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IE49835B1 - 2-piperazinone derivatives - Google Patents

2-piperazinone derivatives

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Publication number
IE49835B1
IE49835B1 IE625/85A IE62585A IE49835B1 IE 49835 B1 IE49835 B1 IE 49835B1 IE 625/85 A IE625/85 A IE 625/85A IE 62585 A IE62585 A IE 62585A IE 49835 B1 IE49835 B1 IE 49835B1
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Ireland
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formula
solution
compound
hydrogen
alkyl
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IE625/85A
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IE850625L (en
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Merrell Dow Pharma
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Priority claimed from US06/130,431 external-priority patent/US4341698A/en
Application filed by Merrell Dow Pharma filed Critical Merrell Dow Pharma
Publication of IE850625L publication Critical patent/IE850625L/en
Publication of IE49835B1 publication Critical patent/IE49835B1/en

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Description

This invention relates to novel compounds which are derivatives of 2-piperazinone. The novel compounds are of utility as intermediates in the preparation of the pharmaceutically active enkephalin derivatives disclosed and claimed in Patent Specification No. A3834· The novel compounds of this invention have the formula W wherein W is hydrogen, CHjCOOH or CH2COO(Cj_4 alkyl); (i) Z is hydrogen or n-alkyl and Χχ is CH2, S or optionally blocked CO or CHOH, (ii) Z is C^_^ alkyl and Χχ is SO or S02, or (iii) Z and Χχ together are -CH»; either Ra is hydrogen, halogen or protected hydroxy and R^ is hydrogen or R& and R^ are each protected hydroxy; and R , R and R are each alkyl; x y z with the provisos that Ra is halogen when W is hydrogen and Χχ is CH2 and that Rfl is not hydrogen when W is hydrogen and Z and X^ together are -CH=.
It will be appreciated that, when X^ and Z together are -CH», the double bond of this methylidene group is attached to the piperazine ring.
Suitable blocking groups, and their chemistry, are described in the above-identified Patent Application.
Z is preferably hydrogen. Xj is preferably CH?.
R is preferably protected hydroxy, fl A compound of the invention may be prepared starting from the known compound piperazinone. Piperaz5 inone is reacted with a tertiary-alkoxycarbonyl blocking reagent such as 2-(t-butoxycarbonyloxyimino)-2-phenyl acetonitrile (BOC-ON), t-butoxycarbonylazide or t-amyl chloroformate, in the presence of an anhydrous solvent such as tetrahydrofuran, dimethoxyethane (DME), chloroform, 1,2-dichlorobenzene or toluene, at a temperature of from 0°C to the boiling point of the solvent, preferably at room temperature, for from % hour to 18 hours, preferably about 2 hours, to yield a blocked piperazinone of fonnula VI wherein R , R and R_ are each alkyl. x y z 2 A dianion of formula VII wherein . B is as defined above, is then generated by reaction of the blocked piperazinone of formula VI with a slight excess over 2 equivalents, preferably about 2.2 equivalents, of a dianion-generating strong base selected from alkali metal amides such as sodium amide and dialkylaminolithiums such as diethylaminolithium, dicyclo10 hexylaminolithium and (the preferred reagent) diisopropylaminolithium, which is generated in situ by reaction of an alkyllithium such as n-butyllithium with a dialkylamine such as diisopropylamine. The piperazinone of formula VI is reacted with the base in the presence of an ether solvent such as diethyl ether, THF, DME, 1,4-dioxane or diglyme at a temperature of from -40°C to 20°C, preferably about 0°C, for from 1 to 5 hours, preferably about 3 hours, to yield the dianion.
A suitable electrophilic reagent is added to the reaction mixture and stirred for an additional 1 to 24 hours, preferably about 4 hours, at from 0°C to 50°C, preferably at room temperature, to yield a monoanion of formula VIII wherein Rfi, R^ and B are as defined above and X is CH2, CO, CHOH, S, SO or S02.
Suitable electrophilic reagents for the preparation cf compounds of formula VIII wherein X is CH2 are benzyl halides of the formula wherein halo is bromine, chlorine or iodine and R and 3 Rb are as defined above.
Suitable electrophilic reagents for the preparation of compounds of formula VIII wherein X is CO are benzoyl halides of the formula and benzoate esters of the formula wherein Ra, and halo are as defined above and R is lower alkyl.
When X is CHOH, the dianion of formula VII is reacted with a benzaldehyde of the formula wherein Rfl and R^ are as defined above.
When X is S, the dianion of formula VII is reacted with a benzenesulfenyl halide of the formula halo a bis(benzene) disulfide of the formula or a benzenesulfonothiolic acid ester of the formula wherein Ra, R^ and halo are as defined above.
When x’ifi SO, the dianion of formula VII is reacted with a sulfinyl halide of the formula wherein Rft, R^ and halo are as defined above.
When X’is SOj, the dianion of formula VII is reacted with a sulfonyl halide of the formula RrO~S-halo wherein Rft, and halo are as defined above.
All the reactants illustrated above, for reaction with the dianion of formula VII, are known compounds or may be prepared by methods known in the art.
Compounds of formula VIIIB are compounds of the IS invention in which W and Z are each hydrogen and X^ is X as defined above. A compound of formula VIIIB may be converted to other corresponding compounds of the invention, i.e. X is converted to X^(as defined above), by reaction with a suitable protecting reagent when X is CO or CHOH or by dehydration when X* is CHOH and it is desired that X^ and Z together should be -CH=.
When X*is CO, it is necessary to block the carbonyl moiety of a ketone of formula VIXIB with a carbonyl protecting reagent before attempting to alkylate the 1-nitrogen atom of the piperazine ring. For example, a cyclic ketal may be formed by reacting the ketone with an alkylene glycol of from 2 to 8, preferably 2 to 5 carbon atoms, having 2 to 3 carbon atoms in the chain linking the 2 hydroxy groups. The reaction is conducted in a solvent such as benzene or toluene, in the presence of p-toluenesulfonic acid, for from 12 to 72 hours. The water generated by the reaction is removed azeotropically, typically by use of Dean-Stark trap. Exemplary alkylene glycols are 1,2-ethanediol, which converts the carbonyl moiety to ethylenedioxymethylene, and .2,2-dimethylpropane-1,3-diol, which converts the carbonyl moiety to 2,2-dimethylpropylenedioxymethylene. Similarly, a dialkyl ketal may be formed by reaction of the ketone with a lower alkyl ester of orthoformic acid in the presence of an alcohol solvent such as methanol, and an acidic catalyst such as toluenesulfonic acid or ferric chloride, and ammonium chloride. As acid conditions are employed in forming the ketal-protected carbonyl, it is possible that the nitrogen blocking group will be removed from the piperazine ring during the reaction, . necessitating the reblocking of the nitrogen atom of the ketal-substituted derivative. A dialkyl hydrazone may be formed, for example by reaction of the ketone at the reflux temperature of an alcohol solvent with an. asymmetrical dialkyl hydrazine such as dimethyIhydrazine. Deprotection of the carbonyl moiety may take place at any stage. 49838 When X^ and Z together are methylidene, a compound of formula VIIIB wherein X* la hydroxymethylene, or its alkoxide ion, may be reacted for a period of about 12 minutes to 16 hours, preferably for about >s hour, with an acyl halide such as acetyl chloride; alternatively, the compound is reacted with a hydroxy protecting reagent to afford the protected derivative. For example, the carbinol of formula VIIIB may be reacted in an ice-bath with sodium hydride in dry THF, (2-methoxy10 ethoxy)methyl chloride then being added and the mixture stirred at room temperature for from about % to about 3 hours to yield the (2-methoxyethoxy)methoxy derivative.
When it is desired that Z should be hydrogen, a compound of formula VIIIB in which X* is CHj, S or blocked CO or CHOH is reacted with a slight excess, e.g. about 1.1 equivalents, of a strong base in a suitable solvent for from 3 to 30 hours, preferably about 8 hours, at from -40°C to 20°C, preferably about 0°C. The strong base may be any of those named above, lithium or sodium hydride or sodium hexamethyldisilazine. The reaction generates a monoanion corresponding to formula VIIIB which is then reacted with a Cj_4, preferably methyl, ester df an α-haloacetlc acid, in which the halogen atom is chlorine, bromine or iodine. Stirring for frOm 1 to 24 hours at from 0 to 50°C yields a compound of the invention in which W is CH2COO(Cj_4alkyl) and Z is hydrogen. This compound may be hydrolised by standard methods, e.g. by reaction with aqueous lithium hydroxide in a lower alcohol solvent for from 3 minutes to 4 hours, preferably about fe hour, to yield the corresponding compound in which W is CHjCOOH.
When it is desired that Z should be alkyl, a compound of formula VIIIB, which is protected when X is CHOH, is reacted with an additional 2.2 equivalents of a dianion-generating base (of the type described above) to generate the corresponding dianion which is reacted with an alkyl halide such as methyl iodide or ethyl chloride to yield a 3,3-disubstituted monoanion which is worked up to give a compound of the invention in which W Is hydrogen and Z is alkyl.
Alternatively, the reaction sequence may be performed without interruption. A monoanion of formula VIII wherein X is CHj or S, which is produced by the reaction of an electrophilic reagent with dianion VII, may be reacted without isolation with a e-haloacetic acid ester as defined above to give a compound of the invention in which W is CH2C00(C^_^ alkyl) and Z is H.
A monoanion of formula VIII, wherein X is CHj, CO, SO or SO2, may be reacted without isolation with 1.1 equivalents of strong base, as described above, and the resulting dianion alkylated sequentially by an alkyl halide and an α-haloacetic acid to give a compound of the invention wherein W is CHjCOOfCj-^ alkyl) and Z is alkyl.
When Z is alkyl, the order of alkylation may be reversed. The dianion of formula VII may be reacted with an alkyl halide and the regenerated dianion reacted with an electrophilic reagent of the above-defined type, to give a compound of formula VIIIC wherein X, B, and R^ are as defined above. This π compound of the invention may then be reacted with a base to give tbe monoanion and subsequently with an α-haloacetic acid ester, as described above.
Alternatively, compounds of formula VIIIB or VIIIC wherein X is methylene may be prepared by reductive cyclisation of the corresponding (N-benzyl-N-cyanomethyiphenylalanine derivative according to the general method disclosed in DOS 2,438,965, followed by debenzylation and protection of the ring nitrogen and of hydroxy substituents when they are present. Analogues of formula VIIIB wherein X and Z form methylidene may alternatively be prepared by dehydrohalogenation of the corresponding 3- (α-halobenzyl)piperazinone, for example by the general method disclosed by B. Moureu et al., Bull. Soc. Chim. France (1956) 1785-7, followed by suitable protecting procedures. Compounds of formula VIIIB and Vine so prepared may be alkylated by α-haloacetic acid esters in the above-described manner.
If desired, the individual enantiomers of the piperazinone derivatives may be separated at any stage following the introduction of the asymmetric carbon atom at C-3, by any known means of resolution.
The following Examples illustrate how the compounds of the Invention may be prepared. The Preparation illustrates the synthesis of starting materials.
(Celite is a Trade Mark).
Preparation I t-Butyl 3-Oxo-l-piperazineeaxboxyla.te To a mixture of 2-piperazinone (prepared according to the procedure of S. R. Asplnall, J.A.C.S. 62 (1940) 1202) (1.0 g, 1.0 x lo”2 mole) and sieve-dried THF (15 ml) is added dropwise a solution of dl-tert-butyl dicarbonate (2.4 g, 1.1 χ 10-2 mole) and sieve-dried THF (5 ml). Evolution of CO? occurs immediately and the starting material slowly dissolves. After stirring at room temperature overnight, the solvent is evaporated at reduced pressure affording the title product as a beige solid which crystallises from ethyl acetate/hexane as colourless plates: 1.2 g (60%), m.p. 159 - 161°C.
Example 1 t-Buty1 3-0XO-2-(4-benzyloxybenzyl)-l-piperazlnecarboxy20 late To a solution of dry diisopropylamine (7.7 ml, 5.5 _ A _ Q x 10 mole) and dry THF (25 ml) under argon at OC is added dropwise a hexane solution of n-butyllithium (21.1 ml, 5.5 x lo-2 mole). After stirring % hour at o°C, a solution of t-boc-piperazinone (5.0 g, 2.5 x IO-2 mole) and dry THF (125 ml) is added dropwise. The resultant mixture is stirred at 0°C for 3 hours before a solution of £-benzyloxybenzyl chloride (6.40 g, 2.75 x 10-2 mole) and dry THF (20 ml) is added dropwise via syringe. This mixture is stirred an additional hour at 0°C before the cooling bath is removed and the reaction allowed to warm to room temperature. After stirring overnight, the mixture is quenched into saturated aqueous NB4C1. The aqueous phase Is extracted with EtjO (3 tines) and CHgClg (2 times). The ethereal extracts are combined and subsequently washed with saturated aqueous NaCl, as are the CELgClj extracts. The ethereal and CH^Clj extracts are then combined and dried over NajSO^. Filtration of the drying agent and evaporation of the filtrate gives the title product as an almost colourless solid which crystallises from ethyl acetate as colourless prisms,5.2 g (53%), m.p. 145 - 147°c.
Example 2 t-Butyl 3-ΟΧΟ-2- (4-fluorobenzyl) -1-plperazlnecarboxylate When, in the procedure of Example 1, 4-fluorobenzyl chloride is substituted for p-benzyloxybenzyl chloride, the title compound is produced. M.p. 145 - 147°C.
Example 3 t-Butyl 3-Oxo-2-benzyl-l-plperazlnecarboxylate When, in the procedure of Example 1, benzyl bromide is substituted for p-benzyloxybenzyl chloride, the title compound is produced. M.p. 152-4°C.
Example 4 Methyl 4-(t-Butoxycarbonyl)-2-oxo-3-(4-benzyloxybenzyl)1-plperazlneacetate To a solution of t-boc-(4-benzyloxybenzyl)piperazinone (2.66 g, 6.72 x 10~3 mole) and dry THF (20 ml) under argon at room temperature is added portionwise NaH (0.30 g, 7.4 x 10~3 mole, 59% oil dispersion).
After stirring % hour at room temperature, a solution of methyl o-bromoacetate (0.62 ml, 7.4 x lo”3 mole) is added via syringe. After stirring overnight, the reaction mixture is poured into water which is subsequently extracted with EtjO (3 times). The combined ethereal extracts are washed with saturated aqueous NaCl before being dried over Na2SO4> Filtration of the drying agent and evaporation of the filtrate affords a viscous oil which after column chromatography (silica gel, lo% EtOAc/CHClg) gives a clear, colourless oil. After standing in the refrigerator this oil crystallises. The resulting solid is triturated with hexane and collected by filtration affording the title product as colourless matted needles: 2.3 g (74%), m.p. 84 - 87°C.
Example 5 Methyl 4-(t-Butoxycarbonyl)—2-oxo—3—(4-benzyloxybenzyl)1-piperazlneacetate To a solution of dry dilsopropylamine (0.31 ml, 2.2 mmole) in 2 ml of dry THF at 0°C under argon is added dropwise via syringe a hexane solution of n-butyllithium (0.9 ml, 2.2 mmole). After about ij hour, a solution of t-boc piperazinone (0.200 g, 1.00 mmole) in 5 ml of THF is added dropwise via syringe. The resulting solution is allowed to metallate at 0°C for 3 hours after which a solution of 4-benzyloxybenzyl chloride (0.256 g, 1.1 mmole) in 2 ml of dry THF is added and the resulting solution stirred at 0°C for one hour, allowed to warm to room temperature and stirred overnight.
Methyl α-bromoacetate (0.095 ml, 1.1 mmole) is added to the solution via syringe and the solution stirred overnight at room temperature and quenched into ethyl ether/water. The aqueous phase .is extracted twice with ether and the combined ethereal extracts washed with saturated sodium chloride solution and dried over Na2SO4· The solvent is evaporated and the resulting yellow oil chromatographed with 20% ethyl acetate/chloroform to yield the title product as an oil which crystallises upon standing. M.p. 84 - 87°C.
Example 6 4- (t-Butoxycarbonyl) -2-oxo-3—(4-benzyloxybenzyl) -1piperazineacetic acid t-Boc-plperazlnoneacetate (0.251 g, 5.37 x 10 -4 mole), IK aqueous LIOH (0.59 ml, 5.9 x 10 mole), and methanol 12 ml) are stirred at room temperature for 2 hours. The solvent 1* then evaporated and the resulting yellow oil is dissolved in CHjClj and transferred to a separatory funnel where it is washed with 0.5M agueous HCl. The CH2C12 layer is separated and the acidic agueous phase is extracted with CH2C12 (3 times). The CB2C12 extracts are combined and washed with saturated agueous NaCl before being dried over Na2SOj. Filtration of the drying agent and evaporation of the filtrate gives the title product as a colourless foam, which is shown to be homogeneous by TLC on silica gel plates.
The product's structure is corroborated by NMR.
NMR (CDClj) 6 1.27 (S, 9, t-boc), 3.09-4.07 (m, 8, methylenes), 4.68 (t, 1, Cj-H), 4.97 (S, 2, benzyloxy methylene), 6.89 (g, 4, aromatic), 7.30 (S, 5, aromatic), 9.99 (broad S, 1, acid).
The two enantiomers are separated via salt formation with d-(+)-u-methylbenzylamine and subsequent crystallisation by procedures known in the art.
Following the procedures of Examples 4, 5 and 6, but substituting the product of Example 2 for that of Example 1, methyl 4-(t-butoxycarbonyl)-2-oxo-3-(4-fluorobenzyl) -1-piperazine acetate and then 4-(t-butoxycarbonyl) -2-ΟΧΟ-3-(4-fluorobenzyl)-1-piperazineacetic acid may be prepared. The corresponding 3-benzyl compounds are prepared using the product of Example 3, instead of that of Example 1, in Example 4.
Example 7 t-Buty 1 3—oxo-2-phenyl thio-1-piperazinecarboxylate To a solution of dry diisopropylamine (0.31 ml, 2.2 mmole) and dry THF (2 ml) at 0°C under argon is added, dropwise, a hexane solution of n-butyllithium (0.90 ml, 2.2 mmole). After % hour of stirring a solution of the product of Preparation 1 (0.200 g, 1.00 mmole) in ml of dry THF ls added dropwise and stirring continued for 3 hours. A solution of diphenyldisulfide (0.240 g, 1.10 mmole) in dry THF is added dropwise and the mixture is stirred for 1 hour at 0°C before being allowed to warm to room temperature. Stirring is continued over5 night and the reaction is quenched into ether/water and the aqueous phase extracted twice with ether. The ethereal extracts are washed with brine and dried over Na2S04, and the solvent is evaporated. The resulting yellow oil is chromatographed with 50% ethyl acetate/ chloroform and trlturaturated with ether to afford 0.180 g (59%) of the title product as a colourless solid. M.p. 138-14O°C. Alternatively, the phenyl ester of benzenesulfonothioic acid may be employed in place of diphenyldisulfife.
Methyl 4-(t-Butoxycarbonyl)-2-oxo-3-phenylthio-lpiperazineacetate may be prepared when the product of Example 7 is substituted for that of Example 1 in the procedure of Example 4.
Example 8 t-Butyl 3-oxo-3-benzylidenyl-l-plperazlnecarboxylate To a solution of diisopropylamine (0.31 ml, 2.2 mmole) and dry THF (2 ml) at 0°C under argon is added dropwise a hexane solution of n-butyllithium (0.90 ml, 2.2 mmole). After % hour, a solution of the product of Preparation 1 (0.200 g, 1.00 ssnole) in dry THF is added dropwise and stirred at 0°C for 3 hours, and benzaldehyde (0.11 ml, 1.1 mmole) added dropwise. The reaction is stirred for 1 hour, the cooling bath is removed and the reaction stirred for an additional 2 hours. Acetyl chloride (0.078 ml, 1.1 mmole) is added and the mixture stirred overnight, quenched into ether/water, and purified as described in Example 7. Chromatography on silica gel with 10% methanol/ehloroform yields the title product as a colourless solid.
M.p. 191-193°C.
Methyl 4-(t-Butoxycarbonyl)-2-oxo-3-benzylidenyl) 1-piperazineacetate nay be prepared when the product of Example 8 1» substituted for that of Example 1 in the procedure of Example 4.
Derivatives of t-butyl 3-oxo-l-piperazinecarboxylate which have a 2-substituent which is 4-chlorophenylthio, phenylsulfinyl, phenylsulfonyl or benzoyl may be prepared by following the procedure of Example 1 and replacing the p-benzyloxybenzyl chloride by (4-chloro10 phneyllsulfenyl chloride, benzenesulfinyl chloride, benzenesulfonyl bromide or benzoyl chloride, respectively Alternatively, the 2-benzoyl derivative may be obtained by using ethyl benzoate instead of g-benzyloxybenzyl chloride. t-Butyl 2-(4-chlorophenylthio)-2-methyl-3-oxo1-piperazinecarboxylate and the corresponding 2-phenylsulfinyl, 2-phenylsulfonyl and 2-benzoyl compounds may be prepared following the procedure of Example 1 but substituting the products of the preceding paragraph for the product of Preparation 1 and methyl iodide for g-benzyloxybenzyl chloride.
Methyl 4-(t-butoxycarbonyl)-2-oxo-3-(4-chlorophneylthio)-3-methy1-1-piperazineaoetate and the corresponding 3-phneylsulfinyl, 3-phenylsulfonyl and 3-benzoyl compounds may be prepared following the procedure of Example 4 but substituting the products of the preceding paragraph for that of Example 1.
Example 9 t-Butyl 3-0ΧΟ-2- (a-hydroxy-4-f luorobenryl) -1-piperaalne carboxylate To a solution of diisopropylamine (3.1 ml, 22 mmole) and dry TBE (5 ml) at 0°C under argon is added dropwise a hexane solution of n-butylllthium (13.8 ml, mmole). After i hour, a solution of the product of Preparation 1 (2.0 g, 10 mmole) in 75 ml of dry THF is added dropwise and stirred at 0°C for 3 hours and 4-fluorobenzaldehyde (13.6 g, 11 mmole) added dropwise. The reaction is stirred at room temperature for 68 hours, poured into water, and extracted into ether.
The extract is washed with brine, dried over MgSO4, and concentrated under reduced pressure, and the residue recrystallised from ethanol to give the title product. M.p. 219°C (dec.).
Example 10 t-Buty1 3-Oxo-2-(a (2-methoxyethoxy)methoxy—4 -fluorobenzyl) -1-piperazine carboxylate To 0.13 g (0.0054 mole) of NaH (0.22 g of a 61% dispersion in oil, washed with hexane) in 10 ml of dimethylformamide (DMF) is added 1.6 g of the product of Example 9 in 20 ml of dry DMF, and the mixture stirred at 0°C for 30 minutes. A solution of 0.67 g (0.0055 mole) of (2-methoxyethoxy)methyl chloride in 5 ml of dry DMF is added and the mixture allowed to warm to room temperature, stirred for 1 hour, and poured into 50 ml of water. The product is extracted into ethyl acetate and the extract washed with brine and dried over MgSO^. After filtration, the solvent is removed at removed at reduced pressure and the residue triturated with hexane and filtered to give the title compound.
Example 11 t—Butyl 3-0xo—2- (o-ethylenedioxybenzyl)-1-piperazine carboxylate ' · A mixture of 2.0 g (6.5 nmole) of t-butyl 2-benzoyl-3cxd-1-piperazine cartmcyiate, 1.25 g (20.0 nmole) of ethylene glycol, and 1.0 g of p-toluenesulfonic add ncnohydrate is refluxed in 50 ml of benzene in a Dean-Stark apparatus until the collection of water ceases. The reaction mixture is cooled, washed with saturated NafCO. solution and brine, dried over MgSO^, and filtered. The filtrate is stirred with 2.2 g (10 nmole) of dl-t-butyldicarbonate at reflux temperature, concentrated to a solid residue and recrystallised fran benzene/hexane to yield the title unbound.

Claims (5)

1. λ compound of the formula I ? R *- R y R_ % R. wherein W is hydrogen, CHjCOOH or CH 2 COO(C 1-4 alkyl); 5 (i) z is hydrogen or Cj_ 4 n-alkyl and X^ is -CHj-, -S- or optionally blocked -CO- or -CHOH-, (ii) Z is Cj_ 4 alkyl and is -SO- or -SOj-, or (ill) Z and Xj together are -CH»; either R # is hydrogen, halogen or protected 10 hydroxy and R^ is hydrogen or R ft and R^ are each protected hydroxy; and R x , Ry and R z are each alkyl; with the provisos that R & is halogen when W is hydrogen and X^ is -CHj- and that R& is not hydrogen when 15 W is hydrogen and Z and Xj together are -CH».
2. A compound as claimed in claim, wherein Z is hydrogen.
3. A compound as claimed in claim 2, wherein X^ is CHj.
4. A compound as claimed in any preceding claim, 20 wherein R ft is protected hydroxy.
5. A compound as claimed in claim 1, which is named herein.
IE625/85A 1979-06-21 1980-06-04 2-piperazinone derivatives IE49835B1 (en)

Applications Claiming Priority (3)

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US5095079A 1979-06-21 1979-06-21
US06/130,431 US4341698A (en) 1979-06-21 1980-03-14 Enkaphalin derivatives
IE1152/80A IE49834B1 (en) 1979-06-21 1980-06-04 Enkephalin derivatives

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