10 ml of CH ₂ Cl ₂ were added dropwise to the diamine solution while stirring with a magnetic stirrer.

After 3 hours, the reaction mixture was brought to room temperature and stirred overnight. Ten
was added ml of water, the separated organic layer was dried over Na ₂ SO _4, dryness and evaporated under reduced pressure.

_{CH 2 Cl 2 / MeOH / 28} % NH 4 OH ( respectively 95: 5: 0.5) on silica gel flash column chromatography eluting the crude product was purified to give the title compound 0.8g in ethyl acetate / n- Recrystallized from hexane.

C ₁₉ H ₂₂ Cl ₂ N ₄ O Melting point = 78-80 ° C. Molecular weight = 393.312 Elemental 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 IR (KBr): 2980; 2800; 1635; 1615; 1470cm -1 NMR (80MHz) CDCl 3: δ6.85~7.45 (m, 5H) , 4.50-5.
80 (m, 2H), 2.90 to 4.30 (m, 7H), 2.30 to 2.80 (m, 4H),
1.65 to 1.85 (m, 4H) Example 2 8- (1-Pyrrolidinylmethyl) -7-[(4-trifluoromethylphenyl) acetyl] -5,6,7,8-tetrahydroimidazo [1,2 -a] starting from dry CH ₂ Cl ₂ in 1 g (4.85 mmol) of chloride (4-trifluoromethylphenyl) acetyl compound of Description 4 and 1.2 g (5.40 mmol) of pyrazine 30 ml, example 1 It was manufactured in the same manner as described above.

Crystallization from ethyl acetate / n-hexane gave 0.7 g of the title compound as white crystals.

C ₂₀ H ₂₃ F ₃ N ₄ O Melting point = 124-125 ° C. Molecular weight = 392.416 Elemental 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 IR (KBr): 2960; 2790; 1650; 1490; 1415; 1320cm -1 NMR (80MHz) CDCl 3: δ7.25~7.60 (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), 1.5
5 to 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
Diastereomer mixture 0.8 g (3.60 mmol) of 8-[(3
-Hydroxy-1-pyrrolidinyl) methyl] -5,6,7,8
-Prepared as described in Example 1 starting from tetrahydroimidazo [1,2-a] pyrazine diastereomeric mixture and 0.96 g (4.32 mmol) (3,4-dichlorophenyl) acetyl chloride.

Purify the crude product by silica gel flash column chromatography, eluting with CH ₂ Cl ₂ / MeOH / 28% NH ₄ OH (86: 10: 0.6 each) to give 0.4 g of the title compound, which is recrystallized from ethyl acetate did.

C ₁₉ H ₂₂ Cl ₂ N ₄ O ₂ Melting point = 160-175 ° C. Molecular weight = 409.312 Elemental 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 IR (KBr): 3250; 2920; 2790; 1650; 1435cm -1 NMR (80MHz) CDCl 3: δ6.75~7.45 (m, 5H) , 4.50-5.
80 (m, 2H), 3.30 to 4.40 (m, 5H), 1.50 to 3.30 (m, 10H) Example 4 7-[(3,4-dichlorophenyl) acetyl] -8-
(1-pyrrolidinylmethyl) -5,6,7,8-tetrahydro - [1,2,4] triazolo [1, 5-a] 1.5 g of dry CH ₂ Cl ₂ pyrazine 50 ml (7.24 mmol) Description example 9
And 1.86 g (8.32 mmol) of (3,4-dichlorophenyl) acetyl chloride as described in Example 1.

_{CH 2 Cl 2 / MeOH / 28} % NH 4 OH ( respectively 86: 12: 0.6) The crude product was purified by silica gel flash column chromatography eluting with to give the title compound 0.1 g.

C ₁₈ H ₂₁ Cl ₂ N ₅ O Melting point = 113-116 ° C. Molecular weight 394.302 Elemental analysis: Calculated 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 IR (KBr): 2980; 2790; 1645; 1400cm -1 NMR (80MHz) CDCl 3: δ7.90 (s, 1H), 7.00~7.45 (M,
3H), 4.60-6.10 (m Broad, 1H), 3.40-4.50 (m, 6
H), 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-trifluoromethylphenyl) acetyl] -5,6,7,8-tetrahydro- [1,2,4 ] triazolo [1,5-a] Description of pyrazine dihydrochloride 50ml of dry CH ₂ Cl ₂ in 1.5 g (7.24 mmol) 9
From 1.85 g (8.32 mmol) of (4-trifluoromethylphenyl) acetyl chloride as described in Example 1.

_{CH 2 Cl 2 / MeOH / 28} % NH 4 OH ( respectively 86: 15: 0.7) in the crude product was purified by silica gel flash column chromatography eluting to give the free base of 1.2g, which dihydrochloride And recrystallized from EtOAc / acetone.

C ₁₉ H ₂₂ F ₃ N ₅ O.2HCl Melting point = 176-177 ° C. Molecular weight = 466.336 Elemental analysis: Calculated C, 48.93; H, 5.19; N, 15.02; Cl, 15.21;
F, 12.22; found C, 48.22; H, 5.19; N, 14.69; Cl, 15.09; F,
11.86 IR (KBr): 3420; 2560; 1660; 1330 cm ^-1 NMR (80 MHz) CDCl ₃ + NaOD: δ 7.90 (s, 1H), 7.25 to 7.
70 (m, 4H), 4.60 to 6.10 (m broad, 1H), 3.50 to 4.5
0 (m, 6H), 2.90 to 3.15 (m, 2H), 2.20 to 2.70 (m, 4H), 1.
50-1.90 (m, 4H) The following compounds may be prepared in a manner analogous to the methods of Examples 1 to 5: 7-[(3,4-dichlorophenyl) acetyl] -8-
(1-pyrrolidinylmethyl) -5,6,7,8-tetrahydro-1,2,4-triazolo [4,3-a] pyrazine 8- (1-pyrrolidinylmethyl) -7-[(4 -Trifluoromethylphenyl) acetyl] -5,6,7,8-tetrahydro-1,2,4-triazolo [4,3-a] pyrazine 7-[(3,4-dichlorophenyl) acetyl] -8-
(1-pyrrolidinylmethyl) -5,6,7,8-tetrahydrotetrazolo [1,5-a] pyrazine 8- (1-pyrrolidinylmethyl) -7-[(4-trifluoromethylphenyl) [Acetyl] -5,6,7,8-tetrahydrotetrazolo [1,5-a] pyrazine.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61P 9/06 A61P 9/06 11/06 11/06 11/14 11/14 25/04 25/04 25/08 25/08 29/00 29/00 43/00 111 43/00 111 (72) Inventor Gruni, Mario Milan, Italy 20021, Baranzate, Via Zamberetti (without address indication) Smithkline Beecham Farmustiichi Societa Per Acioni (72) Inventor Colle, Roberto Milan, Italy 20021 Baranzate, Via Zamberetti (No indication of address) Smithkline Beecham Farmacutici Societa Per Acioni (58) Survey Field (Int. Cl. ⁷ , DB name) C07D 487/04 145 C07D 487/04 144 A61K 31/495 CA (STN) REGISTRY (STN)

Claims (5)

(57) [Claims] (1) Formula (I): Wherein each of X and Y is independently CH or N; R is formula (II): Wherein n is 0, 1 or 2; m is 0, 1 or 2; m 'is 0, 1 or 2; m + m' is 3 or less; X ₁ is a direct bond. Or O, S or NR ₈ , wherein R ₈ is hydrogen or C _1-6 alkyl; Ar is a substituted or unsubstituted carbocyclic or heterocyclic group; R ₆ and R _6a is bromine, chlorine, CF ₃ , 2-furanyl, 2-pyryl, 2-thiazolyl, 2-imidazolyl,
R ₇ is hydrogen or C _1-6 alkyl); or R is of the formula (IIa): Wherein the group — (CHR ₇ ) _n —X ₁ — is in the meta or para position to Y ₁ R _x or R _y ; n is 0, 1 or 2; R ₇ is hydrogen or C ₁ There _-6 alkyl; X ₁ is either a direct bond, or O, S or NR _8, wherein the R ₈ is hydrogen or _{C 1 to 6} alkyl; Y ₁ is> C = O,> CHOH ,> S = O or> SO ₂ ; R _x and R _y are C _1-6 alkyl, or R _x and R _y are taken together and R _x is — (Z _{m ″} ) — Where m ″ is 0 or 1, and Z is O, S or
NR _z , wherein R _z is hydrogen or C _1-6 alkyl;
_y is - (CH ₂₎ q _-, and the here q are those having an a) an integer from 1 None 4; may be the each of R ₁ and R ₂ different even for the same, at least 1 Halogens, hydroxy, C
_1-6 alkoxy, acyloxy, thiol, C _1-6
Alkylthio, acylthio, halo _{-C 1 to 6} alkoxy, COR _h, COOR _h, CONHR _h or NCHOR _h optionally _{C 1 to 6} alkyl optionally substituted by, here R _h is hydrogen or _{C 1 to 6} alkyl Or each of R ₁ and R ₂ is hydrogen, C _2-6 alkenyl, C _3-6 cycloalkyl, or C _4-12 cycloalkylalkyl; or R ₁ and R ₂ together are Optionally substituted _C2-8 branched or linear polymethylene or C2
_Which forms a _2-6 alkylene group] or a solvate or salt thereof. 2. R is a monocyclic or condensed carbocyclic ring having 6 to 12 ring carbon atoms, or a monocyclic or condensed heterocyclic ring having 5 to 12 ring atoms. The heterocyclic ring is in the ring or in each ring,
A compound according to claim 1 which contains up to 4 heteroatoms selected from oxygen, nitrogen and sulfur. 3. The compound according to claim 1, wherein R is benzyl substituted by dichloro or trifluoromethyl. 4. R ₁ and R ₂ together form a group: Wherein R _b may be bonded to the same or different carbon atom as R _c , is hydrogen, hydroxy, C _1-6 alkoxy or halogen, R _c is hydrogen or C _1-6 alkyl , A is 1 or 2]. The compound according to any one of claims 1 to 3, wherein 5. A compound according to any one of claims 1 to 4 for use as an active therapeutic substance.