PIPERAZINE COMPOUND AS PAF-ANTAGONIST

Abstract: Piperazine compounds of the formula: wherein R¹ is aryl; ar(lower)alkyl which may have lower alkoxy; or heterocyclic(lower)alkyl which may have sub­ stituent(s) selected from the group of lower alkyl and aryl on the heterocyclic ring; R² is lower alkyl; higher alkyl; lower alkylthio(lower)alkyl; lower alkenylthio(lower)alkyl; hydroxy(lower)alkyl; protected hydroxy(lower)alkyl; amino(lower)alkyl; protected amino(lower) alkyl; carboxy(lower)alkyl; protected carboxy(lower alkyl) arylthio(lower)alkyl; ar(lower)alkylthio(lower)alkyl; or heterocyclic­ (lower)alkyl which may have lower alkyl on the heterocyclic ring; and R³ and R⁴ are each hydrogen or lower alkyl, or pharmaceutically acceptable salt thereof. Processes for the preparation of these piperazine com­ pounds are also described, together with pharmaceutical compositions comprising them. The compounds are PAF (Platelet Activating Factor)anta­ gonists and are therefore useful in the prevention and treatment of diseases caused by PAF, such as asthma, thrombosis and nephritis.

Description: PIPERAZINE COMPOUND AS PAF-ANTAGONIST This invention relates to new PAF (Platelet Activating Factor) antagonists, piperazine compounds (I) and pharmaceutically acceptable salt thereof. More particularly, it relates to a pharmaceutical composition comprising the piperazine compounds (I) or pharmaceutically acceptable salt thereof as an active ingredient, and to a new piperazine compound (Ia) and pharmaceutically acceptable salt thereof and to processes for the preparation thereof. This invention based on new discovery by the present inventors that certain piperazine compounds (I) and pharmaceutically acceptable salt thereof are highly potent antagonists of PAF and therefore useful for the prevention and treatment of diseases caused by PAF. The piperazine compounds of this invention can be represented by the following formula EMI2.1 wherein R1 is aryl; ar(lower)alkyl which may have lower alkoxy; or heterocyclic(lower)alkyl which may have substituent(s) selected from the group of lower alkyl and aryl on the heterocyclic ring, R2 is lower alkyl; higher alkyl; lower alkylthio (lower) alkyl; lower alkenylthio(lower)alkyl; hydroxy (lower) alkyl; protected hydroxy(lower) alkyl; amino (lower) alkyl; protected amino (lower) alkyl; carboxy (lower) alkyl; protected carboxy(lower)alkyl; arylthio(lower)alkyl; ar (lower) alkylthio (lower) alkyl; heterocyclic(lower)alkyl which may have lower alkyl on the heterocyclic ring; and R3 and R4 are each hydrogen or lower alkyl. The piperazine compounds (I) include known and novel compounds. Among the piperazine compound (I), the new and preferred stereochemically specific compound can be represented by the following formula EMI3.1 wherein R1 is aryl; ar(lower)alkyl which may have lower alkoxy; or heterocyclic(lower)alkyl which may have substituent(s) selected from the group of lower alkyl and aryl on the heterocyclic ring; R2is lower alkyl; higher alkyl; lower alkylthio (lower) alkyl; lower alkenylthio(lower)alkyl; hydroxy (lower) alkyl; protected hydroxy(lower)alkyl; amino (lower) alkyl; protected amino (lower) alkyl; carboxy (lower) alkyl; protected carboxy(lower)alkyl; arylthio(lower)alkyl; ar (lower) alkylthio (lower) alkyl; or heterocyclic(lower)alkyl which may have lower alkyl on the heterocyclic ring; ; and R3 and R4 are each hydrogen or lower alkyl. The pharmaceutically acceptable salt of the compound (I) and (Ia) may include an organic or inorganic acid addition salt (e.g. hydrochloride, etc.) and a salt wit an organic or inorganic base (e.g. sodium salt, etc.). According to this invention, the piperazine compounds (I) and pharmaceutically acceptable salt thereof can be prepared by, for example, the following processes. Process 1 EMI4.1 or its reactive derivative at the carboxy or amino group or salt thereof or salt thereof Process 2 EMI4.2 or salt thereof or salt thereof Process 3 EMI4.3 or its reactive derivative or salt thereof at the amino group or salt thereof Process 4 EMI5.1 or salt thereof or salt thereof Process 5 EMI5.2 or salt thereof or salt thereof Process 6 EMI5.3 or salt thereof or salt thereof R1 R2 R3 and R4 wherein , , R3 and R4 are each as defined above, R2 and R2 are each amino(lower)alkyl, a f is is acylamino(lower)alkyl, Rc is hydroxy(lower)alkyl, R2 is acyloxy(lower)alkyl, d R2 is a protected amino(lower)alkyl, e R2 is a protected carboxy(lower)alkyl, is is carboxy(lower)alkyl, R3 and R4 are each lower alkyl, a a R5 is hydrogen or amino-protective group and R 6. is carboxy or a protected carboxy. The starting compound (II) include known compounds and new ones and can be prepared by subjecting the corresponding two amino acids to peptide linkage formation reaction in a conventional manner. In the above and subsequent descriptions of this specification, suitable examples and illustrations of the various definitions are explained in detail in the followings. The term "lower" is intended to mean 1 to 6 carbon atom(s), unless otherwise indicated. The term "higher" is intended to mean more than 6 carbon atoms, preferably 7 to 22 carbon atoms and more preferably 7 to 18 carbon atoms. Suitable "aryl" group and "aryl" moiety in the term "arylthio(lower)alkyl" may include phenyl, tolyl, naphthyl, anthryl, phenanthryl and the like. Suitable "ar(lower)alkyl" group and "ar(lower)alkyl" moiety in the term "ar(lower)alkylthio(lower)alkyl" may include mono(or di or tri)phenyl(lower)alkyl (e.g. benzyl, phenethyl, benzhydryl, trityl, l-phenylethyl etc.) naphthyl (lower) alkyl (e.g. naphthylmethyl, l-naphthylethyl, etc.), anthryl (lower) alkyl (e.g. anthrylmethyl, etc.), phenanthryl (lower) alkyl (e.g. phenanthrylmethyl, etc.) and the like. Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like. Suitable "lower alkyl" group and "lower alkyl" moiety in the terms "heterocyclic(lower)alkyl", "lower alkylthio (lower) alkyl", "hydroxy(lower) alkyl", "protected hydroxy (lower) alkyl", "amino (lower) alkyl", "protected amino (lower) alkyl", "carboxy (lower) alkyl", "protected carboxy(lower) alkyl", "arylthio (lower) alkyl", "ar(lower) alkylthio(lower) alkyl" and "acyloxy(lower)alkyl" may include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,hexyl and the like. Suitable "heterocyclic" moiety in the term "heterocyclic (lower) alkyl" may include benzene-fused heterocyclic group containing at least one hetero-atom such as oxgen, sulfur and nitrogen (e.g. indolyl, benzothienyl, etc.), heteromonocyclic group containing one nitrogen atom (e.g. pyridyl, etc.), and the like. Suitable "higher alkyl" may include heptyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl and the like. Suitable "lower alkenyl" moiety in the term "lower alkenylthio (lower) alkyl" may include lower alkenyl having 2 to 6 carbon atoms such as vinyl, allyl, isopropenyl, 2-butenyl, 3-pentenyl, 4-hexenyl and the like. Suitable "protected hydroxy" group may include acyloxy such as lower alkanoyloxy (e.g. acetoxy, propionyloxy, etc.) ant the like, ar(lower)alkoxy such as mono(or di or tri)phenyl(lower)alkoxy (e.g. benzyloxy, etc.), and the like. The "amino-protective group" and "amino-protective" moiety in the term "protected amino" include a conventional amino-protective group which is used in the field of amino acid and peptide chemistry, and suitable "aminoprotective group" may include acyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, etc.), aroyl (e.g. benzoyl, etc.), lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), ar(lower)alkoxycarbonyl [e.g. mono(or di or tri)phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.), etc.] and the like. Suitable "protected carboxy" may include esterified carboxy such as lower alkoxycarbonyl as aforementioned, ar(lower)alkoxycarbonyl as aforementioned, and the like. Preferable embodiments of the object compound (I) are as follows. Preferable embodiment of R1 is aryl (more preferably phenyl); ar(lower)alkyl [more preferably mono (or di)phenyl(lower)alkyl,naphthyl(lower)alkyl or anthryl(lower)alkyl]; ar(lower)alkyl having lower alkoxy [more preferably phenyl(lower)alkyl having lower alkoxy]; heterocyclic (lower) alkyl [more preferably benzene-fused heterocyclic(lower)alkyl containing one sulfur or nitrogen atom [most preferably, indolyl (lower) alkyl and benzothienyl (lower) alkyl] or heteromonocyclic (lower)alkyl containing one nitrogen atom [most preferably pyridyl(lower)alkyl]] heterocyclic (lower) alkyl having lower alkyl on the heterocyclic ring [more preferably N-lower alkyl-benzene-fused he tero cyclic (lower) alkyl containing one nitrogen atom [most preferably N-lower alkylindolyl (lower) alkyl]]; ; or heterocyclic (lower) alkyl having lower alkyl and aryl on the heterocyclic ring [more preferably N-lower alkyl-benzene-fused heterocyclic (lower) alkyl containing one nitrogen atom having aryl on the heterocyclic ring [most preferably N-lower alkylindolyl(lower)alkyl having phenyl on the indole ring)); R2 is lower alkyl; higher alkyl; lower alkylthio(lower)alkyl; lower alkenylthio(lower)alkyl; hydroxy (lower) - alkyl; protected hydroxy (lower) alkyl [more preferably acyloxy(lower)alkyl[most preferably lower alkanoyloxy (lower)alkyl] and ar(lower)alkoxy(lower)alkyl[most preferably phenyl (lower) alkoxy (lower) alkyl]]; amino (lower) alkyl; protected amino(lower)alkyl[more preferably acylamino (lower) alkyl [most preferably lower alkanoylamino(lower)alkyl, benzamido (lower) alkyl, lower alkoxycarbonylamino(lower)alkyl or phenyl(lower)- alkoxycarbonylamino (lower) alkyl]]; carboxy (lower) alkyl; protected carboxy(lower)alkyl[more preferably esterified carboxy(lower)alkyl[most preferably lower alkoxycarbonyl (lower) alkyl or phenyl(lower) alkoxycarbonyl (lower) alkyl]] ; arylthio (lower) alkyl [more preferably phenylthio(lower)alkyl]]; ar (lower) alkylthio (lower) alkyl [more preferably phenyl (lower) - alkylthio(lower)alkyl]; orheterocyclic(lower)alkyl having lower alkyl on the heterocyclic ring [more preferably N-lower alkyl-benzene-fused heterocyclic(lower) - alkyl containing one nitrogen atom [most preferably N-lower alkylindolyl(lower)a1il11; and R3 and R4 are each hydrogen or lower alkyl. The salts of the compounds (Ib), (Ic), (Id), (Ie), (If) , (Ig) , (Ih) , (li) , (Ij), (Ik) and (II) are substantially the same salt as those exemplified in the explanation of the pharmaceutically acceptable salt of the compound (I). The processes as illustrated above are explained in more detail in the followings. Process 1 The object compound (I) or salt thereof Ca be prepared by subjecting the compound (II) or its reactive derivative at the carboxy or amino group or salt thereof to ring closure reaction. Suitable reactive derivative at the amino group of the compound (II) may include Schiff's base type imino or its tautomeric enamine type isomer formed the reaction of the compound (II) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as bis(trimethylsilyl)acetamide, trimethylsilylacetamide or the like. The suitable reactive derivative at the carboxy of the compound (II) may be a conventional one such as an acid halide (e.g. acid chloride, acid bromide, etc.), an acid azide, an acid anhydride, an activated amide, an activated ester and the like. When free acid is used as starting compound (II), the reaction may preferably be conducted in the presence of a conventional condensing agent. The reaction can also be conducted in the presence of an organic or inorganic base such as alkali metal (e.g. sodium), alkaline earth metal (e.g. calcium), alkali or alkaline berth metal hydride (e.g. sodium hydride, calcium hydride, etc.), alkali or alkaline earth metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.), alkali or alkaline earth metal carbonate or bicarbonate (e.g. sodium carbonate, potassium carbonate, sodium bicarbonate), alkali or alkaline earth metal alkoxide (e.g. sodium ethoxide, lithium methoxide, magnesium methoxide), trialkylamine (e,g. triethylamine), pyridine, bicyclodiaza compound (e.g. 1,5-diazabicyclo [3,4,0]nonene-5, 1,5-diazabicyclot5,4,0]undecene-5, etc.) and the like. This reaction is usually carried out without solvent or in the presence of a solvent which does not adversely influence the reaction such as methanol, ethanol, propanol, acetic acid, dimethylformamide, dichloroethane, toluene, benzene, xylene and the like. The reaction temperature is not critical, and the reaction is usually carried out under heating to under cooling. When the compound (II) having amino-protective group for R5 is used as a starting compound, it may often give preferred results to remove the aminoprotective group in a conventional manner (e.g. hydrolysis, catalytic reduction, etc.) prior to this ring closure reaction. Process 2 The object compound (Ic) or salt thereof can be prepared by reacting the compound (Ib) or salt thereof with a lower alkylating agent. The lower alkylating agent may include lower alkyl halide (e.g. methyl iodide, etc.), di(lower)alkylsulfate (e.g. dimethylsulfate, etc.), diazo(lower)alkane (e.g. diazomethane, etc.), lower alkyl sulfonate (e.g. methyl sulfonate, etc.) and the like. This reaction can be conducted in the presence of an organic or inorganic base as those exemplified in the explanation of Process 1. This reaction is usually carried out in the presence of a solvent which does not adversely influence the reaction such as dichloromethane, dimethylformamide and the like. The reaction temperature is not critical and the reaction is sufficiently carried out at ambient temperature. Process 3 The object compound (Ie) or salt thereof can be prepared by reacting the compound (Id) or its reactive derivative at the amino group or salt thereof with an acylating agent. Suitable reactive derivative at the amono group of the compound (Id) is substantially the same as that of the compound (II) explained in the Process 1. The acylating agent to be used in this reaction includes an organic acid (i.e. R7 OH (IV), in which R7 is acyl) and its reactive derivative. The suitable reactive derivative of the compound (IV) is substantially the same as that of the compound (II) explained in Process 1. When free acid is used as an acylating agent, the acylation reaction may preferably be conducted in the presence of a conventional condensing agent. The reaction can preferably be conducted in the presence of an organic or inorganic base as those exemplified in the explanation of the above Process 1. This reaction is usually carried out in a solvent which does not adversely influence the reaction such as methanol, ethanol, propanol, tetrahydrofuran, chloroform, pyridine and the like. The reaction temperature is not critical and the reaction can be carried out under heating to under cooling. Process 4 The compound (Ig) or salt thereof can be prepared by reacting the compound (If) or salt thereof with an acylating agent. The reaction conditions and the acylating agent are substantially the same as those explained in the Process 3. Process 5 : The compound (Ii) or salt thereof can be prepared by subjecting the compound (Ih) or salt thereof to removal reaction of amino-protective group. The removal reaction of this process is carried out in a conventional manner (e.g. hydrolysis, catalytic reduction, reduction, etc.). The hydrolysis is preferably carried out in the presence of inorganic or organic acid (e.g. hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, etc.), or inorganic or organic base (e.g. sodium hydroxide, etc.). The catalytic reduction can be carried out in the presence of a conventional catalyst for catalytic reduction (e.g. paradium on charcoal, etc.) at atmospheric pressure. The reaction of this process is usually carried out in a solvent which does not adversely influence the reaction such as methanol, ethanol, propanol, acetic acid and the like, at a temperature range of cooling to heating. Process 6 The compound (Ik) or salt thereof can be prepared by subjecting the compound (Ij) or salt thereof to removal reaction of the carboxy-protective group. The removal reaction is carried out in substantially the same manner as that of Process 5. The object compound (I), (Ic), (Ie), (Ig), (Ii) and (Ik) in the above processes can be purified and converted to the desired salts in a conventional manner. The object compounds (I) and pharmaceutically acceptable salt thereof are antagonists of PAF and therefore useful as a medicine for preventing and treating diseases caused by PAF such as allergic manifestation (e.g. astbjna, etc.), thrombosis, nephritis, endotoxin shock (ARDS), and the like. The following Tests are given for the purpose of illustrating antagonism of the compounds (I) against PAF. The test compounds are listed below. Test compound EMI15.1 EMI15.2 <tb> Test <SEP> 3 <SEP> 4 <tb> compound <SEP> R1 <SEP> 2 <SEP> R <SEP> R <tb> No. <SEP> R <tb> <SEP> 1 <SEP> CH2 <SEP> 2 <SEP> HzCH2CH2-SCH3 <SEP> H <SEP> H <tb> <SEP> CH3 <tb> <SEP> 2 <SEP> 1·¸1CH2 <SEP> w <SEP> <SEP> CH2CHs <SEP> $C; <SEP> H <SEP> H <tb> <SEP> CH3 <tb> EMI16.1 <tb> Test <tb> compound <SEP> R <SEP> I <SEP> R <SEP> t <tb> No. <tb> <SEP> 3 <SEP> 1·11CH2 <SEP> -4CH2-SCH3 <SEP> H <SEP> H <tb> <SEP> CH3 <tb> <SEP> 4 <SEP> ¯ <SEP> CH2 <SEP> ¯ <SEP> ¯ <SEP> CH2CH2SCH3 <SEP> -CR3 <SEP> -CH3 <tb> <SEP> CR3 <tb> <SEP> 5 <SEP> > <SEP> CH2 <SEP> ¯ <SEP> X <SEP> (CH2)3SCH3 <SEP> H <SEP> H <tb> <SEP> CH3 <tb> <SEP> 6 <SEP> / <SEP> CR <SEP> ¯ <SEP> ¯ <SEP> CH2CH2SCH3 <SEP> H <SEP> H <tb> <SEP> 7 <SEP> CH2 <SEP> - <SEP> CH <SEP> H <SEP> H <tb> <SEP> 2t <tb> <SEP> 7 <SEP> $1N11 <SEP> CR2 <SEP> CR2·)i·i) <SEP> H <SEP> H <tb> <SEP> CH3 <SEP> CH3 <tb> EMI17.1 <tb> Test <tb> compound <SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4 <tb> No. <tb> <SEP> 8 <SEP> CR <SEP> F <SEP> < <SEP> (CH2) <SEP> 3CH3 <SEP> H <SEP> H <tb> <SEP> CH3 <tb> <SEP> H <SEP> CR3 <tb> <SEP> "'I <tb> <SEP> 9 <SEP> N <SEP> ¯ <SEP> CH2CH2SCH <SEP> 3 <SEP> H <SEP> H <tb> <SEP> 2 <SEP> 3 <tb> <SEP> 10 <SEP> N1CH2 <SEP> ¯ <SEP> CH2CH2SCH3 <SEP> | <SEP> H <SEP> | <SEP> H <tb> <SEP> 11 <SEP> XCH2 <SEP> t <SEP> CR2 <SEP> CH2CH2SCH3 <SEP> H <SEP> H <tb> <SEP> NI <tb> <SEP> NI <tb> <SEP> RCIH3 <tb> <SEP> 12 <SEP> C <SEP> ¯ <SEP> CH2CH2SCH3 <SEP> H <SEP> H <tb> EMI18.1 <tb> Test <SEP> R2 <SEP> R3 <SEP> 4 <tb> compound <SEP> R <SEP> R2 <SEP> R <tb> No. <tb> <SEP> 13 <SEP> | <SEP> I",- <SEP> CH2CH2SCH3 <SEP> H <SEP> H <tb> <SEP> 3 <tb> <SEP> 14 <SEP> CR2 <SEP> I"- <SEP> ¯ <SEP> ¯ <SEP> CE2CE2CH3 <SEP> H <SEP> H <tb> <SEP> N <tb> <SEP> CR3 <tb> <SEP> 15 <SEP> 9 <SEP> - <SEP> CE2 <SEP> t <SEP> 4C <SEP> CR2)Àj <SEP> H <SEP> H <tb> <SEP> CR <SEP> 3 <tb> <SEP> H <SEP> CH3 <tb> <SEP> 16 <SEP> CR2CH2SCR3 <SEP> -CR3 <SEP> -CR3 <tb> <SEP> L <SEP> Ç <SEP> H3 <SEP> 1 <SEP> ¯Z(CE2)3cH3 <SEP> 'CH3 <SEP> CH3 <tb> Test 1 (Inhibition of platelet aggregation) Test method Blood was collected through the polyethylene catheter introduced into the carotid artery of male Japanese white rabbit (2.5 to 3 kg body weight). The blood was anticoagulated with 1 volume of 3.8% sodium citrate to 9 volume of blood. Platelet rich plasma (PRP) was prepared by centrifugation of the blood at 150 g for 10 minutes at room temperature. The PRP was diluted with platelet poor plasma obtained by further centrifugation of the blood at 1,000 g for 20 minutes. The platelet number was 5 x 105 cells/mm Platelet aggregation induced with PAF was measured by the nephelometric technique of Born and Cross [cf. Journal of Physiology 168, 178-188 (1963)) using HKK Hema tracer (trade name, made by Niko Bioscience Inc.). Activities of inhibitors were expressed as IC50 value, i.e. concentrations required to inhibit the platelet aggregation response by 50%. The final concentration of PAF was usually 20 nM. The test results are shown in the following table. Test result EMI20.1 <tb> Test <SEP> compound <SEP> No. <SEP> IC50 <SEP> ( g/ml) <SEP> <tb> <SEP> 1 <SEP> 0.71 <tb> <SEP> 2 <SEP> 1.04 <tb> <SEP> 3 <SEP> 2.5 <tb> <SEP> 4 <SEP> 0.84 <tb> <SEP> 5 <SEP> 0.55 <tb> <SEP> 6 <SEP> 0.75 <tb> <SEP> 7 <SEP> 1.2 <tb> <SEP> 8 <SEP> 0.58 <tb> <SEP> 9 <SEP> 0.061 <tb> <SEP> 10 <SEP> 0.48 <tb> <SEP> 11 <SEP> 0.58 <tb> <SEP> 12 <SEP> 0.65 <tb> <SEP> 13 <SEP> 0.72 <tb> <SEP> 14 <SEP> 0.93 <tb> <SEP> 15 <SEP> 0.82 <tb> <SEP> 16 <SEP> 0.59 <tb> <SEP> 17 <SEP> 0.55 <tb> Test 2 (Inhibition of hypotensive effect induced by intraveneously injected PAF in rats) Test method Seven-week old Sprague-Dowley rats were anesthetized with urethane (1 g/kg, i. p.). Catheters were introduced into the femoral artery and vein for the measurement of arterial pressure and the administration of the test compound, respectively. Blood pressure was recorded from femoral artery using a transducer coupled to the Biophysiograph 180 System (San-Ei Instrument Co., Ltd.). Inhibitory activity of the test compound was shown in the following Table as the inhibition percentage of the synthetic PAF induced hypotension. PAF was administered intravenously at a dose of 1 pg/kg. The test compound was administered intravenously 3 minutes before PAF injection. Test result EMI21.1 <tb> Test <SEP> <tb> compound <SEP> Dose <SEP> Inhibition <SEP> maximum(%) <SEP> of <tb> No. <SEP> (mg/kg) <SEP> hypotensive <SEP> effect <tb> <SEP> 2 <SEP> 10 <SEP> 75 <tb> <SEP> 9 <SEP> 3 <SEP> 51 <tb> Test 3 (Inhibition of vascular permeability increase induced by intradermally injected PAF in mice) Test method Six-week old male ddY mice were used. The test compound was administered intraperitoneally 15 minutes before the Evans blue injection (0.125% solution in saline, 0.2 ml/mouse, i.v.). PAF (50 ng, 50 VQ per site) was injected intradermally to the depilated back of the mice 5 minutes after the Evans blue injection. The inhibitory activity of the test compound was monitored 30 minutes after the PAF injection by assessment of blueing reaction with Evans blue dye in mice skin. The test results are shown in the following table. EMI22.1 <tb> Test <SEP> Dose <SEP> Inhibition-of <SEP> vascular <tb> compound <SEP> (mg/kg) <SEP> permeability <SEP> increase <tb> No. <SEP> (%) <tb> <SEP> 2 <SEP> 10 <SEP> 30 <tb> <SEP> 9 <SEP> 10 <SEP> 40 <tb> The compounds (I) or pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers can be administered orally or parenterally to mammals including human being in a form of a pharmaceutical composition such as capsules, tablets, granules, powders, buccal tablets, sublingual tablets, and solutions. The pharmaceutically acceptable carriers may include various organic or inorganic carrier materials, which are conventionally used for pharmaceutical purpose, such as excipient (e.g. sucrose, starch, mannit, sorbit, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc.), binding agent (cellulose, methyl cellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose, starch, etc.), disintegrator (e.g. starch, carboxymethyl cellulose, calcium salt of carboxymethyl cellulose, hydroxypropyl-starch, sodium glycole-starch, sodium bicarbonate, calcium phosphate, calcium citrate, etc.), lubricant (e.g magnesium stearate, aerosil, talc, sodium laurylsulfate, etc.), flavoring agent (e.g. citric acid, mentol, ammonium salt of glycyrrhizin, glycine, orange powders, etc.), preservative (sodium benzoate, sodium bisulfite, methylparaben, propylparaben, etc.), stabilizer (citric acid, sodium citrate, acetic acid, etc.), suspending agent (e.g. methyl cellulose, polyvinylpyrrolidone, aluminum stearate, etc.), dispersing agent [e.g. surface active agent, etc.], aqueous diluting agent (e.g. water), base wax (e.g. cacao butter, polyethyleneglycol, white petrolatum, etc.). A dosage of the object compounds is to be varied depending on various factors such as kind of diseases, weight and/or age of a patient, and further the kind of administratior route. The optimal dosage of the compounds (I) is usually selected from a dose range of 1 mg - 1 g/day, preferably 10 mg - 500 mg/day. The total daily amount mentioned above may be divisionally given to the patient at the interval of 6-12 hours per day. The following Examples are given for the purpose of illustrating this invention. Example 1 (1) To a suspension of N-tert-butoxyearbonyl-l- methyl-D-tryptophan (1.60 g) and hydrochloric acid salt of D-methionine ethyl ester (1.06 g) in dry methylene chloride (30 ml) which was cooled on an ice bath and stirred was added a solution of triethylamine (0.50 g) in dry methylene chloride (10 ml). The mixture was stirred for 30 minutes, and to the mixture was added a solution of N,N'-dicyclohexylcarbodiimide (1.04 g) in dry methylene chloride (10 ml). The resulting mixture was stirred overnight. After removal of the solvent, crude residue was taken up with a mixture of ethyl acetate and water, filtered, and organic layer was washed with 10% hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulfate, and evaporated to give crystalline N-tert-butoxycarbonyl-l- methyl-D-tryptophyl-D-methionine ethyl ester (2.43 g) NMR (CDCl3) # : 1.21 (3H, t, J=7Hz), 1.36 (9H, s), 1.95 (2H, m), 1.97 (3H, s), 2.25 (2H, m), 3.13 (1H, dd, J=14Hz, 7Hz), 3.35 (1H, dd, J=14Hz, 6Hz), 3.73 (3H, s), 4.14 (2H, q, J=7Hz), 4.50 (2H, m), 5.12 (1H, d, J=7Hz), 6.50 (1H, d, J=7Hz), 6.95 (1H, s), 7.25 (3H, m), 7.66 (1H, m) (2) A mixture of N-tert-butoxycarbonyl-l-methyl D-tryptophyl-D-methionine ethyl ester (2.4 g), formic acid (25 ml), and saturated solution of hydrogen chloride in formic acid (10 ml) was stirred on an ice bath for 1.5 hours. After removal of the solvent, the crude residue was dissolved in ethanol (20 ml) and saturated ammonia in ethanol (10 ml) was added. The resulting mixture was stirred for 16 hours at room temperature and precipitated mass was collected, washed with ethanol, and dried. Recrystallization from ethanol gave (3R,6R)-3-(1-methylindol-3-ylmethyl)-6-(2- methylthioethyl)piperazine-2,5-dione (1.16 g). mp : 229-2310C IR (Nujol) : 1165 cm 1 NMR (DMSO-d6) 6 : 1.05 (2H, m), 1.50 (2H, m), 1.65 (3H, s), 2.90 (1H, dd, J=14Hz, 5Hz), 3.25 (1H, dd, J=14Hz, 5Hz), 3.62 (1H, m), 3.67 (3H, s), 4.08 (1H, m), 6.98 (1H, s) 7.00 (2H, m), 7.30 (1H, dd, J=7Hz, 2Hz), 7.59 (1H, dd, J=7Hz, 2Hz), 7.91 (1H, m), 8.08 (1H, m) Exmaple 2 A mixture of N-tert-butoxycarbonyl-D-phenylalanyl S-methyl-D-cysteine ethyl ester (0.41 g), ethyl acetate (10 ml), and saturated solution of hydrogen chloride in ethyl acetate (10 ml) was stirred for 4 hours at room temperature. After removal of the solvent, the residue was dissolved in ethanol (10 ml) and saturated ammonia in ethanol (10 ml) was added to the solution. The resulting mixture was stirred for 17 hours at room temperature and the solvent was evaporated off. Recrystallization from acetic acid. gave (3R,6S)-3- benzyl-6-methylthiomethylpiperazine-2,5-dione (0.08 g). mp : 246-2470C IR (Nujol) : 1660 cm NMR (DMSO-d6) 6 : 1.63 (1H, dd, J=14Hz, 7Hz), 1.85 (3H, s), 2.35 (1H, dd, J=14Hz, 4Hz) 2.92 (1H, dd, J=14Hz, 5Hz), 3.18 (1H, dd, J=14Hz, 5Hz), 3.82 (1H, m), 4.21 (1H, m), 7.22 (5H, s), 7.95 (1H, bs), 8.18 (1H, bs) Example 3 The following compounds were prepared in a similar manner to those of Example 1 and 2. (1) (3R,6R) -3-Benzyl-6- (2-methylthioethyl)piperazine 2,5dione mp : 253-2540C -1 IR (Nujol) : 1665 cm NMR (DMSO-d6) 6 : 1.15 (2H, m), 1.90 (3H, s), 1.95 (2H, m), 2.88 (1H, dd, J=13Hz, 5Hz), 3.20 (1H, dd, J=13Hz, 3Hz), 3.75 (1H, m), 4.23 (1H, m), 7.25 (5H, m), 8.10 (1H, s), 8.23 (1H, s) (2) (3S,6R)-3-Benzylthiomethyl-6-(1-methylindol- 3-ylmethyl)piperazine-2,5-dione. mp. 229-231 C IR (Nujol) : 3180, 3050, 1660 cm 1 NMR (DMSO-d6) 6 : 1.73 (1H, dd, J=14Hz, 7Hz), 2.35 (1H, dd, J=14Hz, 4Hz), 3.16 (2H, m), 3.40 (2H, s), 3.65 (3H, s), 3.85 (1H, m), 4.13 (1H, m), 6.85-7.6 (10H, m), 7.92 (1H, d, J=lHz), 8.06 (lH, d, J=0.5Hz), (3) (3R,6S)-3-Benzyl-6-methylthiomethylpiperazine- 2, 5-dione mp. 246-247 C IR (Nujol) : 1660 cm-1 NMR (DMSO-d6) 6 : 1.63 (1H, dd, J=14Hz, 7Hz), 1.85 (3H, s), 2.35 (1H, dd, J=14Hz, 4Hz), 2.92 (1H, dd, J=14Hz, 5Hz), 3.18 (1H, dd, J=14Hz, 5Hz), 3.82 (1H, m), 4.21 (1H, m), 7.22 (5H, s), 7.95 (1H, bs), 8.13 (1H, bs) (4) (3R,6R)-3-Indol-3-ylmethyl-6-(2-methylthioethyl) - piperazine-2,5-dione. mp. 240-2410C IR (Nujol) : 3350, 3210, 3070, 1670 cm-1 NMR (DMSO-d6) 6 : 1.20 (2H, m), 1.70 (2H, m), 1.76 (3H, s), 3.18 (2H, m), 3.72 (1H, m), 4.19 (1H, m), 7.00 (3H, m), 7.20 (1H, m), 7.55 (1H, m), 7.90 (1H, m), 8.05 (1H, m), 10.68 (1H, bs) (5) (3R,6S) -3-Indol-3-ylmethyl-6-methylthiomethyl piperazine-2,5-dione. mp. 265-268 C (dec.) IR (Nujol) : 3430, 3190, 3050, 1680, 1660 cm NMR (DMSO-d6) d : 1.58 (1H, dd, J=14Hz, 7Hz), 1.70 (3H, s), 2.30 (1H, dd, J=14Hz, 4Hz), 3.06 (1H, dd, J=17Hz, 6Hz), 3.35 (1H, dd, J=17Hz, 6Hz), 3.80 (1H, m), 4.16 (1H, m), 7.05 (3H, m), 7.35 (1H, dd, J=6Hz, 2Hz), 7.58 (1H, dd, J=6Hz, 2Hz), 7.90 (1H, bs), 8.08 (1H, bs), 10.85 (1H, bs) (6) (3R, 6RS) -3-Methylthiomethyl-6-phenethylpiperazine 2,5-dione mp. 221-228 C -1 IR (Nujol) : 3310, 3180, 3030, 1685 cm NMR (DMSO-d6) 6 : 2.10 (2H, m), 2.11 (3H, s), 2.70 (2H, m), 2.90 (2H, m), 4.00 (1H, m), 4.20 (1H, m), 7.25 (5H, m), 8.13 (1H, bs), 8.40 (1H, bs) (7) (3S,6R)-3-Allylthiomethyl-6-(1-methylindol-3-yl methyl)piperazine-2,5-dione. mp. 210 - 211 C -1 IR (Nujol) : 3180, 1660 cm NMR (DMSO-d6) 6 : 1.78(1H, dd, J=14,6Hz), 2.35(1H, dd, J=14,4Hz), 2.85(2H, d, J=7Hz), 3.19(2H, m), 3.70(3H,s), 3.80(1H, m) , 4.13(1H, m), 4.92(1H, bs), 5.07(1H, m), 5.60(lH, m), 7.04(2H, m), 7.07(1R, s), 7.36(1H, d, J=7Hz), 7.56(1H, d, J=7Hz), 7.92(1H,ks), 8.06(1H, bs) (8) (3R,6S)-3-(Indol -3-ylmethyl)-6-(2 methylthioethyl)piperazine-2,5-dione mp. 254-255 C -1 IR (Nujol) : 3430, 3200, 1680 cm NMR (DMSO-d6) 6: 1.80 (2H, m), 1.95 (3H, s), 2.40 (2H, m) , 3.15 (2H, m) , 3.35 (1H, m) 4.15 (1H, m) , 7.10 (3H, m) , 7.40 (1H, m), 7.63 (1H, m), 7.97 (1H, s), 8.11 (1H, d, J=0.5Hz), 10.84 (1H, bs) (9) (3R, 6R) -3-n-Butylthiomethyl-6- (1-methylindol 3-ylmethyl)piperazine-2,5-dione mp. 200-2010C IR (Nujol) : 3180, 1675 cm 1 NMR (DMSO-d6) 6 : 0.84 (3H, m), 3.35 (4H, m), 2.4 (2H, m), 2.65 (1H, dd, J=14,4Pz), 2.87 (1H, dd, J=14,4Hz) , 3.16 (2H; m) 3.47 (1H, m), 3.71 (3H, s), 4.20 (1H, m), 7.10 (3H, m), 7.40 (1H, m), 7.65 (1H, m), 7.85 (1H, bs), 8.18 (1H, bs) (10) (3R,6S)-3-(1-Methylindol-3-ylmethyl)-6-(2- methylthioethyl)piperazine-2,5-dione mp. 234-235 C IR (Nujol) : 3190, 3050, 1675 cm NMR (DMSO-d6) 6: 1.80 (2H, m), 1.94 (3H, s), 2.35 (2H, m), 3.20 (3H, m), 4.70 (3H, s), 5.07 (1H, m), 6.95 (-H, m), 7.04 (1H, s), 7.15 (1H, m), 7.36 (1H, d, J=7.5Hz), 7.59 (1H, d, J=7.5Hz), 7.95 (1H, s), 8.05 (1H, bs) (11) (3R, 6R)-3-(Benzo[b]thien-3-ylmethyl)-6-(2- methylthioethyl)piperazine-2,5-dione IR (Nujol) : 3180, 1660 cm NMR (DMSO-d6) 6 : 1.25(2H, m), 1.78(2H, m), 1.80(3H, s), 3.20(1H, dd, J=14, 5Hz), 3.43 (1H, dd, J=14, 4Hz), 3.76(1H, m), 4.30(1H, m), 7.35(2H, m), 7.40(1B, s), 7.95(28, m), 8.10 (1H, bs), 8.26(1H, bs) (12) (3RS, 6S)-3-Diphenylmethyl-6-methylthiomethyl- piperazine-2,5-dione mp. 250-253 C IR (Nujol) : 3180, 3050, 1670, 1655 cm 1 (13) (3S,6RS)-3-Methylthiomethyl-6-((RS)-1- phenylethyl)piperazine-2,5-dione mp. 258-2610C IR (Nujol) : 3180, 3050, 1655 cm 1 (14) (3R,6RS)-3-Methylthiomethyl-6-((RS)-l phenylethyl)piperazine-2,5-dione mp. 264-264.5 C IR (Nujol) : 3190, 3050, 1660 cm NMR (DMSO-d6) 6: 0.82 (0.5H, d, J=9Hz), 0.97 (0.5H, d, J=9Hz), 1.34 (3H, d, J=7.5Hz), 1.80 (1.5H, s), 1.96 (1.5H, s), 2.06 (0.5H, d, J=4Hz), 2.21 (0.5H, d, J=4Hz), 2.70 (1H, m), 3.50 (1H, m), 4.00 (111, m), 7.20 (5H, m), 7.79 (0.5H, s), 7.89 (0.5H, d, J=3Hz), 8.43 (1H, m) (15) (3RS, 6R) -3-Methylthiomethyl-6-phenylpiperazine 2, 5-dione mp. 189-190 C IR (Nujol) : 3200, 1675 cm NMR (DMSO-d6) 6 : 2.07 and 2.13 (3x0.25H, s, 3 x 0.75H, s, respectively), 2.85-3.20 (2H, m), 4.25 and 4.37 (2x0.25H, m, 2x0.75H, m, respectively), 5.00 and 5.02 (1x0.25H, s, lx0.75H, s, respectively), 7.40 (5H, m), 8.16 and 8.25 (1x0.75H, bs, 1x0.25H, bs, respectively), 8.67 (1H, bs) (16) (3R, 6R) -3-Isobutyl-6- (1-methylindol-3-ylmethyl) piperazine-2,5-dione. mp. 234-235 C IR (Nujol) : 3200, 1665 cm NMR (DMSO-d6) 6 : 0.15 (1H, m), 0.45 (3H, d, J=8Hz), 0.51 (3H, d, J=8Hz), 0.75 (1H, m), 1.20 (1H, m), 3.00 (1H, dd, J=14Hz, 5Hz), 3.26 (1H, m), 3.45 (1H, m), 3.70 (3H, s), 4.10 (1H, m), 6.96 (1H, m), 7.02 (1H, s), 7.10 (1H, m), 7.35 (1H, d, J=8Hz), 7.60 (1H, d, J=8Hz), 7.92 (1H, m), 8.03 (1H, m) Example 4 To a solution of (3R,6R)-3-(1-methylindol-3- ylmethyl)-6-(2-methylthioethyl)piperazine-2,5-dione (0.33 g) in dry dimethylformamide (20 ml) was added potassium tert-butoxide (0.27 g). After stirring at room temperature for 30 minutes, methyl iodide (0.5 ml) was added to the mixture. The reaction mixture was stirred for 5 minutes, diluted with water (200 ml), acidified to pH 3 with 10% hydrochloric acid, and extracted with ethyl acetate (50 ml x 2). Combined organic extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue (0.25 g) was chromatographed on silica gel (11 g) using chloroform as eluent to give (3R,6R)-1,4-dimethyl-3-(l-methylindol-3- ylmethyl)-6-(2-methylthioethyl)piperazine-2,5-dione (0.08 g) as an oil. IR (CHCl3) : 2990, 2920, 1650 cm 1 NMR (CDCl3) 6 : 0.40 (1H, m), 0.75 (1H, m), 1.83 (3H, s), 2.06 (2H, dd, J=7Hz, 7Hz), 2.70 (3H, s), 3.00 (3H, s), 3.23 (1H, dd, J=14Hz, 4Hz), 3.54 (1H, dd, J=6Hz, 4Hz), 3.70 (1H, dd, J=14Hz, 4Hz), 3.73 (3H, s), 4.19 (1H, t, J=4Hz) , 6.80 (1H, s) 7.20 (3H, m) , 7.55 (1H, m) Example 5 (1) Sodium borohydride (2.1 g) was added to a solution of l-acetylnaphthalene (18.86 g) in ethanol (200 ml) at room temperature and the mixture was stirred at the same temperature for 2 hours. The mixture was diluted with water (50 ml), acidified to pH 3 with 1N hydrochloric acid and concentrated to about 70 ml. The concentrate was extracted with ethyl acetate (100 ml x 2). The extract was dried over magnesium sulfate and evaporated to give l-(l-hydroxyethyl)naphthalene as an oil which was used in a next reaction without further purification. Hydrogen bromide was bubbled into a solution of l-(l-hydroxyethyl)naphthalene (18.96 g in ether (180 ml) for 2 hours under ice-bath cooling. The reaction mixture was washed with water {50 ml x 2), 2.5% sodium bicarbonate (50 ml x 2) and water (50 ml x 2), dried over magnesium sulfate and evaporated to give l-(l-bromoethyl)naphthalene (22.63 g). NMR (CDC13) 6 : 2.23 (3H, d, J=6Hz), 5.97 (1H, q, J=6Hz), 7.2-8.3 (7H, m) (2) 2-Acetylaminopropanedioic acid diethyl ester (20.8 g) was added to a solution of sodium ethoxide in ethanol (prepared from sodium (2.2 g) and ethanol (100 ml)). After the mixture was stirred for 10 minutes at ambient temperature, l-(l-bromoethyl)naphthalene was added. The reaction mixture was stirred for 18 hours at room temperature. The precipitated solid was collected by filtration and dissolved in chloroform. The chloroform solution was dried over magnesium sulfate and evaporated to give 2-acetylamino-2-[l-(1- naphthyl)ethyl]propanedioic acid diethyl ester (21.59 g). NMR (CDC13) 6 : 0.87 (3H, t, J=9Hz), 1.27 (3H, t, J=9Hz), 1.58 (3H, d, J=9Hz), 1.97 (3H, s), 3.1-4.0 (2H, m), 4.27 (2H, q, J=2Hz), 5.00 (1H, q, J=9Hz), 6.57 (1H, s), 7.2-8.3 (7H, m) (3) A solution of 2-acetylamino-2- [1- (1-naphthyl) ethyl] - propanedioic acid diethyl ester (21.59 g) in a mixture of concentrated hydrochloric acid (100 ml) and acetic acid (70 ml) was refluxed for 13 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in water (100 ml). The soluiton was neutralized to pH 5 with 30% sodium hydroxide. The precipitated crystalline solid was collected by filtration to give 2-amino-3-(1-naphthyl)butyric acid (9.76 g). Mass : 229 (M ) (4) A solution of di-tert-butyl dicarbonate (13.95 g) in dioxane (128 ml) was added to a solution of 2-amino3-(1-naphthyl)butyric acid (9.76 g) in 1N sodium hydroxide (128 ml) and the mixture was s-tirred for 1 hour at 500C. The mixture was acidified to pH 3 with concentrated hydrochloric acid and concentrated to about 100 ml. The concentrate was extracted with ethyl acetate (100 ml x 2). The extract was dried over magnesium sulfate and evaporated. The residue was chromatographed on a silica gel (500 ml) using chloroformmethanol (50:1) as eluent to give erythro-2-tert butoxycarbonylamino-3- (1-naphthyl) butyric acid (6.58 g). NMR (CDCl3) 6 : 1.3-1.6 (12H, br s), 3.9-5.0 (3H, m), 7.3-8.3 (8H, m) Mass : 329 (}1 ) (5) To a suspension of erythro-2-tert-butoxycarbonylamino-3-(1-naphthyl)butyric acid (2.50 g) and hydrochloric acid salt of D-methionine ethyl ester (1.62 g) in dry methylene chloride (60 ml) which was cooled on an ice bath and stirred was added triethylamine (0.77 g). The mixture was stirred at ambient temperature for 30 minutes, and to the mixture was added N,N'-dicyclohexylcarbodiimide (1.57 g) .- The resulting mixture was stirred overnight. After removal of the solvent, crude residue was taken up with a mixture of ethyl acetate and water and filtered and the organic layer was washed with 10% hydrochloric acid and saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate and evaporated to give a solid (4.29 g). To a solution of the solid in ethyl acetate (40 ml) was added a saturated solution of hydrogen chloride in ethyl acetate (40 ml) and the mixture was set aside at room temperature overnight. After removal of the solvent, crude residue was chromatographed on silica gel (200 g, a mixture of chloroform and methanol as an eluent). The fractions containing the object compound was collected and concentrated under reduced pressure to give hydrochloric acd salt of N-[(2R,3R)-2-amino-3-(1- naphthyl)butyryl]-D-methionine ethyl ester (1.60 g) as an oil. -l IR (Neat) : 3200, 1710, 1670 cm (6) To a solution of hydrochloric acid salt of N-[(2R,3R)-2-amino-3-(1-naphthyl)butyryl]-D-methionine ethyl ester (1.60 g) in ethanol (30 ml) was added a saturated solution of ammonia in ethanol (30 ml) and the mixture was set aside overnight at ambient temperature, and precipitated mass was collected, washed with ethanol, and dried to give (3R,6R)-3-(2-methylthioethyl)-6-[(R)-1-(1-naphthyl)ethyl]piperazine-2,5-dione (0.68 g). mp : 265-2680C -l IR (Nujol) : 3200, 1675, 1660 cm NMR (DMSO-d6) 6 : 0.38 (1H, m), 1.02 (1H, m), 1.49 (3H, d, J=8.1Hz), 1.69 (2H, t, J=8.1Hz), 1.73 (3H, s), 3.60 (1H, m), 4.19 (1H, s), 4.41 (1H, m), 7.51 (4H, m), 7.95 (3H, m), 8.30 (1H, m), 8.54 (1H, m) Example 6 The following compounds were prepared in a similar manner to that of Example 5 (6). (1) (3R,6R)-3-(2-Ethoxycarbonylethyl)-6-(1- methylindol-3-ylmethyl)piperazine-2,5-dione mp : 197-2020C IR (Nujol) : 3180, 3050, 1730, 1670 cm-1 NMR (DMSO-d6) 6 : 1.14 (3H, t, J=6Hz), 1.25 (4H, m), 2.97 (1H, dd, J=14, 5Hz), 3.26 (1H, dd, J=i4, 4Hz), 3.65 (lH, m), 3.96 (2H, q, J=6Hz), 4.15 (1H, m), 7.03 (1H, s), 7.05 (2H, m), 7.32 (1H, dd, J=7, 1Hz), 7.65 (1H, dd, J=7, 1Hz), 7.96 (1H, br s), 8.20 (1H, br s) (2) (3R,6R)-3-[(R)-sec-Butyl]-6-(1-methylindol-3- ylmethyl)piperazine-2,5-dione IR (Nujol) : 3180, 3040, 1660 cm-1 NMR (DMSO-d6) 6 : 0.14 (3H, d, J=7Hz), 0.65 (3H, m), 1.00 (2H, m), 1.40 (1H, m), 3.05 (1H, dd, J=15, 5Hz), 3.25 (1H, dd, J=15, 4Hz), 3.63 (1H, m), 4.16 (1H, m), 7.04 (1H, s), 7.05 (2H, m), 7.35 (1H, dd, J=7, 1Hz), 7.65 (1H, dd, J=7, 1Hz), 7.75 (1H, s), 7.97 (1H, s) (3) (3R,6R)-3-(1-Methylindol-3-ylmethyl)-6-(2- phenylthioethyl)piperazine-2,5-dione mp : 176-182 C IR (Nujol) : 3180, 1675, 1660 cm NMR (DMSO-d6) 6 : 1.20 (2H, m), 1.9-2.2 (2H, m), 2.9-3.5 (6H, m), 4.15 (1H, m), 6.9-7.4 (9H, m), 7.60 (1H, m), 8.00 (1H, d, J=lHz), 8.17 (1H, br s) (4) (3R,6R)-3-Diphemethyl-6-(2-methylthioethyl) - piperazine-2,5-dione mp : 279-2810C IR (Nujol) : 3200, 3050, 1665 cm NMR (DMSO-d6) 6 : 1.05 (1H, m), 1.40 (1H, m), 1.93 (3H, s), 2.16 (2H, t, J=7.5Hz), 3.80 (1H, m), 4.60 (1H, d, J=4.5Hz), 4.80 (1H, m), 7.30 (10H, s), 7.96 (1H, d, J=1Hz), 8.16 (1H, d, J=lHz) (5) (3R,6R)-3-[(R)-&alpha;-Methoxybenzyl]-6-(2-methylthio- ethyl)piperazine-2,5-dione mp : 253-2580C IR (Nujol) : 3190, 3050, 1670, 1660 cm-1 (6) (3R,6R)-3,6-bis(1-Methylindol-3-ylmethyl)piperazine-2,5-dione mp : 263-265 C NMR (DMSO-d6) 6 : 2.21 (2H, dd, J=14, 6Hz), 2.75 (2H, dd, J=14, 4.5Hz), 3.67 (6H, s), 3.90 (2H, m), 6.59 (2H, s), 6.9-7.5 (8H, m), 7.74 (2H, d, J=0.5Hz) (7) (3R,6S)-3-(1-Methylindol-3-ylmethyl)-6- phenylthiomethylpiperazine-2,5-dione mp : 216-219 C IR (Nujol) : 3190, 3050, 1670 cm 1 NMR (DMSO-d6) 6 : 2.06 (1H, dd, J=13, 7Hz), 2.73 (1H, dd, J=13, 4Hz), 3.06 (1H, dd, J=14, 4Hz), 3.30 (1H, dd, J=14, 5Hz), 3.65 (3H, s), 4.83 (1H, m), 4.17 (1H, m), 6.9-7.4 (9H, m), 7.61 (1H, d, J=8Hz), 8.06 (1H, d, J=lHz), 8.20 (1H, d, J=0.5Hz) (8) (3R,6R)-3-(1-Methylindol-3-ylmethyl)-6-(3- methylthiopropyl)piperazine-2,5-dione mp : 209-210 C IR (Nujol) : 3180, 3040, 1675, 1660 cm 1 NMR (DMSO-d6) # : 0.55-1.2 (4H, m), 1.83 (3H, s), 1.98 (2H, t, J=7Hz), 2.97 (1H, dd, J=14, 5Hz), 3.26 (1H, dd, J=14, 4Hz), 3.55 (1H, m), 3.73 (3H, s), 4.14 (1H, m), 6.9-7.2 (2H, m), 7.03 (1H, s), 7.38 (1H, d, J=8Hz), 7.62 (1H, d, J=8Hz), 7.96 (1H, br s), 8.06 (1H, d, J=0.SHz) (9) (3R,6RS)-3-(2-Methylthioethyl)-6-(2-naphthyl- methyl) piperazine-2 , 5-dione mp : 1790C IR (Nujol) : 3170, 3040, 1670 cm-1 (10) (3R,6R)-3-(4-Methoxybenzyl)-6-(2-methylthio- ethyl)piperazine-2,5-dione mp : 266-267 C IR (Nujol) : 3180, 1660 cm-1 NMR (DMSO-d6) 6 : 1.25 (2H, m), 1.88 (3H, s), 1.93 (2H, t, J=8Hz), 2.78 (1H, dd, J=14, 5Hz), 3.13 (1H, dd, J=14, 4Hz), 3.71 (3H, s), 3.75 (1H, m), 4.17 (1H, m), 6.85 (2H, d, J=9Hz), 7.11 (2H, d, J=9Hz), 8.08 (1H, s), 8.19 (1H, s) (11) (3R,6RS)-3-(2-tlethylthioethyl)-6-(2-pyridyl- methyl)piperazine-2 ,5-dione mp : 163-165 C IR (Nujol) : 3180, 3040, 1675 cm-1 (12) (3R,6R)-3-(2-Methylthioethyl)-6-(1-naphthyl- methyl)piperazine-2,5-dione mp : 236-240 C -1 IR (Nujol) : 3180, 3050, 1670 cm NMR (DMSO-d6) # : 1.20 (2H, m), 1.86 (3H, s), 1.90 (2H, m), 3.49 (1H, m), 3.55 (1H, m), 3.71 (1H, m), 4.30 (1H, m), 7.50 (4H, m), 7.90 (2H, m), 8.20 (3H, m) (13) (3R,6R)-3-(1-Methylindol-3-ylmethyl)-6methylthiomethylpiperazine-2,5-dione mp : 244-247 C (14) (3R,6R)-3-Butyl-6-(1-methylindol-3-ylmethyl)piperazine-2,5-dione mp : 237-239 C IR (Nujol) : 3180, 3040, 1665 cm NMR (DIGO-d6) # : 0.4-1.2 (9H, m), 3.00 (1H, dd, J=15, 5Hz), 3.25 (1H, dd, J=15, 4Hz), 3.53 (1H, m), 3.70 (3H, s), 4.13 (1H, m), 7.01 (1H, s), 7.03 (2H, m), 7.33 (1H, dd, J=8, 1Hz), 7.62 (1H, dd, J=8, 1Hz), 7.89 (1H, br s), 8.01 (1H, br s) (15) (3R,6R)-3-(1-Methylindol-3-ylmethyl)-6- Octylpiperazine-2,5-dione mp : 211-213 C IR (Nujol) : 3170, 3040, 1660 cm-1 NMR (DMOS-d6) 6 : 0.5-1.4 (17H, m), 3.03 (1H, dd,J=15, 5Hz), 3.30 (1H, dd, J=15, 4Hz), 3.55 (1H, m), 3.73 (3H, s), 4.15 (1H, m), 7.03 (1H, s), 7.05 (2H, m), 7.35 (1H, dd, J=7, 1Hz), 7.63 (1H, dd, J=7, 1Hz), 7.92 (1H, br s), 8.03 (1H, br s) (16) (3R,6R)-3-Dodecyl-6-(1-methylindol-3-ylmethyl)- piperazine-2,5-dione mp : 207-209 C IR (Nujol) : 3160, 3030, 1660 cm NMR (DMSO-d6) # : 0.4-1.4 (25H, m), 2.95 (1H, dd, J=14, 5Hz), 3.23 (1H, dd, J=14, 4Hz), 3.47 (1H, m), 3.68 (3H, s), 4.09 (1H, m), 7.00 (1H, s), 7.00 (2H, m), 7.30 (1H, dd, J=7, 1Hz), 7.58 (1H, dd, J=7, 1Hz), 7.87 (1H, br s), 8.00 (1H, br s) (17) (3R,6R)-3-[(S)-1-(2-Naphthyl)ethyl]-6-(2 methylthioethyl)piperazine-2,5-dione mp : 287-288 C IR (Nujol) : 3190, 3140, 1660 cm NMR (DMSO-d6) 6 : 0.60 (1H, m), 1.00 (1H, m), 1.46 (3H, d, J=8Hz), 1.48 (3H, s), 1.70 (2H, t, J=8Hz), 3.65 (2H, m), 4.10 (1H, m), 7.3-7.9 (7H, m), 8.01 (1H, m), 8.40 (1H, m) (18) (3R,6R)-3-(2-Methylthioethyl)-6-[(RS)-1- phenylethyl ]piperazine-2,5-dione mp : 273-276 C IR (Nujol) : 3180, 1660 cm-1 NMR (DMSO-d6) 6 : 0.60(1H, m), 1.10 (1H, m), 1.33 (3H, d, J=7Hz), 1.83 (3H, s), 1.93 (2H, t, J=7.5Hz), 3.5 (2H, m), 3.96 (1H, m), 7.20 (5H, m), 8.00 (1H, br s), 8.30 (1H, br s) (19) (3R,6R)-3-(3-Benzyloxycarbonylaminopropyl)-6- (1-methylindol-3-ylmethyl)piperazine-2,5-dione mp : 170-172 C IR (Nujol) : 3310, 3190, 1715, 1665 cm NMR (DMSO-d6) 6 : 0.6-1.2 (4H, m), 2.60 (2H, m), 3.02 (1H, dd, J=15, 5Hz), 3.26 (1H, dd, J=15, 4Hz), 3.57 (1H, m), 3.70 (3H, s), 4.13 (1H, m), 5.00 (2H, s), 7.00 (4H, m), 7.30 (1H, m), 7.35 (5H, s), 7.60 (1H, d, J=7, 1Hz), 7.92 (1H, d, J=1Hz), 8.01 (1H, d, J=lHz) (20) (3R,6R)-3-(9-Anthrylmethyl)-6-(2-methylthioethyl)piperazine-2,5-dione mp : 299-304 C -1 IR (Nujol) : 3180, 3050, 1660 cm NMR (DMSO-d6) # : 1.56 (1H, m), 1.74 (1H, m), 2.02 (3H, s), 2.37 (2H, t, J=7.5Hz), 3.78 (1H, m), 4.02 (1H, dd, J=13.5, 7.5Hz), 4.12 (1H, dd, J=13.5, 5Hz), 7.52 (4H, m), 7.96 (111, d, J=2.5Hz), 8.09 (2H, dd, J=8, 2Hz), 8.33 (2H, d, J=8Hz), 8.35 (1H, s), 8.55 (1H, s) (21) (3R,6R)-3-(1-Methylindol-3-ylmethyl)-6- pentylpiperazine-2,5-dione mp : 2280C -1 IR (Nujol) : 3190, 3050, 1680, 1670 cm NMR (DMSO-d6) 6 : 0.5-1.2 (11H, m), 2.98 (1H, dd, J=15, 5Hz), 3.25 (1H, dd, J=15, 4Hz), 3.50 (1H, m) , 3.70 (3H, s) , 4.10 (1H, m) 6.8-7.2 (2H, m), 7.00 (1H, s), 7.31 (1H, dd, J=8, lHz), 7.60 (1H, dd, J=8, 1Hz) 7.89 (1H, br s), 7.99 (1H, br s) (22) (3R,6R)-3-[(S)-1-(1-Naphthyl)ethyl]-6-(2- methylthioethyl)piperazine-2,5-dione mp : 290-2930C -1 IR (Nujol) : 3180, 3040, 1660 cm (23) (3R,6S)-3-(1-Methylindol-3-ylmethyl)-6-(2- phenylthioethyl)piperazine-2,5-dione mp : 204-208 C IR (Nujol) : 3180, 3050, 1675 cm-1 (24) (3R,6R)-3-(1-Methylindol-3-ylmethyl)-6- phenylthiomethylpiperazine-2,5-dione mp : 213-2140C IR (Nujol) : 3180, 3050, 1660 cm-1 NMR (DMSO-d6) 6 : 3.02 (1H, dd, J=14, 4.5Hz), 3.23 (3H, m) , 3.50 (1H, m) , 3.70 (3H, s), 4.20 (1H, m), 6.9-7.4 (3H, m), 7.05 (1H, s), 7.29 (5H, s), 7.62 (1H, dd, J=8, 1Hz), 7.95 (1H, s) , 8.23 (1H, s) (25) (3R,6S)-3-(1-Methylindol-3-ylmethyl)-6-(3- methylthiopropyl)piperazine-2,5-dione mp : 205-206 C IR (Nujol) : 3230, 1670, 1635 cm NMR (DMSO-d6) # : 1.59 (4H, m), 2.00 (3H, s), 2.38 (2H, t, J=7Hz), 2.95-3.5 (3H, m), 3.75 (3H, s), 4.13 (1H, m), 6.9-7.3 (2H, m), 7.10 (1H, s), 7.42 (1H, d, J=8Hz) 7.65 (1H, d, J=8Hz), 7.98 (1H, s), 8.05 (1H, d, J=lHz) (26) (3R,6S)-3-(1-Methylindol-3-ylmethyl)-6- octylpiperazine-2,5-dione mp : 201-202 C IR (Nujol) : 3170, 3040, 1665 cm-1 NMR (DMSO-d6) 6 : 0.86 (3H, m) , 1.20 (12H, m) 1.53 (2H, m) , 3.15 (3H, m) , 3.72 (3H, s) 4.10 (1H, m) , 7.05 (2H, m) , 7.06 (1H, s) 7.36 (1H, dd, J=7, 1Hz), 7.60 (1H, dd, J=7, lHz), 7.88 (1H, br s), 7.98 (1H, br s) (27) (3S,6R)-3-Dodecyl-6-(1-methylindol-3-ylmethyl)- piperazine-2,5-dione mp : 187-188 C IR (Nujol) : 3160, 1670, 1660 cm NMR (DMSO-d6) 6 : 0.8-1.6 (25H, m) , 3.1 (3H, m) 3.70 (3H, s), 4.05 (1H, m), 6.9-8.0 (7H, m) (28) (3S,6R)-3-(3-Benzyloxycarbonylaminopropyl)-6- (1-methylindol-3-ylmethyl)piperazine-2,5-dione mp : 128-130 C -1 IR (Nujol) : 3330, 3190, 1670 cm NMR (DMSO-d6) # : 1.43 (4H, m), 2.8-3.3 (55, m), 3.70 (3H, s), 4.05 (1H, m), 4.97 (2H, s), 7.03 (4H, m) , 7.30 (5H, s), 7.30 (1H, m) 7.58 (1H, dd, J=8, 1Hz), 7.87 (1H, s), 8.00 (1H, d, J=lHz) (29) (3R,6RS)-3-(1-Methylindol-3-ylmethyl)-6pentylpiperazine-2,5-dione mp : 204-212 C -1 IR (Nujol) : 3200, 1680 cm NMR (DMSO-d6) 6 : 0.80 (3H, m), 1.15 (6H, m), 1.46 (2H, m), 2.9-3.3 (3H, m), 3.70 (3H, s), 4.07 (1H, m), 6.85-7.2 (2H, m), 7.02 (1H, s), 7.33 (1H, dd, J=7, 2Hz), 7.57 (1H, dd, J=7, 2Hz), 7.86 (1H, s), 7.92 (1H, br s) (30) (3R,6R)-3-(1-Methyl-2-phenylindol-3-ylmethyl)- 6- (2-methylthioethyl) piperazine-2 , 5-dione mp : 295-298 C IR (Nujol) : 3200, 1670, 1660 cm-1 NMR (DMSO-d6) # : 1.0-1.6 (2H, m), 1.90 (3H, s), 2.03-2.90 (2H, m), 2.8-3.1 (2H, m), 3.50 (3H, s), 3.5-4.0 (2H, m), 7.0-8.1 (11H, m) (31) (3R,6R)-3-(1-Methylindol-3-ylmethyl)-6propylpiperazine-2,5-dione mp : 241-243 C IR (Nujol) : 3200, 1665, 1660 cm-1 NMR (DMSO-d6) # : 0.3-1.2 (7H, m), 3.0-3.3 (2H, m), 3.4-3.6 (1H, m), 3.70 (3H, s), 4.0-4.2 (1H, m), 6.9-8.1 (7H, m) (32) (3R,6R)-3-Butyl-6-[(R)-1-(1-naphthyl)ethyl]- piperazine-2,5-dione mp : 279-281 C -1 IR (Nujol) : 3200, 1670, 1660 cm NMR (DMSO-d6) # : -0.21-0.0 (1H, m), 0.34-0.82 (8H, m), 1.47 (3H, d, J=7.9Hz), 3.32 (1H, m), 4.11 (1H, s), 4.34 (1H, m), 7.39 (4H, m), 7.76 (3H, m), 8.16 (1H, m), 8.42 (1H, m) (33) (3R,6R)-3-(1-Methylindol-3-ylmethyl)-6- benzylpiperazine-2,5-dione mp : 283-284 C IR (Nujol) : 3110, 1660 cm-1 NMR (DMSO-d6) 6 : 2.00 (1H, dd, J=13.5, 6Hz), 2.37 (1H, dd, J=14.5, 6Hz), 2.46 (1H, dd, J=13.5, 6Hz), 2.77 (1H, dd, J=14.5, 4Hz), 3.45 (1H, m), 3.90 (1H, m), 6.78 (2H, m), 6.97 (1H, s), 7.0-7.25 (5H, m), 7.38 (1H, d, J=8Hz), 7.48 (1H, d, J=8Hz), 7.80 (1H, br s), 7.93 (1H, br s) (34) (3R,6R)-3-(1-Methylindol-3-ylmethyl)-6- phenethylpiperazine-2,5-dione mp : 240-242 C IR (Nujol) : 3170, 1660 cm-1 NMR (DMSO-d6) # : 0.97 (1H, m), 1.25 (1H, m), 1.79 (2H, m), 3.00 (1H, dd, J=15, 4.5Hz), 3.30 (1H, dd, J=15, 4Hz), 3.53 (3H, s), 3.62 (1H, m), 4.27 (1H, br s), 6.77 (2H, d, J=7.5Hz), 7.0-7.3 (7H, m), 7.65 (1H, d, J=7.5Hz), 8.03 (1H, s), 8.17 (1H, s) (35) (3R,6S)-3-(1-Methylindol-3-ylmethyl)-6phenethylpiperazine-2,5-dione mp : 218-220 C IR (Nujol) : 3170, 1660 cm NMR (DMSO-d6) # : 1.81 (2H, m), 2.50 (2H, m), 3.0-3.3 (2H, m), 3.71 (3H, s), 4.10 (1H, m), 7.0-7.3 (8H, m), 7.36 (1H, d, J=8Hz), 7.60 (1H, d, J=8Hz), 8.08 (1H, s), 8.11 (1H, s) (36) (3R,6RS)-3-(2-Methylthioethyl)-6-phenethylpiperazine-2,5-dione mp : 231-233 C NMR (DMSO-d6) 6 : 1.98 (4H, m), 2.05 (3H, s), 2.55 (4H, m), 3.90 (1H, m), 4.00 (1H, m), 7.25 (5H, m), 8.28 (1H, s), 8.35 (lH, s) (37) (3R,6R)-3-Hydroxymethyl-6-(1-methylindol-3- ylmethyl)piperazine-2,5-dione mp : 233-235 C IR (Nujol) : 3150, 1670 Cm-1 NMR (DMSO-d6) 6 : 3.2 (4H, m) , 3.7 (1H, m) 3.73 (3H, s), 4.02 (1H, m), 4.92 (1H, t, J=5Hz), 7.1 (3H, m), 7.40 (1H, dd, J=7, 2Hz), 7.57 (1H, dd, J=7, 2Hz), 7.85 (2H, m), 7.38 (1H, d, J=8Hz), 7.58 (1H, d, J=8Hz), 8.16 (1H, m), 8.22 (1H, m) (38) (3R,6R)-3-(2-Benzyloxycarbonylethyl)-6-(1- methylindol-3-ylmethyl)piperazine-2,5-dione mp : 207-208 C IR (Nujol) : 3160, 1720, 1655 cm-1 NMR (DMSO-d6) 6 : 1.15 (2H, m), 1.25 (2H, m), 2.97 (1H, dd, J=14, 4.5Hz), 3.28 (1H, dd, J=14, 3.5Hz), 3.60 (3H, s), 3.68 (1H, m), 4.15 (1H, m), 4.99 (2H, s), 6.92-7.48 (9H, m), 7.61 (1H, d, J=8Hz), 7.97 (1H, s), 8.22 (1H, s) (39) (3R,6R)-3-Benzyloxymethyl-6-(1-methylindol-3- ylmethyl)piperazine-2,5-dione mp : 210-211 C IR (Nujol) : 3170, 1660 cm-1 NMR (DMSO-d6) 6 : 2.71 (1H, dd, J=10, 5Hz), 3.05 (1H, dd, J=14.5, 4.5Hz), 3.18 (1H, dd, J=14.5, 5Hz), 3.26 (1H, dd, J=10, 3Hz), 3.68 (3H, s), 3.81 (1H, m), 4.06 (1H, m), 4.15 (1H, d, J=13Hz), 4.23 (1H, d, J=13Hz), 6.94-7.50 (10H, m), 8.05 (2H, s) (40) (3R,6R)-3-(1-Methylindol-3-ylmethyl)-6 (2-pyridylmethyl)piperazine-2,5-dione mp : 188-1920C (41) (3R,6S)-3-(l-Methylindol-3-ylmethyl)-6-(2- pyridylmethyl)piperazine-2,5-dione mp : 197-2010C (42) (3R,6R)-3-[(S)-1-(1-Methylindol-3-yl)ethyl]- 6-(2-methylthioethyl)piperazine-2,5-dione mp : 264-2670C (43) (3R,6R)-3-[(R)-1-(l-Methylindol-3-yl)ethyl]-6- (2-methylthioethyl)piperazine-2,5-dione mp : : 279-2800C (44) (3R,6R)- 3-Butyl-6-[ (R) -1-( l-methylindol-3-yl) - ethyl]piperazine-2,5-dione mp : 285-2880C (45) (3R,6S)-3-(1-Elethylindol-3-ylmethyl)-6- methylthiomethylpiperazine-2,5-dione mp : > 2600C Example 7 (1) To a mixture of l-methylindole (4.26 g) and methyl (2R,3R)-N-benzyloxycarbonyl-3-methyl-2- aziridinecarboxylate (2.70 g) in dry methylene chloride (50 ml) was added boron trifluoride etherate (1.33 ml) under ice-bath cooling. The mixture was stirred for five minutes at ambient temperature and the solvent was evaporated off. The residue was chromatographed on silica gel (chloroform and a 1:1 mixture of hexane and ether as eluent) to give (aR,BR)-N-benzyloxycarbonyl-l, B-dimethyltryptophane methyl ester (1.62 g) as an oil. IR (Neat) : 1715, 1670 cm 1 (2) A solution of (aR,BR)-N-benzyloxycarbonyl-1,8, dimethyltryptophane methyl ester (1.62 g) in methanol (50 ml) containing 10% paradium charcoal (300 mg) was hydrogenated at the ambient temperature and atmospheric pressure. After removal of the catalyst and evaporation of the solvent, the residual oil (1.13 g) was dissolved in methanol (5 ml) and to the solution, a solution of p-toluenesulfonic acid mono hydrate (0.81 g) in a mixture of water (2 ml) and methanol (2 ml) was added. The solution was evaporated to dryness to give p-toluenesulfonic acid salt of (aR,BR)-1,B-dimethyltryptophane methyl ester (1.77 g). -l IR (Neat) : 3200, 1715 cm (3) The following compound was prepared in a similar manner to that of Example 5 (1). N-[N-tert-Butoxycarbonyl-D-leucyl]-(&alpha;R,ssR)-1,ss- dimethyltryptophane methyl ester -l IR (Nujol) : 1715, 1670 cm (4) The following compound was prepared in a similar manner to that of Example 5 (2). (3R,6R)-3-Isobutyl-6-[(R)-l-(l-methylindol-3-yl)- ethyl]piperazine-2,5-dione IR (Nujol) : 3150, 1680 cm 1 Example 8 A solution of (3R,6R)-3-(3-benzyloxycarbonylamino propyl)-6-(1-methylindol-3-ylmethyl)piperazine-2,5- dione (1.2 g) in ethanol (240 ml) containing 10% paradium on charcoal (0.6 g) was hydrogenated at ambient temperature and atmospheric pressure. After catalyst was filtered off and solvent was evaporated, crude solid was taken up with ethanol, and dried in vacuo to give (3R,6R) -3-(3-aminopropyl) -6- (1-methylindol- 3-ylmethyl)piperazine-2,5-dione. mp : 148 C Example 9 The following compound was prepared in a similar manner to that of Example 8. (3S,6R)-3-(3-Aminopropyl)-6-(1-methylindol-3- ylmethyl)piperazine-2,5-dione mp : 175-1770C Example 10 To a solution of (3R,6R)-3-(3-aminopropyl)-6-(1methylindol-3-ylmethyl)piperazine-2,5-dione (100 mg) in dry N,N-dimethylformamide (3 ml) was added benzoyl chloride (60 mg). The mixture was stirred at ambient temperature for 2 hours, diluted with water (15 ml) and allowed to stand overnight. The precipitated mass was collected, washed with water, and dried in vacuo to give (3R,6R)-3-(3-benzamidopropyl)-6-(1-methyl- indol-3-ylmethyl)piperazine-2,5-dione (45 mg). mp : 238-2390C IR (Nujol) : 3320, 1675, 1630 cm-1 NMR (DMSO-d6) 6 : 0.85 (3H, m), 1.08 (1H, m), 2.87 (2H, m), 3.00 (1H, dd, J=14, 4.5Hz), 3.23 (1H, dd, J=14, 4Hz), 3.59 (1H, m), 3.70 (3H, s), 4.11 (1H, m), 7.05 (3H, m), 7.29 (111, d, J=8Hz), 7.45 (3H, m), 7.58 (111, d, J=8Hz), 7.80 (2H, m), 7.99 (1H, s), 8.09 (1H, s), 8.24 (1H, t, J=5.5Hz) Example 11 A mixture of (3R,6R)-3-hydroxsZmethyl-6-(1- methylindol-3-ylmethyl)-piperazine-2,5-dione (0.10 g), dry pyridine (1.0 ml) and acetic anhydride (0.08 g) was heated at 1000C for 1 hour. After the mixture was cooled to ambient temperature, the pricipitated mass was collected, washed with pyridine and then ethanol, and dried to give (3R,6R)-3- acetoxymethyl-6-(1 methylindol-3-ylmethyl)piperazine-2,5-dione (61.8 mg). mp : 250-2520C IR (Nujol) : 3180, 1735, 1670, 1660 cm NMR (DMSO-d6) d : 1.85 (3H, s), 3.10 (1H, dd, J=15, 4.5Hz), 3.18 (1H, dd, J=15, 4.5Hz), 3.23 (1H, dd, J=10.5, 5.5Hz), 3.73 (3H, s), 3.81 (1H, dd, J=10.5, 3.5Hz), 3.98 (1H, m), 4.11 (1H, m), 7.00 (1H, dd, J=8, 7Hz), 7.09 (1H, s), 7.12 (1H, t, J=8 .7Hz) Example 12 A mixture of (3R,6R)-3- (3-aminopropyl)-6-(1- methylindol-3-ylmethyl)piperazine-2,5-dione (0.1 g) and acetic anIlydride (0.08 g) in pyridine (1.0 ml) was heated at 1000C for 1 hour. After the mixture was cooled to ambient temperature, the precipitated solid was collected by filtration and washed with pyridine (2 ml) and ethanol (5 ml) to give (3R,6R)-3-(3acetamidopropyl)-6-(1-methylindol-3-ylmethyl)piperazine 2,5-dione (0.1 g). mp : 1380C IR (Nujol) : 3190, 1660 cm-1 NMR (DMSO-d6) a : 0.70 (3H, m), 1.00 (1H, m), 1.75 (3H, s), 2.40 (2H, m), 3.00 (1H, dd, J=13Hz, 4.5Hz), 3.22 (1H, dd, J=13Hz, 4Hz), 3.52 (1H, m), 3.74 (3H, s), 4.11 (1H, m), 7.05 (3H, m) , 7.33 (1H, d, J=8Hz), 7.58 (1H, d, J=8Hz), 7.96 (1H, s), 8.05 (1H, s) Example 13 The following compound was prepared in a similar manner to that of Example 12. (3S, 6R) - 3- (3-Acetamidopropyl) -6- (1-methylindol- 3ylmethyl)piperazine-2,5-dione mp : 124-1260C -1 IR (Nujol) : 3280, 3180, 1670 cm NMR (DMSO-d6) 6 : 1.30 (2H, m), 1.48 (2H, m), 1.75 (3H, s), 2.93 (2H, m), 3.10 (1H, m), 3.15 (1H, m) , 3.22 (1H, m) , 3.72 (3H, s) 4.05 (1H, m), 7.05 (3H, m), 7.35 (1H, d, J=8Hz), 7.60 (1H, d, J=8Hz), 7.75 (1H, m) Example 14 To a solution of (3R,6R)-3-(2-methylthioethyl)-6 [(R)-l-(l-naphthyl)ethyl]piperazine-2,5-dione (0.40 g) in dry dimethylformamide (40 ml) was added sodium hydride (116 mg). After the mixture was stirred at ambient temperature for 10 minutes, methyl iodide (0.19 ml) was added to the mixture. The reaction mixture was stirred for 5 minutes and the solvent was evaporated off under reduced pressure. The residue was extracted with chloroform (40 ml). The organic extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (8 g) using a mixture of chloroform and methanol as eluent to give (3R,6R)-1,4-dimethyl-3-(2methylthioethyl)-6- [(R)-1-(1-naphthyl)ethyl]piperazine- 2,5-dione (0.16 g). mp : 88-900C (recrystallized from isopropyl ether) IR (Chloroform) : 1655 cm-1 NMR (CDC13) 6 : 0.7-1.3 (2H, m), 1.63 (3H, d, J=6Hz), 2.03 (3H, s), 2.50 (2H, t, J=6Hz), 2.77 (3H, s), 2.80 (3H, s), 3.77 (1H, m), 4.30 (2H, m), 7.3-8.2 (7H, m) Example 15 The following compounds were prepared in a similar manner to that of Example 13. (1) (3R,6R)-3-Butyl-1,4-dimethyl-6-[(R)-1-(1- naphthyl)ethyl]piperazine-2,5-dione mp : 71-730C -1 IR (Nujol) : 1650 cm NMR (CDC13) : 0.88 (3H, m), 1.25 (6H, m), 1.63 (3H, d, J=7Hz), 2.60 (3H, s), 2.83 (3H, s), 3.56 (1H, m), 4.23 (1H, m), 4.28 (1H, m), 7.4-8.2 (7H, m) (2) (3R,6R)-3-Butyl-1,4-dimethyl-6-[(R)-1-(1- methylindol-3-yl)ethyl)piperazine-2,5-dione -l IR (Neat) : 1650 cm (3) (3R,6R)-1,4-Dimethyl-3-[(R)-1-(1-methylindol- 3-yl)ethyl]-6-(2-methylthioethyl)piperazine-2,5-dione IR (CHC13) : 1650 cm (4) (3R,6R)-1,4-Dimethyl-3-[(S)-1-(1-methylindol- 3-yl)ethyl)-6-(2-methylthioethyl)piperazine-2,5-dione -1 IR (CHC13) : 1650 cm Example 16 A solution of (3R,6R)-3-(2-benzyloxycarbonylethyl)6- (1-methylindol-3-ylmethyl)piperazine-2,5-dione (1.50 g) in ethanol (300 ml) containing 10% paradium on charcoal (0.75 g) was hydrogenated at ambient temperature and atanospheric pressure. After catalyst was filtered off and solvent was evaporated, crude solid was recrystallized from ethanol and dried in vacuo to give (3R,6R)-3-(2 carboxyethyl)-6-(1-methylindol-3-ylmethyl)piperazine-2,5- dione (0.58 g). mp : 2280C IR (Nujol) : 1720, 1660 cm-1 NMR (DMSO-d6) 6 : 1.14 (3H, m), 1.38 (1H, m), 2.98 (1H, dd, J=14, 4.5Hz), 3.23 (1H, dd, J=14, 4Hz), 3.63 (1H, m), 3.70 (3H, s), 4.12 (111, m), 7.00 (3H, m), 7.28 (1H, d, J=8Hz), 7.59 (1H, d, J=8Hz), 7.97 (1H, s), 8.14 (1H, s) Example 17 (3R,6R)-3-(2-Methylthioethyl)-6- [(R)-1-(1- naphthyl)ethyl]piperazine-2,5-dione 500 (g) Sucrose 9000 Hydroxypropylcellulose 250 Starch 250 The above ingredients are blended and granulated or grained in a conventional manner into granules or small granules.

Claims: We claim 1. Piperazine compound of the formula EMI51.1 wherein R1 is aryl; ar(lower)alkyl which may have lower alkoxy; or he terocyclic (iower alkyl which may have substituent(s) selected from the group of lower alkyl and aryl on the heterocyclic ring; R2 is lower alkyl; higher alkyl; lower alkylthio (lower) alkyl; lower alkenylthio(lower)alkyl; hydroxy (lower) alkyl; protected hydroxy(lower)alkyl; amino (lower) alkyl; protected amino(lower)alkyl; carboxy (lower) alkyl; protected carboxy (lower) alkyl; arylthio(lower)alkyl; ar(lower)alkylthio(lower)alkyl; or heterocyclic (lower) alkyl which may have lower alkyl on the heterocyclic ring; and R3 and R4 are each hydrogen or lower alkyl, or pharmaceutically acceptable salt thereof. 2. A compound of claim 1, in which R3 and R4 are each as defined in claim 1; R1 is aryl; ar(lower)alkyl; ar(lower)alkyl having lower alkoxy; benzene-fused heterocyclic (lower) alkyl containing one sulfur or nitrogen atom; heteromonocyclic(lower)alkyl containing one nitrogen atom; N-lower alkyl-benzene-fused heterocyclic (lower)alkyl containing one nitrogen atom; or N-lower alkyl-benzene-fused heterocyclic (lower)alkyl containing one nitrogen atom having aryl on the heterocyclic ring; and R2is lower alkyl; higher alkyl; lower alkylthio (lower)alkyl; lower alkenylthio(lower)alkyl; hydroxy(lower)alkyl; acyloxy (lower) alkyl; ar(lower)alkoxy(lower)alkyl; amino (lower) alkyl; acylamino (lower) alkyl; carboxy (lower) alkyl; esterified carboxy (lower) alkyl; arylthio(lower)alkyl; ar (lower) alkylthio (lower) alkyl; or N-lower alkyl-benzene-fused heterocyclic (lower)alkyl containing one nitrogen atom. 3. A compound of claim 2, in which R3 and R4 are each as defined in claim 2; R1 is phenyl; mono (or di)phenyl(lower)alkyl; naphthyl (lower) alkyl; anthryl (lower) alkyl; phenyl(lower)alkyl having lower alkoxy; indolyl(lower)alkyl; benzothienyl(lower)alkyl; pyridyl(lower)alkyl; N-lower alkylindolyl(lower)alkyl; or N-lower alkylindolyl(lower)alkyl having phenyl on the indole ring; and R2 is lower alkyl; higher alkyl; lower alkylthio (lower) alkyl; lower alkenylthio(lower)alkyl; hydroxy(lower)alkyl; lower alkanoyloxy(lower)alkyl; phenyl(lower)alkoxy(lower)alkyl; amino (lower) alkyl; lower alkanoylamino(lower)alkyl; benzamido (lower) alkyl; phenyl(lower)alkoxycarbonylamino(lower)alkyl; carboxy (lower) alkyl; lower alkoxycarbonyl (lower) alkyl; phenyl (lower) alkoxycarbonyl (lower) alkyl; phenylthio(lower)alkyl; phenyl(lower)alkylthio(lower)alkyl; or N-lower alkylindolyl(lower)alkyl. 4. A compound of claim 3, in which R1 is phenyl; benzyl; phenethyl; diphenylmethyl; l-phenylethyl; l-naphthylmethyl; 2-naphthylmethyl; 1-(1-naphthyl)ethyl; 1-(2-naphthyl)ethyl; 9-anthrylmethyl; a-methoxybenzyl; 4-methoxybenzyl; 3-indolylmethyl; benzo[b]thien-3-yl; 2-pyridylmethyl; l-methylindol-3-ylmethyl; 1-(1-methylindol-3-yl)ethyl; or l-methyl-2-phenylindol-3-ylmethyl; R2 is butyl, iso-butyl; sec-butyl; pentyl; octyl; dodecyl; methylthiomethyl; 2-methylthioethyl; 3-methylthiopropyl; butylthiomethyl; allylthiomethyl; hydroxymethyl; acetoxymethyl; benzyloxymethyl; 3-aminopropyl; 3-acetamidopropyl; 3-benzamidopropyl; 3-benzyloxycarbonylaminopropyl; 2-carboxyethyl; 2-ethoxycarbonylethyl; 2-benzyloxycarbonylethyl; phenylthiomethyl; 2-phenylthioethyl; benzylthiomethyl; or l-methylindol-3-ylmethyl; and R3 and R4 are each hydrogen or methyl. 5. A compound of claim 3, in which R3 and R4 are each as defined in claim 3; R1 is mono(or di)phenyl(lower)alkyl; naphthyl (lower) alkyl; anthryl (lower) alkyl; N-lower alkylindolyl (lower) alkyl; or N-lower alkylindolyl(lower)alkyl having phenyl on the indole ring; and R2 is lower alkyl; lower alkylthio(lower)alkyl; or N-lower alkylindolyl (lower) alkyl. 6. A compound of claim 5, which is (3R,6R)-3-(2-methylthioethyl)-6-[(R)-1-(1-naphthyl)- ethyl]piperazine-2,5-dione or pharmaceutically acceptable salt thereof. 7. A process for preparing a piperazine compound of the formula EMI55.1 wherein R1 is aryl; ar(lower)alkyl which may have lower alkoxy; or heterocyclic(lower)alkyl which may have substituent(s) selected from the group of lower alkyl and aryl on the heterocyclic ring; R2 is lower alkyl; higher alkyl; lower alkylthio (lower) alkyl; lower alkenylthio(lower)alkyl; hydroxy(lower)alkyl; protected hydroxy(lower)alkyl; amino (lower) alkyl; protected amino(lower)alkyl; carboxy (lower) alkyl; protected carboxy (lower) alkyl; arylthio(lower)alkyl; ar (lower) alkylthio (lower) alkyl; or heterocyclic (lower) alkyl which may have lower alkyl on the heterocyclic ring; and R3 and R4 are each hydrogen or lower alkyl, or salt thereof, which comprises, (a) subjecting a compound of the formula EMI56.1 wherein R1 R2 R3 and R4 are each as defined above, R5 is hydrogen or amino-protective group, and R6 is carboxy or protected carboxy or its reactive derivative at the carboxy or amino group or salt thereof, to ring closure reaction, to give a compound of the formula EMI57.1 wherein R1, R2, R3 and R4 are each as defined above or salt thereof; (b) reacting a compound of the formula EMI57.2 wherein R1 and R2 are each as defined above or salt thereof, with a lower alkylating agent, to give a compound of the formula EMI57.3 wherein R1 and R2 are each as defined above, 3 4 Ra and Ra are each lower alkyl, a or salt thereof; ; (c) reacting a compound of the formula EMI58.1 wherein R1, R3 and R4 are each as defined above and R2 a is amino(lower)alkyl, or its reactive derivative at the amino group or salt thereof, with an acylating agent to give a compound of the formula EMI58.2 wherein R1, R3 and R4 are each as defined above and is acylamino(lower)alkyl, or salt thereof; (d) reacting a compound of the formula EMI58.3 wherein R11 R3 and R4 are each as defined above and R2 is hydroxy(lower)alkyl, or salt thereof, with an acylating agent to give a compound of the formula EMI59.1 wherein R1, R3 and R4 are each as defined above and Rd2 is acyloxy(lower)alkyl, or salt thereof; ; (e) subjecting a compound of the formula EMI59.2 wherein R1, R3 and R4 are each as defined above and R2 is a protected amino(lower)alkyl, or salt thereof, to removal reaction of amino-protective group to give a compound of the formula EMI59.3 wherein R1, R3 and R4 are each as defined above and R2 is amino(lower)alkyl, f or salt thereof; or (f) subjecting a compound of the formula EMI60.1 wherein R11 R3 and R4 are each as defined above and R2 is a protected carboxy(lower)alkyl, g or salt thereof to removal reaction of the carboxy-protective group to give a compound of the formula EMI60.2 wherein R1, R3 and R4 are each as defined above and is carboxy(lower)alkyl, or salt thereof. 8. A pharmaceutical composition comprising, as an effective ingredient, a piperazine compound of the formula EMI60.3 wherein R1 is aryl; ar(lower)alkyl which may have lower alkoxy; or heterocyclic(lower)alkyl which may have substituent(s) selected from the group of lower alkyl and aryl on the heterocyclic ring; R2 is lower alkyl; higher alkyl; lower alkylthio(lower)alkyl; lower alkenylthio(lower)alkyl ; hydroxy (lower) alkyl; protected hydroxy(lower) alkyl; amino (lower) alkyl; protected amino(lower)alkyl; carboxy (lower) alkyl; protected carboxy(lower)alkyl; arylthio(lower)alkyl; ar (lower) alkylthio (lower) alkyl; heterocyclic (lower) alkyl which may have lower alkyl on the heterocyclic ring; and R3 and R4 are each hydrogen or lower alkyl, or pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier. 9. The piperazine compound as claimed in claim 8 or pharmaceutically acceptable salt thereof for use as PAF antagonist.

Inventors: HASHIMOTO, MASASHI, HEMMI, KEIJI, MIYAZAKI, YOSHIO, NAKAGUTI, OSAMU, SHIMAZAKI, NORIHIKO
Applicants: FUJISAWA PHARMACEUTICAL CO., LTD.
Application year: 1985
Main classification: C07D403
IPC codes: C07D401, C07D403, C07D241, C07D409