HUT76265A - Pyrimidine derivatives, pharmaceutical compositions containing them, process for producing them and their use - Google Patents

Description

The present invention relates to novel pyrimidine derivatives of formula (I) capable of effectively inhibiting lipid peroxidation. More particularly, the present invention relates to novel pyrimidine derivatives, their salts, and pharmaceutical compositions containing them. The invention further relates to a process for the preparation of said pyrimidine derivatives. The present invention also encompasses novel intermediates of formula (II) for the preparation of the above novel pyrimidine derivatives.

It is known that peroxidation of living body lipids is a metal-catalyzed radical process in which oxygen-containing free radicals (e.g., hydroxyl radical, radical superoxide anion and the like) are also involved. This process alters cell membranes, causes disruption of membrane transport, and can eventually lead to cell death. Lipid peroxidation plays an important role in many disease states and conditions, and even in aging. Examples of such diseases and conditions include brain and spinal cord injuries, acute cerebral catastrophe (stroke), certain types of cerebral vasospasm, cardiac infarction, heart failure, and cardiovascular damage, particularly during and after recovery of blood flow, coronary artery disease, atherosclerosis, inflammatory diseases such as rheumatoid arthritis or certain inflammatory diseases of the gastrointestinal tract such as pancreatitis or ulcerative colitis, certain autoimmune diseases, certain drug side effects, asthma, and certain chronic diseases of the nervous system, such as Parkinson's disease, Alzheimer's disease and the like [see, for example, B. Halliwell, FASEB J. 1, 358 (1987); J. M. Gutteridge, B. Halliwell, Methods in Enzymology, 186, 1-84. (1990); and D. Salvemini and R. Botting, Drug News & Perspectives 6, 274 (1993)].

Intensive worldwide research is under way to find substances that generally inhibit or inhibit oxidative processes in the body (antioxidants) and, more specifically, agents that inhibit lipid peroxidation. Lipid peroxidation inhibitory agents may be used for their prophylaxis and / or treatment of diseases and conditions associated with said process in mammals, including man. These agents may have enormous therapeutic importance and, for example, such agents for the treatment of central nervous system injuries may be used as life-saving drugs (see, for example, J. Lehman, Drug News & Perspectives 5, 252 (1992)).

There are several endogenous substances in the mammalian internal regulatory system that inhibit lipid peroxidation, such as alpha-tocopherol, also known as vitamin E (see, for example, MJ Kelly in Progress in Medicinal Chemistry, Vol. 25, p. 250, edited by GP Ellis and GB West, 1988, Elsevier Science Publisher). The importance of lipid peroxidation inhibitors is illustrated, for example, by two studies of more than 100,000 people that reduce the risk of certain diseases, such as coronary heart disease, by regularly taking vitamin E [M. J. Stampfer et al., The New England Journal of Medicine 328, 1444 (1993) and E. B. Rimm et al., The New England Journal of Medicine 328, 1450 (1993).

It was an object of the present invention to provide novel synthetic pyrimidine derivatives which are effective in inhibiting lipid peroxidation and thus useful in the treatment of certain diseases and conditions in mammals, including humans, in which inhibition of lipid peroxidation is desired.

It has been found that pyrimidine derivatives having two - optionally substituted - amino groups in which the pyrimidine ring is attached to one nitrogen atom of a piperazine ring or homopiperazine ring, and at the same time a certain nitrogen atom of said piperazine ring or homopiperazine ring,

Bears a structural unit containing a -4-phenyl group (described in more detail below) in a defined bond system.

The literature describes several compounds whose structure is somewhat similar to the structure of our compounds. Thus, for example, compounds are known in which one nitrogen atom of a piperazine ring is bonded to an open or cyclic hydrocarbon group and the other nitrogen atom is bonded to a six-membered nitrogen containing heterocycle, such as a substituted pyridine ring, pyrimidine ring or triazine ring. These known compounds have various physiological effects.

One important group is molecules in which the said nitrogen-derived heterocycle derivative is, for example, a pyridyl group having an optionally substituted amino group (s), a pyrimidinyl group such as the 2,6-diol of the compounds of the present invention (substituted amino) -4-pyrimidinyl] or triazinyl. However, in these compounds, said hydrocarbon group may vary within wide limits; for example, a steroid skeleton group (PCT applications WO 87/01706 and WO 87/07895), a secosteroid skeleton group (PCT application WO 88/07527), or various medium chain substituted alkyl groups, various mono- and bicyclic groups, e.g. , phenoxyalkyl, benzopyranyl and the like (PCT applications published as WO 88/08424 and WO 91/06542). These families of compounds have been reported to have lipid peroxidation inhibitory activity. It should be noted that these compounds do not include molecules containing either naphthyl or benzyl or benzoyl groups attached via nitrogen or sulfur. PCT application WO 88/08424, cited above, discloses a piperazine ring-linked nitrogen containing a type of the compounds described in the present application.

heterocyclic compounds and the other nitrogen atom of the piperazine ring includes, inter alia, 2,5-dihydroxybenzyl derivatives and substituted benzoylamino derivatives linked to the piperazine ring via a C 2 -C 4 alkylene chain, In compounds II, both said 2,5-dihydroxybenzyl group and the substituted benzoyl group are directly attached to the piperazine ring. Further, neither the examples nor the claims in the above-mentioned publication disclose 2,5-dihydroxybenzoylamino compounds wherein this group is attached to the piperazine ring via an alkylene chain of more than 4 carbon atoms.

European Patent Application EP 400661A discloses 2-pyrimidinylpiperazine derivatives having an anti-ischemic effect analogous to those described above, but does not include 2,6-diamino-4-pyrimidinyl compounds.

In a further large group of known compounds containing the above-mentioned three representative structural elements (i.e., a hydrocarbon group, a piperazine ring and a six-membered nitrogen containing heterocycle), the hydrocarbyl group is similar in nature to the one mentioned above. groups include, for example, phenyl, benzyl, benzhydryl, directly attached to one of the nitrogen atoms in the piperazine ring, as a typical structural element [French Patent No. 1,507,062; German Patent Nos. 1,947,332 and 2,211,738; Belgian Patent Nos. 739,283 and Canadian Patent Nos. 983,497 and Japanese Patent Publication No. 74/76887 (Kokai)], benzodioxolyl and benzodioxanyl [979,894; 983.493; 983.494; U.S. Patent No. 983,495; and 74/72270; 74/72271; Japanese Patent Laid-open Publication Nos. 74/72272 and 74/72273 (Kokai)] and 3-trityl-n-propyl [G. R. Regnier et al., J. Med. Chem. 15, 295 (1972)]. (Note that these compounds do not include derivatives containing naphthyl groups.) The latter, a large number of compounds, describe a wide variety of physiological effects, such as vasodilator, sedative, analgesic, respiratory and analgesic. Their lipid peroxidation inhibitory activity is not mentioned.

In addition to the previously mentioned families of compounds containing piperazine ring and other nitrogen-containing heterocycle (s), such as pyrimidine ring, several other types of compounds have been reported in the literature to have lipid peroxidation inhibitory activity. The following are examples of some of these families of compounds:

cyclic hydroxamic acids [Y. Teshima et al., J. Antibiot. 44, 685 (1991)];

dehydroalanine derivatives [P. Buc-Calderon et al., Arch. Biochem. Biophys. 273: 339 (1989)];

acylated polyamines [J. M. Braughler et al., Biochem. Pharmacol. 37: 3853 (1988)];

glutathione analogs (Drug Data Reports 12, 339 (1990));

amino analogs of vitamin C (European Patent Application Nos. 446,539 and 447,325);

monocyclic vitamin E analogs (Japanese Patent Application No. 01,226,843); other vitamin E derivatives [R. Nikolov, Drug News & Perspectives 5, 507 (1992)];

1,4-benzoquinones [e.g., G. Goto, Chem. Pharm. Bull. 33: 44222 (1985)]; naphthoquinones (Drugs of the Future 14, 692 (1989));

carboxyalkyl and hydroxyalkylnaphthoquinones [K. Okamoto et al., Chem. Pharm. Bull. 30, 2797 (1982)];

salicylidene amine derivatives [W. Musleh et al., 1994, Neuropharmacology 33: 929];

···· · · · · · · · · · · · · · · · · · · · · ···

-7 acylamino-7-hydroxyindan derivatives [Y. Oshiro et al., J. Med. Chem. 34, 2014 (1991)];

methyl prednisolone [e.g., Η. B. Demopoulos et al., J. Physiol. Pharm. 60, 1415 (1982)];

flavonoids (e.g., R. Campos et al., Planta Med. 55, 417 (1989)); pyrazolinone derivatives [K. Abe et al., Stroke 19: 480 (1988)]; pyrazolone derivatives (Japanese Patent No. 62,149,617); thiazolidinediones [T. Yoshioka et al., 1989, J. Med. Chem. 32, 421]; piperidine derivatives [T. Kaneko et al., 1989, Arzneimittelforschung 39, 445];

4-arylthiopiperidine derivatives (European Patent Publication No. 433,167); dihydropyridinediones [A. G. Odynets et al., Exp. Med (Riga) 21, 127. (1986); Chem. Abstr. 106, 148956];

tetrahydropyridine derivatives [T. Gizur et al., Eur. J. Med. Chem. 29, 349 (1994)];

pyrimidine dione (European Patent Application Publication No. 447,324);

bis-nicotinoyl-alkylene diamines (Drugs of the Future 61, 586 (1992)); dihydroquinoline derivatives [A. Blázovics et al., Free Radical Slit. Commun. 4, 409 (1988)];

quinazoline derivatives (European Patent Publication No. 302,967); pyridylquinolines (EP 289,365); pyrimido-pyrimidines [I. Bellido et al., Meth. Find. Exp Clin. Pharmacol. 13, 371 (1991)];

benzothiazines (Japanese Patent Application No. 01,287,077);

carbazole derivatives [R. Feuerstein, 1994, Pharmacology 48, 385];

anthrone and acridine derivatives [P. Frank, Biochem. Biophys. Gap. Commun.

140, 797 (1986)];

methylated uric acid analogs [Y. Nishida, J. Pharm. Pharmacol. 43, 885 (1991)];

selenium compounds [A. Müller et al., Biochem. Pharmacol. 33. 3235 (1984) and A. L. Tappel, Fed. Proc. 24, 73 (1965)];

curcuminoids [S. Toda et al., J. Ethnopharmacology 23, 105 (1988).

The literature data detailed above illustrate, on the one hand, that compounds containing the piperazine ring and the mono- or diamino-nitrogen heterocycle associated therewith do not have a legally inhibitory effect on lipid peroxidation, and that, on the other hand, presence of the above nitrogen-containing heterocycles.

Example 35 of Hungarian Patent Application P92 02172 describes a compound which is structurally somewhat similar to a benzoyl-containing version of the compounds of the present invention, namely 1- [6- (2,5-dihydroxybenzoyl). amino) caproyl] -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine, which has a remarkable lipid peroxidation inhibitory activity.

Also known are compounds of general formula (A) having lipid peroxidation inhibitory activity, which are structurally related to the compounds of formula (I) of the present invention and are disclosed in European Patent Application Publication No. 0574906A, and wherein

Lip represents, inter alia, 1- or 2-naphthyloxy or oxo-substituted 1,2,3,4-tetrahydro-6-naphthyloxy,

A1 and A2 represent a single bond or an alkylene group having 2 to 3 carbon atoms optionally substituted with hydroxy or oxo, n being 1 or 2, and

-9We is inter alia a group of the formula B wherein R is an amino group or a 1-pyrrolidinyl group.

However, these compounds do not include those containing a naphthylamino group, a naphthylthio group, or a naphthyl group as part of an acyl group.

Said compounds of formula (A) showed remarkable inhibition of lipid peroxidation in vitro. For example, compounds of Examples 22, 23, 26, 27, 30, 33 and 36 of European Patent Application 0574906A, containing naphthyloxy or oxo-tetrahydro-naphthyloxy, have a rat brain homogenate with an IC50 of less than 30 pmol. inhibited lipid peroxidation induced by iron ions (see below for the assay method). The most potent two compounds in in vitro assays are 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (1-naphthyloxy) propyl] according to Example 23. homopiperazine (IC 50 value: 9 μηηόΙ) and 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthyloxy) propyl according to Example 27 ] -homopiperazine (IC 50: 8 pmol). The most potent of these naphthyloxy derivatives, in in vivo studies, is the compound 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthyloxy) of Example 27. ) -propyl] -homopiperazine at a dose of 20 mg / kg in a model of head injury in mice caused an 82% increase in the overall score for the animals' neurological status (see below for the test method). However, 21- [4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -1-piperazinyl] -16alpha-methyl-pregna-1,4,9 (11) -triene-3 used as a comparator A dose of 30 mg / kg of 20-dione (U74006F, see, for example, Drugs of the Future 20, 218 (1995)) resulted in a 77% improvement in the same study.

In contrast, it has surprisingly been found that some of the compounds of formula (I) of the present invention have the same properties as the compounds of European Patent Application Publication No. 0574906A above. ································································· ··· di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) propyl] piperazine IC 50: 2 pmol, 1- [2, 6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) propyl] -homopiperazine IC 50: 4 μιτιόΙ and 1 - [ 2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylthio) propyl] -homopiperazine IC 50: 10 pmol}, much more in in vivo studies stronger - results in inhibition of lipid peroxidation in vitro in other words, they have a surprisingly additive effect, whether compared with known compounds which are distant from the general formula (I) or have a certain structural relationship thereto, such as the naphthyloxy group of the general formula (A).

For example, the 1- [6-amino-2- (1-pyrrolidinyl) -4-pyrimidinyl] -4- (1-hydroxy-2-naphthoyl) piperazine of the present invention (the compound of Example 37) has the above-mentioned head injury. In the vehicle test, the compound of formula (A) or the above-mentioned compound U74006F, used as a reference substance, resulted in a greater (132%) improvement in overall score than one of these compounds (1.25 mg / kg). Similarly, the 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) propyl] -homopiperazine of the present invention (Example 26). example compound)

A dose of 2.5 mg / kg increased the overall score by 119% in the same test. Furthermore, the 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) propyl] piperazine of the present invention has been found to be even more favorable. (Example 23), which increased the overall score by 151% at a dose of two orders of magnitude lower (0.31 mg / kg) than the known compounds.

In summary, novel synthetic pyrimidine derivatives have been found to be particularly effective in inhibiting lipid peroxidation which

In 11 derivatives, said pyrimidine ring has two identical or different optionally substituted amino groups and the carbon at the 4-position of the ring is attached to a nitrogen atom of a piperazine or homopiperazine ring. The other nitrogen atom of said piperazine or homopiperazine ring, however, bears an optionally substituted naphthyl or substituted phenyl moiety, as detailed below.

Accordingly, the present invention provides novel pyrimidine derivatives of formula (I) and salts thereof, wherein:

R1 is a group of formula (a) wherein

Price report is a C 6 -C 10 aromatic homocyclic group,

R 4 and R 5 are independently hydrogen, halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy optionally substituted with phenyl, C 1-4 alkylthio, C 1-4 alkylsulfinyl, C4 alkylsulfonyl group, nitro group, C1-C4 alkanoyl group, optionally substituted amino group, carboxyl group, C1-C4 alkoxycarbonyl group, carboxamido group, cyano group, sulfo group and / or sulfonamido group, and p, q and r are independently 0 or 1,

R2 and R3 are independently selected from the group consisting of amino and a 5-8 membered saturated heterocycle containing at least one nitrogen atom,

X is a single bond, sulfur atom optionally substituted with one or two oxygen atoms, or nitrogen atom optionally substituted,

· 9

- 12 • · · · · · · · · · · · · · · · · · · · · · ·

A is a linear or branched C 1 -C 8 alkylene group optionally substituted by halogen, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkanoyloxy, optionally substituted amino and / or oxo, and n is 1 or 2, with the proviso that if

R1 is a group of formula (a) wherein Ar is phenyl,

At least one of R 4 and R 5 is halogen, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 4 alkanoyloxy or methanesulfonyloxy, and p, q and r are each independently 0 or 1, then

A may be other than an unsubstituted alkylene group having 1 to 4 carbon atoms, with the proviso that if

R ¹ is 2,5-dihydroxybenzoyl then

The meaning may only be different from oxo substituted alkylene.

When R4 and / or R5 is an optionally substituted amino group in the formula (a) at R1 and / or when A is an alkylene group optionally substituted with an amino group, said substituent on such a substituted amino group may be, for example, one or two alkyl, C 1 -C 4 alkanoyl, C 1 -C 4 alkoxycarbonyl optionally substituted with phenyl, C 1 -C 4 alkylsulfonyl or arylsulfonyl.

Furthermore, when X is a substituted nitrogen atom, said substituent may be, for example, C 1 -C 4 alkyl, C 1 -C 4 alkanoyl, optionally C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylsulfonyl-. or an arylsulfonyl group.

Certain representatives of the compounds of formula (I) of the present invention contain one or more asymmetric carbon atoms and may thus exist in the form of pure stereoisomers (e.g., enantiomers or diastereomers) or mixtures thereof, such as racemic mixtures of enantiomers. Pure stereoisomers of the compounds of formula (I), racemic and other mixtures thereof, and salts thereof, and in particular pharmaceutically acceptable salts thereof.

The following is a description of the typical meanings of each of the symbols in formula (I).

Examples of R 1 include, but are not limited to, 1-naphthyl, 2-naphthyl, 1-chloro-2-naphthyl, 4-chloro-1-naphthyl, 5-chloro-2-naphthyl, 1-bromo-2-naphthyl, 5-bromo-2-naphthyl, 6-bromo-2-naphthyl, 1,6-dibromo-2-naphthyl, 5,8-dibromo-2 naphthyl, 2-hydroxy-1-naphthyl, 4-hydroxy-1-naphthyl, 3-hydroxy-2-naphthyl, 1-hydroxy-2-naphthyl, 4-methoxy-1 naphthyl, 6-methoxy-1-naphthyl, 6-methoxy-2-naphthyl, 7-methoxy-2-naphthyl, 4-benzyloxy-1-naphthyl, 1-methylthio, 2-naphthyl, 1-methylsulfinyl-2-naphthyl, 1-methylsulfonyl-2-naphthyl, 3-methylthio-2-naphthyl, 3-methylsulfinyl-2 naphthyl, 3-methylsulfonyl-2-naphthyl, 4-acetyl-1-naphthyl, 5-acetyl-1-naphthyl, 4-nitro-1-naphthyl, 6-nitro- 2-naphthyl, 4-amino-1-naphthyl, 3-amino-2-naphthyl, 6-amino-2-naphthyl, 3-methylamino-1-naphthyl, 3- dimethylamino-1-naphthyl-p oport, 3-dimethylamino-2-naphthyl, 3-acetylamino-1-naphthyl, 4-methylamino-1-naphthyl, 4-dimethylamino-1-naphthyl, 6-dimethylamino-2-naphthyl, 4-acetylamino-1-naphthyl, 4-ethoxycarbonylamino-1-naphthyl,

- 141 • · • ·

4-benzyloxycarbonylamino-1-naphthyl, 4-methanesulfonylamino-1-naphthyl, 4- (p-toluenesulfonylamino) -1-naphthyl, 3-carboxy- 2-naphthyl,

3-methoxycarbonyl-2-naphthyl, 3-carboxamido-2-naphthyl, 7-carboxy-2-naphthyl, 7-methoxycarbonyl-2-naphthyl, 7-carboxamido-2- naphthyl, 3-cyano-2-naphthyl, 5-cyano-2-naphthyl, 6-cyano-2-naphthyl,

1-sulfo-2-naphthyl, 4-sulfo-1-naphthyl, 5,8-disulfo-2-naphthyl,

4-sulfonamido-1-naphthyl, 4- (N, N-diethyl) sulfonamido-1-naphthyl,

4- (N, N-dimethyl) sulfonamido-1-naphthyl, 1-naphthylmethyl, 2-naphthylmethyl, 2- (2-naphthyl) ethyl, 2-oxo- 2- (2-naphthyl) ethyl, 1-naphthoyl, 2-naphthoyl, 1-hydroxy-2-naphthoyl, 3-hydroxy-2-naphthoyl,

2-hydroxybenzoyl, 2-benzyloxybenzoyl, 2-benzyloxybenzyl, 2,4-dihydroxybenzoyl, 2,5-dihydroxybenzoyl, 2,5-dibenzyloxy, benzoyl, 2- (1-naphthyl) acetyl, 2- (2-naphthyl) acetyl and the like. In particular, when X is a single bond, R1 is preferably, for example, 3-hydroxy-2-naphthyl or 1-hydroxy-2-naphthyl, whereas when X is other than a chemical bond , R1 is preferably, for example, 1-naphthyl, 2-naphthyl, 2-naphthylmethyl, 2- (2-naphthyl) acetyl or 2,5-dihydroxybenzoyl.

As can be seen from the above list, the optional substituent on the naphthyl group may be attached to any carbon atom in any ring of the naphthyl group, but preferably is attached to a carbon atom of the same ring which also carries the X group.

Certain R ⁴ and R 5 substituents (e.g., a hydroxy group, an amino group and / or a carboxyl group) at R ¹ may also be protected. Thus, for example, in the above definitions, a C 1-4 alkoxy group or a C 1-4 alkoxy group having a phenyl group may be considered as a protected form of a hydroxy group.

Similarly, for example, an amino group substituted with a C 1 -C 4 alkanoyl group, a C 1 -C 4 alkoxycarbonyl group optionally substituted with a phenyl group, a C 1 -C 4 alkylsulfonyl group or an arylsulfonyl group can be considered as a protected form of an amino group. Further, for example, a C 1 -C 4 alkoxycarbonyl group may also exist as a protected form of a carboxyl group.

R2 and R3 independently of one another include, but are not limited to, amino, 1-pyrrolidinyl, 1-piperidinyl, hexahydro-1H-azepin-1-yl or octahydroazocin-1-yl, and preferably an amino group and / or a pyrrolidino group.

X may be, but is not limited to, a single chemical bond, a sulfur atom optionally substituted with one or two oxygen atoms, or unsubstituted or optionally substituted with, for example, methyl, ethyl, formyl, acetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxy, nitrogen substituted with carbonyl, methanesulfonyl or p-toluenesulfonyl, and is preferably a single bond, sulfur or unsubstituted nitrogen.

Examples of A include, but are not limited to, methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene, 1,7-heptylene, 1,8-octylene, carbonyl, 1-oxo-1,2-ethylene, 1-oxo-2-methyl-1,2-ethylene, 1-oxo- 1,3-propylene, 2-oxo-1,3-propylene, 1-oxo-2-amino-1,3-propylene, 1-oxo-2-dimethylamino-1,3- propylene, 1-oxo-2- (tert-butoxycarbonylamino) -1,3-propylene, 2-hydroxy-1,3-propylene, 2-acetoxy-1,3-propylene, a group, 2-methoxy-1,3-propylene, 2-benzyloxy-1,3-propylene, 2-bromo-1,3-propylene, 2-chloro-1,3-propylene, 2-amino-1,3-propylene, 2-methylamino-1,3-propylene, 2-dimethylamino-1,3-propylene, 2-acetylamino-1,3- propylene, 2- (benzyloxycarbonylamino) -1,3-propylene, 2- (methanesulfonylamino) -1,3-propylene, and the like, and preferably 1 , 2- ethylene, 1,3-propylene, 1,6-hexylene, carbonyl, 1-oxo-1,2-ethylene or 2-hydroxy-1,3-propylene.

Similarly to the description of the substituents on the R1 group, the substituents on the alkylene chain at the A site may be considered, for example, a C1-C4 alkoxy optionally substituted with a phenyl group, and a C1-C4 alkanoyl optionally substituted with a C1-C4 alkanoyl group. An amino group substituted with a C 4 alkoxycarbonyl group or a C 1-4 alkylsulfonyl group can be considered as a protected form of an amino group.

In the formula (I), n is 1 or 2, and preferably 1.

Suitable salts of the compounds of formula I containing basic groups include, for example, inorganic acids (e.g., hydrochloric, hydrobromic, sulfuric, phosphoric, and the like) and organic acids (e.g., acetic, tartaric, citric, fumaric, succinic, maleic acid, methanesulfonic acid, ethane sulfonic acid, p-toluenesulfonic acid and the like. In addition to the acid addition salts, the compounds of formula I containing a hydroxy and / or carboxyl substituted phenyl or naphthyl group may also form salts with bases. Suitable bases include alkali metal salts (e.g., sodium salt, potassium salt), alkaline earth metal salts (e.g., calcium salt, magnesium salt) and the like, as well as some organic bases, such as ethanolamine, diethanolamine, ethylenediamine, and the like. salts formed with the like.

The present invention further relates to a process for the preparation of compounds of formula (I) which is illustrated in Schemes A to G below. Accordingly, the process of the present invention comprises:

(a) for the preparation of compounds of the formula I in which:

R 1, R 2, R 3, X and n are as defined in the preamble, and

- 17 'η

A has the same meaning as defined herein, with the proviso that only halogen or optionally substituted amino substituted with a linear or branched C 1 -C 8 alkylene group of formula (II) wherein

R1, X, A and n are as defined above, a compound of formula (III) wherein

R2 and R3 are as defined above and Z is a leaving group, or

(b) for the preparation of compounds of the formula I in which:

R1, R2, R3, and n are as defined herein,

A is as defined herein, with the proviso that it may be other than a linear or branched C 1 -C 8 alkylene substituted with only a halogen or an optionally substituted amino group, and

X has the meaning given to formula (I), with the proviso that it can only be different from a chemical bond and a sulfur atom substituted with one or two oxygen atoms, having the formula:

R1 and X are as defined above, a compound of formula (V) wherein

R2, R3, A and n are as defined above and Z is a leaving group, or

c) for the preparation of compounds of the formula I in which:

R1, R2, R3, and n are as defined herein,

Its meaning is given in the scope, with the proviso that

- may be other than linear or branched C 1 -C 8 alkylene substituted with 18 halogen or optionally substituted amino groups, and

X is as defined herein, with the proviso that it can only be different from a chemical bond, a compound of formula (VI) wherein R1, X and A are as defined above and Z is a leaving group, a compound of formula (VII) wherein R2, R3 and n are as defined above, or

d) for the preparation of a compound of formula Ia which is a narrow group of compounds of formula I, wherein:

R1, R2, R3 and n are as defined herein, and X is as defined herein, with the proviso that they may only be different from a chemical bond, of formula (VIII) wherein

R1 and X are as defined above, a compound of formula VII wherein

R2, R3 and n are as defined above, or

e) for the preparation of a compound of formula Ia which is a narrower group of compounds of formula I, wherein:

R1, R2, R3 and n are as defined herein, and X is as defined for formula (I), with the proviso that it may only be different from a chemical bond and a sulfur atom substituted with one or two oxygen atoms, of the formula wherein

- 191

R1 and X are as defined above, a compound of formula IX wherein

R2, R3 and n are as defined above, or

f) for the preparation of a compound of general formula (Ib) which is a narrower compound of formula (I), wherein

R 1, R ² , R 3, X and n are as defined herein and B 1 is a single bond or optionally substituted with C 1 -C 4 alkoxy, C 1 -C 4 alkanoyloxy, optionally substituted with halogen, optionally phenyl, and / or optionally substituted amino substituted straight or branched C 1 -C 7 alkylene of formula X wherein

R1, X and B1 are the above carboxylic acid or a reactive derivative thereof activated on a carboxyl group of the formula (VII) wherein

R2, R3 and n are as defined above, or

g) for the preparation of a compound of general formula (le), which is a narrow group of compounds of formula I, wherein:

R1, R2, R3 and n are as defined herein,

X is nitrogen optionally substituted with C 1-4 alkyl; and

B2 is a linear or branched C2-C8 alkylene group optionally substituted by hydroxy, C1-C4 alkoxy optionally substituted by phenyl, C1-C4 alkanoyloxy and / or di (C1-C4 alkyl) amino;

-20 of the general formula (XI) wherein

Z is a leaving group or a hydroxy group, and R1 is as defined above, provided that when Z is a hydroxy group, p, q and r are both 0, a compound of formula (XII) wherein

R2, R3, B2, X and n are as defined above, and if desired, a compound of formula (I) obtained by any one of process variants (a) to (g) is converted into another compound of formula (I) in a manner known per se. and / or deprotecting an optional protecting group and / or, if desired, preparing the base from a salt of a compound of formula (I) so prepared, or converting the resulting base into a salt form, for example an acid addition salt.

Pure enantiomers of a compound of formula I having a single asymmetric center may be prepared, for example, by resolution of a racemic compound of formula I prepared using racemic reagent (s) by known methods (e.g., formation and resolution of diastereomeric salts or other derivatives), or by carrying out the corresponding variations of the above procedures with the pure enantiomeric forms of the required reagents.

The diastereomers of a compound of formula (I) having several centers of asymmetry may be separated by methods known per se, for example, chromatography, fractional crystallization or the like.

It will be apparent to those skilled in the art that when certain substituents on the starting compounds, such as R 1 and / or A, carry a reactive group (s) (e.g., hydroxy, amino, carboxyl, or the like) that are not desired in a particular reaction

this group (s) may be protected in a manner known per se in organic chemistry, and after the desired conversion, the protecting group (s) will be cleaved so that other parts of the molecule will not undergo unwanted transformation. Such protecting groups may be protected by conventional protecting groups known in the art, such as hydroxy groups optionally substituted with C 1 -C 4 alkyl groups (e.g. tert-butyl or benzyl), amino groups such as optionally substituted with aryl groups such as phenyl. C4 -C4 alkoxycarbonyl groups (e.g. tert-butoxycarbonyl or benzyloxycarbonyl groups), C1 -C4 alkanoyl groups (e.g. formyl or acetyl), C1 -C4 alkanesulfonyl groups (e.g. a sulfonyl group) or an arylsulfonyl group (e.g., p-toluenesulfonyl group) and the carboxyl group may be protected, for example, as a C 1 -C 4 alkyl ester (e.g., ethyl ester). In addition to the protecting groups exemplified above, any other protecting group known per se, such as TW Greene and P. Wuts in Protective Groups in Organic Synthesis, may be used (John Wiley & Sons, New York, NY, 1991). ). See the same work for suitable cleavage methods for protecting groups.

It will be appreciated that certain reaction steps of the process of the present invention may be carried out without the temporary protection of the aforementioned reactive groups which are not involved in the desired reaction.

Preferred embodiments of certain embodiments of the process of the present invention are described in detail below.

-22 ···· ·

(a) Elemental variant (Scheme A)

Compounds of formula (II) in a suitable solvent, such as chlorobenzene, dimethylformamide, dimethylacetamide, N-methylpyrrolidone or the like, or optionally in the absence of a solvent, at a temperature of 100 to 200 ° C, are required. in the presence of a base such as an inorganic base such as potassium carbonate or sodium hydroxide or an organic base such as triethylamine or pyridine as an acid scavenger. If the reaction is carried out in the absence of a base, the liberated H-Z acid can be bound by the product of the formula I itself.

The starting compounds of formula (II) used in the present process variant are novel and as such are also within the scope of the present invention. These compounds can be prepared, for example, by a variety of reaction routes, selected from X and A, illustrated in Scheme H and I.

A common feature of these methods is that their starting compound is a compound of formula (XIII) wherein n is as defined for formula (I) and R ⁴ is an amine protecting group, by one of the methods A) -E) described below. a compound of formula XIV wherein:

R 1, X, A and n are as defined for formula (I) and R 4 is an amine protecting group, then deprotected to give the compound of formula (II). Said methods, starting from the compounds of the formula (XIII), differ in that they provide the intermediate of the formula (XIV) using different reagents. The following is a detailed description of the preparation of the intermediates of formula (XIV) • ····

Some variants of -23 (Methods A) -C) are illustrated in Scheme H, Methods D and E are illustrated in Scheme I],

Method A)

When R1 and n in the compound of formula (II) to be prepared are as defined for formula (I),

X is sulfur or optionally substituted nitrogen optionally substituted with one or two oxygen atoms, and A is alkylene substituted with C 1-8 hydroxy, C 1-4 alkoxy, C 1-4 alkanoyloxy or carbon attached to X, then a process for the preparation of compounds of formula (XIV) by reacting compounds of formula (XIII) wherein:

R4 is an amine protecting group and n is as described above, compound of formula (VI) wherein R1, X and A are as defined above and Z is a leaving group are reacted to give a compound of formula (XIV) where

R1, R4, X, A and n are as defined above.

This reaction is conveniently carried out in a solvent such as ethanol, propanol, acetonitrile or the like in the presence of a base such as an inorganic base such as potassium carbonate or sodium hydroxide at a temperature between 20 and 100 ° C.

In the starting compounds of formula (XIII), R 1 is an amine protecting group, such as an alkanoyl group such as formyl, or a preferred group. - (C 1 -C 4) alkoxycarbonyl optionally substituted with aryl, such as tert-butoxycarbonyl or benzyloxy; carbonyl group. The protected piperazine or XIII compounds of formula XIII. Homopiperazine derivatives are partially known (see, e.g., T. R. Herrin et al., J. Med. Chem. 18, 1216 (1975)) or may be prepared by methods analogous to those known in the art.

In the compounds of formula VI used as starting materials in Method A, Z is a leaving group, preferably, for example, a halogen atom such as chlorine, bromine or iodine, or an aliphatic or aromatic sulfonyloxy group such as methanesulfonyloxy or p-toluenesulfonyloxy. -group. The compounds of formula (VI) are partially known (see, e.g., E. K. Harwill et al., J. Org. Chem. 17. 1957 (1952); and L.M. Werbel, J. Med. Chem. 6, 637 (1963)] or can be prepared simply by methods known per se. Thus, the compounds of formula (VI) wherein A is C 2 -C 8 alkylene may be prepared, for example, as shown in Scheme J, by the corresponding formula (XIX) wherein

R1 and X are as defined above, and

B2 is a C2-C8 alkylene group starting from alcohols according to methods known per se.

On the other hand, compounds of formula (VI) wherein A is C2-C8 substituted with oxo on the carbon atom to which X is attached are suitably represented by the corresponding formula (IV):

R1 and X are, starting from the compounds described above, prepared by reaction with a carboxylic acid or a reactive derivative thereof activated by carboxylic acid, wherein B3 is a C1-C7 alkylene group and Z is a leaving group. Scheme A).

-25 ··· · · · · · · · · · · · · · ·

Compounds of formulas XIX and XX are known in the art (see, e.g., JS Pierce and R. Adams, J. Am. Chem. Soc. 45, 790 (1923) and RE Foster et al., J. Am. Chem. Soc. 68, 1328 (1946)] and partly commercial products.

Method B

If in the formula (II)

R ¹ and n are as defined for formula (I),

X is a sulfur atom optionally substituted with one or two oxygen atoms, or an optionally substituted nitrogen atom, and A is a 2-hydroxy-1,3-propylene group, can be prepared by reacting a compound of formula XIII wherein

R4 is an amine protecting group, and n is the above protected compound by reaction with an epoxide of formula (VIII) wherein R1 and X are as defined above to form a compound of formula (XIV) wherein

^R1, R4, X, A and n are as defined above.

The reaction is conveniently carried out in a solvent such as an alcohol, such as ethanol, at a temperature between 20 and 100 ° C, and preferably at the reflux temperature of the solvent.

The starting compounds of the general formula (VIII) are partly known (see, for example, GB 1,592,524, U.S.S.R. SU 1,286,596 and Jpn. Tokkyo Koho 79 01,300], or analogously to those known in the art, for example by the methods illustrated in the examples below.

-26 · · · · · · · · · · · · · · ·

Method C

In the case of the general formula (II)

R 1, X and n are as defined for formula (I) and A is a C 1 -C 8 alkylene group substituted with an oxo group on the carbon atom to which the nitrogen-containing heterocycle is attached, then the compounds of formula XIV can be prepared by , where

R4 is an amine protecting group, and n is a protected compound of formula X wherein R1 and X are as defined above, and

B1 is a single bond or a C 1 -C 7 alkylene group reacted with a carboxylic acid or a reactive derivative thereof activated on a carboxyl group to give a compound of formula XIV wherein

R1, R4, X, A and n are as defined above.

The compounds of formula (XIII) may be reacted with the free acid form of the compounds of formula (X), in which case the reaction may be carried out in a neutral solvent such as dimethylformamide, dichloromethane, ethanol or the like with a condensing agent such as N, N. This may be carried out in the presence of '-dicyclohexylcarbodiimide or carbonyldiimidazole, optionally using an excipient such as 1-hydroxybenzotriazole. However, the compounds of formula (X) are preferably used in their free form but in the form of their reactive derivatives activated on the carboxyl group. Such a reactive form may be, for example, an acid halide such as an acid chloride or an acid bromide, an active ester such as an aryl ester such as a phenyl ester, a symmetric anhydride, a mixed anhydride such as

-27 for example mixed anhydride prepared with a chloro-formic acid ester and the like. Carboxylic acids of formula (X) wherein

R1 is as defined for formula (I), provided that at least one of R4 and R5 in formula (a) is a hydroxyl group attached to the carbon atom of the aromatic ring adjacent to the carbon atom bearing X, and p, q and r is both 0, they may be represented by formula (XXI) wherein

X and B1 are as defined for formula (X) and Ar, R4 and R5 are the same as Ar, R4 and R5 which are part of the group of formula (a) wherein R1 is represented by formula I, with the proviso that R4 and R5 is other than an unsubstituted amino group or an amino group substituted with a C 1-4 alkyl group, also in the form of its lactones, which are intramolecular aryl esters of the corresponding acids.

Certain compounds of formula X, such as 1-naphthylcarboxylic acid, 2-naphthylcarboxylic acid, 1-naphthylacetic acid, 1-hydroxy-2-naphthylcarboxylic acid, 3-hydroxy-2-naphthylcarboxylic acid commercial products while others, such as 2- (2-hydroxy-1-naphthyl) acetic acid, 2- (3-hydroxy-2-naphthyl) acetic acid, 3- (2-hydroxy-1-naphthyl) propionic acid, Lactones of formula XXI [see, e.g., Y. Ogata et al., J. Org. Chem., 16, 1588 (1951); A. F. Hardman, J. Am. Chem. Soc. 70, 2119 (1948); and H. Krzikalla and B. Eistert, J. Pract. Chem. 143, 50 (1935)] and 2- (2-naphthylthio) acetic acid and 2- (2-naphthylamino) acetic acid (see, e.g., TM Furman et al., J. Am. Chem. Soc., 82, 1450 (1960) and CA Bischoff and A. Hausdörfer, Chem. 23, 2005 (1890)]. To-28 Further compounds of formula (X) may be prepared by methods analogous to those described above.

Method D

If in the formula (II)

R1 and n are as defined for formula (I),

X has the meaning given to formula (I), provided that it can only be different from a chemical bond and a sulfur atom substituted with one or two oxygen atoms, and

A is alkylene substituted with C 1 -C 8 hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkanoyloxy, or carbon atoms attached to group X, then compounds of formula (XIV) may be prepared by reacting compounds of formula (XIII) of the formula wherein

R4 is an amine protecting group, and n is as defined above, a compound of formula Z1-A-Z2 wherein

A has the meaning given above, and

Z ¹ and Z 2 independently represent a leaving group, with a compound of formula (XV), wherein

R4, A, Z1 and n are as defined above.

If the latter is of formula IV, wherein

R1 and X are reacted with the above compound to give a compound of formula (XIV) wherein

R1, R4, X, A and n are as defined above.

-29 • ·· ·

These two reactions may be carried out in substantially the same manner as described in Method A above.

The starting compounds Z1-A-Z2 are commercially available or can be prepared by simple methods known per se.

On the other hand, when the Z1 leaving group in the compound of formula XV prepared as described above is replaced by an amino group or a C 1 -C 4 alkylamino group in a manner known per se, the compound of formula XVI wherein

R4, A and n are as defined above, and

X is a nitrogen atom optionally substituted with C 1-4 alkyl. (This substitution reaction may be carried out, for example, by reacting a compound of Formula XV with an ammonium, C1-C4 alkylamine or phthalimide potassium in a neutral solvent such as an aliphatic alcohol, dimethylformamide or the like. in the latter case, the resulting phthalimido compound is treated with hydrazine in a manner known per se, for example in an aliphatic alcohol, to give the desired compound (XVI).

Subsequently, if the compound of formula XVI is, for example, in a manner similar to that described in the following description of process variant g, a compound of formula XI wherein

R1 is as defined above, and

Z is a hydroxyl group or a leaving group which is also reacted with a compound of formula (XIV) wherein

R1, R4, A and n are as defined above, and

X is a nitrogen atom optionally substituted with C 1-4 alkyl.

-30E)

If in the formula (II)

R1 and n are as defined for formula (I),

X has the meaning given to formula (I), with the proviso that it can only be different from a chemical bond and a sulfur atom substituted with one or two oxygen atoms, and

A is 2-hydroxy-1,3-propylene, a compound of formula (XIV) may be prepared by reacting a compound of formula (XIII) wherein

R4 is an amine protecting group, and n is the aforementioned protected compound is first reacted with epichlorohydrin and then the resulting compound of formula (XVII) wherein

R4 and n are as defined above, an epoxide of the formula IV wherein

R1 and X are reacted with the above compound to give a compound of formula XIV wherein

R1, R4, X, A and n are as defined above.

For example, compounds of formula (XIII) may be reacted with epichlorohydrin to produce compounds of formula (VIII) as described above. On the other hand, the intermediates of formula (XVII) may be reacted with compounds of formula (IV) under the conditions described in Method B above.

A further variant of Method E comprises reacting the epoxide of formula (XVII) prepared as described above in a suitable solvent, such as water, an aliphatic alcohol, or a mixture thereof, with ammonia or a C 1 -C 4 alkylamine. of the formula wherein

-31 R4 and n are as defined above, and

X is a nitrogen atom optionally substituted with (C 1 -C 4) alkyl, and is then prepared by a process of formula (XI) as described in Method D, wherein

R1 is as defined above, and

Z is a leaving group, is reacted with a compound and so is a compound of formula (XIV) wherein

R1, R4, A and n are as defined above, and

X is a nitrogen atom optionally substituted with C 1-4 alkyl.

The compounds of formula (XIV) obtained by the above methods A) -E) can be deprotected by methods known per se to give compounds of formula II. Thus, alkanoyl-type protecting groups may be removed, for example, by acidic or basic treatment, C 1-4 -alkoxycarbonyl groups may be removed, for example, by acidic treatment, and C 1-4 -alkoxycarbonyl groups bearing aryl may be removed, for example, by catalytic hydrogenation.

The starting compounds of formula (III) used in process variant (a) are partially known (see, for example, B. Roth et al., J. Am. Chem. Soc. 72, 1914 (1950), and PCT Application Publication No. WO 87/01706). and in part, as illustrated in Scheme K, a compound of formula (XXII) wherein

R2 and R3 can be prepared by methods known per se from the compounds of formula (I).

The present process variant (a) provides, for example, the following representative compounds of the present invention:

-32 ··· · ·· «* • * w ·· · • '· · · · · · · · · · · · · ···

1- [2,6-Diamino-4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylthio) -propyl] -piperazine, 1- [2,6-di (1-pyrrolidinyl) - 4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylthio) -propyl] -piperazine, 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2 -hydroxy-3- (2-naphthylamino) propyl] piperazine;

1- [2,6-diamino-4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) propyl] piperazine;

1- [2,6-diamino-4-pyrimidinyl] -4- [N- (2-naphthyl) carbamoylmethyl] piperazine,

1- [2,6-diamino-4-pyrimidinyl] -4- [2- (2-naphthylthio) acetyl] piperazine;

1- [6-amino-2- (1-pyrrolidinyl) -4-pyrimidinyl] -4- [3- (2-hydroxy-1-naphthyl) propionyl] piperazine.

Process variant b (Scheme B)

The compounds of formula (IV) in a suitable solvent such as ethanol are preferably in the presence of a base such as an inorganic base such as potassium carbonate or sodium hydroxide or an organic base such as pyridine or triethylamine at room temperature and reacting the compounds of formula (V) at a temperature between the reflux temperature of the solvent used.

Among the starting materials, the compounds of formula (IV) are commercially available and the compounds of formula (V) are known in part (see, for example, European Patent Application Publication No. 0574906A) and may be prepared in some manner analogously to known methods.

The present process variant (b) provides, for example, the following representative compounds of the present invention:

- [2,6-di (1-pyrrolidinyl) -4-pyrimidin: 1] -4- [2- (2-naphthylamino) acetyl] piperazine, 1- [2,6-di (1-pyrrolidinyl) ) -4-pyrimidinyl] -4- [2- (4-nitro-1-naphthylamino) acetyl] -piperazine, 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] - 4- [2- (2-naphthylthio) acetyl] piperazine, ♦ * ♦> «

33 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2- (2-naphthylthio) acetyl] -homopiperazine.

Process variant c (Scheme C)

Compounds of formula (VI) are reacted with compounds of formula (VII) in an inert solvent such as acetone, acetonitrile, dimethylformamide, preferably in the presence of a base such as potassium carbonate or the like, at room temperature to the reflux temperature of the solvent used. .

The preparation of compounds of formula VI is described above, see Method A for the preparation of starting compounds of formula II used in process variant a).

Compounds of formula (VII) are known in part (see, for example, PCT Application Publication No. WO 87/01706) and may be prepared, in part, in an analogous manner to methods known per se.

The present process variant c) provides, for example, the following representative compounds of the present invention:

1- {6- [N- (2,5-dibenzyloxybenzoyl) amino] hexyl} -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [N- (2-naphthyl) carbamoylmethyl] piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [N- (2-methyl-1-naphthyl) carbamoylmethyl] piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [N- (1-sulfo-2-naphthyl) carbamoylmethyl] piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [3- (2-naphthylamino) propyl] piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2- (7-ethoxycarbonyl-2-naphthyl) acetyl] piperazine;

· 5

-34 ···· • ·

··

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [N- (7-ethoxycarbonyl-2-naphthylamino) -benzoic carbamoyl-piperazine,

1- {N- [4- (N, N-dimethylsulfamoyl) -1-naphthylamino] carbamoylmethyl} -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine .

Process variant d (Scheme D)

Compounds of formula VIII are reacted with compounds of formula VII in an inert solvent such as a halogenated hydrocarbon such as dichloromethane or an alcohol such as ethanol or the like at room temperature to the reflux temperature of the solvent used.

For the preparation of starting compounds of formula (VIII), see above for the preparation of starting compounds of process variant (a).

The present process variant (d) provides, for example, the following representative compounds of the present invention:

1- [2,6-diamino-4-pyrimidinyl] -4- [2-hydroxy-3- (1-naphthylamino) propyl] piperazine;

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (1-naphthylamino) propyl] piperazine;

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (1-naphthylamino) propyl] homopiperazine,

1- [2,6-diamino-4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) propyl] piperazine;

1- [6-amino-2- (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) propyl] piperazine;

1- [6-amino-2- (1-piperidinyl) -4-pyrimidinyl] -4- [2-hydroxypropanoic-3- (2-naphthylamino) propyl] piperazine;

-35 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) propyl] piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- {2-hydroxy-3 - [(2-naphthyl) azetidin-ylamino] -propyl} -piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- {2-hydroxy-3 - [(2-naphthyl) methyl] propyl} piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) propyl] homopiperazine,

1- [2,6-diamino-4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylthio) propyl] piperazine;

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylthio) propyl] piperazine;

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylthio) propyl] homopiperazine.

Process variant e (Scheme E)

Compounds of formula (IV) are reacted with compounds of formula (IX) under the conditions described in process variant (d).

The starting compounds of formula (IX) can be readily prepared by reacting the compounds of formula (VII) with epichlorohydrin, for example as described for the preparation of compounds of formula (VIII) and illustrated in Scheme L.

The present process variant (e) provides, for example, the following representative compounds of the present invention:

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylthio) propyl] piperazine;

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) propyl] piperazine;

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4 - [? - hydroxy-3- (7-ethoxycarbonyl-2-naphthylamino) propyl] piperazine.

Process variant -36f (Scheme F)

Compounds of formula (X) are reacted with compounds of formula (VII), either in free acid form or in their activated reactive form on the carboxyl group. The reaction may be carried out under conditions similar to those used to prepare the starting compounds of formula (II) of process variant (a) according to Method C described above.

The present process variant (f) provides, for example, the following representative compounds of the present invention:

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- (1-naphthoyl) -piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- (1-naphthoyl) homopiperazine,

- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- (1-hydroxy-2-naphthoyl) piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- (1-hydroxy-2-naphthoyl) homopiperazine,

1- [6-amino-2- (1-pyrrolidinyl) -4-pyrimidinyl] -4- (1-hydroxy-2-naphthoyl) piperazine,

1- [6-amino-2- (1-piperidinyl) -4-pyrimidinyl] -4- (1-hydroxy-2-naphthoyl) piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- (3-hydroxy-2-naphthoyl) piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- (3-hydroxy-2-naphthoyl) homopiperazine,

1- [6-amino-2- (1-piperidinyl) -4-pyrimidinyl] -4- (3-hydroxy-2-naphthoyl) piperazine, (-) - 1- [2,6-di (1-pyrrolidinyl) ) -4-pyrimidinyl] -4- [2- (6-methoxy-2-naphthyl) -propionyl] -piperazine, (±) -1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] - 4- [N- (tert-butoxycarbonyl) -3- (1-naphthyl) alanyl] piperazine,

1- (5-Bromo-2-naphthoyl) -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -piperazine, 1- (5,8-dibromo-2-naphthoyl) -4- [ 2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine, 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [3- (2-hydroxy-1-naphthyl) ) -propionyl] -piperazine, 1- [6-amino-2- (1-pyrrolidinyl) -4-pyrimidinyl] -4- [3- (2-hydroxy-1-naphthyl) -propionyl] -piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2- (3-hydroxy-2-naphthyl) acetyl] piperazine;

-37 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- (3-tert-butoxycarbonylamino-2-naphthoyl) piperazine,

1- (3-acetylamino-2-naphthoyl) -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine,

1- (3-dimethylamino-2-naphthoyl) -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- (3-amino-2-naphthoyl) piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- (3-methylthio-2-naphthoyl) piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- (3-methylsulfinyl-2-naphthoyl) piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- (3-methylsulfonyl-2-naphthoyl) piperazine,

1- (5-cyano-2-naphthoyl) -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine,

1- (4-acetyl-1-naphthoyl) -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine,

1- (5-acetyl-2-naphthoyl) -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine,

1- [6-amino-2- (hexahydro-1H-azepin-1-yl) -4-pyrimidinyl] -4- (1-hydroxy-2-naphthoyl) piperazine.

g) Elemental variant (Scheme G)

Suitably, the compounds of formula (XI) wherein Z is hydroxy are employed in a suitable solvent such as water, an alcohol such as ethanol, or a polar aprotic solvent such as dimethylformamide, dimethylacetamide and the like, or mixtures thereof. at a temperature of 100 to 250 ° C, optionally under pressure, in the presence of a suitable catalyst, such as sodium bisulfite or the like, optionally in a sealed vessel.

Compounds of formula (XI) containing a Z substituent may be reacted with compounds of formula (XII), for example, under the conditions described in process variant (c).

The starting compounds of formula (XI) are partly commercially available and partly prepared by methods known in the literature (see, e.g., K. Fries, Bér. 58, 2848 (1925)].

The compounds of formula (XII) may be prepared, for example, by the methods outlined in Scheme M. This can be done, for example, by using a compound of formula (VII) wherein

R ² , R 3 and n are represented by formula (XXIII) in conditions similar to those given for formula (I), such as for example c)

B ² is a linear or branched C 2 -C 8 alkylene group optionally substituted by hydroxy, C 1 -C 4 alkoxy and / or di (C 1 -C 4 alkyl) amino;

Z is a leaving group,

R6 is an amine protecting group, and

X is nitrogen optionally substituted with C 1 -C 4 alkyl, or

R6-X together is a divalent amine protected nitrogen atom, such as a phthalimido group, and the amine protecting group of compound (XXIV) thus obtained is cleaved in a manner known per se, for example by hydrogenolysis, hydrolysis or hydrazinolysis.

Alternatively, compounds of formula (XII) wherein B ² is 2-hydroxy-1,3-propylene may be prepared by reacting a compound of formula (VII) wherein

R 2, R ³ and n are as defined for formula (I)

-39 is first reacted with epichlorohydrin as described in Scheme e and illustrated in Scheme L, wherein:

R2, R3 and n are the epoxides represented by formula (I) which are then reacted with ammonia, a reagent suitable for introducing an amino group (e.g. hexamethylenetetramine and the like) or a C1-C4 alkylamine.

The present process variant g) provides, for example, the following representative compounds of the present invention:

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2- (2-naphthylamino) ethyl] piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2- (2-naphthoyl) ethyl] piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- {2- [2- (2-naphthyl) acetylamino] ethyl} piperazine;

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- {2- [2- (2-naphthyl) -2-oxo-ethylamino] ethyl} piperazine.

If desired, a compound of formula (I) prepared by the above process variants (a) to (g) may be converted to other compounds of formula (I) by methods known per se. For example, an aromatic ring in R 1 may be halogenated with a suitable halogenating agent such as elemental halogen (such as chlorine, bromine) or other suitable reagent (such as an N-halosuccinimide or sulfuryl halide); or by nitration with a suitable nitrating reagent such as concentrated nitric acid or an alkali metal nitrate and a strong acid (such as sulfuric or trifluoroacetic acid).

A nitro group which is a substituent on R 1 can be reduced to an amino group with a suitable reducing agent, for example, in the presence of a noble metal catalyst, elemental hydrogen, a complex hydride such as sodium tetrahydroborate or the like.

-40Valamely, an aliphatic part of the group R ¹ may be present in a carbonyl group such as a complex metal hydride such as LAH-aluminate (optionally a Lewis acid such as aluminum trichloride in the presence of a) be reduced to the methylene with an appropriate reducing agent. A suitable sulfur atom in the alkylthio group substituted with R 1 or in the X position is a suitable oxidizing agent, e.g. An appropriate amount of m-chloroperbenzoic acid may be oxidized singly or twice to convert a sulfur atom at said site to a sulfur atom substituted with one or two oxygen atoms.

A carboxyl group which is a substituent on R 1 may be esterified with an alcohol such as an aliphatic alcohol, preferably an inorganic or organic acid (such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and the like) as a catalyst. On the other hand, the carboxylic acid ester group which is a substituent on R 1 can be hydrolyzed, for example, with an aqueous base (such as an alkali metal hydroxide or carbonate) to the free acid; or by reaction with, for example, ammonia or an aliphatic amine, to form the corresponding carboxamide. Treatment of the unsubstituted carboxamide on the nitrogen atom with a suitable dehydrating agent (such as sulfuric acid, phosphorus pentoxide, polyphosphoric acid or the like) gives the corresponding cyano compound. Further, a cyano group can be hydrolyzed to a carboxamide group or a carboxyl group, depending on the reaction conditions, using a strong acid (such as hydrochloric acid, sulfuric acid, and the like) or a base (such as sodium hydroxide, potassium carbonate, and the like).

A NH or OH group, which is a substituent on R 1 or A, may be converted to a Ν-acyl or O-acyl derivative by a conventional acylating agent (for example, an acid chloride, acid anhydride, active ester, mixed anhydride or the like); with a conventional alkylating agent (such as

-41, for example, with an alkyl halide, an alkyl sulfate, an aromatic sulfonic acid ester or the like) can be converted to a Ν-alkyl or O-alkyl derivative. On the other hand, the acylamino group or acyloxy group optionally present as a substituent on R1 or A can be converted into a free amino group or a hydroxy group, for example, by use of a suitable organic or inorganic acid or base. Similarly, the acylated nitrogen at X can be converted in the same way to an unsubstituted nitrogen. In addition, the optionally substituted C 1-4 alkoxy optionally substituted as a substituent on R 1 or A can be converted to the free hydroxy group using a suitable reagent such as an acid or a reducing agent.

Finally, the optional hydroxyl group as a substituent on Group A can be replaced by a suitable halogenating agent (such as thionyl chloride, phosphorus pentachloride, phosphorus pentabromide, and the like) and the halogen atom can then be replaced with an amine or alcoholate.

Exemplary compounds of the present invention may be prepared by the methods exemplified above for the following transformations: 1- {6- [N- (2,5-Dihydroxybenzoyl) amino] hexyl} -4- [2,6 -di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine, (±) -1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [3- (1-naphthyl) alanyl] ] -piperazine, (±) -1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [3- (1-naphthyl) -N, N-dimethylalanyl] -piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2- (2-naphthyl-methylamino) ethyl] piperazine,

- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2- [2- (2-naphthyl) ethylamino] ethyl] piperazine, 1- [2-acetoxy-3 - (N-acetyl-2-naphthylamino) propyl] -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl-piperazine,

1- (3-amino-2-naphthoyl) -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine,

-42 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [N- (7-carboxy-2-naphthylamino) carbamoylmethyl] piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2- (7-carboxy-2-naphthyl) acetyl] piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [N- (7-carboxamido-2-naphthyl) carbamoyl] piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2- (7-carboxamido-2-naphthyl) acetyl--benzoic piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthyl-sulfinyl) -propyl] -piperazine,

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylsulfonyl) propyl] piperazine;

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-methoxy-3- (2-naphthylamino) propyl] piperazine;

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-benzyloxy-3- (2-naphthylamino) propyl] piperazine;

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-chloro-3- (2-naphthylamino) propyl] piperazine;

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-bromo-3- (2-naphthylamino) propyl] piperazine;

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-methyl-3- (2-naphthylamino) propyl] piperazine;

- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-dimethylamino-3- (2-naphthylamino) -propyl] -piperazine.

The compounds of formula (I) of the present invention and their pharmaceutically acceptable salts have valuable physiological effects. More specifically, these compounds inhibit lipid peroxidation and are therefore diseases

-43 and for the treatment of conditions in which inhibition of lipid peroxidation is desired.

The inhibitory effect of the compounds of the present invention and their pharmaceutically acceptable salts on lipid peroxidation can be demonstrated and measured by biochemical and pharmacological assays. The following are some of these studies and the results obtained with these representative compounds of the present invention. Compounds known in the biological assays for use as lipid peroxidation inhibitors are 3,5-di-tert-butyl-4-hydroxytoluene [butylated hydroxytoluene, BHT, see, e.g., W. Snipes et al., Science 188 64, 1975]; alpha-tocopherol (vitamin E, see, for example, M. J. Kelly, cited above); and 21- [4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -1-piperazinyl] -16alpha-methyl-pregna-1,4,9 (11) -triene-3,20 -dione (U74006F, see, e.g., EJ Jacobsen et al., J. Med. Chem. 33, 1145 (1990)); and 2 - [[4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -1-piperazinyl] methyl] -6-hydroxy-2,5,7,8-tetramethyl-3,4 -dihydro-2H-1-benzopyran (U78517F, see, e.g., EJ Jacobsen et al., J. Med. Chem. 35, 4464 (1992)).

Biochemical test

Inhibition of iron (II) -dependent lipid peroxidation in rat brain homogenate is described by J. M. Braughler et al. Biol. Chem. 262: 10438 (1987)] and J. A. Buege and S. D. Aust (Methods in Enzymology 52: 302 (1978)). Table 1 below shows the IC50 values for some representatives of the compounds of the present invention and comparators measured in this assay in micromoles. The IC50 value is the concentration of the test compounds which reduces by 50% the amount of the substance (primarily malondialdehyde) that is considered to be relevant for the degree of lipid peroxidation.

-441. spreadsheet

Compound (example number) JC5o, micromoles Reference substances BHT 1 Vitamin E 7 U74006F 39 U78517F 0.3 Compounds of the present invention 9 2.5 17 7 18 3 19 10 20 6 21 5 23 2 25 5 26 4 29 10 31 15 35 14 36 16 37 15 39 15 47 12

-45 Pharmacological Study

E. D. Hall et al., J. Med. Neurosurg. 68, 456 (1988)], in mice, representatives of the compounds of the present invention and comparators, at the intravenous doses given below, inhibit brain damage (improve the neurological status of the animals) to the extent indicated. The percentage improvement is the change in the sum of the scores for the animals' neurological status.

Table 2

Compound (example number) Dose in mg / kg Improvement,% Reference substances Vitamin E 30 97 U74006F 30 77 U78517F 20 31 The compounds of the present invention 18 10 80 23 0.3 151 25 5 80 26 2.5 119 35 30 134 37 1.25 132 47 20 85 49 5 83

-46Toxicity studies

The acute toxicity of the compounds of the present invention was determined in rats. The toxicity of these compounds is generally mild, for example the 500 mg / kg intraperitoneal (intraperitoneal) dose of the compounds of Examples 23, 26 and 35 does not cause any death (LD50> 500 mg / kg), as a comparator. , similar to the aforementioned compound U74006F.

The data presented above demonstrate that many of the compounds of formula (I) of the present invention significantly inhibit lipid peroxidation under in vitro conditions and are therefore capable of suppressing various pathological processes in the living body associated with increased lipid peroxidation as this is also supported by the above in vivo results. Furthermore, these beneficial effects are accompanied by moderate toxicity.

For therapeutic purposes, the compounds of the present invention and their pharmaceutically acceptable salts may be used alone or conveniently in the form of pharmaceutical compositions, and such compositions are also included within the scope of the present invention.

These pharmaceutical compositions contain as an active ingredient an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in association with pharmaceutically acceptable carriers, excipients, diluents and / or other pharmaceutical excipients, which are conventionally used in the preparation of pharmaceutical compositions.

Suitable carriers, diluents or fillers as described above include water, alcohols, gelatin, lactose, sucrose, starch, pectin, magnesium stearate, stearic acid, talc, various animal or vegetable oils, and glycols such as propylene glycol or polyethylene. glycol. Pharmaceutical excipients include preservatives, antioxidants, various natural or

-47 · · · · synthetic emulsifying, dispersing or wetting agents, coloring agents, flavoring agents, buffering agents, disintegrating agents and other agents promoting the bioavailability of the active ingredient.

The pharmaceutical compositions of the present invention may be in the usual dosage forms. Examples of such conventional dosage forms are oral (oral) formulations which may be prepared using the aforementioned pharmaceutical excipients, which may be solid dosage forms such as tablets, capsules, powders, pills, dragees or granules, or liquid dosage forms such as syrup, solution, an emulsion or suspension; rectal (rectal) formulations such as suppositories; and parenteral (gastrointestinal bypass) formulations, such as injectable or infusion formulations.

Although the dosage of the compounds of the present invention to produce a therapeutic effect will vary depending upon the individual condition and age of the patients being treated, it may vary and will ultimately be determined by the attending physician; for the prevention and / or treatment of diseases in which inhibition of lipid peroxidation is desirable, generally about 0.1 mg to about 100 mg, preferably about 1 mg to about 20 mg, per day of oral (oral) administration of these compounds. administered) or parenteral (bypassing the gastrointestinal tract), for example, intravenous (intravenous).

The compounds of the present invention and the process for their preparation will now be described by way of example without limiting the scope of the invention.

-48 Example 1

1-f6-FN (2.5-Dihydroxy-benzoyl) -amino1-hexyl) -4-F2.6-di (1-pyrrolidinyl) -4-pyrimidinyl-piperazine

the step

1- {6- [N- (2,5-Dibenzyloxybenzoyl) amino] hexyl} -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine

1.45 g (4.8 mmol) of 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine, 3.1 g (5.7 mmol) 6- [N- (2.5 -dibenzyloxybenzoyl) amino] hexyl iodide and 0.96 g (6.9 mmol) of anhydrous potassium carbonate in 36 ml of anhydrous dimethylformamide was stirred at 55 ° C for 5 hours under nitrogen. The reaction mixture was then diluted with ice water (120 mL), sodium chloride (2 g) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and the ethyl acetate was distilled off under reduced pressure. The residue was washed with diethyl ether to give the title compound (2.47 g, 72%, mp 131-132 ° C).

Step b)

1- {6- [N- (2,5-Dihydroxybenzoyl) amino] hexyl} -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl-piperazine

2.4 g (3.3 mmol) of 1- {6- [N- (2,5-dibenzyloxybenzoyl) amino] hexyl} -4- [2,6-di (1-pyrrolidinyl) -4- The solution of oirimidinyl] piperazine in 120 ml of 80% aqueous ethanol was adjusted to pH 3 with concentrated hydrochloric acid and hydrogenated in the presence of 1.1 g of 10% palladium on carbon. The solution obtained after filtration of the catalyst was adjusted to pH 5 with concentrated ammonium hydroxide and the solvent was distilled off under reduced pressure. The residue thus obtained was dissolved in water (30 ml), the pH of the solution was adjusted to 8.5 with concentrated ammonium hydroxide, and the mixture was extracted with chloroform. The organic portion was dried over chloroform

After distillation under reduced pressure, the residue was chromatographed on a silica gel column eluting with ethyl acetate. 0.76 g of the title compound is obtained. Yield: 43%, m.p. 182-183 ° C.

From the base thus obtained, the dihydrochloride was prepared by dissolving it in ethanol, acidifying it with hydrochloric acid in diethyl ether and distilling off the solvent, m.p. 173-175 ° C.

Example 2

1- [2,6-Diamino-4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylthio) -propyl-piperazine 2.41 g (8 mmol) 1- [2-hydroxy-3- ( A solution of 2-naphthylthio) -propyl] -piperazine and 1.13 g (7.85 mmol) of 2,6-diamino-4-chloropyrimidine in 20 ml of chlorobenzene was stirred at reflux under nitrogen for 4 hours. After cooling, chlorobenzene is distilled off under reduced pressure to remove a slightly sticky substance. The residue was stirred with 60 ml of a 2 M aqueous sodium hydroxide solution until it dissolved into a filterable powder. The solid product is filtered off, washed with water to neutral and recrystallized from ethyl acetate. Yield: 1.95 g, m.p. 165-168 ° C, 59.5%.

3-7. example

Using appropriately substituted starting compounds and following the procedure described in Example 2, compounds of formula I wherein

R1 is 2-naphthyl, and

X, A, n, R2 and R3 are as defined in the table below.

-50 • · · ··· · · *% · · · ·

Example number X THE n R2 R3 M.p. Yield, % 3 S -CH2CH (OH) CH2- 1 1-pyrrolidinyl 1-pyrrolidinyl 135-1381) 18.3 4 NH -CH2CH (OH) CH2- 1 1-pyrrolidinyl 1-pyrrolidinyl 198-200 31,42) 5 NH -CH2CH (OH) CH2- 1 NH2 NH2 154-1593) 50.6 6 NH -C (O) -CH2- 1 NH2 nh ₂ 165-173 40.6 7 S -CH2-C (O) - 1 NH2 NH2 185-188 89.7

1) Chromatography on a silica gel column using ethyl acetate as eluent. The product is identical to the compounds of Examples 28 and 31, respectively.

2) The reaction is carried out in the presence of 1 equivalent of sodium iodide. The product is identical to the compound of Examples 23 and 32, respectively.

3) Recrystallized from methanol. The product is identical to the compound of Example 20.

Example 8

1- [6-Amino-2- (1-pyrrolidinyl) -4-pirimidinil1-4- [3- (2-hydroxy-1-naphthyl) piperazin--propionil1

0.33 g (1.0 mmol) of 6-amino-2- (1-pyrrolidinyl) -4-tosyloxypyrimidine, 0.3 g (1.05 mmol) of 1- [3- (2-hydroxy-1-) A mixture of naphthyl) propionyl] piperazine and 20 ml of chlorobenzene was heated in a bomb tube in an oil bath at 200-210 ° C for 10 hours and then cooled. The solvent was distilled off and the oily material was dissolved in hot methanol (30 mL) and, after cooling, the resulting brown precipitate was filtered off. The solvent was distilled off from the methanolic filtrate and the residue was chromatographed on a silica gel column eluting with 10: 3 ethyl acetate: methanol. 15 mg of the title compound is obtained in the form of a light brown powder which is identical to the compound of Example 47 in a yield of 3.8%.

- 51 »·· · · · · · · ·· '···· ♦ • · · · the" * · · · · · · · · ·· ·· "·"

Example 9

1 í2,6-di (1-pyrrolidinyl) -4-pyrimidinyl-4- [2- (2-naphthyl anriino) phenylacetyl-piperazine

0.70 g (4.88 mmol) of 2-naphthylamine and 1.90 g (5 mmol) of 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- (2-chloro- A suspension of acetylpiperazine in 70 ml of ethanol was refluxed for 6 hours. The solvent was then distilled off under reduced pressure and the residue was stirred with 50 ml of a saturated aqueous sodium bicarbonate solution and 50 ml of dichloromethane for half an hour. The aqueous layer was separated, extracted with dichloromethane (2 x 50 mL), and the combined organic layers were washed with brine (50 mL), dried (MgSO4) and the solvent was distilled off under reduced pressure. The crude product was triturated with 25 mL of acetonitrile with gentle heating, the solid product was filtered off and washed with acetonitrile. Yield: 1.31 g (55%), m.p. 200-202 ° C.

Example 10

-1,6,6-Di (1-pyrrolidinyl) -4-pyrimidinyl-4- {2- (4-nitro-1-naphthylamino} acetylpiperazine

0.38 g (1.0 mmol) of 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- (2-chloroacetyl) -piperazine, 0.19 g (1.0 mmol) A suspension of 4-nitro-1-naphthylamine and 0.2 g (1.45 mmol) of potassium carbonate in 40 mL of acetonitrile was heated to reflux for 30 hours. The insolubles were filtered off and the filtrate was evaporated under reduced pressure, and the residue was purified by chromatography on a silica gel column using dichloromethane: methanol (20: 1) as eluent. 90 mg of the title compound are obtained in a yield of 17.0%, m.p. 192-201 ° C.

• · »« · · · · · · · ·

-52 • · · · ····· «V ·· ·· * ·· ·« ·

Example 11

Γ 2,6-Ρΐ (1-Pyrrolidinyl) -4-pyrimidinine-4 - [(2-naphthylthio) acetyl] piperazine 0.64 g (4 mmol) of 2-thionaphthol in 80 mL of ethanol and 4 mL of 1 M To a solution of aqueous sodium hydroxide solution was added 1.51 g (4 mmol) of 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- (2-chloroacetyl) piperazine at room temperature. After stirring for 2 hours at the same temperature, the solvent was distilled off under reduced pressure. The residue was worked up as in Example 9. The crude product (2.19 g) was recrystallized from ethanol to give 1.57 g (78.2%) of pure title compound, mp 135-138 ° C.

Example 12

1 í2.6-di (1-pyrrolidinyl) -4-pirimidinil1-4- [2- (2-naphthylthio) homopiperazine -acetil1

The title compound was prepared in the same manner as in Example 11 except that 2-thionaphthol was 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- (2-chloroacetyl). Instead of piperazine, 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- (2-chloroacetyl) -homopiperazine is reacted and the crude product is stirred with 50 ml of water until it becomes a filterable powder. . Yield: 1.77 g (86%), m.p. 56-63 ° C.

Example 13

1 í2.6-di (1-pyrrolidinyl) -4-pyrimidinyl-4-IN- (2-naphthyl) carbamoyl-methyl-1-piperazine

To a boiling suspension of 1.2 g (4 mmol) of 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -piperazine and 0.68 g (5 mmol) of anhydrous potassium carbonate in 120 ml of acetonitrile 0 86 g (4.9 mmol) of N- (2-chloroacetyl) -2-naphthylamine are added and the reaction mixture is refluxed for 2 hours. The solvent was evaporated and the residue was partitioned between water (100 mL) and dichloromethane (100 mL). The aqueous layer was extracted with two additional 40 mL portions of dichloromethane, and the combined organic extracts were washed with water to neutral, dried over magnesium sulfate and the solvent was distilled off under reduced pressure. . This gave 1.82 g of the title compound, which was recrystallized from ethyl acetate, yield 94.7%, m.p. 212-214 ° C.

14-15. example

Using appropriately substituted starting compounds and following the procedure described in Example 13, compounds of formula I wherein

X is NH,

A is -C (O) -CH 2 -, n is 1,

R2 and R3 are both 1-pyrrolidinyl and R1 is as shown in the table below.

Example number R1 M.p. Yield% 14 2-methyl-1-naphthyl 174-176 60.5 15 1-sulfo-2-naphthyl 202-205 56.4

Example 16

1-f2.6-di (1-pyrrolidinyl) -4-pyrimidinyl-4- [3- (2-naphthylamino) propyl-piperazin

0.45 g (2.25 mmol) of N- (3-hydroxypropyl) -2-naphthylamine and 0.37 ml (0.27 g; 2.7 mmol) of triethylamine were prepared in 10 ml of anhydrous toluene, A solution of methanesulfonic chloride (0.17 mL, 0.27 g, 2.3 mmol) in dry toluene (2.5 mL) was added dropwise to a solution of 0 ° C over 10 minutes, and the mixture was stirred at the same temperature for one hour. The reaction mixture was washed with water (2 x 5 ml), neutralized, dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The thus obtained 0.55 g (2 mmol) of N- (3-methanesulfonyloxypropyl) -2-naphthylamine is dissolved in 10 ml of acetonitrile and 0.6 g (2 mmol) of 1- A suspension of [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine, 0.31 g (2.2 mmol) of potassium carbonate and 0.01 g of sodium iodide in 10 ml of acetonitrile was added and the reaction mixture was stirred for 5 min. stir for an hour. The final mixture was worked up as in Example 12 to give 0.87 g of crude product which was chromatographed on a silica gel column using benzene: methanol 9: 1 as eluent. Yield: 0.55 g (56.7%), m.p. 70-71 ° C.

Example 17

1- [2,6-diamino-4-pirimidinil1-4- [2-hydroxy-3- (1-naphthylamino) propyl-piperazine

A suspension of 2.11 g (5 mmol) of 1- (2,6-diamino-4-pyrimidinyl) piperazine-bis-trifluoroacetate and 2.07 g (15 mmol) of potassium carbonate in 100 ml of ethanol is stirred vigorously for 30 minutes. while boiling. The insolubles were filtered off hot and a solution of 1.0 g (5 mmol) of N- (2,3-epoxypropyl) -1-naphthylamine in 20 ml of ethanol was added to the filtrate. The reaction mixture was refluxed for 3 hours, then the solvent was distilled off and the residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous layer was partitioned between ethyl acetate (50 mL), and the combined organic layers were washed with brine (50 mL), dried over magnesium sulfate and the solvent was distilled off. The residue was chromatographed on a silica gel column using benzene: methanol (2: 8) as eluent. 0.95 g of the title compound is obtained, which is triturated with diethyl ether. Yield: 48.4%, m.p. 105-109 ° C.

18-29. example

Using appropriately substituted starting compounds and following the procedure described in Example 17, compounds of formula (Ia) are prepared wherein

R1, X, n, R2 and R3 are as defined in the table below.

• * »·

Example number R1 X n R2 R3 M.p. Yield, % 18 1 naphthyl NH 1 1-pyrrolidinyl 1-pyrrolidinyl 84-85 65.6 19 1 naphthyl NH 2 1-pyrrolidinyl 1-pyrrolidinyl 62-65 53.4 20 2-naphthyl NH 1 NH2 NH2 185-188 35.8 21 2-naphthyl NH 1 1-pyrrolidinyl NH2 140-142 14,51) 22 2-naphthyl NH 1 1-piperidinyl NH2 128-129 56.8 23 2-naphthyl NH 1 1-pyrrolidinyl 1-pyrrolidinyl 198-201 76.0 24 2-naphthyl N (MS) 2) 1 1-pyrrolidinyl 1-pyrrolidinyl 159-160 79.3 25 2-naphthyl N (CH ₃ ) 1 1-pyrrolidinyl 1-pyrrolidinyl 134-138 66.8 26 2-naphthyl NH 2 1-pyrrolidinyl 1-pyrrolidinyl 103-106 71.8 27 2-naphthyl S 1 nh ₂ NH ₂ 158-163 35.8 28 2-naphthyl S 1 1-pyrrolidinyl 1-pyrrolidinyl 136-140 56.6 29 2-naphthyl S 2 1-pyrrolidinyl 1-pyrrolidinyl 83-86 61.0

1) Dichloromethane is used as solvent instead of ethanol.

2) Ms = mesyl

Example 30

Salts of 1- [2,6-Di (1-pyrrolidinyl) -4-pyrimidinine-4- [2-hydroxy-3- (2-naphthylamino) propyl] piperazine

(a) Salicylic acid salt

0.25 g (0.5 mmol) of 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) -methrone from Example 23 To a solution of the propyl] -piperazine base in 7 ml of benzene is added 10 ml of a 0.1 molar solution of salicylic acid in ethanol. After allowing the mixture to cool to room temperature, the precipitated crystalline material is filtered off, washed with ice-cold ethanol and air-dried.

This gave the monosalicylate of the above base, m.p. 200-206 ° C, with a salt formation yield of 77.4%.

b) p-Toluene sulfonic acid salt

In the same manner as in a) above, the mono-p-toluene sulfonate of the above base is obtained, m.p. 173-176 ° C, yield 74.7%.

(c) Phosphoric acid salt

According to a) above, the diphosphate of the above base was crystallized with 2 moles of water, m.p. 260-265 ° C (dec.), 98.2% yield.

(d) Sulfuric acid salt

0.25 g (0.5 mmol) of 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) -methrone from Example 23 The propyl base is dissolved in 10 ml of 0.1 M aqueous sulfuric acid and 13 ml of ethanol with heating and allowed to cool. The precipitated crystalline material is filtered off, washed with ice-cold ethanol and air-dried. This gives a disulfate of the above base containing 2 moles of crystalline water. 228-230 ° C (dec.), Yield 75.7%.

Example 31

1- [2,6-Di (1-pyrrolidinyl) -4-pyrimidinyl-4-1,2-hydroxy-3- (2-naphthylthio) -propinepiperazine 0.53 g (1.5 mmol) 1- [2, A solution of 6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- (2,3-epoxypropyl) piperazine and 0.24 g (1.5 mmol) of 2-thionaphthol in 10 mL of ethanol was catalytic (ca. (0.03 mL) was stirred with triethylamine for 1 hour. After cooling, the precipitated crystalline material is filtered off and washed with 2 ml of cold ethyl acetate. 0.64 g of the title compound is obtained, which is identical to the compound of Examples 3 and 28, respectively. Yield: 83.1%, m.p. 136-143 ° C.

- 57 32, Example

1-F2.6-di (1-pyrrolidinyl) -4-pyrimidinyl-4-f2-hydroxy-3- (2-naphthylamino) propyl-piperazine

The title compound was prepared in a similar manner to Example 31 except that 2-naphthylamine was used in place of 2-thionaphthol and the reaction mixture was refluxed for 24 hours. The title compound thus prepared is identical to the compound of Example 23. Yield 28.7%, m.p. 198-201 ° C. In a similar manner, but using about 0.05 mL of concentrated aqueous hydrochloric acid as the catalyst instead of triethylamine, the title compound was obtained in 39.0% yield.

Example 33

1-f2.6-di (1-pyrrolidinyl) -4-pyrimidinyl-4- (1-naphthoyl) -piperazine

0.60 g (2 millimoles) of 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine and 0.30 ml (0.22 g, 2.2 millimoles) of triethylamine in 20 ml of anhydrous A solution of 0.45 g (2.2 mmol) of naphthalene-1-carboxylic acid chloride in 5 ml of anhydrous dichloromethane was added dropwise to a solution of dichloromethane in dichloromethane at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours and then diluted twice with dichloromethane. The solution was washed with water (2 x 20 mL) to neutral, dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The crude product thus obtained was purified by column chromatography on silica gel using n-hexane: ethyl acetate (1: 2) as the eluent. Yield: 0.51 g (54.4%), m.p. 211-214 ° C.

34-41. example

Using appropriately substituted starting compounds and following the procedure described in Example 33, compounds of formula (Ib) were prepared wherein

X and B1 together form a single chemical bond and R1, n, R2 and R3 are as defined in the table below.

Example number R1 n R2 R3 M.p. Yield, % 34 1-naphthyl 2 1-pyrrolidinyl 1-pyrrolidinyl 188-191 61.5 35 1-hydroxy- 2-naphthyl 1 1-pyrrolidinyl 1-pyrrolidinyl 215-219 50.3 36 1-hydroxy- 2-naphthyl 2 1-pyrrolidinyl 1-pyrrolidinyl 110-118 38.2 37 1-hydroxy- 2-naphthyl 1 1-pyrrolidinyl NH2 > 240 (Dec) 44,81) 38 1-hydroxy- 2-naphthyl 1 1-piperidinyl NH2 170-171 26.6 39 3-hydroxy- 2-naphthyl 1 1-pyrrolidinyl 1-pyrrolidinyl 231-235 36.8 40 3-hydroxy- 2-naphthyl 2 1-pyrrolidinyl 1-pyrrolidinyl 239-242 72.1 41 3-hydroxy- 2-naphthyl 1 1-pyrrolidinyl NH2 > 240 (Dec) 38.21)

1) The reaction is carried out in acetonitrile at the boiling point of the solvent.

I

- 59 Example 42 (-) - 1-1,2,6-Di (1-pyrrolidinyl) -4-pyrimidinyl-4- [2- (6-methoxy-2-naphthyl) -propionine-piperazine

A suspension of 2.0 g (6.61 mmol) of 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine and 1.24 g (9 mmol) of potassium carbonate in 160 ml of dimethylformamide was added. 1.64 g (6.60 mmol) of [S - (+) - 2- (6-methoxy-2-naphthyl) -propionic acid in benzene, in the presence of pyridine, with thionyl chloride, is added at room temperature, with stirring, over a quarter hour. )] acid chloride and the reaction mixture was stirred for 4 hours at 60 ° C. The reaction mixture was cooled and poured into 750 ml of a saturated aqueous solution of sodium chloride. The precipitated crystalline material is filtered off, washed with water, air dried and chromatographed on a silica gel column using chloroform / acetone 9: 1 as eluent. Thus 1.5 g of crystalline title compound are obtained, yield 44.9%, m.p .: 151-154 ° C, [otfo = -38.4 ⁰ (c = 1, chloroform).

Example 43 (1) -1,2,6-Di (1-Pyrrolidinyl) -4-pyrimidine-N- (N-tert-butoxycarbonyl) -3- (1-naphthyl) alanylpiperazine

To a solution of (±) -N- (tert-butoxycarbonyl) -3- (1-naphthyl) -alanine (0.90 g, 2.9 mmol) in anhydrous dimethylformamide (15 mL) was added 0.62 g (3 g) under nitrogen. N, N'-dicyclohexylcarbodiimide followed by 1-hydroxybenzotriazole (0.45 g, 3 mmol). After stirring for half an hour, a solution of 0.91 g of 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -piperazine in 5 ml of anhydrous dimethylformamide was added. After stirring for 24 hours at room temperature, the precipitated dicyclohexylurea was filtered off and the filtrate was poured into 100 ml of a 20% aqueous solution of sodium chloride. The precipitated product is filtered off, washed with water, then dried with hexane and air dried. The resulting crude product 60 (1.20 g, 66.7%) was recrystallized twice from ethanol to give 0.72 g of pure title compound, 40.0%, mp 174-176 ° C.

44-45. example

Using appropriately substituted starting compounds and following the procedure described in Example 43, compounds of formula Ib were prepared wherein

X and B1 together form a single bond, n is 1,

R2 and R3 are both 1-pyrrolidinyl and R1 is as shown in the table below.

Example number R1 M.p. Yield% 44 5-bromo-2-naphthyl 174-176 44.8 45 5,8-dibromo-2-naphthyl 193-195 50.8

Example 46 (±) -1- [2,6-Di (1-Pyrrolidinyl) -4-pyrimidinyl-4- [3- (1-naphthyl) alanyl] piperazine 0.24 g (0.4 mmol) (±) ) -1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [N- (tert-butoxycarbonyl) -3- (1-naphthyl) alanyl] piperazine and 2 ml 97% formic acid mixture was stirred at room temperature for 24 hours. It was then poured into water (5 mL) and basified to pH 10 with 10M sodium hydroxide solution under ice-cooling. The precipitate was washed with water and, after drying, triturated with diethyl ether. Yield: 0.15 g (75%), m.p. 142-143 ° C.

* '«· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

-61 Example 47

-2.6-Di (1-pyrrolidinyl) -4-pyrimidin-4- [3- (2-hydroxy-1-naphthyl-propionine-piperazine)

1- (2,6-Di (1-pyrrolidinyl) -4-pyrimidinyl) -piperazine (3.0 g, 9.91 mmol) was dissolved in anhydrous acetonitrile (300 mL) and 2.0 g (10.1 mmol) was added with stirring. [3- (2-hydroxy-1-naphthyl) propionate] -laktont. The mixture was refluxed for 22 hours and then cooled. The precipitate from the reaction mixture was filtered, washed with ice-cold acetonitrile and air-dried. Yield: 4.36 g (95.7%), m.p. 274-275 ° C.

Example 48

-6-Amino-2- (1-pyrrolidinyl) -4-pyrimidin-4-yl- (2-hydroxy-1-naphthyl) -propionine-piperazine

0.25 g (1.0 mmol) of 1- [6-amino-2- (1-pyrrolidinyl) -4-pyrimidinyl] piperazine and 0.2 g (1.0 mmol) of [3- (2-hydroxy) 1-Naphthyl) -propionic acid] -actone is dissolved in 25 ml of anhydrous acetonitrile. The mixture was refluxed for 16 hours and then cooled. Two-thirds of the solvent was distilled off, and the precipitate from the concentrated solution was filtered, washed with acetonitrile and air-dried. This gave 0.38 g (85.9%) of the title compound as an off-white powder, identical to Example 8, m.p. 285-287 ° C (dec.).

Example 49

1-f2.6-di (1-pyrrolidinyl) -4-pyrimidinyl-4- [2- (3-hydroxy-2-naphthyl) piperazin--acetil1

0.42 g (1.5 mmol) of 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -piperazine and 0.32 g (1.74 mmol) of [2- (3-hydroxy-2) -naphthyl) -acetic acid] -actone is dissolved in 50 ml of anhydrous acetonitrile. The reaction mixture was stirred for 1 hour at 40 ° C, whereupon a white precipitate began to form. The precipitated precipitate was filtered off, washed with acetonitrile and air-dried. Ily • · · «*

Yield: 0.52 g (77.3%, m.p. 210-221 ° C) as an off-white powder.

Example 50

1-F2.6-di (1-pirrolidiniQ pirimidinil1-4-4-2- (2-naphthylamino) ethyl piperazin-

Method A)

0.14 g (1 mmol) of 2-naphthol and 0.35 g (1 mmol) of 1- (2-aminoethyl) -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine The mixture was heated in a bomb tube in an oil bath at 220-225 ° C for 3 hours. After cooling, it is dissolved in 20 ml of chloroform, the solution is extracted with 1M sodium hydroxide solution, washed neutral with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was chromatographed on a silica gel column using benzene / methanol 9: 1 as eluent. This gives 0.08 g of the title compound, which is recrystallized from isopropanol, m.p. 109-110 ° C, 17%.

Method B

0.29 g (2 mmol) of 2-naphthol, 0.76 g (2.2 mmol) of 1- (2-aminoethyl) -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] A solution of piperazine and 0.35 g (2 mmol) of sodium dithionite in 10 mL of water was heated in a bomb tube at 150-155 ° C for 7 hours. After cooling, the reaction mixture was extracted with benzene, and the organic layer was washed with 1M aqueous sodium hydroxide solution, then water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from isopropanol. Yield: 0.20 g (21.3%), m.p. 110-112 ° C as a colorless crystalline solid.

-63 Example 51

1- {2,6-Di (1-Pyrrolidinyl) -4-pyrimidinir-4-yl- (2-naphthoylamino) ethynylpiperazine 1.0 g (2.9 mmol) 1- (2-aminoethyl) ) To a solution of -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine and 0.5 ml (3.5 mmol) of triethylamine in 20 ml of dichloromethane is added dropwise 0.6 A solution of naphthalene-2-carboxylic acid chloride (3.2 g) in dichloromethane (6 ml) was added and the mixture stirred for 1 hour without cooling. The reaction mixture was washed with water (2 x 20 mL), 5% sodium bicarbonate solution (2 x 20 mL) and water (2 x 20 mL), dried over magnesium sulfate and evaporated under reduced pressure. The solid residue was triturated with acetonitrile to give 1.4 g (96.6%) of the title compound, mp 221-222 ° C.

Example 52

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl-4- (2- [2- (2-naphthyl) acetyl-amino-1-ethyl) piperazine

The title compound was prepared in a similar manner to Example 51 except that 2- (2-naphthyl) acetyl chloride was used in place of naphthalene-2-carboxylic acid chloride. Yield: 91.3%, m.p. 214-215 ° C.

Example 53

1- [2,6-Di (1-Pyrrolidinyl) -4-pyrimidinine-4- [2- (2-naphthylmethylamino) ethynyl] piperazine To a solution of anhydrous tetrahydrofuran (91 mg, 2.4 mmol) was added lithium tetrahydr aluminate followed by 80 mg (0.6 mmol) of aluminum chloride. The resulting suspension is cooled to -78 ° C and 0.15 g (0.3 mmol) of 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2- (2- naphthoylamino) ethyl] piperazine. The mixture was then allowed to warm to 0 ° C and stirred at this temperature for 2 hours. Then, 2 ml of water and 5 ml of 5M aqueous sodium hydroxide solution are added dropwise under ice-cooling. The resulting milky mixture was extracted with ethyl acetate (20 mL) and the organic layer was washed with water (3 x 10 mL) until neutral.

After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. Yield: 94.6% of crude title compound as a yellow oil. Melting point of L - (+) - tartaric acid salt: 90-95 ° C (crystallized from ethanol).

Example 54

1-r2,6-Di (1-pyrrolidinyl) -4-pyrimidinyl-4- (2-2- (2-naphthyl) -ethyl-amino-1-piperazine etiiy

The title compound is prepared from 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- {2- [2- (2-naphthyl) acetylamino] ethyl} piperazine, and prepared in a similar manner to that described in Example 53. Yield: 55.2%, m.p. 105-115 ° C (crystallized from ethanol), L - (+) - tartaric acid salt.

Example 55

-f2-Acetoxy-3- (N-acetyl-2-naphthylamino-propyl-4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl-piperazine)

0.17 g (0.34 mmol) of 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) propyl] piperazine Dissolve in 3 ml of acetic anhydride by heating to about 50 ° C and allow the solution to stand at room temperature for 2 hours. The reaction mixture was poured into water and, after dissolution of the excess acetic anhydride, the mixture was extracted three times with 10 ml of chloroform each time. The combined organic extracts were washed three times with water, dried over magnesium sulfate and the solvent was distilled off under reduced pressure. Trituration of the oily residue with water gave 0.16 g of a solid, which was chromatographed on a silica gel column using dichloromethane: methanol (9: 1) as eluent. Yield: 0.13 g (65.0%), m.p. 70-75 ° C.

-6 556. Example 14 - (-) - 142.6-Di (1-Pyrrolidinyl) -4-pyrimidinine-4-f-hydroxy-3- (2-naphthylamino) -propinepiperazine

Method A)

A solution of 1.02 g (7.1 mmol) of 2-naphthylamine and 0.73 g (0.62 mL, 7.9 mmol) of S - (+) - epichlorohydrin in 10 mL of ethanol and 2.4 mL of water was added. Stir for 3 hours. The solvent was then distilled off under reduced pressure, and about 10-10 ml of ethanol was added to the residue three times, and then the solvent was distilled off. 1.78 g (7 mmol) of crude corresponding chlorohydrin, i.e. N- (2-hydroxy-3-chloropropyl) -2-naphthylamine, are obtained, which product is used without further purification.

A suspension of the above crude chlorohydrin, 2.1 g (7 mmol) of 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -piperazine and 1.8 g (13 mmol) of potassium carbonate in 40 ml of acetonitrile was stirred vigorously. while stirring for 5 hours. The solvent was distilled off under reduced pressure and the residue was triturated with 50 ml of water and 100 ml of ethanol. The resulting slurry was cooled to room temperature, the precipitate was filtered off, washed with water to neutral and dried in air. This gave 1.4 g of the title compound which was refluxed for a few minutes with a 1: 1: 1 mixture of ethanol: ethyl acetate: acetonitrile (140 mL). After cooling, the purified product was filtered off, washed with the above solvent mixture and air dried. . Yield: 2.1 g (59.0%), m.p. 217-221 ° C, [?] D = -4.4 ° (c = 2.1 M aqueous hydrochloric acid).

Method B

Step a) (+) - N- (2,3-Epoxypropyl) -2-naphthylamine

A solution of 1.02 g (7.1 mmol) of 2-naphthylamine and 0.73 g (0.62 mL, 7.9 mmol) of S - (+) - epichlorohydrin in 10 mL of ethanol and 2.4 mL of water was added. Stir for 3 hours

boil. The solvent was then distilled off under reduced pressure, and about 10-10 ml of ethanol was added to the residue three times, and then the solvent was distilled off. 1.78 g (7 mmol) of crude corresponding chlorohydrin, i.e. N- (2-hydroxy-3-chloropropyl) -2-naphthylamine, are obtained, which product is used without further purification.

To a solution of the above crude chlorohydrin in a mixture of 3.5 ml of anhydrous methanol and 1.6 ml of anhydrous diethyl ether are added 0.25 g (10.87 mmol) of metal sodium in three equal portions over a quarter hour. After stirring for 1 hour at 0 ° C, the solvent was distilled off under reduced pressure. The residue was chromatographed on a silica gel column eluting with a 96: 4 mixture of benzene and methanol. The resulting crystalline title compound (0.52 g) was washed with diisopropyl ether, filtered and air-dried. This product was not completely homogeneous by TLC. Yield: 0.53 g (37.4%), m.p. 119-121 ° C, [α] _D = +16.4 ° (c = 1, chloroform).

Step b - (-) - 1- [2,6-Di (1-Pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) -propyl] -piperazine

0.39 g (1.95 mmol) of (+) - N- (2,3-epoxypropyl) -2-naphthylamine and 0.57 g (1.90 mmol) of 1- [2,6-di A solution of (1-pyrrolidinyl) -4-pyrimidinyl] -piperazine in 30 ml of ethanol is heated under reflux for 2 hours. After cooling, the precipitated crystalline material is filtered off, washed with ice-cold ethanol and air-dried. Yield: 0.70 g (0.70 g, 73.4%), m.p. 220-221 ° C, [α] D = -4.5 ° (c = 2.1 molar). aqueous hydrochloric acid solution).

-67 • · ·· «

Example 57 (+) - 1- [2,6-Di (1-Pyrrolidinyl) -4-pyrimidinine-4- [2-hydroxy-3- (2-naphthylamino) -propinepiperazine

Method A)

All were carried out as described in Example 56, Method A, except that R - (-) - epichlorohydrin was used in place of S - (+) - epichlorohydrin. Yield: 1.9 g (53.4%), m.p. 216-219 ° C, [α] D = + 4.3 ° (c = 2.1 M aqueous hydrochloric acid).

Method B

Step a) (-) - N- (2,3-Epoxypropyl) -2-naphthylamine

All were carried out as described in Example 56, Method B, step a, except that R - (-) - epichlorohydrin was used instead of S - (+) - epichlorohydrin. Yield: 0.49 g (0.50 g, 35.3%), mp 116-118 ° C, [α] _D = -22.8 ° (c = 1, chloroform). .

Step b) (+) - 1- [2,6-Di (1-Pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) -propyl] -piperazine

All were carried out as described in Example 56, Method B, step b, except that (+) - N- (2,3-epoxypropyl) -2-naphthylamine was replaced by the method of Example B, Method B, above. (-) - N- (2,3-epoxypropyl) -2-naphthylamine as described in step a). Yield: 0.58 g (60.8%), m.p. 218-220 ° C, [α] D = + 4.4 ° (c = 2.1 M aqueous hydrochloric acid).

-68. the preparation of the novel intermediates used in Examples 58-73 below. examples.

Example 58

1-f2-Hydroxy-3- (2-naphthylamino) piperazine -propil1

the step

N- (2,3-epoxypropyl) -2-naphthylamine

A solution of 2-naphthylamine (5.16 g, 36 mmol) and epichlorohydrin (4.4 g, 3.7 mL, 47.5 mmol) in ethanol (12 mL) and water (6 mL) was heated to reflux for 3 hours. The reaction mixture was cooled, diluted to 100 ml with water and extracted with ethyl acetate (3 x 30 ml). The combined organic extracts were washed with water, dried over magnesium sulfate and the solvent was distilled off. The residue was stirred with 100 ml of diethyl ether and 20 ml of 10M aqueous sodium hydroxide solution for 2 hours. The organic layer was separated, washed with water to neutral, dried over magnesium sulfate and the solvent was distilled off. The residue was chromatographed on a silica gel column, eluting with a 95: 5 mixture of benzene and methanol. This gives 4.33 g of the title compound which is triturated with diisopropyl ether. 101-102 ° C, 60.3% yield.

Using the appropriately substituted starting compounds and following the procedure described in step a) above, the compounds of formula (VIII) are prepared in the form of an oil, wherein

R1 and X are as defined in the table below.

• · »» · · · · · · · · · · · · · · · · ···

Example number R1 X Rf1) Yield % 59-a) 1-naphthyl NH 0.76 70.7 60-a) 2-naphthyl N (CH ₃ ) 0.85 45.0 61-a) 2-naphthyl S 0.90 85.7

1) Rf for TLC on silica gel 60 silica gel plate using 95: 5 benzene: methanol.

Step b)

1- [2-Hydroxy-3- (2-naphthylamino) propyl] -4- (tert-butoxycarbonyl) piperazine

Method A)

1.47 g (7.35 mmol) of N- (2,3-epoxypropyl) -2-naphthylamine prepared as described in a) above and 1.38 g (7.4 mmol) of 1- ( of tert-butoxycarbonyl) piperazine in 30 ml of ethanol was refluxed for 2 hours. The alcohol was then distilled off and the resulting crystalline residue was washed with ethyl acetate. Yield: 1.97 g (65.9%), m.p. 131-132 ° C.

Method B

1.21 g (5 mmol) of 1- (2,3-epoxypropyl) -4- (tert-butoxycarbonyl) piperazine and 0.59 g (4.2 mmol) of 2-naphthylamine in 20 mL of ethanol The mixture was refluxed for 15 hours. The solvent was distilled off and the crude product was chromatographed on a silica gel column using ethyl acetate as the eluent. Yield: 0.89 g (55.3%).

In a similar manner to that described in Method A or B above, compounds of formula XIV are prepared wherein

A is 2-hydroxy-1,3-propylene, n is 1,

R4 is tert-butoxycarbonyl and R1 and X are as defined in the table below.

Example number R ¹ X Method Rf ¹ ) Yield% 59-b) 1-naphthyl NH THE 0.71 67.5 60-b) 2-naphthyl N (CH ₃ ) THE 0.69 90.0 61-b) 2-naphthyl S B 0.78 80.7

1) Rf value for TLC on Kieselgel 60 silica gel plate, 95: 5 benzene: methanol.

step c)

1- [2-Hydroxy-3- (2-naphthylamino) propyl] piperazine

1.85 g (4.79 mmol) of 1- [2-hydroxy-3- (2-naphthylamino) propyl] -4- (tert-butoxycarbonyl) piperazine prepared by any of the steps b) above are added. Trifluoroacetic acid (6 ml) was added at 0 ° C and the mixture was stirred for 1.5 hours while maintaining the temperature at 0 ° C. The excess acid was then distilled off under reduced pressure, and anhydrous diethyl ether (2 x 10 mL) was distilled off. The resulting crystalline material was dissolved in water (30 mL), made basic with stirring and cooling with 10 M aqueous sodium hydroxide and extracted with ethyl acetate (4 x 30 mL). The combined ethyl acetate portions were washed with water (40 mL), dried over magnesium sulfate, and the solvent was distilled off. 0.67 g of crystalline title compound is obtained in a yield of 45.9%, m.p. 142-144 ° C.

In a similar manner to that described in step c) above, compounds of formula II are prepared wherein

A is 2-hydroxy-1,3-propylene, n is 1, and

-71 ·· «· *

R1 and X are as defined in the table below.

Example number R1 X Mp, ° C ¹ ) Yield % 59-c) 1-naphthyl NH 112-117 61.3 60-c) 2-naphthyl N (CH ₃ ) oil ² ) 76.1 _ 2-naphthyl S 130-133 98.0

1) Bis-trifluoroacetate salts.

2) TLC on Kieselgel 60 silica gel plate, 75:20: 5 ethyl acetate: methanol: concentrated aqueous ammonium hydroxide: 0.58.

Example 62

- [3- (2-Hydroxy-1-naphthyl-propionyl-piperazine)

the step

1- [3- (2-Hydroxy-1-naphthyl) propionyl] -4- (tert-butoxycarbonyl) piperazine 0.85 g (5.0 mmol) of 1- (tert-butoxycarbonyl) piperazine Dissolve in 75 ml of anhydrous acetonitrile and add 1.0 g (5.04 mmol) of 3 - [(2-hydroxy-1-naphthyl) -propionic acid] lactone and reflux for 4 hours. The solvent was then distilled off. In this way it is in the form of a colorless oil

1.85 g of the title compound are obtained, which product is used in the next step without further purification. Yield: 97%.

Step b)

- [3- (2-Hydroxy-1-naphthyl) -propionyl] -piperazine

1- (3- (2-Hydroxy-1-naphthyl) propionyl) -4- (tert-butoxycarbonyl) piperazine (0.37 g, 1.0 mmol) was dissolved in 10 mL of 16% ethyl acetate at room temperature with stirring. hydrochloric acid. After a few minutes, a fine, white precipitate begins to precipitate out of the reaction mixture. The mixture was stirred for 1 hour and then a

The precipitate was filtered off, washed with a little ethyl acetate and dried at room temperature. The dried material is dissolved in 5 ml of 5% sodium bicarbonate solution with stirring. The basic form of the product rapidly precipitates out of solution as a white solid. After stirring for a further ten minutes, the resulting precipitate was filtered off, washed with a little cold water and air-dried. Yield: 0.31 g (99%), m.p. 107-109 ° C.

Example 63

1-F2- (2-naphthylamino) piperazine -acetil1

the step

1- (2-chloroacetyl) -4- (tert-butoxycarbonyl) piperazine

A solution of 1.86 g (10 mmol) of 1- (tert-butoxycarbonyl) piperazine and 1.53 ml (1.11 g; 11 mmol) of triethylamine in 50 ml of anhydrous chloroform was added dropwise at 0 ° C with stirring. A solution of 2-chloroacetyl chloride (0.88 mL, 1.24 g, 11 mmol) in anhydrous chloroform (10 mL) was added. After stirring for an additional hour at room temperature, the reaction mixture was washed with water to neutral, dried over magnesium sulfate and the solvent was distilled off under reduced pressure. Yield: 1.91 g (72.9%), m.p. 91-93 ° C.

Step b)

1- [2- (2-Naphthyl) acetyl] -4- (tert-butoxycarbonyl) piperazine

0.78 g (3 mmol) of 1- (2-chloroacetyl) -4- (tert-butoxycarbonyl) piperazine, 0.43 g (3 mmol) of 2-naphthylamine and 0.42 g of millimolar potassium carbonate suspension in 30 ml of acetonitrile was heated at reflux for 8 hours. The solvent was distilled off and the residue was partitioned between dichloromethane (30 mL) and water (30 mL). The organic phase is washed three times with 10 ml of water until neutral, »··· ·

It was dried over magnesium sulfate and the solvent was distilled off. This gives 1.03 g of crude product which is chromatographed on a silica gel column using n-hexane / ethyl acetate 1: 1 as eluent. Yield: 0.34 g of crystalline title compound, m.p. 190-192 ° C, yield 30.9%.

step c)

1- [2- (2-naphthyl) acetyl] piperazine

The title compound was prepared starting from the compound prepared in step b) above and proceeding as in Example 58 c). 102-108 ° C (trifluoroacetate), 85.3% yield.

Example 64

1 2- (2-naphthylthio) phenylacetyl-piperazine

the step

1- [2- (2-naphthylthio) acetyl] -4- (tert-butoxycarbonyl) piperazine

0.48 g (3 mmol) of 2-thionaphthol, 70 mL of ethanol, 3 mL of 1 M aqueous sodium hydroxide and 0.78 g (3 mmol) of 1- (2-) as prepared in Example 63 a) above. chloroacetyl) -4-tert-butoxycarbonylpiperazine was stirred for 2 hours at room temperature. The solvent was distilled off under reduced pressure and the residue was partitioned between dichloromethane (30 mL) and water (30 mL). The organic layer was washed with water to neutral, dried over magnesium sulfate and the solvent was distilled off under reduced pressure. 0.68 g of the title compound is obtained, m.p. 80-82 ° C, yield 58.6%.

Step -74b)

1- [2- (2-naphthylthio) acetyl] piperazine

The title compound is prepared starting from the compound prepared in step a) above and following the procedure in Example 58 step c). The product was obtained in the form of an oil, Rf = 0.64 (TLC on silica gel 60, silica gel 60, ethyl acetate: methanol: concentrated aqueous ammonium hydroxide 75: 20: 5): 96.8 %.

Example 65

1- [N- (2-naphthyl) carbamoyl-methyl-1-piperazin

the step

1- [N- (2-naphthyl) carbamoyl] -4- (tert-butoxycarbonyl) piperazine

1.48 g (8 mmol) of 1- (tert-butoxycarbonyl) piperazine, 1.36 g (9.8 mmol) of powdered potassium carbonate and 1.76 g (8 mmol) of N- (2-chloro- acetyl) -2-naphthylamine in 60 ml of acetonitrile was heated to reflux for 2 hours. The solvent was distilled off and the residue was partitioned between dichloromethane (60 mL) and water (60 mL). The organic layer was washed with water to neutral, dried over magnesium sulfate and the solvent was distilled off. The crude product was chromatographed on a silica gel column using n-hexane: ethyl acetate (1: 2) as eluent. This gave 2.05 g of crystalline title compound, m.p. 124-128 ° C, 69.5%.

Step b)

1- [N- (2-naphthyl) carbamoylmethyl] piperazine

The title compound was prepared starting from the compound prepared in step a) above and as described in example 58 c). The product was identified as its bis-trifluoroacetate salt, m.p. 169-175 ° C, 80.6%.

- 75 Example 66

1-f6-Amino-2- (1-pyrrolidinyl) -4-pyrimidinyl-piperazine

the step

1-amidino-pyrrolidin-hydroiodide

S-Methylisothiourea hydroiodide (174.32 g, 0.8 mol) was dissolved in methanol (600 ml) and pyrrolidine (60.53 g, 70.2 ml, 0.85 mol) was added with stirring. The reaction mixture is then refluxed for 3 hours until gas evolution ceases. After cooling, the solvent was evaporated and the residue was recrystallized from methanol. 169.3 g of the title compound are obtained in a yield of 87.9%, m.p. 192-193 ° C.

Step b)

6-amino-4-hydroxy-2- (1-pyrrolidinyl) pyrimidine

8.1 g (0.35 mol) of sodium metal are dissolved in 240 ml of anhydrous methanol, and 72.3 g (0.3 mol) of 1-amidinopyrrolidine hydroiodide are added. In another flask, dissolve 8.1 g of metal sodium in 240 ml of anhydrous methanol and dissolve in 34.2 g (0.3 mol) of ethyl cyanoacetic acid in this solution and add the resulting mixture to the solution prepared previously. The reaction mixture was refluxed for 3 hours and then cooled. The solvent was distilled off under reduced pressure, the residue was dissolved in 150 ml of water and the solution was acidified to pH 5 with acetic acid with stirring. The precipitated white solid was filtered off, washed several times with water and air dried. Yield: 39.0 g (71.0%), mp 264-266 ° C.

step c)

6-Amino-2- (1-pyrrolidinyl) -4-tosyloxy-pyrimidine

6-Amno-4-hydroxy-2- (1-pyrrolidinyl) -pyrimidine (3.6 g, 20 mmol) was suspended in pyridine (20 ml) and 5.0 g at room temperature was added.

- 76 (25 mmol) tosyl chloride. The reaction mixture is stirred at room temperature for half an hour, during which time the starting materials are dissolved. The reaction mixture was then poured into water (100 mL) to give a solid. The precipitate is filtered off, washed with plenty of water and air dried. This gave 3.0 g (45%) of the title compound, m.p. 155-168 ° C (dec.).

Step d)

1- [6-Amino-2- (1-pyrrolidinyl) -4-pyrimidinyl] piperazine

A mixture of 17.0 g (50.9 mmol) of 6-amino-2- (1-pyrrolidinyl) -4-tosyloxypyrimidine, 150 mL of chlorobenzene and 15 g (175 mmol) of anhydrous piperazine in a bomb tube for 4 hours 140-145 Heat in an oil bath at 0 ° C. The next day, the precipitated crystals (excess piperazine) were filtered off, washed with a little chlorobenzene, and the solvent was removed from the combined chlorobenzene filtrate. The residue was dissolved in methanol (15 mL) and the solution was acidified to pH 6 with hydrochloric acid ethyl acetate. The precipitated crystalline material is filtered off, washed with ethyl acetate and dried. The resulting hydrochloride (m.p.> 280 ° C) was dissolved in a little water, basified to pH 10 with 1M sodium hydroxide solution, and the product was extracted with dichloromethane (3 x 100 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was 3.7 g of a pale yellow oil which solidified on standing. Yield: 30%.

Example 67

-6-Amino-2- (1-piperidinyl) -4-pyrimidinine-piperazine

the step

Amidino-piperidine hydroiodide

The title compound was prepared as described in Example 66 (a) except that piperidine was used in place of pyrrolidine. Yield: 72.3%, m.p.

118-120 ° C.

- 77 b)

6-amino-4-hydroxy-2- (1-piperidinyl) pyrimidine

The title compound was prepared starting from the compound prepared in step a) above and following the procedure described in example 66 b). Yield: 97.3%, m.p. 182-192 ° C (dec.).

step c)

6-Amino-2- (1-piperidinyl) -4-chloropyrimidine

A mixture of 7.29 g of 6-amino-4-hydroxy-2- (1-piperidinyl) -pyrimidine and 37.5 ml of phosphorus oxychloride was stirred at 100 ° C for 2 hours, then excess phosphorus oxychloride was distilled off under reduced pressure. The residue was stirred with twice the volume of water and the yellow viscous oil dissolved in a few minutes under strong heating and gas evolution. The solution was basified to pH 8 with 10% aqueous sodium carbonate solution and cooled. The precipitated crystalline material is filtered off, washed with water to neutral and dried in air. Yield: 73.3%, m.p. 148-149 ° C.

Step d)

- [6-Amino-2- (1-piperidinyl) -4-pyrimidine] -piperazine

The title compound was prepared from the compound prepared in step c) above and in the same manner as in Example 66 step d) in 66.7% yield. The product was a yellow oil, rf = 0.3 (TLC: ethyl acetate: methanol: concentrated aqueous ammonia 10: 5: 0.3).

-78t

Example 68

N- (2,3-epoxy-propih-N- (methanesulfonyl) -2-naphthylamine

To a solution of 0.5 g (2.5 mmol) of N- (2,3-epoxypropyl) -2-naphthylamine in 5 ml of anhydrous pyridine was added dropwise 0.24 ml (0.35 g, 3 ml) with stirring in an ice bath. (0 mmol) methanesulfonyl chloride and the mixture was stirred for one hour in an ice bath. An additional 0.24 mL of methanesulfonyl chloride was added and stirring was continued at the same temperature for an additional 2 hours. The mixture was allowed to warm to room temperature and then poured into water. The precipitate was filtered off, washed with water and recrystallized from methanol. This gives 0.37 g (52.9%) of the title compound as a light yellow crystalline solid, m.p. 114-115 ° C.

Example 69

1-F2.6-di (1-pyrrolidinyl) -4-pyrimidinyl-4- (2,3-epoxypropyl) piperazine

A solution of 1.5 g (5 mmol) of 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -piperazine in 0.5 ml (0.59 g; 6.4 mmol) of epichlorohydrin in 10 ml of ethanol Stir at room temperature for 24 hours. The precipitate was filtered off and washed with 2 ml of ethanol. The wet material was dissolved in a mixture of diethyl ether (50 mL) and ethanol (5 mL) and stirred with 10 mL aqueous 10 M sodium hydroxide for 2 hours. The organic layer was separated, washed with water to neutral, dried over magnesium sulfate and the solvent was distilled off. Yield: 1.18 g of crystalline title compound, m.p. 107-112 ° C, 66.4%.

-7970, example

1- (2-Aminoethyl) -4-F2.6-di (1-pyrrolidinyl) -4-piperazin-pirimidinil1

the step

1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- (2-phthalimidoethyl) piperazine

6.04 g (20 mmol) of 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine, 6.35 g (25 mmol) of N- (2-bromoethyl) phthalimide, A suspension of 45 g (25 mmol) of potassium carbonate and 3.0 g (20 mmol) of sodium iodide in 100 ml of acetonitrile was heated to reflux for 3 hours. After cooling in an ice bath, the solids were filtered off and washed first with acetonitrile and then with plenty of water. 6.03 g of crude product are obtained. The acetonitrile filtrate was distilled off under reduced pressure and the residue was chromatographed on a silica gel column using ethyl acetate as eluent. The product (2.2 g), which is not completely pure, is recrystallized from acetonitrile and isopropanol (yield: 86.2%) to give the crude product (6.03 g). This gave 4.85 g (51.0%) of the title compound as a yellow crystalline solid, mp 153-154 ° C.

Step b)

1- (2-Aminoethyl) -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine

4.25 g (8.9 mmol) of 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- (2-phthalimidoethyl) piperazine are dissolved in 100 ml of ethanol at 60-70 ° C. , 4.6 ml (90 mmol) of 98% hydrazine hydrate is added and the mixture is refluxed for 1 hour. After cooling, the phthalyl hydrazide precipitated is filtered off, washed with ethanol and the filtrate is distilled off under reduced pressure. Dichloromethane (15 mL) was added to the residue and a small amount of insoluble phthalyl hydrazide was filtered off. The filtrate was washed with water, dried over magnesium sulfate and the solvent was distilled off under reduced pressure. In this way, it is a colorless powder

Yield: 2.91 g (94.8%), m.p. 99-100 ° C.

Example 71

N- (2-chloroacetyl) -2-methyl-1-naphthylamine

To a solution of 0.5 g (3.18 mmol) of 2-methyl-1-naphthylamine in 5 mL of Ν, Ν-dimethylacetamide was added 0.3 mL (0.45 g, 4.0 mmol) of stirring at room temperature. 2-chloroacetyl chloride. After half an hour, the solvent was distilled off under reduced pressure and the residue was recrystallized from 5 ml of isopropanol. Yield: 78.0%, m.p. 177-178 ° C.

Example 72

FN-2 (2-Chloro-acetyl) -amino1-naphthalene-1-sulfonic acid

The title compound was prepared starting from 2-amino-1-naphthalenesulfonic acid and in a manner similar to that described in Example 71, yield 94.4%, mp 145 ° C.

Example 73

6- [N- (2,5-Dibenzyloxybenzoyl) -amino1-hexyl iodide

the step

6- [N- (2,5-Dibenzyloxybenzoyl) amino] hexyl alcohol

To a solution of 6- [N- (2,5-dibenzyloxybenzoyl) amino] hexanoic acid (15.1 g, 33.7 mmol) in dry tetrahydrofuran (390 mL) and triethylamine (3.4 g, 33.7 mmol) A solution of 3.65 g (33.7 mmol) of ethyl distilled chloroformate in 17 ml of anhydrous tetrahydrofuran is added with stirring at -5 ° C and the reaction mixture is stirred at the same temperature for 30 minutes. The precipitated salt is then filtered off and washed with anhydrous tetrahydrofuran. The combined filtrate and washings over 30 minutes,

The reaction mixture was added with stirring at 15 ° C to a solution of 3.1 g (82 mmol) of sodium tetrahydroborate in 78 ml of water and the reaction mixture was stirred for 4 hours at room temperature. The pH of the solution was then adjusted to 4 with 5 M hydrochloric acid and the mixture was stirred at room temperature for 3 hours. If necessary, the pH of the solution is again adjusted to 4 in this manner. Water (240 mL) and diethyl ether (240 mL) were added, the aqueous portion was separated and partitioned between diethyl ether and tetrahydrofuran (6: 1). The combined organic layers were washed with water and 5% sodium hydroxide solution and dried over magnesium sulfate. The residue obtained by solvent evaporation was washed with petroleum ether (bp .: 40-70 ° C), thereby obtaining 11.7 g of product, yield 80%, m.p .: 90-92 C. ^e

Step b)

6- [N- (2,5-Dibenzyloxybenzoyl) amino] hexyl iodide

3.44 g (7.9 mmol) of 6- [N- (2,5-dibenzyloxybenzoyl) amino] hexyl alcohol with 24 mL of anhydrous dichloromethane and 1.2 g (12 mmol) of anhydrous triethylamine A solution of methanesulfonyl chloride (1.1 g, 9.6 mmol) was added at 0 ° C with stirring, and the reaction mixture was stirred at 0 ° C for 30 minutes. Water (24 mL) was added and, after separation, the aqueous portion was extracted with dichloromethane. The organic layer was dried (MgSO4) briefly, and the solvent was distilled off under reduced pressure, and the residue was stirred with 25 ml of sodium iodide-saturated acetone under nitrogen and 0.09 g (0.7 mmol) of diisopropylethylamine with stirring. Boil for 30 minutes. The reaction mixture was then diluted with water (25 mL) and extracted with diethyl ether. The diethyl ether solution was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was washed with petroleum ether (b.p. 40-70 ° C). Yield: 3.83 g (89%), m.p. 80-82 ° C.

Λ /)

Example 74

Intravenous medicinal product

Ingredients:

1- {6- [N- (2,5-Dihydroxybenzoyl) amino] hexyl} -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine dihydrochloride 5.00 g

Sodium chloride 4.00 g

Distilled water for injection gives 1000.00 ml

Making:

The pyrogen-free 1- {6- [N- (2,5-dihydroxybenzoyl) amino] hexyl} -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine dihydrochloride and the Dissolve sodium chloride in 800 ml distilled water for injection and make up to 1000.00 ml with distilled water for injection.

Subsequently, the solution is filtered through a 0.2 µm cellulose membrane for germ-free filtration, aseptically filled into glass ampoules and sealed with an inert gas atmosphere.

Example 75

Using appropriately substituted starting materials, and following the procedure described in Example 2, 1- (2,6-diamino-4-pyrimidinyl) -4- [2- (2-naphthylamino) acetyl] piperazine was prepared. mp 212-215 ° C, yield 60.0%.

76-78. example

Using appropriately substituted starting compounds and following the procedure described in Example 13, compounds of formula I wherein

X is NH,

A is -C (O) -CH 2 -, n is 1,

-83R2 and R3 are both 1-pyrrolidinyl and Rt is as defined in the table below.

Example number Ltd. M.p. Yield% 76 7-ethoxycarbonyl-1-naphthyl 182-185 58.7 77 7-acetyl-2-naphthyl * oil** 98.0 78 4- (dimethylamino-sulfonyl) - 1-naphthyl 224-228 54.4

Contains about 30% of the 6-acetyl isomer.

** TLC on Kieselgel 60 silica gel plate, 10: 3 ethyl acetate: methanol: 0.70.

Example 79

Using appropriately substituted starting materials and following the procedure described in Example 33, 1- [6-amino-2- (hexahydro-1H-azepin-1-yl) -4-pyrimidinyl] -4- (1-hydroxy) 2-naphthoyl) piperazine, m.p. 18%, TLC on Kieselgel 60 silica gel plate, ethyl acetate: methanol (2: 1): 0.73.

80-81. example

Using appropriately substituted starting compounds and following the procedure described in Example 42, compounds of formula I wherein

Rt is 6-methoxy-2-naphthyl,

X is a single bond,

A is -CH (CH 3) -C (O) - and »

-84R2, R3 and n are as defined in the table below.

Example number R1 R2 n M.p. Yield, % [?] D * 80 1-pyrrolidinyl 1-pyrrolidinyl 2 84-88 76.0 -19.25 ° 81 nh ₂ nh ₂ 1 122-130 38.6 -28.56 °

* (c = 1, chloroform)

82-84. example

Using appropriately substituted starting compounds and following the procedure described in Example 43, compounds of formula Ib were prepared wherein

X is a single bond,

B1 is -CH2-CH [NH-CO-OC (CH3) 3j-, n is 1,

R2 and R3 are both 1-pyrrolidinyl and R1 is as shown in the table below.

Example number R1 M.p. Yield% [<X] D * 82 2-naphthyl 188-190 46.7 racemic 83 4-hydroxyphenyl 142-144 84.8 -5.87 ° 84 phenyl 141-144 74.4 + 15.1 °

* (c = 1, chloroform)

85-87. example

Using appropriately substituted starting materials and following the procedure described in Example 43, compounds of formula Ib were prepared wherein:

- 85 X and B1 together form a single bond, n is 1,

R2 and R3 are both 1-pyrrolidinyl and R1 is as shown in the table below.

Example number R1 M.p. Yield% 85 3-methylamino-2-naphthyl 110-140 (b) 15.4% 86 3-dimethylamino-2-naphthyl oil* 98.0% 87 3-acetylamino-2-naphthyl 192-194 31.1%

TLC on Kieselgel 60 silica gel plate, 10: 3 ethyl acetate: methanol: 0.80.

88-90. example

Using appropriately substituted starting compounds and following the procedure described in Example 46, compounds of formula Ib were prepared wherein

X is a single bond,

B1 is -CH2-CH (NH2) -, n is 1,

R2 and R3 are both 1-pyrrolidinyl and R1 is as shown in the table below.

Example number R1 M.p. Yield% [Cd] d * 88 2-naphthyl 166-169 78.3 racemic 89 4-hydroxyphenyl 212-214 61.6 + 14.3 ° 90 phenyl 180-182 88.9 + 21.2 °

(c = 1, chloroform)

-86 • ·· «··

Example 91

1-F2.6-di (1-pyrrolidinyl) -4-pyrimidinyl-4-FN (7-carboxy-1-naphtyl) carbamoyl-methyl-1-piperazine

0.4 g (0.7 mmol) of 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [N- (7-ethoxycarbonyl-1-naphthyl) carbamoylmethyl] To a suspension of piperazine in 10 ml of ethanol was added a solution of 0.20 g (3.56 mmol) of potassium hydroxide in 2 ml of ethanol and the mixture was heated under reflux for 1 hour. The solvent was distilled off under reduced pressure and the residue was chromatographed on a silica gel column using benzene: methanol (1: 1) as eluent. This gives the potassium salt of the title compound, 0.16 g, m.p.> 360 ° C, 41.0%.

Example 92

- [2,6-Di (1-pyrrolidinyl) -4-pyrimidinine-4-f-hydroxy-3- (2-naphthylsulfinyl) -propyl] -piperazine

0.58 g (1.12 mmol) of 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylthio) -propyl] -piperazine To a solution of 5 ml of acetic acid in an ice bath was added 0.35 ml of 30% aqueous hydrogen peroxide solution and the mixture was allowed to stand at room temperature for 60 hours. The reaction mixture was diluted with water (20 ml) and neutralized with saturated sodium bicarbonate solution in an ice bath with stirring. The reaction mixture was extracted with chloroform (3 x 40 mL), the combined organic layers were washed with brine (30 mL), dried (MgSO4) and the solvent was distilled off under reduced pressure. The residue was chromatographed on a silica gel column eluting with ethyl acetate: methanol (4: 1). This gives 0.12 g of the title compound, m.p. 184-186 ° C, yield 20.0%.

- 87 • · · · · · · · · ·

Example 93

-f2,6-Di (1-pyrrolidinyl) -4-pyrimidin-4-1,2-hydroxy-3- (2-naphthylamino) -propinepiperazine

To a suspension of 1.0 g (26.4 mmol) of lithium tetrahydro-aluminate in 50 ml of anhydrous tetrahydrofuran was added dropwise 0.5 g (0.86 mmol) of 1- [2,6-di (1-pyrrolidinyl)] over 20 minutes at room temperature. A solution of -4-pyrimidinyl] -4- [2-hydroxy-3- (N-methanesulfonyl-2-naphthylamino) propyl] piperazine in 15 ml of anhydrous tetrahydrofuran was added and the mixture was stirred at the same temperature for 2 hours. . 10 ml of ethyl acetate, 10 ml of water and 20 ml of 10N aqueous sodium hydroxide solution are then added dropwise under ice-cooling. The aqueous portion was separated and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed three times with water (3 x 20 mL), dried over magnesium sulfate and the solvent was distilled off under reduced pressure. Trituration of the solid with acetonitrile gave the title compound as a pale beige powder (0.27 g, m.p. 188-190 ° C, 62.8%).

Example 94

-1,2,6-Di (1-pyrrolidinyl) -4-pyrimidinine-4-f-hydroxy-3- (N-ethoxycarbonyl-2-naphthylamino) -propyl-1-piperazine

0.50 g (1 mmol) of 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) propyl] piperazine 15 mL To a suspension of anhydrous pyridine cooled to -5 ° C, 0.15 ml (0.17 g, 1.56 mmol) of ethyl chloroformate was added dropwise and the mixture was stirred at 0 ° C for 1 hour. During this time, the suspension turns to a yellow solution. The final reaction mixture was poured into water (100 mL) and extracted with diethyl ether (3 x 50 mL). The combined organic extracts were washed with water (2 x 50 mL), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. 0.47 g of the title compound is obtained, m.p. 70-77 ° C, m.p. 82.8%.

95-96. example

Using appropriately substituted starting compounds and following the procedure described in Example 71, compounds of formula VI wherein

X is NH,

A is -C (O) -CH 2 -,

Z is chlorine, and

R1 has the meaning given in the table below.

Example number R1 M.p. Yield% 95 7-ethoxycarbonyl-1-naphthyl 173-175 59.4 96 7-acetyl-2-naphthyl * 117-122 99.0

Contains about 30% of the 6-acetyl isomer

Example 97

- [6-Amino-2- (hexahydro-1H-azepin-1-yl) -pyrimidinyl-piperazine

the step

6-Amino-2- (hexahydro-1H-azepin-1-yl) -4-chloropyrimidine

6-Amino-2,4-dichloropyrimidine (6.56 g, 40 mmol) was dissolved in anhydrous dimethylformamide (200 mL) and hexamethyleneimine (4.2 g, 4.8 mL, 43 mmol) was added. After stirring for 24 hours at room temperature, anhydrous pyridine (8 ml) was added and the mixture was stirred at the same temperature for an additional 24 hours. The solvent was then distilled off under reduced pressure. The remaining white solid was chloroform and me ···· «1 • ·

Extract with hot 89: ethanol (10: 2) (2 x 100 mL). The solvent was distilled off under reduced pressure. The residue was chromatographed on a silica gel column using chloroform / methanol (20: 1) as eluent. This gave 1.97 g of the title compound as a white powder, m.p. 152-154 ° C, 21.7%.

Step b)

6-Amino-2- (hexahydro-1H-azepin-1-yl) -4- [4- (tert-butoxycarbonyl) -1-piperazinyl] pyrimidine

1.97 g (8.68 mmol) of 6-amino-2- (hexahydro-1H-azepin-1-yl) -4-chloropyrimidine and 5.55 g (32.6 mmol) of 1-tert-butoxy Carbonylpiperazine was dissolved in 55 ml of anhydrous chlorobenzene and the reaction mixture was heated under reflux for 24 hours under dry nitrogen. A small amount of solid precipitated from the reaction mixture is filtered off and the filtrate is distilled off under reduced pressure. The residue was chromatographed on a silica gel column eluting with ethyl acetate. The title compound was obtained as a pale yellow oil (3.05 g, 97.0%). TLC on Kieselgel 60 silica gel plate, 10: 2 ethyl acetate: methanol: 0.48.

step c)

- [6-Amino-2- (hexahydro-1H-azepin-1-yl) -4-pyrimidinyl] -piperazine

2.92 g (8.1 mmol) of the compound obtained in step b) above are dissolved with stirring in 20 ml of anhydrous ethyl acetate, and 10.8 ml of a 16% strength solution of hydrochloric acid in ethyl acetate are added. As a result, a white precipitate begins to precipitate out of solution immediately. After stirring for 1 hour at room temperature, the precipitate was filtered off, washed with ethyl acetate and air-dried. The resulting dry intermediate was dissolved in 30 ml of des-90% distilled water and basified to pH 9 with 4% sodium hydroxide solution. The resulting oil was partitioned between dichloromethane and the dichloromethane dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The title compound was obtained as a yellow powder (1.13 g, m.p. 122-124 ° C, 50.5%).

Example 98

4- (Dimethylamino-sulfonyl) -N- (2-chloroacetyl) -1-naphthylamine

A solution of 0.63 g (2 mmol) of N- (2-chloroacetyl) -4- (chlorosulfonyl) -1-naphthylamine in 50 ml of tetrahydrofuran was added dropwise at room temperature with 0.5 ml (4 mmol) of 40% aqueous dimethylamine solution. After stirring for half an hour, the solvent was distilled off under reduced pressure and a further 5 ml of ethanol was distilled off. The residue was hot triturated with ethyl acetate and kept overnight in the refrigerator. The next day, the solid product was filtered off to give 0.58 g of the title compound, m.p. 186-190 ° C, yield 89.2%.

Claims (13)

PATENT CLAIMS A compound of formula (I) wherein R1 is a group of formula (a) wherein Price report is a C 6 -C 10 aromatic homocyclic group, R 4 and R 5 are independently hydrogen, halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy optionally substituted with phenyl, C 1-4 alkylthio, C 1-4 alkylsulfinyl, C4 alkylsulfonyl group, nitro group, C1-C4 alkanoyl group, optionally substituted amino group, carboxyl group, C1-C4 alkoxycarbonyl group, carboxamido group, cyano group, sulfo group and / or sulfonamido group, and p, q and r are independently 0 or 1, R2 and R3 are independently selected from the group consisting of amino and a 5-8 membered saturated heterocycle containing at least one nitrogen atom, X is a single bond, sulfur atom optionally substituted with one or two oxygen atoms, or nitrogen atom optionally substituted, A is a linear or branched C 1 -C 8 alkylene group optionally substituted by halogen, hydroxy, C 1 -C 4 alkoxy, optionally substituted C 1 -C 4 alkanoyloxy, optionally substituted amino and / or oxo, and n is 1 or 2, -84 with the proviso that if R1 is a group of formula (a) wherein Ar is phenyl, At least one of R 4 and R 5 is halogen, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 4 alkanoyloxy or methanesulfonyloxy, and p, q and r are each independently 0 or 1, then A may be other than an unsubstituted alkylene group having 1 to 4 carbon atoms, with the proviso that if R1 is 2,5-dihydroxybenzoyl then A may be other than oxo-substituted alkylene, compounds, pure stereoisomers thereof, mixtures of stereoisomers, and addition salts thereof with acids or bases, and in particular pharmaceutically acceptable salts thereof. 2. 1- [2,6-Di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) propyl] piperazine and acid addition salts thereof. 3. (+) - 1- [2,6-Di (1-Pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) -propyl] -piperazine and its acid addition salts. 4. (-) - 1- [2,6-Di (1-Pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) -propyl] -piperazine and its acid addition salts. 5. 1- [2,6-Di (1-pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) -propyl] -homopiperazine and its acid addition salts. 6. (+) - 1- [2,6-Di (1-Pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) -propyl] -homopiperazine and its acid addition salts. -85 7. (-) - 1- [2,6-Di (1-Pyrrolidinyl) -4-pyrimidinyl] -4- [2-hydroxy-3- (2-naphthylamino) -propyl] -homopiperazine and its acid addition salts. 8. 1- [6-Amino-2- (1-pyrrolidinyl) -4-pyrimidinyl] -4- (1-hydroxy-2-naphthoyl) piperazine and its salts. 9. 1- {6- [N- (2,5-Dihydroxybenzoyl) amino] hexyl} -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine and its salts. 10. A pharmaceutical composition comprising as active ingredient a compound of formula (I) wherein R 1, R 2, R 3, X, A and n are as defined in claim 1, or a pharmaceutically acceptable salt thereof, as is conventionally used in pharmaceutical preparation. with solvents, diluents, carriers and fillers. 11. A process for preparing pyrimidine derivatives of formula I wherein R 1 is a group of formula a wherein Price report is a C 6 -C 10 aromatic homocyclic group, R 4 and R 5 are independently hydrogen, halogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy optionally substituted with phenyl, C 1-4 alkylthio, C 1-4 alkylsulfinyl, C4 alkylsulfonyl group, nitro group, C1-C4 alkanoyl group, optionally substituted amino group, carboxyl group, C1-C4 alkoxycarbonyl group, carboxamido group, cyano group, sulfo group and / or sulfonamido group, and p, q and r are independently 0 or 1, R2 and R3 are independently selected from the group consisting of amino and a 5-8 membered saturated heterocycle containing at least one nitrogen atom, X is a single bond, sulfur atom optionally substituted with one or two oxygen atoms, or nitrogen atom optionally substituted, A is a linear or branched C 1 -C 8 alkylene group optionally substituted by halogen, hydroxy, C 1 -C 4 alkoxy, optionally substituted C 1 -C 4 alkanoyloxy, optionally substituted amino and / or oxo, and n is 1 or 2, with the proviso that if R1 is a group of formula (a) wherein Ar is phenyl, At least one of R 4 and R 5 is halogen, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 4 alkanoyloxy or methanesulfonyloxy, and p, q and r are each independently 0 or 1, then A may be other than a C 1-4 unsubstituted alkylene group, with the proviso that if R1 is 2,5-dihydroxybenzoyl then It can only be other than an oxo substituted alkylene group for its preparation, characterized in that: (a) for the preparation of compounds of the formula I in which: R1, R2, R3, X and n are as defined in the scope, and A is in the scope, with the proviso that only - may be other than a linear or branched alkylene group having from 1 to 8 carbon atoms substituted with a halogen atom or an optionally substituted amino group, having the formula: R1, X, A and n are as defined above, a compound of formula (III) wherein R2 and R3 are as defined above and Z is a leaving group, or (b) for the preparation of compounds of the formula I in which: R1, R2, R3, and n are as defined herein, A is as defined herein, with the proviso that it may be other than a linear or branched C 1 -C 8 alkylene substituted with only a halogen or an optionally substituted amino group, and X has the meaning given to formula (I), with the proviso that it can only be different from a chemical bond and a sulfur atom substituted with one or two oxygen atoms, having the formula: R1 and X are as defined above, a compound of formula (V) wherein R2, R3, A and n are as defined above, and Z is a halogen moiety, or c) for the preparation of compounds of the formula I in which: R1, R2, R3, and n are as defined herein, A is as defined herein, with the proviso that it may be other than a linear or branched C 1 -C 8 alkylene substituted with only a halogen or an optionally substituted amino group, and X is as defined herein, with the proviso that it can only be different from a chemical bond, a compound of formula (VI) wherein R1, X and A are as defined above and Z is a leaving group, a compound of formula (VII) wherein R2, R3 and n are as defined above, or d) for the preparation of a compound of formula Ia which is a narrow group of compounds of formula I, wherein: R ¹ , R 2, R 3 and n are as defined in the preamble, and X is as defined in the preamble, with the proviso that it can only be different from a chemical bond, having the general formula (VIII) wherein R1 and X are as defined above, a compound of formula VII wherein R2, R3 and n are as defined above, or e) for the preparation of a compound of formula Ia which is a narrower group of compounds of formula I, wherein: R1, R2, R3 and n are as defined herein, and X is as defined for formula (I), with the proviso that it may only be different from a chemical bond and a sulfur atom substituted with one or two oxygen atoms, where 'Χ --89 • ·· «·· · · ··· ······· R1 and X are as defined above, a compound of formula IX wherein R2, R3 and n are as defined above, or f) for the preparation of a compound of general formula (Ib) which is a narrower compound of formula (I), wherein R 1, R 2, R 3, X and n are as defined herein and B 1 is a single bond or optionally substituted with C 1 -C 4 alkoxy, C 1 -C 4 alkanoyloxy, and / or optionally substituted amino optionally substituted by halogen, phenyl , a linear or branched C 1 -C 7 alkylene group of formula X wherein R1, X and B1 are the above carboxylic acid or a reactive derivative thereof activated on a carboxyl group of the formula (VII) wherein R2, R3 and n are as defined above, or g) for the preparation of a compound of general formula (le), which is a narrow group of compounds of formula I, wherein: R1, R2, R3 and n are as defined herein, X is nitrogen optionally substituted with C 1-4 alkyl; and B2 is a linear or branched C2-C8 alkylene group optionally substituted by hydroxy, C1-C4 alkoxy optionally substituted by phenyl, C1-C4 alkanoyloxy and / or di (C1-C4 alkyl) amino; Η -J> 0 is a compound of general formula (XI) wherein Z is a leaving group or a hydroxy group, and R1 is as defined above, provided that when Z is a hydroxy group, p, q and r are both 0, a compound of formula (XII) wherein R2, R3, B2, X and n are as hereinbefore defined and, if desired, converting a compound of formula (I) obtained by any one of process variants (a) to (g) into another compound of formula (I) and / or deprotecting an optionally present protecting group and / or, if desired, separating the stereoisomers of a compound of formula (I) thus obtained and / or converting a compound of formula (I) thus obtained into a base or salt form, e.g. . Compounds of formula (I) wherein R 1, R 2, R 3, X, A and n are as defined in claim 1, pure stereoisomers thereof, mixtures of stereoisomers, and pharmaceutically acceptable salts thereof, various diseases associated with pathological lipid peroxidation of lipids, for example, for use in the treatment of disorders of the central nervous system such as stroke, stroke, brain and / or spinal cord injuries or ischemic disorders. 13. Compounds of formula (II) wherein R1 is a group of formula (a) wherein Price report is a C 6 -C 10 aromatic homocyclic group, R4 and R5 are independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy optionally substituted by phenyl, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C szén alk alk alkylsulfo ······ · ········ · -9Γ -N ·, -N ·, -N β, -C 1-4 alkanoyl, optionally substituted amino, carboxyl, C 1-4 alkoxycarbonyl. , a carboxamido group, a cyano group, a sulfo group and / or a sulfonamido group, and p, q and r are each independently 0 or 1, X is a single bond, sulfur atom optionally substituted with one or two oxygen atoms, or nitrogen atom optionally substituted, A is a linear or branched C 1 -C 8 alkylene group optionally substituted with halogen, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkanoyloxy, C 1 -C 4 alkanoyloxy, optionally substituted amino and / or oxo, and n is 1 or 2, with the proviso that if R1 is a group of formula (a) wherein Ar is phenyl, At least one of R 4 and R 5 is halogen, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 4 alkanoyloxy or methanesulfonyloxy, and p, q and r are each independently 0 or 1, then A may be other than an unsubstituted alkylene group having 1 to 4 carbon atoms, with the proviso that if R1 is 2,5-dihydroxybenzoyl then 4X -92T · «·« · <· · • · · · · · The meaning may only be different from oxo substituted alkylene.