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WO1997014685A1 - Derives de pyrimidine - Google Patents

Derives de pyrimidine Download PDF

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Publication number
WO1997014685A1
WO1997014685A1 PCT/HU1996/000058 HU9600058W WO9714685A1 WO 1997014685 A1 WO1997014685 A1 WO 1997014685A1 HU 9600058 W HU9600058 W HU 9600058W WO 9714685 A1 WO9714685 A1 WO 9714685A1
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WO
WIPO (PCT)
Prior art keywords
formula
hydroxy
optionally substituted
group
defined above
Prior art date
Application number
PCT/HU1996/000058
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English (en)
Inventor
Zoltán ZUBOVICS
Katalin SZILÁGYI
Franciska Vida
Ferenc ANDRÁSI
Klára SUTKA
Eszter Hodula
Tibor Szekeres
Gábor FEHÉR
Imre Moravcsik
Péter MÁTYUS
László Sebestyén
Hilda SZABÓ
Erzsébet ZÁRA
Edit HORVÁTH
Lajos Toldy
Original Assignee
Gyógyszerkutató Intézet Kft
TOLDY, Rózsa
TOLDY, Márta
TOLDY, András
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Gyógyszerkutató Intézet Kft, TOLDY, Rózsa, TOLDY, Márta, TOLDY, András filed Critical Gyógyszerkutató Intézet Kft
Priority to HU9900088A priority Critical patent/HUP9900088A2/hu
Priority to AU73259/96A priority patent/AU7325996A/en
Publication of WO1997014685A1 publication Critical patent/WO1997014685A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/50—Three nitrogen atoms

Definitions

  • This invention relates to novel pyrimidme deriva ⁇ tives capable to effectively inhibit the peroxidation of lipids. More particularly, the invention refers to novel pyrimidine derivatives of formula (I),
  • R stands for a moiety of formula (a)
  • Ar means a C 6 - ⁇ o aromatic homocyclic group
  • R 4 and R 3 independently from each other, represent hydrogen, halogen, hydroxy, C:- ⁇ al yl, C ⁇ - 4 alkoxy optionally substituted by phenyl, C ⁇ _ 4 alkylthio,
  • R" and R ⁇ independently from each other, stand for ammo; or a moiety derived from a 5-8-membered saturated heterocycle containing at least one nitrogen atom;
  • X means a single bcr. ⁇ ; a sulfur atom optionally substi ⁇ tuted one or two oxygen atcmls, or an optionally substituted nitrogen atom;
  • A stands for a straight or branched chain C ; - alkylene group optionally substituted by halogen, hydroxy, C;- alkoxy optionally substituted by phenyl, c 4 al- kanoyloxy, optionally substituted ammo and/or oxo; and n is 1 or 2, with the proviso that when
  • R" means a moiety cf formula (a) , wherein Ar means phenyl; and at least one of R J and R ; ⁇ .ands for halogen, hy ⁇ droxy, C.-3 al yl, C;. alkoxy, C .., alkanoyloxy or ethanesulfor.yloxy;
  • A may not be unsubstituted C alkylene; and with the further proviso that when R" is 2, 5-dihydroxybenzoyl; A may not be alkylene substituted by oxo; as well as their salts and pharmaceutical compositions containing these compounds.
  • the invention refers also to a process for the prepa ⁇ ration of the above pyri idine derivatives.
  • the novel in ⁇ termediates of formula (II) are also to a process for the prepa ⁇ ration of the above pyri idine derivatives.
  • the objective of the present invention was to find novel synthetic pyrimidme derivatives, which effectively inmbit the lipid peroxidation and are consequently use ⁇ ful to treat certain diseases and conditions in mammals, including man, where the inhibition of lipid peroxidation is desired.
  • One important class of these known compounds is rep ⁇ resented by substances wherein the group derived from the above-mentioned heterocycle containing one or more nitro- gen(s) is e.g. a pyridinyl, pyrimidinyl or triazinyl group bearing optionally substituted amino group (s) [such as the 2, 6-d ⁇ (substituted ammo) -4-pyr ⁇ midinyl moiety oc ⁇ curring also in the compounds of the present invention) .
  • said hydrocarbon group of these compounds may be varied within a wide range: it may be e.g. a group with a steroidal skeleton (see the PCT patent applica ⁇ tions published under Nos.
  • character- istic compounds contain, besides nitrogen heterocycles which are nearly the same as those mentioned in the pre- ceding paragraph, hydrocarbon groups that are either similar to or different from those mentioned above.
  • the characteristic hydrocarbon based moiety is e.g. phenyl, benzyl or benzhydryl group [French patent specification No. 1,507,062; published German patent ap ⁇ plications Nos. 1,947,332 and 2,211,738; Belgian patent specification No. 739,283; Canadian patent specification No. 983,497; as well as published Japanese patent appli ⁇ cation (Kokai) No. 74/76887]; benzodioxolyl or benzodi- oxanyl group [Canadian patent specifications Nos. 979,894, 983,493, 983,494 and 983,495 as well as pub ⁇ lished Japanese patent applications Nos.
  • ether compound types are also reported m the literature to possess a lipid peroxidation inhibitory effecr. This s exemplified by some compound classes as follows:
  • Cyclic hydroxamic acids [Y. Teshima et al . : J. Anti- blot. 44, 685 (1991)]; dehydroalanme derivatives [P. Buc-Calceron et al.: Arch. Biochem. Biophys. 273, 339 (1989)]; acylated polyamines [J. M. Braughler et al.: Biochem. Pharmacol. 37, 3853 (1938)]; glutathione analogues [Drug Data Reports 12, 339 (1990)]; amino analogues of vitamin C (published European pat ⁇ ent applications Nos. 446,539 and 447,325); monocyclic analogues of vitamin E (Japanese patent specification No. 01,226,843); other derivatives of vitamin E [R. Nikolov: Drug News & Perspectives 5, 507 (1992)];
  • methylprednisolone e.g. H. ⁇ . Demopoulos et al . : J. Physiol. Pharm. 60, 1415 (1982)]; flavonoids [e.g. R. Campos et al. : Planta Med. 55, 417 (1989)]; pyrazolmo ⁇ e derivatives [K. Abe et al.: Stroke 19, 480 (1988)]; pyrazolone ⁇ erivatives (published Japanese patent ap ⁇ plication No. 62-149,617); thiazolidinediones [T. Yoshicka et al . : J. Med. Chem.
  • Example 35 of the Hungarian patent application No. P 92 02172 a compound, namely l-[6- (2, 5-d ⁇ hydroxyben- zoylammo) -caproyl]-4-[2, 6-d ⁇ (1-pyrrol ⁇ dmyl) -4-pyr ⁇ m ⁇ d ⁇ - nyl]p ⁇ perazme is described, which is to some degree structurally similar to a variant, containing a benzoyl group, of compounds cf formula (I) of the present inven ⁇ tion, and exerts a remarkable lipid peroxidation mhibi- tory effect.
  • tnere are known compounds showing cer ⁇ tain structural relations to the compounds of formula (I) of the present invention, namely substances of formula (A)
  • Lip means inter alia 1- or 2-naphthyloxy; or 1,2,3,4- -tetrahydro-6-napnthyloxy substituted Dy oxo;
  • a : and A * represent single bond(s) or C ; . alkylene op ⁇ tionally substituted by hydroxy or oxo; n is 1 or 2; and Ke :an ⁇ s i r. ter al ⁇ ⁇ group cr tor: ,3)
  • R means ammo or 1-pyrrol ⁇ dmyl group.
  • the compounds of formula (A) mentioned aoove showed a remarkable lipid peroxidation inhibitory effect under in vi tro conditions.
  • e value of lower than 30 ⁇ M (the test method will be discussed hereinafter) .
  • n mice Under i n vi vo conditions m a head injury model n mice a dose of 20 mg/ g of the most active compound among the napnth ⁇ yloxy derivatives, .e. the l-[2, 6-d ⁇ (1-pyrrol ⁇ dmyl) -4- -pyr ⁇ m ⁇ dmyl]-4-[2-hydrcxy-3- (2-naphthyloxy)propyl]homop ⁇ - perazme of Example 27, induced a 82 . increase in the total score characterizing the neurologic state of the O 97/14685 "" - ,_ _ -_,. PCT/HU96/00058
  • Example 31 the IC value of l-[2, 6-d ⁇ (1-pyrrol ⁇ d ⁇ nyl) - -4-pyr ⁇ m ⁇ dmyl]-4-[2-hydroxy-3- (2-naphthylam ⁇ no)propyl]- piperazme of Example 31 was 2 ⁇ M; that of l-[2,6-d ⁇ (l- -pyrrolicmyl) -4-pyr ⁇ m ⁇ dmyl]-4-[2-hydroxy-3- (2-naphthyl- ammo) propyl]homop ⁇ perazme according to Example 34 was 4 ⁇ M; that cf l-[2, 6-d ⁇ ( 1-pyrrol ⁇ dmyl) -4-pyr ⁇ m ⁇ dmyl]-4-[2- -hyoroxy-3- (2-naphthylth ⁇ o)propyl]homop ⁇ perazme accord ⁇ ing to Example 37 was 10 ⁇ M; and that of l-[6-(2,5- -o ydroxy
  • these compounds exerted a much stronger protective action under in vi vo conditions, and this action can oe explained by their lipid peroxidation nibitory effect detectable under in vi tro conditions.
  • these substances showed a surprising sur ⁇ plus effect when they were compared either to known com ⁇ pounds remote from those of formula (I), or to known com ⁇ pounds m some structural relation to those of formula (I), e.g. compounds of formula (A) containing a naphthy- loxy group.
  • a 2.5 mg/kg dose of l-[2,6- -di (1-pyrrol ⁇ d ⁇ nyl) -4-pyr ⁇ m ⁇ dmyl]-4-[2-hydroxy-3- (2-naph- thylammo) propyl]homop ⁇ perazme according to the present invention (compound of Example 34) augmented the total score by 119 * in the same test; and a 2.5 mg/kg dose of l-[6- (2, 5-d ⁇ hyoroxybenzoylam ⁇ no) hexyl]-4-[2, 6-d ⁇ (1-pyrro- lidinyl) -4-pynm ⁇ dmyi]p ⁇ peraz ⁇ ne (compound of Example 1) of the present invention resulted in a total score in ⁇ crease of 125 _.
  • the present invention relates to novel pyrimidine derivatives of formula (I) and their salts, wherein R', R : , R " , X, A and n are as defined above.
  • Some representative compounds of formula (I) accord ⁇ ing to the present invention contain one or more asymmet ⁇ ric carbon atom(s); therefore, they can exist either in the form of stereoisomers (e.g. enantiomers or diastereo- mers) or their mixtures (e.g. racemates of enantiomers) .
  • the scope of the present invention includes also the pure stereoisomers, the racem c and other mixtures of compounds of formula (I) as well as the salts, especially pharmaceutically acceptable salts, of all these co - pounds.
  • R" or R ; in formula (a) being present as R" means an optionally substituted amino group
  • the said substitu- ent of the amino group may be e.g. one or two C ; - 4 alkyl,
  • C-.-4 alkanoyl C.- 4 alkoxycarbonyl optionally substituted by phenyl, C . - ⁇ alkylsulfonyl or arylsulfonyl group.
  • R may be (but not limited to) 1-naphthyi, 2- -naphthyl, l-chloro-2-naphthyl, 4-chloro-l-naphthyl, 5- -chIoro-2-naphthyl, l-bromo-2-naphthyi, 5-brcmo-2- -naphthyl, 6-bromo-2-naphthyl, 1, 6-d ⁇ bromo-2-naphthyl, 5, 8-dibromo-2-naphthyl, 2-hydroxy-l-naphthyl, 4-hydroxy- -1-naphthyl, 3-hydroxy-2-naphthyi, l-hydroxy-2-naphthyl, 4-methoxy-l-naphthyl, 6-methoxy-i-naphthyl, 6- ⁇ r.ethoxy-2--
  • R" preferably represents e.g. 3- -hydroxy-2-naphthyl or l-hydroxy-2-naphthyl group; whereas in the case, when the meaning of X is different from a single bond, R" preferably stands for 1-naphthyl, 2-naphthyI, 2-naphthylmethyl, 2- (2-naphthyl) acetyl group or 2, 5-d ⁇ hydroxybenzoyl .
  • a substituent optionally being present on the naphthyi group may be at- tached to any carbon atom of any ring of tne naphthyi moiety; but preferably, it is attached to a carbon atom of the same ring, which bears the X group.
  • R 4 and R substituents within the groups of formula (a) being present as R 1 (e.g. hydroxyl, amino and/or carboxyl group) may be protected, if desired.
  • R 1 e.g. hydroxyl, amino and/or carboxyl group
  • substituents within the groups of formula (a) being present as R 1 may be protected, if desired.
  • R 1 e.g. hydroxyl, amino and/or carboxyl group
  • R 1 e.g. hydroxyl, amino and/or carboxyl group
  • R and R " may be (but not limited thereto) , independ ⁇ ently from eacn other, amino, 1-pyrrolidmyl, 1-p ⁇ per ⁇ - dinyl, hexahydro-lH-azepm-1-yi or cctahydroazccm-I-yi group and preferably amino and/or pyrrolidinyl group.
  • X may stand (but not limited thereto) e.g.
  • sulfur optionally substituted by one or more oxygen atom(s), an unsubstituted nitrogen or nitrogen op ⁇ tionally substituted by methyl, ethyl, formyl, acetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, methanesulfonyl or p-toluenesulfonyl group and preferably a simple chemical bond, sulfur or unsubstituted nitrogen.
  • A may be e.g.
  • a C - posture alkoxy group optionally substituted by a phenyl group can be considered as a pro- tected hydroxyl group; whereas e.g. an amino group sub ⁇ stituted by a C - alkanoyl group or a C _ ⁇ alkoxycarbonyl group optionally substituted by a phenyl group or C . - 4 al- kylsulfonyl group may be considered to be a protected amino group.
  • the value of n is 1 or 2, and preferably 1.
  • Suitable salts of the compounds cf formula (I! con ⁇ taining basic groups are e.g. the salts formed with inor ⁇ ganic acids (e.g. hydrochloric, hydrobromic, sulfuric, phosphoric acid and the like) or with organic acids (e.g. acetic, tartar c, citric, fuir.aric, succmic, maleic, methanesulfonic, ethanesulfonic or p-toluenesulfonic acid and the like) .
  • compounds of formula (I) con ⁇ taining a phenyl or naphthyi group substituted by hydroxy and/or carboxy can form salts with bases in addition to the acid-addition salts.
  • Suitable salts formed with bases are e.g. the alkali metal salts (such as sodium or potas- O 97/14685 - I S - PCT/HU96/00O58
  • sium salts alkaline earth metal salts , e.g. calcium or magnesium, salts) and the like; as well as salts formed with some organic bases such as ethanolamme, diethanoia- mine, ethylenedia ine and the like.
  • R " and R" are as defined above and Z means a leaving group; or b) in order to obtain compounds cf formula (I), wherein R', ?.-, R 3 and n are as defined above; A is as defined above, with the proviso that it may not be alkylene substituted by halogen, ammo cr C;-,, alkylaminc; and
  • X is as defined for the formula (I), with the pro ⁇ viso that it may not be a single bond or a sulfur atom substituted by one or two oxygen atom(s), a compound of formula (IV),
  • R : , R 3 , A and n are as defined above and Z means a leaving group; cr c) in order to obtain compounds of formula (I), wherein R", R", R- ' and n are as defined above;
  • A is as defined above, with the proviso that it may not be alkylene substituted by halogen, amino or C;.j alkylaminc; and
  • X is as defined above, with the proviso that it may- net be a single bond, a compound of formula (VI),
  • R -X-A-Z (VI) wr.e em R , X and A are as defined above and 2 ⁇ *ea ⁇ 3 ⁇ leaving group, s reacted with a compound of formula
  • R", R", R 3 and n are as defined above; and X s as defined above, with the proviso that it may not be a single bond, a compound of ormula (VIII) ,
  • R', R", R J and n are as defined above; and X is as defined for formula (I), with the proviso that it may not be a single bono or a sulfur atom substituted by one or two oxygen atom(s), a compound of formula (IV), wherein R and X are as de ⁇ fined above, s reacted with a compound of formula (IX),
  • R', R", R", X and r. are as defined above; and B * means a single bond or a straight or branched chain C -- alkylene group optionally substituted by halogen, C... alkoxy, C - alkanoyloxy and/or an optionally substituted ammo group, a carboxylic acid of formula (X) , R - -X -3 ' -C0CH ( X !
  • R", R", R J and n are as defined above;
  • X stands for a nitrogen atom optionally substituted by a C alky group; and B" means a straight or branched chain C.. 3 alkylene group optionally substituted by hydroxy, C 4 alk ⁇ oxy and/or di;C- . - 4 alkyl) ammo group, a compound of formula ,XI),
  • Z means a leaving or hydroxyl group and R : is as defined above, with the proviso that p, q and r are 0 when Z means a nydrcxyl group, is reacted with a compound of formula (XII) ,
  • R", R 3 , B : , X and n are as defined above, and, if desired, a compound of formula (I) obtained by using any of the process variants a) to g) is transformed to an other compound of formula (I) m a manner known per se; and/or a protective group optionally being present is removed; and/or, if desired, a base is prepared from an obtained salt of the compound cf formula (I); or the ob ⁇ tained base is transformed to one of its salts, e.g. to its acid-addition salt.
  • Pure enantiomers of a compound of formula (I) con ⁇ taining one single centre of asymmetry can be obtained e.g. by resolution cf a racemic compound cf formula (I) prepared by means of racemic reagents by using methods known par se (e.g. by formation and separation of diastereomeric salts or other derivatives) ; or, by carry ⁇ ing out the above process variants with the pure enanti- o eric forms of the required reagents.
  • the diasterecmers of a substance of formula (I) m- eluding more centres of asymmetry can be separated by us ⁇ ing methods known per se, e.g. chromatography, fractional crystallization cr ether similar methods.
  • the protective group (s) is (are) removed without any undesired change in other parts of the molecule.
  • usual protective groups known per se may be employed, e.g. C -4 alkyl groups optionally substituted by an aryl group (such as tert-butyl or benzyl group) for protecting hydroxyl groups; C - 4 alkoxycarbonyl groups optionally substituted by an aryl, e.g. phenyl group (e.g. tert- -butoxycarbonyl or benzyloxycarbonyl group) , C - 4 alkanoyl groups (e.g.
  • C -4 alkanesulfonyl groups e.g. methanesulfonyl group
  • p-toluenesulfonyl group for protecting ammo groups
  • C _ 4 alkyl e.g. ethyl ester groups for protecting carboxyl groups.
  • any other protective group Known per se [such as the ones discussed by T. W. Greene and P. Wuts m: "Protective Groups in Organic Synthesis", John Wiley _ Sons, New York, N.Y. (1991)] may be employed. Suitable methods of cleaving protective groups are discussed the same work cited above.
  • reaction steps of the proc ⁇ ess according tc the present invention can be performed also without t e transient protection of reactive groups not participating in the desired reaction.
  • Process variant a) (Reaction scheme A) A compound of formula (II) is reacted with a compound of formula (III) in a suitable solvent such as chlcroben- zene, dimethylfor amide, dimethylacetamide, N-methylpyr- rolidone or the like; or optionally without any solvent, at a temperature between 100 ⁇ C and 200 °C and, if neces ⁇ sary, in the presence of a base, e.g. inorganic base such as potassium carbonate or sodium hydroxide, or an organic base, e.g. triethyiamine or pyridine as acid-binding agent. When carrying out the reaction in the absence of any base, the liberated acid of formula H-Z may be bound by the product of formula (I) .
  • a suitable solvent such as chlcroben- zene, dimethylfor amide, dimethylacetamide, N-methylpyr- rolidone or the like; or optionally without any solvent, at a temperature
  • n is the same as defined for formula ( I ) ;
  • R" means an amine-protecting group, which i s t rans f ormed to a compound cf formula (XIV) ,
  • R : , X, A and n are as defined for formula (I);
  • R stands for an amine-protect g group, by using any of methods A) to E) to be discussed herein ⁇ after; then, after cleaving the protective group, a com ⁇ pound of formula (II) is obtained.
  • the difference between the methods starting from compounds cf formula (XIII) is that they provide the intermediate of formula (XIV) by means of various reagents.
  • the variants of preparing the intermediates of formula (XIV) are described hereinafter in detail [methods A) to C) are illustrated by reaction scheme H, whereas methods D) and ⁇ ) are shown by reaction scheme I] .
  • R " and n are as defined for formula (I);
  • X means a sulfur atom optionally substituted by one cr two oxygen atom(s) or an optionally substituted ni ⁇ trogen atom; and A stands for C-.- 9 alkylene substituted by hydroxy, C : alkoxy or C-..
  • a compound of formula (XIII), wherein R 4 means an amine- protecting group and n is as defined above, may be re ⁇ acted with a compound of formula (VI), wherein R 1 , X and A are as defined above, and Z is a leaving group, to give a compound of formula (XIV) , wherein R , R , X, A and n are as defined above.
  • This reaction is suitably carried out m a solvent, e.g. ethanol, propanol, acetonitrile or the like, in the presence e.g. of an inorganic base such as potassium car ⁇ bonate or sodium hydroxide, in a temperature range be ⁇ tween 20 °C and 100 ⁇ C.
  • a solvent e.g. ethanol, propanol, acetonitrile or the like
  • an inorganic base such as potassium car ⁇ bonate or sodium hydroxide
  • R 4 means an amme-protective group, e.g. alkanoyl group such as for yl group or preferably a C - 4 alkoxycarbonyl group op ⁇ tionally substituted oy aryl group such as tert-butoxy- carbonyl or benzyloxycarbonyl group.
  • alkanoyl group such as for yl group or preferably a C - 4 alkoxycarbonyl group op ⁇ tionally substituted oy aryl group such as tert-butoxy- carbonyl or benzyloxycarbonyl group.
  • a part of the pro ⁇ tected piperazme and homopiperazine derivatives of for- mula (XIII) is known [see e.g. T. R. Herrm et al.: J. Med. Chem. 18, 1216 (1975)] or can be prepared by methods analogous to known ones.
  • Z means a leaving group, suitably e.g. halogen such as chlorine, bromine or iodine; or an aliphatic or aromatic sulfonyloxy group sucn as methane- sulfonyloxy or p-toluenesulfonyloxy group.
  • a part of the compounds of formula (VI) is known [see e.g. E.K. Harwill et al.: J. Org. Chem. 17, 1957 (1952); and L.M. Schemel : J. Med. Chen. 6, 637 '1963)] or they can be prepared by using simple methods Known per se .
  • compounds of formula (VI) containing C . .- alkylene group as A may be prepared e.g. as illustrated in reaction scne e J start ⁇ ing with alcohols of formula (XIX) ,
  • R' and X are as defined above; and B stands for a C;-. alkylene group by using methods known per se .
  • compounds of formula (VI), con ⁇ taining an alkylene group substituted by oxo at the car ⁇ bon atom attached to X are suitably prepared by reacting an appropriate compound of formula (IV), wherein R * and X are as defined above, with a carboxylic acid of formula (XX) ,
  • B 3 means a C.-- alkylene group
  • Z is a leaving group, or with a reactive derivative thereof activated at the carboxyl group (see reaction scheme J) .
  • X means a sulfur atom optionally substituted by one or two oxygen atom(s) or an optionally substituted ni ⁇ trogen atom; and A stands for 2-hydroxy-l, 3-propylene group, a protected compound of formula (XIII), wherein R' 1 stands for an amme-protective group; and n is as defined above, is reacted with an epoxide of formula (VIII), wherein R' and X are as defined above, to obtain a compound of for- mula (XIV), wherein R', R ⁇ X, A and n are as defined above.
  • This reaction is conveniently performed in a solvent such as an alcohol, e.g. ethanol, at a temperature be ⁇ tween 20 °C and 100 ⁇ C, preferably at the boiling point of the solvent.
  • a solvent such as an alcohol, e.g. ethanol
  • R", X and n are as defined for formula (I); and A stands for C _- alkylene substituted by oxo at the carbon atom attached to the nitrogen-containing het ⁇ erocycle, a protected compound of formula (XIII), wherein R "1 means an amme-protecting group; and n is as defined above, is reacted with a carboxylic acid of formula (X) , wherein R * and X are as defined above; and B- means a single bond or C 1 --1 alkylene, cr a reactive derivative thereof activated at the car ⁇ boxyl group to obtain a compound cf formula (XIV) , wherein R", R ⁇ X, A and n are as defined above.
  • Such reactive forms are e.g.: acyl halides, e.g. an acyl chloride or acyl bromide; active esters, e.g. an aryl ester such as a phenyl ester; sym ⁇ metric or mixed anhydrides, e.g. a mixed anhydride pre ⁇ pared by means of a chloroformate ester and the like.
  • X and B are as defined for formula (X ) ; and Ar, R" and R are as defined for Ar, R" and R , respec ⁇ tively, forming a part of the group of formula (a) , with the proviso that R 4 and R 5 may not mean unsub ⁇ stituted ammo or am o substituted by a C,- 4 alkyl group.
  • lactons are the intramolecular aryl esters of the respective acids.
  • Some compounds of formula (X) such as 1-naphtho ⁇ c acid, 2-naphtho ⁇ c acid, 1-naphthylacet ⁇ c acid, 1-hydroxy- -2-naphtho ⁇ c acid, 3-hydroxy-2-naphtho ⁇ c acid are commer ⁇ cially available; whereas other ones, e.g. 2- (2-hydroxy- -1-naphthyl) acetic acid, 2- (3-hydroxy-2-naphthyl) acetic acid or 3- (2-hydroxy-l-naphthyl) propionic acid and their lactones of formula (XXI) [see e.g. Y. Ogata et al.: J. Org. Chem.
  • R ano n are as defined for formula (I);
  • X is as defined for formula (I), with the proviso that it may not be a single bond or a sulfur atom substi ⁇ tuted by one or two oxygen atom(s); and A stands for C . ._ alkylene substituted by hydroxy, C -; alkoxy, C ;-4 alkancyloxy cr optionally substituted by oxo at the carbon atom attached to X, a compound of formula (XIII), wherein R' means an amme-protective group; and n is as defined above, is first reacted with a compound of formula Z'-A-Z : , wherein
  • A is as defined above; and Z ' as well as Z ⁇ mean, independently from each other, leaving groups, to give a compound of formula (XV) ,
  • Both reactions may be carried out similarly as de- scribed in method A) .
  • the starting compounds cf formula Z"-A-Z " are commer ⁇ cially available cr may be prepared by using simple meth ⁇ ods known per se .
  • R ⁇ A and n are as defined above;
  • X represents a nitrogen atom optionally substituted by a C - 4 alkyl group, is obtained.
  • This suostitution reaction can be performed e.g. by reacting the compound of formula (XV) with ammo ⁇ nia, a C ., alkylamme cr potassium phthalimide in a man ⁇ ner known per se an inert solvent, such as an aii- phatic alcohol, dimethylformamide or the like.
  • an inert solvent such as an aii- phatic alcohol, dimethylformamide or the like.
  • potassium nthalimi ⁇ e the phthalimido compound obtained is treated e.g. with hydrazine an aliphatic alcohol in a manner known per se to provide the required substance of formula (XVI) .
  • R , ?.', A ano n are as defined abcve;
  • R * and n are as defined for formula (I);
  • X is as defined for formula (I), with the proviso that it may not be a single bond or a sulfur atom substi ⁇ tuted by one or two oxygen atoms; and
  • A stands for 2-hydrcxy-l, 3-propylene group, a protected compound cf formula (XIII), wherein R" means an amine-protective group; and n is as defined above, is first reacted with epichlorohyd ⁇ n and then the ob ⁇ tained epoxide of formula (XVII),
  • a compound of formula (XIII I can be reacted with epichiorohydrin e.g. by using methods described above for the preparation of the compounds of formula (VIII) .
  • compounds of formula (XVII; obtained as intermediates can be reacted with compounds of formula .IV) under conditions discussed in method 3) above.
  • an epox ⁇ ide of formula (XVII) prepared as described above is re ⁇ acted with ammonia or a C ; . 4 alkylamine in a suitable sol- vent, e.g. water cr an aliphatic alcohol or a mixture thereof, to give a compound of formula ,
  • R" and n are as defined above;
  • X means a nitrogen atom optionally substituted by a C : . 4 alkyl group, then the obtained compound is reacted with a compound of formula (XI), wherein R- is as defined above;
  • Z stands for a leaving group, under the conditions discussed in method D) , again to ob ⁇ tain a compound of formula (XIV) , wherein R-, R ⁇ A and n are as defined above; and X stands for a nitrogen atom optionally substituted by a C;- 4 alkyl group.
  • the protective group R 4 can be removed from compounds of formula (XIV) prepared by the above methods A) to E) to afford compounds cf formula (II) .
  • alkanoyl type protective groups can be removed by acidic or alkaline treatment; C : - 4 alkoxycarbonyl groups can be removed e.g. by treatment with an acid; whereas C.- 4 alkoxycarbonyl groups substituted by an aryl group can be split off e.g. by catalytic hydrogenation.
  • a part of the starting compounds of formula (III; used in process variant a) is known [see e.g. B. Roth et al.: J. Am. Chem. Soc. 72, 1914 (1950); and published PCT patent application No. WO 87/01706], whereas an ether part thereof can be obtained from starting compounds of formula (XXII! ,
  • R " and R 3 are as defined for formula (I) , by us ⁇ ing methods known per se in a route illustrated by the reaction scne e K.
  • reaction scheme B A compound of formula (IV) is reacted with a compound of formula (V) a suitable solvent, e.g. ethanol, ace ⁇ tone or dimethylformamide, conveniently in the presence of a base such as an inorganic base, e.g. potassium car ⁇ bonate or sodium hydroxide, or an organic base, e.g. pyridme or triethylamine, at a temperature between room temperature and the boiling point of the solvent used.
  • a suitable solvent e.g. ethanol, ace ⁇ tone or dimethylformamide
  • the starting compounds of formula (IV) are commer ⁇ cially available wnereas the compounds of formula (V) are partly known (see e.g. the published European patent ap- plication No. 0,574,906A); or they can be prepared simi ⁇ larly to known substances by using known methods.
  • reaction scheme C A compound of formula (VI) is reacted with a compound of formula (VII) in an inert solvent, e.g. acetone, ace ⁇ tonitrile, or dimethylformamide, suitably in the presence of a base, e.g. potassium carbonate or the like, at a temperature between room temperature and the boiling point of the solvent used.
  • an inert solvent e.g. acetone, ace ⁇ tonitrile, or dimethylformamide
  • a compound of formula (VIII) is reacted with a com ⁇ pound of formula (VII) in an inert solvent, e.g. a halo- genated hydrocarbon such as methylene chloride or in an alcohol, e.g. ethanol or the like, at a temperature be- tween room temperature and the boiling point of the sol ⁇ vent used.
  • an inert solvent e.g. a halo- genated hydrocarbon such as methylene chloride or in an alcohol, e.g. ethanol or the like
  • reaction scheme E A compound of formula (IV) is reacted with a compound of formula (IX) under conditions described for process variant d) .
  • the starting compounds of formula (IX) can simply be prepared by reacting the compounds of formula (VII) with epichlorohydrm in a manner described e.g. for the prepa ⁇ ration of compounds cf formula (VIII) as illustrated by reaction scheme L.
  • reaction scheme F The free acid form of a compound of formula (X) or a reactive form thereof activated at the carboxyl group is reacted with a compound of formula (VII) .
  • This reaction can be carried out under similar conditions as the start ⁇ ing compounds of formula (II) of process variant a) are obtained according to the above-described method C) .
  • the present process variant f) e.g. the following characteristic compounds according to the present invention can be prepared: 1 [2, 6-di (1-pyrrolidinyl) -4-pyr ⁇ m ⁇ d ⁇ nyl]-4- (1-
  • a compound of formula (XI) containing a hydroxyl group as Z is reacted with a compound of formula (XII) suitably m an appropriate solvent, e.g. water, an alco ⁇ hol such as ethanol or in a polar, aprotic solvent such as dimethylformamide, dimethylacetamide and the like, or m the mixture thereof, at the boiling point of the sol ⁇ vent or without any solvent, at a temperature between 120 °C and 250 ⁇ C, optionally in the presence of a suitable catalyst, e.g. sodium hydrogen sulfite or the like, op ⁇ tionally m a closed vessel under pressure.
  • a suitable catalyst e.g. sodium hydrogen sulfite or the like, op ⁇ tionally m a closed vessel under pressure.
  • a compound of formula (XI) containing a leaving group as Z can be reacted with a compound of formula (XII) e.g. under conditions discussed under process variant c) .
  • C . alkylene group optionally substituted by hydroxy, C;- 4 alkoxy and/or di (C.. alkyl) amino; Z means a leaving group; ?" is an amine-protective group; and
  • X means a nitrogen atom optionally substituted by a d- alkyl group; or 5 and X together stand for a nitrogen atom protected by a bivalent amme-protective group, e.g. phthali ido group; e.g. under conditions similar to those described m proc ⁇ ess variant c , then the amine-protective group is re- moved from the obtained compound of formula (XXIV)
  • a compound of formula (I) prepared by employing one of the process variants a) to g) described above can be transformed to other compounds of formula (I) by using methods known per se .
  • an aromatic ring being present in group R " can be halogenated by a suitable halogenatmg agent, e.g. elementary halogen (such as chlorine or bromine) or an other convenient rea- gent (such as an N-halosuccinimide or sulfuryl halide); or nitrated by an appropriate nitrating agent, e.g.
  • Any nitro group occurring as a substituent of the group R" may be reduced to an amino group by means of a suitable reducing agent, e.g. elementary hydrogen in the presence of a noble metal catalyst or by using a complex • hydride, e.g. sodium borohydride.
  • a y carbonyl group optionally being present in the aliphatic moiety of the group R' may be reduced to meth ⁇ ylene group by means of a suitable reducing agent, such as a complex metal hydride, e.g. lithium aluminum hydride optionally in the presence of a Lewis acid, e.g. aluminum trichloride.
  • Any sulfur atom m the alkylthio group being present as a substituent of the group R' cr occurring as X can be oxidized by suitably choosing the amount of an appropri ⁇ ate oxidizing agent, e.g. m-chloroperbenzoic acid, to transform the sulfur atom being present at said site to a sulfur atom substituted by one or two oxygen atom(s) .
  • an appropri ⁇ ate oxidizing agent e.g. m-chloroperbenzoic acid
  • Any carboxyl group occurring as a substituent of the group R " ' may be esterified with an alcohol, e.g.
  • an ali ⁇ phatic alcohol suitably in the presence of an inorganic or organic acid (such as hydrochloric, sulfu ⁇ c, p- -toluenesulfomc acio and the like) as catalyst.
  • an esterified carboxyl group being present as a substituent of the group R' can be hydrolyzed to the free acid by using an aqueous solution of a base (e.g. an al ⁇ kali metal hydrcxide or carbonate) ; or it can be reacted with ammonia or an aliphatic amine to obtain the respec- tive carboxamide.
  • a base e.g. an al ⁇ kali metal hydrcxide or carbonate
  • a nitrogen-unsubstituted carboxamide can be transformed to the corresponding cyano compound by treatment with a suitable dehydrating agent (e.g. sulfu- ric acid, pncs r.crus pentoxide, polyphosphoric acid or the like) .
  • a cyano group can be hydrolyzed with a strong acid (such as hydrochloric, sulfuric or phosphoric acid and the like) or a base (such as sodium hydrcxide, potassium carbonate and the like) to a carbox- amido or carboxyl group depending on the reaction condi ⁇ tions .
  • Any NH or OH group occurring as a substituent of the R' and/or A group can be acylated to an N-acyl or O-acyl derivative, respectively, by means of an appropriate acy- lating agent (e.g. acyl chloride, acid anhydride, active ester, mixed anhydride or the like) ; or can be trans ⁇ formed to an N-alkyl cr O-alkyl derivative, respectively, by means of a usual alkylat g agent (such as an alkyl halide, alkyl sulfate, aromatic sulfonate ester or the like) .
  • an appropriate acy- lating agent e.g. acyl chloride, acid anhydride, active ester, mixed anhydride or the like
  • a usual alkylat g agent such as an alkyl halide, alkyl sulfate, aromatic sulfonate ester or the like
  • a hydroxyl group can be replaced by a halo ⁇ gen atom by means of a convenient halogenating agent (such as thionyl chloride, phosphorus pentachloride, phosphorus pentabromide or the like) and subsequently, this halogen can be replaced by an ammo or alkoxy group by using the respective am e or alkoxide.
  • a convenient halogenating agent such as thionyl chloride, phosphorus pentachloride, phosphorus pentabromide or the like
  • the compounds of formula (I) according to the present invention and their pharmaceutically acceptable salts possess valuable biological effects. More particularly, these compounds inhibit the peroxidation cf lipids and therefore, they are useful to treat diseases and patho ⁇ logical conditions where the inhibition of lipid peroxi- dation is desirable.
  • the lipid peroxidation inhibiting effect of the com ⁇ pounds according to the present invention and their phar- maceutically acceptable salts can be detected or meas ⁇ ured, respectively, by means of biochemical and pharma ⁇ cological investigations.
  • some of these in ⁇ vestigations as well as the results obtained in these m- vestigations with characteristic compounds according to the present invention are given.
  • the following known lipid peroxidation inhibiting compounds were used as ref ⁇ erence substances in these biological tests: 3,5-d ⁇ (tert- -butyll -4-hydroxytoluene ["butylated hydroxytoluene", BHT; see e.g. W.
  • the inhibition of iron (II) ion dependent lipid per ⁇ oxidation was measured in rat brain nomogenate as de ⁇ scribed by J.M. Braughler et al. [J. Biol. Chem. 262, 10438 (1987)] as well as by J. A. Buege and S. D. Aust [Metnocs m Enzy ology 52, 302 (1978)].
  • the IC_- values measured m this experiment and expressed in micromoles of several representatives of compounds according to the invention and reference compounds are shown in Table 1.
  • the IC. value is the concentration of a compound tested, which decreases by 50 % the amount of thiobarbituric acid reactive substances (first of all malondialdehyde) con- sidered to be characteristic for the degree of lipid per ⁇ oxidation.
  • the acute toxicity of compounds of the present inven ⁇ tion was determined in rats.
  • the tcxicity of these com ⁇ pounds was found to be in general favourable, e.g. an in- traperitoneal dose of 500 mg/kg cf the compounds of Exam ⁇ ples 31, 34 or 44, respectively, did not provoke death of any of the treated animals (LD 5 r 500 mg/kg), similarly to tne above-mentioned compound U74006F used as reference compound.
  • the results shown above demonstrate that several rep ⁇ resentatives of the compounds of formula (I) according to the present invention inhibit the lipid peroxidation to a significant degree under in vi tro conditions.
  • these compounds are capable to suppress various pathological processes related to an enhanced peroxida ⁇ tion of lipids in the living organism.
  • these advantageous effects are accompanied by a favourable tox- lcity.
  • the compounds according to the present invention and their pharmaceutically ac ⁇ ceptable salts can be used alone or suitably m the form of pharmaceutical compositions. These compositions also fall within the scope of the present invention.
  • compositions contain an amount required to exert the therapeutical effect of a compound of formula (I) or its pharmaceutically acceptable salt, in admixture with known carriers, excipients, diluents and/or other additives commonly used m the pharmaceuti ⁇ cal practice.
  • the doses required to exert the therapeutical effect of tne compounds according to the invention may be varied depending on the individual condition and age of the pa- tient to be treated and finally these doses are deter ⁇ mined by the attending physician.
  • daily doses of these compounds falling between about 0.1 mg/kg of body weight and about 100 mg/kg of body weight and preferably between about 1 mg/kg of body weight and about 20 mg/kg of body weight are used by the oral or parenteral, e.g. intravenous, route.
  • the compounds according to the invention and the process for the preparation thereof are illustrated in detail by the following non limiting Examples.
  • the reac ⁇ tion mixture is then diluted with 120 ml of ice-water and after addition of 2 g of sodium, chloride, it is extracted with ethyl acetate. The organic layer is washed with wa- ter, drieo and tne ethyl acetate is evaporated under re ⁇ quiz hand. After washing the residue with ethyl ether, 2.4 " g (72 . yield) of title compound are ob ⁇ tained, m.p. 131-132 °C.
  • Step b) l - ⁇ 6-[N- (2 , 5-D ⁇ hydroxybenzoyl) am no]hexyl)-4 -[2 , 6-di (1- -pyrrol idinyl ) -4 -pyr ⁇ m d ⁇ nyl]p ⁇ peraz ⁇ ne
  • the pH value of the solution ob ⁇ tained is adjusted to 5 by using concentrated ammonium hydroxide, then the solvent is evaporated under reduced pressure.
  • the residue is dissolved in 30 ml of water, the pH of the solution is adjusted to 8.5 with concentrated ammonium hydroxide and the mixture is extracted with chloroform.
  • the residue is subjected to chromatography on a silica gel column by us ⁇ ing ethyl acetate as eluent, the title compound is ob ⁇ tained in a yield of 0.76 g (43%), m.p. 182-183 °C.
  • the title compound is prepared as described in Exam ⁇ ple 14, except that 2-thionaphthol is reacted with 1- -[2, 6-di (1-pyrrolidinyl) -4-pyrimidinyl]-4- (2-chloroace- tyl) homopiperazine instead of l-[2, 6-di (1-pyrrolidinyl) - -4-pyrimidinyl]-4- (2-chloroacetyl)piperazine and the crude product is stirred with 50 ml of water until it is disintegrated tc a filtrable powder to give 1.77 g (86 ) of title product, m.p. 56-63 °C.
  • aqueous phase is separated, extracted twice more with 40 ml of methylene cnloride each, the combined organic layers are wasned with water until neutral, dried over anhydrous magnesium sulfate, and the solvent is evapo ⁇ rated under reduced pressure to give 1.82 g (94.7.) of title product, m.p. 212-214 °C (after recrystallization from ethyl acetate) .
  • A represents a -C(0)-CH 2 - group
  • R has the meaning given in the following Table.
  • This intermediate is dissolved in 10 ml of aceto ⁇ nitrile, this solution is added to a suspension contain ⁇ ing 0.6 g (2 mmol) of l-[2, 6-di (l-pyrrolidmyl) -4-pyr ⁇ - m ⁇ d ⁇ nyl]p ⁇ perazme, 0.31 g (2.2 mmol) of potassium car ⁇ bonate and 0.01 g of sodium iodide m 10 ml of acetoni ⁇ trile, and the reaction mixture is stirred under reflux for 5 hours.
  • a suspension containing 2.11 g (5 mmol) of l-(2,6- -diammo- -pyri idinyl(piperazme bisz-t ⁇ fluoroacetate and 2.07 g (15 mmol) of potassium carbonate m 100 ml of ethanol is heated under reflux while vigorously stirring for 30 minutes. After filtering off the msolubles from the hot mixture, 1.0 g (5 mmol) of N- (2, 3-epoxypropyl) -1- -naphthylamme dissolved in 20 ml of ethanol is added to the filtrate.
  • Ms means methanesulfonyl group.
  • Example 1 The title compound is similarly prepared as described in Example 39, except that 2-naphthylamme is used in ⁇ stead of 2-th ⁇ onaphthol and the reaction mixture is heated under reflux for 24 hours.
  • the thus-prepared title compound is identical to the compound of Example 31.
  • the title product is obtained in a yield of 28.7%, m.p. 198- -201 °C.
  • the title compound is obtained m a yield of 39.0t if about 0.05 ml of concentrated aqueous hydrochloric acid is used as catalyst instead of tri ⁇ ethylamine.
  • Example 1 Example 1
  • All 1-naphthyl compounds occurring in the present Example contain the respective 2-naphthyl isomer as a contamination in an amount of about 15 to 20% (see also Example 117) .
  • Tne crude product obtained is purified by chromatograpny en a silica gel column by using a 1:2 mix ⁇ ture of n-hexane and ethyl acetate to obtain 0.51 g (54.4 %) of title compound, m.p. 211-214 °C.
  • R 1 , n, R 2 and R are as shown in the following Table.
  • R 1 means 6-methoxy-2-naphthyl group
  • X represents a single bond
  • A stands for -CH (CH 3 ) -C (0) - group
  • R , R 3 and n are as shown in the following Table.
  • both R and R 3 mean l-pyrrolidinyl group; and R' is as shown m the following Table.
  • X represents a single bond
  • B 1 means -CH -CH[NH-C0-0C (CH 3 ) 3 ] ⁇ group
  • n is 1
  • both R and R J mean l-pyrrolidmyl group
  • R 1 is as shown in the following Table.
  • X represents a single bond
  • B ! means -CH -CH (NH ; ) - group
  • n is 1
  • both R 2 and R 3 mean l -pyrrol idinyl group
  • R 1 is as shown in the following Table .
  • R 1 means 2-hydroxy-l-naphthyl group
  • X represents a single bond
  • n is 1
  • Method B A mixture containing 0.29 g (2 mmol) of 2-naphthol, 0.76 g (2.2 mmolj of 1- (2-ammoethyl) -4-[2, 6-di (l-pyrro ⁇ lidmyl) -4-pyr ⁇ m ⁇ d ⁇ nyl]piperaz ⁇ ne and 0.35 g (2 mmol) of sodium dithionite in 10 ml of water is heated in a steel bomb in an oil bath at 150-155 °C for 7 hours. After cooling down, the reaction mixture is extracted with ben ⁇ zene, the organic phase is washed first with 1 M aqueous sodium hydroxide solution, then with water and dried over anhydrous magnesium sulfate.
  • a solution of 0.6 g (3.2 mmol) of naphthalene-2- -carboxylic acid chloride in 6 ml of methylene chloride is added dropwise to a solution containing 1.0 g (2.9 mmol) of 1- (2-ammoethyl) -4-[2, 6-di (l-pyrrolidinyl) -4- -pyr ⁇ midmyl]piperazme and 0.5 ml (3.5 mmol) of triethy ⁇ lamine in 20 ml of methylene chloride, and the mixture is stirred without cooling for one hour.
  • Example 81 The title compound is prepared by using l-[2,6-di(l- -pyrrolidinyl) -4-pyrimidinyl]-4- ⁇ 2-[2- (2-naphthyl) acetyl- amino]ethyl ⁇ -piperazine as starting substance and follow ⁇ ing a procedure similar to that described m Example 79.
  • the title compound is obtained in a yield of 55.2 %, the L- (+) -tartrate salt melts at 105-115 °C (after crystalli ⁇ zation from ethanol) .
  • Example 81 The title compound is obtained in a yield of 55.2 %, the L- (+) -tartrate salt melts at 105-115 °C (after crystalli ⁇ zation from ethanol) .
  • a solution of 0.20 g (3.56 mmol) of potassium hydrox ⁇ ide in 2 ml of ethanol is added to a suspension contain ⁇ ing 0.4 g (0.7 mmol) of l-[2, 6-di (l-pyrrolidmyl) -4-pyr ⁇ - m ⁇ dmyl]-4-[N- (7-ethoxycarbonyl-l-naphthyl) carbamoyl- methyl]p ⁇ perazme in 10 ml of ethanol and the reaction mixture is heated under reflux for one hour while stir ⁇ ring.
  • the residue is subjected to chromatography on a silica gel column by using an 1:1 mixture of benzene and methanol as eluent to give the potassium salt of the ti ⁇ tle product in a yield of 0.16 g (41.0 %), m.p. above 360 °C.
  • aque ⁇ ous solution is rendered alkaline by adding 5 N sodium hydroxide solution, the precipitate is filtered, washed with water and then with acetonitrile to obtain 0.09 g (90%) of title product, m.p. 280 °C (with decomposition) .
  • Example 88
  • the mixture is ex ⁇ tracted three times with 40 ml of chloroform each, the combined organic solution is washed with 30 ml of satu ⁇ rated aqueous sodium chloride solution, dried over anhy ⁇ drous magnesium sulfate and the solvent is evaporated un ⁇ der reduced pressure.
  • the residue is subjected to chroma ⁇ tography on a silica gel column by using a 4:1 mixture of ethyl acetate and methanol as eluent to give 0.12 g (20.0%) of title compound, m.p. 184-186 ⁇ C.
  • a suspension containing the above chlorohydrm, 2.1 g (7 mmol) of l-[2, 6-di (1-pyrrol ⁇ d ⁇ nyl) -4-pyr ⁇ m ⁇ dmyl]p ⁇ per- azme and 1.8 g (13 mmol) of potassium carbonate in 40 ml of acetonitrile is heated under reflux under vigorous stirring for 5 hours. After evaporating the solvent under reduced pressure and triturating the residue with the mixture of 50 ml of water and 100 ml of ethanol while boiling, the suspension obtained is cooled to room tem ⁇ perature, tne precipitate is filtered off, washed with water until neutral and dried on air.
  • R 4 stands for a tert-butoxycarbonyl group
  • R 1 and X are as shown in the following Table, are prepared similarly to the procedures described in the above methods A) or B) , respectively.
  • the crystal ⁇ line product obtained is dissolved in 30 ml of water, the solution is rendered alkaline by adding 10 M aqueous so ⁇ dium hydroxide solution under stirring and cooling, then the mixture is extracted 4 times with 30 ml of ethyl ace ⁇ tate each. After washing the combined ethyl acetate lay ⁇ ers with 40 ml of water and drying over anhydrous magne ⁇ sium sulfate, the solvent is evaporated to obtain 0.67 g (45.9%) of crystalline title compound, m.p. 142-144 °C.
  • compounds of formula (II) are prepared, wherein A means 2-hydroxy-l, 3-propylene group; n is 1; and R' and X are as shown m the following Table.
  • Thin layer chromatography R f value is 0.58 on a Kiesel- gel 60 silica gel plate, by elut g with a 75:20:5 mixture of etnyl acetate, methanol and concentrated aqueous ammonium hydroxide solution.
  • a solution of 0.45 mi (0.66 g, 5.7 mmol) of mesyl chloride m 5 mi cf methylene chloride is added dropwise to a solution containing 1.7 g (4.2 mmol) of l-[2- -hydroxy-3- (2-napnthylth ⁇ o)propyl]-4- (tert-butoxycarbo ⁇ nyl)piperazme ana 0.87 ml (0.64 g, 63 mmol) of triethy ⁇ lamine m 30 ml of methylene chloride at a temperature between 20 and 25 ⁇ C.
  • the aqueous layer is separated and extracted twice with 15 ml of ethyl acetate each.
  • the combined organic solution is ex ⁇ tracted three times with 15 ml of 1 N hydrochloric acid each, then the pH of the combined aqueous-acidic solution is adjusted to 10 by adding a 5 N sodium hydroxide solu ⁇ tion and extracted three times with 20 ml of ethyl ace ⁇ tate each.
  • the organic layers obtained in the latter ex ⁇ traction are combined, washed with water until neutral, dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure.
  • the base form of the product precipitates from the solution in the form of a white solid within a short time. After stirring the mixture for additional 10 min ⁇ utes, the precipitate is filtered off, washed with a small volume of cold water and dried on air to give 0.31 g (99%) of title product, m.p. 107-109 °C.
  • a suspension containing 0 . 78 g ( 3 mmol ) of 1- ( 2- -chloroacetyl ) -4- ( tert-butoxycarbonyl ) piperazine, 0.43 g ( 3 mmol ) of 2-naphthylamme and 0. 42 g ( 3 mmol ) of potas ⁇ sium carbonate in 30 ml of acetonitrile is heated under reflux for 8 hours under vigorous stirring. Then, the solvent is distilled off and the residue is partitioned between 30 ml of methylene chloride and 30 ml of water.
  • the title compound is prepared by starting from the compound prepared as described in the preceding step b) and following the procedure described m step c) of Exam ⁇ ple 93.
  • the t ⁇ fluoroacetate salt melts at 102-108 °C; a yield of 85.3* is achieved.
  • Step b) l-[2-(2-Naphthyith o)ac tyl]p ⁇ peraz ne
  • the title compound is prepared by starting from the compound prepared as described m the preceding step a) and following the procedure described under step c) of Example 93.
  • the product is obtained as an oil with a thin layer chromatography R f value of 0.64 (on a Kieselgel 60 silica gel plate, by elutmg with a 75:20:5 mixture of ethyl acetate, methanol and concentrated aqueous ammonium hydroxide solution) in a yield of 96.8%.
  • the title compound is prepared by starting from the compound prepared as described in the preceding step a) by following the procedure described in step c) of Exam ⁇ ple 93.
  • the product is identified in the form of its bis- -trifluoroacetate salt, m.p. 169-175 °C. A yield of 80.6% is achieved.
  • 6-Am no-4-hydroxy-2-(1-pyrrolidinyl)pyrimidine After dissolving 8.1 g (0.35 mol) of sodium metal in 240 ml of anhydrous methanol under stirring, 72.3 g (0.3 mol) of 1-am ⁇ d ⁇ nopyrrol ⁇ dme hydroiodide are added to the obtained solution. In an other flask 8.1 g of sodium metal are dissolved in 240 ml of anhydrous methanol and 34.2 g (0.3 mol) of ethyl cyanoacetate are dissolved in this latter solution. The mixture obtained is added to the solution prepared above. The reaction mixture is stirred under reflux for 3 hours and then cooled down.
  • 6-Am no-2- (1-pyrrolidinyl) -4-tosyloxypyr ⁇ m ⁇ d-.ne To a suspension containing 3.6 g '20 mmol) of 6- -ammo-4-hydroxy-2- (1-pyrrol ⁇ d ⁇ nyl) pyrimid e in 20 ml of pyridme, 5.0 g (25 mmol) of tosyl chloride are added at room temperature. The reaction mixture is stirred at room temperature for 30 minutes, during this time the starting compounds are dissolved. Then, the reaction mixture is poured onto 100 ml of water whereupon the product is pre ⁇ cipitated m solid form. The precipitate is filtered off, washed with a large volume of water and dried on air to yield 3.0 g (45 c ) of title product, m.p. 155-168 ⁇ C (with decomposition) .
  • the residue is dissolved in 15 ml of methanol and the solu ⁇ tion is acidified to pH 6 by adding ethyl acetate con ⁇ taining hydrogen chloride.
  • the crystalline precipitate is filtered, washed with ethyl acetate and dried.
  • the hydro- chloride obtained (m.p. above 280 °C) is dissolved m a small volume of water, made alkaline to pH 10 by adding 1 M sodium hydroxide solution and the product is extracted into methylene chloride (3 x 100 ml) . After combining the organic phases, the solution is dried over anhydrous mag ⁇ nesium sulfate and the solvent is distilled off to give 3.7 g (30%) of title product as a light yellow oil, which solidifies upon standing.
  • Step d) l-[6-Amino-2- (1-piperidinyl) -4-pyrimidinyl]piperazine
  • the tile compound is prepared starting with the com ⁇ pound prepared as described in the preceding step c) and by following the procedure described in step d) of Exam ⁇ ple 102 to give a yield of 66.7%.
  • the product is a yellow oil having a thin layer chromatography R ; value of 0.3 (on a Kieselgel 60 silica gel plate, by eluting with a 10:5:0.3 mixture of ethyl acetate, methanol and concen ⁇ trated aqueous ammonium hydroxide solution) .
  • Step c) l-[6-Am ⁇ no-2- (hexahydro-lH-azepm-1-yl) -4-pyr m ⁇ d - nyl]p ⁇ peraz ne
  • a solution containing 1.5 g (5 mmol) of l-[2,6-di(l- -pyrrolidinyl) -4-pyrimidinyl]piperazine and 0.5 ml (0.59 g, 6.4 mmol) of epichlorohydrm in 10 ml of ethanol is stirred at ambient temperature for 24 hours.
  • the precipi- tate is filtered off and washed with 2 ml of ethanol.
  • the wet material is dissolved in the mixture of 50 mi of ethyl ether and 5 ml of ethanol and stirred with 10 ml of a 10 M aqueous sodium hydroxide solution for 2 hours.
  • Example 107 Preparation of 1- (2-am ⁇ noethyl) -4-[2, 6-di (1-pyrrol ⁇ - d yl) -4-pyr ⁇ m ⁇ d ⁇ nyl]p ⁇ peraz ⁇ ne
  • Step a) l-[2 , 6-D ⁇ (1-pyrrolidinyl) -4-pyr m ⁇ d ⁇ nyl]-4-(2-phthal- lmidoethyl)piperazine
  • A represents -C(0)-CH 2 - group
  • R' is as shown in the following Table.
  • the precipitated salt is filtered off and washed with anhy- drous tetrahydrofuran.
  • the combined filtrate and washings are added portionwise to the solution of 3.1 g (82 mmol) of sodium borohydride in 78 ml of water at a temperature of 15 °C under stirring during 30 minutes, then the reac ⁇ tion mixture is stirred at ambient temperature for 4 hours.
  • the pH of the solution is again adjusted to 4 as men ⁇ tioned above.
  • the organic solution is briefly dried over an ⁇ hydrous magnesium sulfate, the solvent is evaporated un ⁇ der reduced pressure and the residue is stirred under re ⁇ flux in 25 ml of acetone saturated with sodium iodide, in the presence of 0.09 g (0.7 mmol) of diisopropylethy- lamine under nitrogen for 30 minutes.
  • the ethereal solution is dried over anhy ⁇ drous magnesium sulfate, the solvent is evaporated under reduced pressure and the residue obtained is washed with petroleum ether (b.p. 40-70 °C) to yield 3.83 g (89%) of title compound, m.p. 80-82 ⁇ C.
  • Intravenous pharmaceutical formulation Ingredients l- ⁇ 6-[N- (2, 5-D ⁇ hydroxybenzoyl) -amino]- hexyl ⁇ -4-[2, 6-di ( l-pyrrolidmylj -4-
  • the solution is filtered germ-free through a cellulose membrane of 0.2 ⁇ m pore diameter, filled into glass ampoules under aseptic conditions and the ampoules are sealed in an inert gas atmosphere.

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Abstract

L'invention concerne de nouveaux dérivés de pyrimidine représentés par la formule (I), dans laquelle: R1 représente un groupe de formule (a), dans laquelle: Ar signifie un groupe aromatique homocyclique, R4 et R5 représentent hydrogène, halogène, hydroxy, alkyle, alcoxy éventuellement substitué, un groupe alkylthio et ses dérivés oxydés, amino éventuellement substitué, carboxy et ses dérivés, sulfo et/ou sulfonamido, p, q et r sont 0 ou 1, R2 et R3 représente amino ou une fraction dérivée d'un hétérocycle contenant azote, X signifie une liaison simple, un atome de soufre éventuellement oxydé ou un atome d'azote éventuellement substitué, A représente un groupe alkylène éventuellement substitué, n est 1 ou 2. L'invention concerne également un procédé, ainsi que les intermédiaires de préparation des composés représentés par la formule (I). Ces composés présentent un effet remarquable d'inhibition de la peroxydation des lipides, détectable à la fois in vitro et in vivo. De ce fait, ces composés sont utiles pour la prévention et/ou le traitement, notamment, des lésions de la tête, du cerveau et de la moelle épinière, ainsi que des lésions tissulaires provenant de l'ischémie (y compris, les lésions de reperfusion), de l'infarctus du myocarde ou de la cardiopathie ischémique.
PCT/HU1996/000058 1995-10-19 1996-10-14 Derives de pyrimidine WO1997014685A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
HU9900088A HUP9900088A2 (hu) 1995-10-19 1996-10-14 Pirimidinszármazékok, ezeket tartalmazó gyógyászati készítmények és eljárás előállításukra
AU73259/96A AU7325996A (en) 1995-10-19 1996-10-14 Pyrimidine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP9503012 1995-10-19
HU9503012A HUT76265A (en) 1995-10-19 1995-10-19 Pyrimidine derivatives, pharmaceutical compositions containing them, process for producing them and their use

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WO1997014685A1 true WO1997014685A1 (fr) 1997-04-24

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999023072A1 (fr) * 1997-10-31 1999-05-14 Suntory Limited Rylpiperidinopropanol et derives d'arylpiperazinopropanol et produits pharmaceutiques contenant lesdits composes
WO2004050639A3 (fr) * 2002-12-03 2004-12-09 Edward J Hessler Composes nitroso pour traiter l'ischemie
JP2007532678A (ja) * 2004-04-13 2007-11-15 セフアロン・インコーポレーテツド 二環式芳香族スルフィニル誘導体
WO2008016165A3 (fr) * 2006-07-31 2008-04-03 Asubio Pharma Co Ltd Préparation liquide
US7709640B2 (en) 2000-11-01 2010-05-04 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
US8895717B2 (en) 2005-04-15 2014-11-25 The Board Of Regents Of The University Of Texas System Delivery of siRNA by neutral lipid compositions

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010058809A1 (fr) * 2008-11-19 2010-05-27 国際先端技術総合研究所株式会社 Puce holographique en relief et procédé de fabrication de celle-ci

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0574906A2 (fr) * 1992-06-17 1993-12-22 Nisshin Flour Milling Co., Ltd. Dérivés de pipérazine et homopipérazine, compositions pharmaceutiques les contenant et procédé pour leur préparation
EP0576941A1 (fr) * 1992-06-30 1994-01-05 Nisshin Flour Milling Co., Ltd. Dérivés d'un acide N-benzoylamino, compositions pharmaceutiques les contenant et procédé de leur préparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0574906A2 (fr) * 1992-06-17 1993-12-22 Nisshin Flour Milling Co., Ltd. Dérivés de pipérazine et homopipérazine, compositions pharmaceutiques les contenant et procédé pour leur préparation
EP0576941A1 (fr) * 1992-06-30 1994-01-05 Nisshin Flour Milling Co., Ltd. Dérivés d'un acide N-benzoylamino, compositions pharmaceutiques les contenant et procédé de leur préparation

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7642262B2 (en) 1997-10-31 2010-01-05 Asubio Pharma Co., Ltd. Arylipiperdinopropanol and arylipiperazinopropanol derivatives and pharmaceuticals containing the same
US6407099B1 (en) 1997-10-31 2002-06-18 Suntory Limited Arylpiperidinopropanol and arylpiperazinopropanol derivatives and pharmaceuticals containing the same
US6525199B1 (en) 1997-10-31 2003-02-25 Suntory Limited Arylpiperidinopropanol and arylpiperazinopropanol derivatives and pharmaceuticals containing the same
WO1999023072A1 (fr) * 1997-10-31 1999-05-14 Suntory Limited Rylpiperidinopropanol et derives d'arylpiperazinopropanol et produits pharmaceutiques contenant lesdits composes
US6838470B2 (en) 1997-10-31 2005-01-04 Daiichi Suntory Pharma Co., Ltd. Arylpiperidinopropanol and arylpiprazinopropanol derivatives and pharmaceuticals containing the same
US8536184B2 (en) 2000-11-01 2013-09-17 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
USRE43098E1 (en) 2000-11-01 2012-01-10 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
US7709640B2 (en) 2000-11-01 2010-05-04 Millennium Pharmaceuticals, Inc. Nitrogenous heterocyclic compounds and process for making nitrogenous heterocyclic compounds and intermediates thereof
WO2004050639A3 (fr) * 2002-12-03 2004-12-09 Edward J Hessler Composes nitroso pour traiter l'ischemie
US7423176B2 (en) 2004-04-13 2008-09-09 Cephalon, Inc. Bicyclic aromatic sulfinyl derivatives
US8314155B2 (en) 2004-04-13 2012-11-20 Cephalon, Inc Bicyclic aromatic sulfinyl derivatives
JP2007532678A (ja) * 2004-04-13 2007-11-15 セフアロン・インコーポレーテツド 二環式芳香族スルフィニル誘導体
US8895717B2 (en) 2005-04-15 2014-11-25 The Board Of Regents Of The University Of Texas System Delivery of siRNA by neutral lipid compositions
WO2008016165A3 (fr) * 2006-07-31 2008-04-03 Asubio Pharma Co Ltd Préparation liquide

Also Published As

Publication number Publication date
HUP9900088A2 (hu) 2000-03-28
AU7325996A (en) 1997-05-07
HU9503012D0 (en) 1995-12-28
HUT76265A (en) 1997-07-28

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