RU98117457A - COMPOUNDS OF OXA- AND TIA-DIAZOLE DERIVATIVES, METHOD FOR PRODUCING THEM, PHARMACEUTICAL COMPOSITION AND METHODS OF TREATMENT - Google Patents

Claims (23)

1. The compound of the formula

where R ¹ represents C ₁ -C ₆ alkyl, halo (C ₁ -C ₆ alkyl), C ₃ -C ₇ cycloalkyl, C ₂ -C ₆ alkynyl, hydroxy- (C ₂ -C ₆ alkynyl), (C ₁ -C ₄ alkoxy) - (C ₂ -C ₆ alkynyl), aryl, aryl- (C ₁ -C ₄ alkyl), heteroaryl or heteroaryl- (C ₁ -C ₄ alkyl);
R ² represents H or C ₁ -C ₄ alkyl;
R ³ represents aryl, heteroaryl, 2,3-dihydrobenzofuranyl or C ₄ -C ₇ cycloalkyl;
X = 0 or S;
Y represents a direct bond, —CH ₂ -, - (CH ₂ ) ₂ -, or —CH ₂ O—,
or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, in which the aryl group is phenyl or naphthyl, each of which optionally has up to three substituents and is independently selected from C ₁ -C ₄ alkyl, C ₄ -C ₄ alkoxyl, hydroxyl, halogen and trifluoromethyl. 3. The compound of claim 2, wherein the aryl group is selected from phenyl optionally substituted with one or two substituents, each independently selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxyl, hydroxyl, na, and trifluoromethyl, and also naphthyl.  4. The compound according to claim 3, in which the aryl group is phenyl, fluorophenyl, dichlorophenyl, hydroxyphenyl, methoxyphenyl or naphthyl. 5. A compound according to any one of the preceding claims wherein the heteroaryl group is thienyl, pyridyl, thiazolyl, benzothiazolyl, thiadiazolyl, pyrazolyl or pyrimidinyl, each of which is optionally substituted with one or two substituents and is independently selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxyl, hydroxyl and halogen.  6. The compound according to claim 5, in which the heteroaryl group is thienyl, pyridyl, itazolyl or benzothiazolyl. 7. The compound according to any one of the preceding paragraphs, in which R ¹ represents C ₁ -C ₆ alkyl, pentafluorozyl, C ₄ -C ₆ cycloalkyl, ethynyl, -C≡C-CH ₂ OH, -C≡C- (CH ₂ ) ₄ -OH; a phenyl group optionally substituted with one or two substituents, each independently selected from halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxyl and hydroxyl; a naphthyl or heterocyclic group selected from thienyl, pyridyl, thiazolyl and benzothiazolyl, each of which is optionally substituted with halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxyl or hydroxyl. 8. The compound according to any one of the preceding paragraphs, in which R ² represents H or CH. 9. A compound according to any one of the preceding claims wherein R ³ is phenyl optionally substituted with one or two substituents, each independently selected from halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxyl and hydroxyl; 2,3-dihydrobenzofuranyl; C ₄ -C ₇ cycloalkyl or thienyl.  10. The compound according to any one of the preceding paragraphs, in which X = 0. 11. The compound according to any one of the preceding paragraphs, in which Y is a direct bond, —CH ₂ - or —CH ₂ O—.  12. The compound according to claim 1, which represents 3- (1-cyclobutyl-1-phenyl-1-hydroxymethyl) -5- [4- (1-benzylpiperidinyl)] -1,2, 4-oxadiazole; or (+) - 3- (1-cyclobutyl-1-phenyl-1-hydroxymethyl) - 5- [4- (1-benzylpiperidinyl)] -1,2,4-oxadiazole.  13. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of the preceding claims and a pharmaceutically acceptable diluent or carrier. 14. The compound of formula II:

where X, Y, R ² and R ³ have the meanings indicated in claim 1. 15. A method of obtaining a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it comprises reacting a compound of formula III according to claim 16 with a Grignard reactor, an organolithium or organoterium reactor of the formula:
R ¹ MgHal, R ¹ Li or R ¹ CeCl ₂
where Hal = Cl or Br, and R ¹ has the meanings indicated in claim 1, in an organic solvent; however, this method also optionally includes the conversion of the product of formula I into a pharmaceutically acceptable salt. 16. The method according to p. 15, characterized in that they use a reagent of the formula R ¹ MgBr or R ¹ Li, while R ¹ has the meanings indicated in clause 15. 17. A method of obtaining a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it comprises the reaction of a compound of formula III or its basic salt:

where R ¹ and X have the meanings indicated in claim 1, or (a) with a compound of formula IV:
Q-CH (R ² ) -YR ³
where Q is a leaving group, a R ² , R ³ and Y have the meanings specified in paragraph 1;
or (b) with an aldehyde or ketone of the formula

where R ² , R ³ and Y have the meanings indicated in claim 1, in the presence of a reducing agent and in an organic solvent; however, this method also optionally includes the conversion of the product of formula I into a pharmaceutically acceptable salt.  18. The method of claim 17, wherein the leaving group is tosyloxy, mesyloxy, trifluoromethanesulfonyloxy, Cl or Br, and wherein the reducing agent is sodium triacetoxyborohydride or sodium cyanoborohydride.  19. The method according to 17 or 18, characterized in that in (a) the free base of compound III is used and the reaction is carried out in the presence of an acid acceptor.  20. The method according to claim 19, wherein the acid acceptor is sodium bicarbonate or ethyldiisopropylamine.  21. The method according to any one of claims 15 to 20, characterized in that the compounds according to any one of claims 2 to 12 are obtained.  22. The method according to p. 17 to obtain the compound 3- (1-cyclobutyl-1-phenyl-1-hydroxymethyl) -5- [4- (1-benzylpiperidinyl)] - 1,2,4-oxadiazole, characterized in that cyclobutyl magnesium bromide reacts with 3-benzoyl-5- [4- (1-benzylpiperidinyl)] - 1,2,4-oxadiazole, optionally followed by resolution of the compound into its (+) and (-) enantiomers.  23. The method according to p. 22, characterized in that the separation is carried out using GHUR.