GB2274282A

GB2274282A - Piperazine and piperidine isoxazole derivatives

Info

Publication number: GB2274282A
Application number: GB9300950A
Authority: GB
Inventors: Mario Varasi; Paolo Pevarello; Raffaella Amici; Nicola Carfagna; Alberto Bonsignori
Original assignee: Farmitalia Carlo Erba SRL; Carlo Erba SpA
Current assignee: Pfizer Italia SRL
Priority date: 1993-01-19
Filing date: 1993-01-19
Publication date: 1994-07-20
Anticipated expiration: 2013-01-19
Also published as: DE4401159A1; ITMI940025A0; JPH06247965A; GB9300950D0; ITMI940025A1; GB2274282B; IT1269178B

Description

2274282 PIPERAZINE- AND PIPERIDINEISOXAZOLE DERIVATIVES The present

invention is concerned with isoxazole derivatives, with processes for their preparation and with 5 pharmaceutical compositions comprising them.

In particular, the instant invention provides a compound of the general formula (I) R R1 ro NH Ay 0 0 R2 wherein R is OH, COR2. PO(R2)2, Cl-C4 alkoxy or halogen; R1 is hydrogen, halogen, trifluoromethyl, Cl-C4 alkyl, C3-C, cycloalkyl, C,-C4 alkoxy, benzyloxy, benzyloxy in which the phenyl moiety is substituted by halogen or Cl-C4 alkyl, phenyl or phenyl substituted by halogen; R2 is OH, C,-C4 alkoxy, benzyloxy, substituted benzyloxy, amino or amino substituted by one or two Cl-C4 alkyl groups; A is Cl-C4 alkylene and Y is nitrogen or carbon, A is C2-C4 alkenylene or (CH2) t-CH= wherein t is 0, 1, 2 or 3 and Y is carbon or A is (CH2) P-COor -CO- (CH2) q wherein p and q are independently 0,1 or 2 and Y is nitrogen; and = represents a single or double bond; or a pharmaceutically acceptable salt thereof.

As used in this specification:

a) the term "halogen" refers to a fluorine, chlorine, bromine or iodine atom; b) the term "Cl-C4 alkyll' refers to a branched or straight chain alkyl group containing from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc.; C) the term "Cl-c. alkoxyll refers to a straight or a branched alkoxy group containing from 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n butoxy, isobutoxy, etc.; d) the term %1C.-C7 cycloalkyll' refers to a cycloalkyl group containing from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.; e) the term "substituted benzyloxyll in relation to R2 refers to a benzyloxy moiety which is substituted on the phenyl ring by 1, 2 or 3 substituents, each substituent being independently selected from halogen, Cl-C4 alkyl, Cl C4 alkoxy, CF3, OH, CN, NH2 and N02. These substituents may be the same or different and may be located at any of the ortho, meta, or para positions.

f) the term "Cl-C4 alkylenell refers to an alkylene group which is straight or branched and which contains from 1 to 4 carbon atoms such as -CH2-, -CH2CH2-, -(CH3)CH-, CH2CH2CH2- or -CH2CH2CH2CH2_.

g) the term 11C2-C4 alkenylenetl refers to an alkenylene group containing from 2 to 4 carbon atoms such as -CH=CH-, -CH=CH-CH2-1 -CH=CH-CH,-CH2-, or -CH2-CH=CH-CH2_.

h) the expression Ilpharmaceutically acceptable salts" includes pharmaceutically acceptable addition salts - 3 thereof and refers to either acid addition salts or to base addition salts; i) the term isoxazole derivative refers to compounds containing the moiety:

5. in,' % 0 where -- is a single or double bond.

Particularly preferred are the compounds of formula (1) wherein: R is OH, COOH or P03H.; P.1 is cl-C, alkyl, preferably methyl, ethyl or tert-butyl, bromine or phenyl; R. is OH, C, or C2 alkoxy such as methoxy, benzyloxy, amino or amino substituted by one or two Cl- C2 alkyl groups; and A is C, or C2 alkylene, C2-C4 alkenylene or carbonyl group.

is Examples of compounds encompassed by the present invention include:

1) 4-(2-carboxy-1,4-piperazin-4-yl)methyl-3hydroxy-5-methylisoxazole; 2) 5-(2-carboxy-1,4-piperazin-4-yl)methyl-3- hydroxy-4-methylisoxazole; 3) 4-(2-carboxy-1,4-piperazin-4-yl)ethyl-3- hydroxy-5-methylisoxazole; 4) 5-(2-carboxy-1,4-piperazin-4-yl)ethyl-3- hydroxy-5-methylisoxazole; 5) 5-(2-carboxy-1,4-piperazin-4-yl)methyl-3- hydroxyisoxazole; 6) 5-(2-carboxy-1,4-piperazin-4-yl)carbonylmethyl- 3-hydroxy-isoxazole; 7) 5-(2-carboxy-1,4-piperazin-4-yl)methyl-3-oxo- 1(H)-4,5-dehydroisoxazole; 8) 5-(2-carboxy-1,4-piperazin-4-yl)methyl-3- nethoxy-isoxazole; 9) 3-bromo-5-(2-carboxy-1,4-piperazin-4- yl)methylisoxazole; 10) 3-bromo-5-(2-carboxamido-1,4-piperazin-4- yl)nethylisoxazole; 11) 3-carboxy-4-(2-carboxamido-1,4-piperazin-4- yl)methyl-S-methylisoxazole; and 12) 3-carboxy-5-(2-carboxamido-1,4-piperazin-4yl)methyl-4-methylisoxazole.

The present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises reacting a piperazine or piperidine derivative (II) with an isoxazole derivative (III) according to the following scheme ) l- X NH R N %O5R 2 B NIOR JHN Ay0 0 2 where Z is NH or -C=O; B is (CH2)n wherein n is 1,2,3 or 4 or, additionally only when Z is NH, (CH2) P-CO- or -CO- (CH2) q wherein p and q are as defined above; X is Cl, Br, I, a leaving group such as nesyloxy, toxyloxy or trifluoroacetate, or an imidazole, triphenylphosphonium or dialkyl phosphonate group; and A, Y, R, R,, R2 and the symbol -are as defined above; and optionally converting the resultant compound of formula (I) into another compound of formula (I) and/or converting the resultant compound of formula (I) into a pharmaceutically acceptable salt thereof.

In particular when Z is NH; B is (CH2), or CO-(CH2)q and X is Cl, Br, I or a leaving group such as mesyloxy, tosyloxy or trifluoroacetate, the reaction between compounds (II) and (III) is performed using a suitable base such as anhydrous potassium carbonate, sodium carbonate, triethylamine, pyridine, diisopropylethylanine, etc., in a suitable solvent such as ethanol, acetonitrile, methanol, dimethylformamide, toluene, at a suitable temperature of about VC to 1100C, preferably about 60C, for about 30 minutes to about 4 hours.

When Z is NH and B is (CH2) p CO and X is halogen or imidazole the reaction is performed under suitable conditions, e.g. in a solvent such as dimethylformamide, N- methylpyrrolidone etc., at a temperature between about 200C to about 1000C, in the presence or in the absence of a suitable catalyst, e.g. dimethylaminopyridine, diisopropylethylamine etc.

When Z is -C=0 and B is (CH2) n and X is a triphenylphosphonium or dialkylphosphonate group, the transformation is performed under the conditions of a Wittig reaction; this reaction is generally accomplished by treating the appropriate phosphonate or phosphonium salt with a base, such as sodium hydride, to generate the corresponding sodium salt which is then reacted in a nonreactive solvent, such as dry tetrahydrofuran, with the appropriate 4-oxopiperidine to provide the corresponding 5 alkenes. This reaction is generally carried out between OOC and the reflux temperature of the reaction mixture: when a slight molar excess of the phosphor ylid or of the phosphonate anion is employed, the reaction is generally complete after heating for about six hours at the reflux temperature of the mixture.

The compounds of formula (I) can be transformed into other compounds of general formula (I) by suitable functional group interconversion. For example:

- when R in (I) is halogen it can be transformed into the corresponding ether following methods known in the literature, or into the corresponding hydroxy derivatives by a suitable hydrolytic method; - when R in (I) is an alkoxy group it can be transformed into the corresponding hydroxy derivative (R=OH) by a suitable dealkylating agent, e.g. hydrogen bromide, trimethylsilyl iodide, hydrogen iodide, at a suitable temperature of about 200C to about 140C, preferably about 1100C, for about 15 minutes to about 6 hours; when A is alkenylene the double bond can be - 7 isomerized by known methods, e.g. in the presence of a transition metal catalyst such as a rhodium or a palladium salt in a suitable solvent such as ethanol, at a temperature between about 250C to about 780C, preferably about 780C, for about 1 to 64 hours; when A is alkylene the compound can be transformed into a corresponding saturated alkylene derivative by a suitable hydrogenative method, preferably by catalytic hydrogenation which is preferably effected in the presence of a catalyst such as palladium-on-carbon and in an inert solvent such as ethanol; and when R2 in (I) is an amide derivative it can be transformed into the corresponding acid or ester by method known in the literature.

When Z in the compound of formula (II) is CO and B in the compound of formula (III) is (CH2)n, the resulting Wittig reaction forms a compound of formula (I) in which A is (CH2)t-CH= and Y is carbon. This compound of formula (I) may then be transformed into a corresponding compound of f ormula (I) in which A is C, -C4 alkylene by hydrogenation or into a corresponding compound of formula (I) in which A is C2-C4 alkylene by ef fecting isomerisation of the double bond in the group (CH 2) t-CH=.

The compounds of formula (II) are known compounds or compounds which can be prepared by methods known in the literature. Some of compounds of formula (III) are known in the literature. Others are new. These are the compounds of formula (1110) and (III"):

R R RI R 1' (CH2) m- X (CH2) m- X wherein R' is chlorine, bromine or ethoxycarbonyl; R,, is methyl, ethyl, t-butyl or phenyl; m is 1,2,3 or 4; W' is a dialkylphosphoric group or a fluorine atom; and X is as defined above; which also form part of the present invention. The new compounds of formula (IIII) and (IIIII) are prepared from compounds of formula (M) or (IVIt) below. The compounds of formula (M) and (IVIt) form part of the invention as well.

The compounds of general formula (M) where R11 is methyl, ethyl, tertbutyl or phenyl, R' is chlorine, bromine or ethoxycarbonyl and m is 1,2,3 or 4 are prepared by a 1,3-dipolar cycloaddition of a suitable alkyne derivative (V) where R1 1 is as def ined above with a suitable haloxime (VI) where Rt is as defined above and W is chlorine or bromine in the presence of a suitable R R base R1 0 -C=C- (CH2) m-OH + N 1 (CH2)jOH OH (V) (VI) base, e.g. triethylamine, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium fluoride, 4A-molecular - 9 sieves etc., in a suitable solvent, e.g. water, methanol, ethanol, isopropanol, tert-butylalcohol, dimethylformamide, toluene, ethyl acetate, tetrahydrofuran, monoethy1glycol diethylether etc., at a suitable temperature of from 109C 5 to 1106C, preferably about 60OC# for about 3 to 64 hours. More preferably, the preparation of the compounds of formula (M) is carried out in the presence of potassium fluoride as a base.

Some products of general formula (IV') can be transformed into compounds of general formula (IV#O) R R, (CHz) M-DH where Ri# and m are as defined above and R# # is a dialkylphosphonic group or a fluorine atom. When RO in formula (M) is bromine it can be replaced by a dialkylphosphono group, typically a diethylphosphono group, by reaction with a dialkylphosphite in the presence of a catalyst such as palladium tetrakistriphenylphosphine and of a base such as triethylamine, in a suitable solvent such as toluene at a suitable temperature. e.g. between 50 and 11O.C, for a suitable time, e.g. 2-24 hours. Typically the alkyl group is a Cl-C4 alkyl group. Alternatively. the R# group can be replaced by a fluorine atom by reaction with a suitable alkali metal halide, e.g. potassium fluoride, in a suitable solvent, e.g. an aprotic solvent such as dimethyl sulfoxide, at a suitable temperature, e.g. from about 50 to about 1800C for a suitable time, e.g. from about 4 to about 48 hours.

The compounds of formulae (M) and (IVft) are then transformed into the compounds of formula (IIIt) and (III'f). This may be achieved by known reactions, such as halogenation and optional subsequent phosphorane preparation or conversion of the hydroxy group into a common leaving group.

The term Ilpharmaceutically acceptable salts" embraces salts of addition with pharmaceutically utilizable acids, either inorganic acids such as hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric or phosphoric acid, or appropriate organic acids such as aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and alkylsulfonic acids, specific examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicylic, phenylacetic, mandelic, embolic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, panthotenic. benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, alginic, P-hydroxybutyric, malonic, galactaric and galacturonic acid. Also embraced are metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, and organic - 11 salts made from benzathine (N,N-dibenzyl-ethylenediamine), chloroprocaine, choline, diethanolamine, meglumine (Nmethy1glucamine) and procaine.

The compounds of formula (I) can posses one or more asymmetric centers and are thus capable of existing in the form of different, pure optical isomers as well as in the form of racemic or non- racemic mixtures thereof. All these forms fall within the scope of the present invention. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by formation of diastereoisomereic salts by treatment with an optical active acid, such as tartaric, diacetyltartic, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid, followed by separation of the mixture of diastereoisomers by cristallization and then followed by liberation of the optically active bases from these salts.

Separation of optical isomers may also be achieved by passing the isomers mixture through a chiral chromatography column optimally chosen to maximize the separation of the enantiomers of the products of the invention or derivatives thereof. Still another available method involves synthesis of covalent stereoisomeric molecules by reacting the compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can then be separated by conventional means such as chromatography, distillation, crystallization or sublimation and submitted to an hydrolytic step which will deliver the enantiomerically - 12 pure compound. The optically active compounds according to formula (I) can likewise be obtained by utilizing optically active starting materials. All of these stereoisomers, optical isomers, diastereoisomers, as well as mixtures thereof, such as racemic mixtures, are within the scope of the invention.

A therapeutically-active compound of formula (I) may be administered alone, or in a solvent, but is more likely to be included in a pharmaceutically-acceptable composition. Such pharmaceutical compositions may contain, as active ingredient, at least one compound of formula (I) or a salt of addition thereof with a pharmaceutically utilizable acid, a pharmaceutically acceptable carrier or diluent. Thus one or more suitable excipients may be present in the composition. These compositions are prepared in such a manner that they can be administered by oral, rectal, parenteral or local route. The compositions can be solids, liquids or gel forms and may be utilized, according to the administration route, in the form of powders, tablets, lozenges, coated tablets, capsules, granulates, syrups, suspensions, emulsion solutions, suppositories or gels. These compositions can likewise comprise another therapeutic agent having an activity similar to or different from that of the compounds of the invention.

The compounds of formula (I) are excitatory amino acid (EAA) antagonists. For example, they antagonize the effects which EAA have upon the N-methylD-aspartate (NMDA) receptor complex. They are useful in the treatment of the human or animal body by therapy. The affinity of the compounds for the MDA receptor was assessed using 3 H-CGS 19755 as a ligand according to Murphy E.D. et al., Br. J. 5 Pharmacol. 95., 932-938, 1988.

The compounds exhibit anti-convulsant properties and are useful in the treatment of epilepsy. One method of demonstrating their antiepileptic properties is by their ability to inhibit the seizures that are caused by administration of NMDA. This test can be conducted in the following manner. Typically, one group of 10 male CD-1 mice are administered with a methocel suspension of a volume of 10 ml/Kg of the test compound. The test compound is administered i.p.. Thirty minutes later the mice are administered subcutaneously with 225 ng/Kg of an aqueous solution of WDA and placed individually in glass jars and observed for 30 minutes. Each mouse is observed during this time for tonic-clonic seizures and/or death. A second group of mice are administered an equal volume of saline control by the same route. The control group will have a statistical higher incidence of seizures than the group which receives the test compound (T. J. Haley et al. Brit.

J. Pharmacol. 1957, 12, 12; J. W. Perkany et al. J.

Pharmacol. Exp. Ther. 1989, 250(1),10).

The compounds of formula (I) are useful for preventing or minimizing the damage which nervous tissues contained within the MS suffer upon exposure to either ischemic, hypoxic. or hypoglycaemic conditions or as the result of physical trauma. Representative examples of such conditions include strokes or cerebrovascular accidents, hyperinsulinemia, cardiac arrest, physical trauma, drownings, suffocation and neonatal anoxic trauma.

The compounds are also useful in the treatment of neurodegenerative disease such as Huntington's disease, Alzheimer's disease, senile dementia, glutaric acidaemia type I, Parkinson's disease, multi-infarct dementia, and neuronal damage associates with uncontrolled seizures. The administration of these compounds to a patient experiencing such a condition will serve to either prevent the patient from experiencing further neurodegeneration or it will decrease the rate at which the neurodegeneration occurs.

The compounds also exhibit an analgesic effect and are useful in controlling pain. The compounds are also useful in the treatment of migraine.

The toxicity of the compounds of the invention is negligible; therefore they can be safely used in therapy. The dosage at which the compounds of the invention may be administered to a patient depends on a variety of factors such as the condition to be treated, the patient's body weight, the condition of the patient, etc. Typically, however, a compound of formula (I) or a salt thereof is administered by any route, for example orally or by injection, at a dose of 0.01 to 30 ng/kg/day.

The following Examples present typical syntheses of the compounds of Formula I through Formula VII. These examples are understood to be illustrative only and are not intended to limit the scope of the invention in any way. As used in the following examples, the following terms have the meanings indicated: OUCII refers to thin layer chromatography, OFC refers to flashchromatography.

Examp_le -1 3-Bromo-4-hydroxymethyl-S-methylisoxazole (1) and 3-Bromo-5hydroxymethyl- 4-methylisoxazole (2).

5g (0.026 mol) of 2-butyn-l-ol were dissolved in ethylene glycol dimethylether (500 mL). The mixture was heated to ref lux, then KF 2H20 (7.35g;0.078 Mol) and dibromoformaldoxime (13.18 g; 0.065 mol) were added in five portions, every one hour. The mixture was refluxed for 6 hours, then filtered, the white precipitate washed several times with ethyl acetate. the filtrates evaporated and the crude residue purified by FC (silica gel; cyclohexane 8-ethyl acetate 2) to give 4.6 g (35%) of 1 and 3.1 g (24%) of 2 as colourless fluids.

1: 'H-NER (6,CDC13): 4.42 (s,2H,QH2OH); 2.48 (s,3H,CH3).

2: 'H-NER (8,CDC13): 4.66 (s,2H,9B2OH); 1.99 (s,3H,CH3).

Analogously the following compounds are prepared:

3-Bromo-4-hydroxyethyl-S-methylisoxazole (3) H-NMR (6,CDC13): 3.76 (t#2H#CH2úH2()H,J-7Hz); 2.60 (t,3H,CH2CH20H,j=7HZ); 2.41 (s,3H,CH3); 3-Bromo-5-hydroxyethyl-4-methylisoxazole (4) H-NMR (8,CDC13): 3.97 (t12HiCH2CU2OH,J=7Hz); 3.01 (t,3H,CH2CH20H,j.7Hz); 2.00 (s,3H,CH3); - 16 Example 2

4-Hydroxymethyl-5-inathyl-3-mathoxyisoxazoic (s) compound (1) (3 g,.O.0156 =01) Was dissolved In methanol/water (10:1/vm50 nl)and heated to reflux; 851r KOH (8.75 g; 0.132 mol) was then added and the mixture refluxed for 8 hours. After cooling, neutralisation and evaporation# the residue was dissolved In waterf extracted with ethyl acetate (3x20 Xl) and the organic phase dried over an. Na2504; after evaporation 1.98 g (894) of (5) were obtained as a colourless fluid.

Ill-MR (6,CDC13): 4.40 (&0211iúU2OH); 3.98 (s,3HtOCH3); 2.37 (s,3H,CH3).

Analogously, the following compounds ware obtained:

5-Hydroxymethyl-4-methyl-3-Methoxyisoxazole (6) h-NMR (S,CDC13): 4.56 (s,2H,=20H); 3.97 (s,3H,OCH3); 1.86 (-%#3H#CH3).

4-Hydroxyethyl-5-methyl-3-mathoxyisoxazole (7) IH-NVIR (60CDC13):3.97 (s$3HiOCK3); J.72 (t,2H,CH2úU2;J=7Hz) 2.51 (t,2H, QH2CH2OH;J=7Hz); 2.28 (sp3HiCH3).

5-hydroxyethyl-4-nethyl-3-methoxyisoxazole (9) H-NMR (B,CDC13):3.98 (t,2H,CH2CE2;jm7Hz); 3.97 (s13HpOCH3); 3.00 (t, 2H#CZ2CH2OH;J-7Hz); 1.99 (s3HgCH3), Uxamnle 3 3-Ethoxycarbonyl-4-bydroxymethyl-S-:methylisoxazolo (9) and 3-Ethoxycarbonyl-S-hydroxyinethyl-4-inathyllaoxazole (1o) 7.5 g (0.107 nol) of 2-butyn-l-ol were dissolved in toluene (150 xnl). To this solution. 27 g of 4A-nolecular sieves were added and the mixture was refluxed for 5 minutes. A solution of ethyl chlorooximidoacetate (16 g;0.107 nol) in toluene (so =l) was added within 45 minutes. Reflux was maintained for an additional hour. The reaction mixture was then filtered, the filtrates evaporated to obtain a crude syrup, which was flash-chromatographed on silica gel (cluant: cyclohexane 75: ethyl acetate 25); 0.42 g (2%) of (10) (pale yellow oil) and 2.1 g (11%) of (9) (colorless oil) are eluted in this order.

9:1H-RM (8,CDC13): 4.59 (d,2HsúH20H); 4.50 (q,2H,OZU2CH3); 3.27 (t,1H,OH); 2.48 (s,3HOCH3); 1.45 (t03H,OCH2úH3).

10:1H-" (&OCDC13): 4.77 (bs,,2H,CH2OH); 4.45 (q02H,0=2CH3); 2.24 (s,3H,CH3); 1.40 (t,3H,OCH2QB3).

rx-ample 4 4-Bromomethyl-3-methoxy-5-methylisoxazole (11) Compound (3) (2.68 g; 0.0187 mol) was mixed, at lowC, in methylene chloride (60 ml) with M3 (5.83 g; 0.0222 nol). While stirring at 1O&C, 4 g (0.00225 mol) of N-bromosuccinimide were added in portions (each 1 g). The mixture was then allowed to reach room temperature; stirring was continued for a further 15 minutes then water was added, the organic phase extracted with ethyl acetate (3x25m1), washed with saturated NaHC03 solution (10m1) and dried over anhydrous sodium sulfate: PC of the crude residue (eluant: cyclohexane 80 - ethyl acetate 20) gave 2.5 g (67%) of a pale yellow fluid.

11:1H-MM (6,CDC13):4.19 (s,2H,Mi2Br); 4.01(ry3H,0=3);2.34 (s,3H,CH3).

Analogously, the following compounds were obtained:

5-Bromonethyl-3-methoxy-4-methylisoxazole (12) H-NMR (6,CDC13):4.32 (s,2H,QB2Br); 3.99 (s,3H,09H3); 1'88 (s,3H,CH3).

4-Bromoethyl-3-methoxy-5-methylisoxazole (13) H-NMP. (S,CDC13): 3.99 (s,3H,0=3); 3.55 (t,2H,CH2.CE2Br;j=7Hz); 2.82 (t, 2H,=2CH2Br;j-7Hz); 2.35 (s,3H,CH3).

5-Bromoethyl-3-methoxy-4-methylisoxazole (14) H-NMR (S,CDC13): 3.98 (s,3H,0=3); 3.59 (t,2H,CH2úH2Br;J=7Hz); 3.17 (t,2H,9H--2CH2Br;j=7Hz); 1.84 (s,3H,CH3).

4-Bromomethyl-3-ethoxycarbonyl-S-methylisoxazole (15) H-NMR (S,CDC13): 4.56 (s,2H,CH2Br); 4.45 (q,2H,09H2CH3); 2.50 (s,3H,CH3); 1.45 (t,3HgOCH2CH3).

5-Bromomethyl-3-ethoxycarbonyl-S-methylisoxazole (16) H-NMR (8,CDC13): 4.48 (s,2H,CH2Br); 4.45 (q,2H,O.=2CH3); 2.23 (s,3H,CH3); 1.41 (t,3H,OCH2CH3) 4-Bromoethyl-3-ethoxycarbonyl-S-methylisoxazole (17) 5-Bromoethyl-3-ethoxycarbonyl-4-methylisoxazole (18) Example 5

4-(2-Carboxamido-1,4-piperazin-4-yl)methyl-3-methoxy-5-methylisoxazole (19).

Compound (11) (1.5 g; 7.28 mmol) was added to a preformed mixture of 2-carboxamido-1,4-piperazine (1.41 g; 10.92 =01), anhydrous X2C03 (1.5 g; 10.92 mmol) In DMF at WC. The mixture was__ heated 2 hours at WC, then cooledi evaporated and directly flash- chromatographed on silica gel (eluant: CH2C1295; CH30H S; 30% NH,&OH_ 0. 5) to afford 1.56 g (84%) of (19) as a thick oil.

H-NMR (6,DMSO): 7.18 and 6.99 (2bs, 1H, CONH 2) 3.84 19 - (5,3H,OCH3); 3.12 (s,2H,CH2N<) 3.08 (dd,1H,CH(NH)CONH2); 1.88-2.92 (M,6H, piperazine); 2.23 (s,3H,CH3).

Analogously, the following compounds were obtained:

5-(2-Carboxamido-1,4-piperazin-4-yl)zethyl-3-methoxy-4-zethyli5OXaZole (20).

IH-IM (6,DMSO): 7.18 and 7.02 (2bs,1H,CONH2); 3.86 (s,3H,0CH3); 3.48 (s, 2H,CH2N<); 3.08 (dd,IH,CH(NH)CONH2); 1.90-2.83 (m#6H,piperazine); 2.12 (bs,1H,NH); 1.81 (s13HtCH3) 4-(2-Carboxamido-1,4-piperazin-4-yl)ethyl-3-inethoxy-5-methylisoxazole (21).

H-NMR (6,CDC13): 6.91 and 5.40 (2bs,1H,CONH2); 3.92 (s,3H,OCH3); 3.50 (s,2H,CH2=2N<); 3.44 (dd, 1H, MI (RH) CONH 2) 2.15-3.05 (m,6H,piperazine); 2.43 (s,3H,OCH3); 2.26 (s,2HtúH2CH2N<) 5-(2-Carboxamido-1,4-piperazin-4-yl)ethyl-3-methoxy-4-methylisoxazole (22).

4-(2-Carboxamido-1,4-piperazin-4-yl)zethyl-3-ethoxycarbonyl5inethylisoxazole (23).

1H- (6,DMSO): 6.92 and 5.73 (2bs,1H,CONH2); 4.42 (cl, 2H,0QB-2CH3); 3.53 (di2HiCH2N<); 3.40 (dd,1Ht=(NH)CONH2)2.08-3.11 (m,6H,piperazine); 2.44 (s, 3H@CH3); 1.42 (t,3H#OCH2CH3).

5(2-Carboxamido-1,4-piperazin-4-yl)methyl-3-ethoxycarbonyl4methylisoxazole (24).

H-NMR (S,DMSO): 7.09 and 7.01 (2bstlH,,CONH2); 4.35 (q,2H,0=2CH3); 3.64 (d12H,CH2N<); 3.12 (dd,,1H@MI(NH)CONH2); 1.95-2.86 (m,6H,piperazine); 2. 13 (s13H,CH3); 1.35 (t13H9OCH2213)m 4-(2-carboxamido-1,4-piperazin-4-yl)ethyl-3.ethoxycarbonyl5methylisoxazole (25).

H- (6,DMSO) 6.88 and 5.80 (2bs,IH,CONH2); 4.41 (q,2H,09H2CH3); 3.40 (dd,1H,CH(NH)C0NH); 2.02-3.05 (=,10H.piperazine + MCE2N<); 2.38 (s,3H,CH3); 1.35 (t,3H,0CH2CHAW 5-(2-Carboxamido-1,4-piperazin-4-yl)ethyl-3-ethoxycarbonyl4-methylisoxazole (26).

Example 6

4-(2-Carboxy-1,4-piperazin-4-yl)methyl-3-hydroxy-5-methyl- isoxazole (27).

Compound (19) (0.4 g;1.57 mmol) was dissolved in 48% HBr (20 ml) and heated to 120C for 3 hours. The mixture was then cooled, evaporated, taken up several times with water and recrystallized from acetone/water to afford (27) (0.52 g; 82%) as an hygroscopic white solid.

H-NMR (6,DMSO): 9.45 (bs,2H,NH2); 4.25 (d,1H,CR(NH2)COOH); 4.05 (d,2H,.QH2NH4<); 2.85-4.12(m,6H,piperazine); 2.38 (s,3H,CH3).

Analogously the following compounds were obtained:

5-(2-Carboxy-1,4-piperazin-4-yl)methyl-3-hydroxy-4-methyl- isoxazole (28).

H-NMR (S,DMSO): 9.25 and 9.03 (bs,2H,NH2+); 4.20 (d,1H,CH(NH2-)COOH); 3.69 (d,2H,MJ2NH+<); 2.08-3.25 (m,6H,piperazine); 1.78 (s,3H,CH3).

4-(2-carboxy-1,4-piperazin-4-yl)ethyl-3-hydroxy-5-methyl- isoxazole (29).

H-NMR (6,DMSO): 9.45 (bs,2H,NH2); 4.42 (d,IH,MJ(NH2)COOH); 2.50-3.82 (m,6H,piperazine); 3.15 (m,2H,CH2MI2NH+<); 2.62 (M,2H,=2CH2NH<); 2.25 (s,3H,CH3).

5-(2-Carboxy-1,4-piperazin-4-yl)ethyl-3-hydroxy-4-methyl- 21 - isoxazole (30).

H-N" (biDMSO): 9.45 (bs,2H,NH2+); 4.38 (d,1H,=(NH2-)CC)OH) 2.653.80 (m,6H,piperazine); 3.18 (m,2H,CH2=2NH<); 2.96 (Tft,2H,CE2CH2NH<); 1.78 (s,3H,CH3).

Example 7

3-Carboxy-4-(2-carboxy-1,4-piperazin-4-yl)methyl- 5-methylisoxazole (31).

Compound (23) (0.5 g; 1.69 mmol) was dissolved in riethanol/water (15/1. 5 ml); to this solution, heated to ref lux, 0. 89 g (13.52 inmol) of 85% KOH (pellets) were added; the mixture was stirred at reflux for a hours, cooled, evaporated,, the residue dissolved in water was neutralised with saturated NaHC03 solution and passed through Amberlite ion-exchange resin, eluting with water, then with 2% NHAOH. The fractions containing the product were collected to yield 0.27 g (60%) of (31) (white prisms (isopropanol); m.p. 145 C).

Analogously, the following compounds were prepared:

3-Carboxy-S-(2-carboxy-1,4-piperazin-4-yl)methyl-4-methylisoxazole (32).

3-Carboxy-4-(2-carboxy-1,4-piperazin-4-yl)ethyl-5-,zethylisoxazole (33).

3-Carboxy-S-(2-carboxy-lt4-piperazin-4-yl)ethyl-4-methylisoxazole (34).

Examole- 8 3-Bromo-S-(2-carboxamido-1,4-piperazin-4-yl)zethyl-4,5-dihydroi soxazole (35).

2 g (0.0123 mol) of 3-bromo-5-bromomethyl-4iS-dihydroisoxazole were added to a stirred mixture of 2-carboxamido-1,4-piperazine (1.58 g; 0.0123 mol) and anhydrous R2C03 (1.70 g; 0.0123 mol) in DHP. (20 ml) at 60 C. The mixture was heated 2 hours at 60 C, then filtered, evaporated and directlyflash-chromatographed (eluant:" CH2C12 185: CH3CH 15: 30% NHAOH 2.5) to give a solid which was taken up with pentane/diisopropyl ether, filtered and dried (0.9 g; 30%; in.p. 93-95 'C).

H-NMR (8,CDC13): 6.91 and 5.48 (2bs,1H,C0NHA; 4.81 (m,1H,CH2- 0); 3.36 (m, 2H, CH 2N<) 3.25 (dd,1H,CH(NH)CONH2); 2.38-3.05 (m,SH,piperazine and CH2CH-0).

Example 9

5-(2-Carboxy-1,4-piperazin-4-yl)methyl-3-oxo-(1H)-4,5-dihydroisoxazole (36).

0.75 g (2.57 mmol) of compound (31) were placed in 15 =l THF; to this solution, 60 ml 2N NaOH and 60 mg of tetrabutylammonium hydrogensulfate were added; the mixture was stirred at 60 C for 5 hours, then left at room temperature overnight. After neutralisation to pH 6, the biphasic solution was evaporated and the residue passed through a column of Amberlite IR-120 (H),, eluting with water and then with 2% NHAOH. The fractions containing the product were evaporated to give 0.52 g (88%) of compound (32).

H- (8,DMSO): 4.40 (m,1H,CH2CU-0); 3.68 (dd,1HOMI(NH)COOHI; 2.40-3.25 (m, 10H,pIperazine + Q2CH-0 + CH2N<).

Example 10

5-(2-Carboxamido-1,4-piperazin-4-yl)carbonyl-3-hydroxyisoxazole (37).

To a stirred solution of 0.7 g (5.41 mmol) of 3-hydroxy-5-carboxyisoxazole in DMF (10 ml) kept under nitrogen at 5 C# 0.8 9 (5. 41 mmol) of 1,11-carbonyldiiraidazole were dropped in DMF (8 M1) within 20 minutes at 5-10 C. To this mixture, a solution of 2-carboxamido-1,4piperazine was added dropwise. The reaction mixture was stirred 1 hour at 5 C, evaporated and directly purified by PC (cluant: CH2C12 120: CH30H 8: 30% NH40H 0.8). The syrup obtained was treated with hot 96% EtOH, cooled, filtered to give 0.42 g (32%) of a light brown solid [=.p. 200C(dec.)].

H-" (6,DMSO): 7.34 and 7.18 (2s,IH,CONH2); 6.23 (5,1H,CH=C(C0)0); 4.22 (dd,1H,Cfl(NH)CONH2);2.52-3.81 (M,6H,piperazine).

Claims

- 24 CLAIMS 1. A compound of the general formula (I)

NH ro, Y 0 0 A JY R2 wherein R is OH, COR2f PO(R2)21 cl-C4 alkoxy or halogen; R1 is hydrogen, halogen, trifluoromethyl, Cl-C4 alkyl, C3-C7 cycloalkyl, C,-C4 alkoxy, benzyloxy, benzyloxy in which the phenyl moiety is substituted by halogen or Cl-C4 alkyl, phenyl or phenyl substituted by halogen; R2 is OH, C,-C4 alkoxy, benzyloxy, substituted benzyloxy, amino or amino substituted by one or two C,-C4 alkyl groups; A is C,-C4 alkylene and Y is nitrogen or carbon, A is C,-C4 alkenylene or (CH,) t-CH= wherein t is 0, 1,,' 2 or 3 and Y is carbon or A is (CH2) p-Co- or -CO- (CH2) q wherein p and q are independently 0, 1 or 2 and Y is nitrogen; and = represents a single or double bond; or a pharmaceutically acceptable salt thereof.
2., A compound according to claim 1 wherein R is OH,, COOH or POA; R, is C,C4 alkyl, bromine or phenyl; R2 is OH, Cl or C2 alkoxy, benzyloxy, amino or amino substituted by one or two C, or C2 alkyl groups; and A is C, or C2 alkylene, C.C4 alkenylene or carbonyl.
3. A compound according to claim 1 selected from:

1) 4-(2-carboxy-1,4-piperazin-4-yl)methyl-3- hydroxy-5-methylisoxazole; 2) 5-(2-carboxy-1,4-piperazin-4-yl)methyl-3- hydroxy-4-methylisoxazole; 3) 4-(2-carboxy-1,4-piperazin-4-yl)ethyl-3- hydroxy-5-methylisoxazole; 4) 5-(2-carboxy-1,4-piperazin-4-yl)ethyl-3- hydroxy-5-methylisoxazole; 5) 5-(2-carboxy-1,4-piperazin-4-yl)methyl-3- hydroxyisoxazole; 6) 5-(2-carboxy-1,4-piperazin-4-yl)carbonylmethyl3-hydroxy-isoxazole; 7) 5-(2-carboxy-1,4-piperazin-4-yl)methyl-3-oxo1(H)-4,5-dehydroisoxazole; 8) 5-(2-carboxy-1,4-piperazin-4-yl)methyl-3- nethoxy-isoxazole; 9) 3-bromo-5-(2-carboxy-1,4-piperazin-4y1)methylisoxazole; 10) 3-bromo-5-(2-carboxamido-1,4-piperazin-4- y1)methylisoxazole; 11) 3-carboxy-4-(2-carboxamido-1,4-piperazin-4- yl)methyl-5-methylisoxazole; and 12) 3-carboxy-5-(2-carboxamido-1,4-piperazin-4yl)methyl-4-methylisoxazole.
4. A process for preparing a compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound - of the formula (II) z R 2 VrH N 0 wherein R2 is as def ined in claim 1 and Z is NH or CO, with a compound of the formula (III) R R1 X 0 (III) wherein R, R, and the symbol are as def ined in claim 1, B is (CH2) n wherein n is 1, 2, 3, or 4 or, additionally only when Z is NH, (CH2) P-CO- or -CO- (CH2) q wherein p and q are defined in claim 1, and X is Cl, Br, I, a leaving group, an imidazole group, triphenylphosphonium or a dialkyl phosphonate group; and optionally converting the resultant compound of formula (I) into another compound of formula (1) and/or converting the resultant compound of formula (I) into a pharmaceutically acceptable salt thereof.
5. A process according to claim 4 in which Z is NH; B is (CH2)n or CO(CH.)q wherein n and q are as defined in claim 4; X is Cl, Br, I or a leaving group; and the reaction is performed in the presence of a base, in a suitable solvent, at a temperature of from OC to 1100C and - 27 for a period of from 30 minutes to 4 hours.
6. A process according to claim 4 in which Z is NH; B is (CH2) pCO wherein p is as def ined in claim 4; X is halogen or imidazole; and the reaction is carried out in a solvent at a temperature of from -20C to 100C and optionally in the presence of catalyst.
7. A process according to claim 4 in which Z is CO; B is (CH2)n in which n is as defined in claim 4; X is a triphenylphosphonium or dialkenylphosphonate group; and the reaction is carried out under the Wittig conditions.
8. A pharmaceutical composition comprising a compound of the formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
9. A compound of formula (M) or (IVtt) R R R (CH2)in-'H (CH 2) Ri-DH 0 (IVO) (Ivrr) wherein R' is chlorine, bromine or ethoxycarbonyl; Rti is methyl, ethyl, t-butyl or phenyl; m is 1, 2, 3 or 4; and ROO is a dialkylphosphoric group or a fluorine atom.
10. A process for preparing a compound of the formula (M) as defined in claim 9, which process comprises reacting a compound of the formula (V) R I -C=C- (CH2) m-OH (V) wherein RO, and m are defined in claim 9, with a compound of the formula (VI) (VI) OH wherein RI1 is as defined in clam 9 and W represents chlorine or bromine, in the presence of a base, in a solvent, at a temperature of from 10C to 1100C and for a period of from 3 to 64 hours.
11. A process for preparing a compound of formula (M1) as defined in claim 9, which process comprises reacting a compound of formula (M) as defined in claim 9 wherein R' is a bromine atom (i) with a dialkylphosphite in the presence of a catalyst and a base in a solvent at a temperature of from 50 to 1100C for a period of from 2 to 24 hours or (ii) with an alkali metal fluoride in a solvent at a temperature of from 50 to 1800C for a period of from 4 to 48 hours.
12. A compound of formula (IIII) or (III,'):

R' R R R (CH2) m- X (CH2) m- X 0 wherein X is as defined in claim 4 and Rf, R,,', Rt' and m 10 are as defined in claim 9.
13. A process for the preparation of a compound of formula (IIII) or (III") as defined in claim 12, which process comprises transforming a compound of formula (M) or (M1) respectively as defined in claim 9 into a said 15 compound of formula (IIII) or (IIII0).