Derivatives of 1-Phenylalkanecarboxylic Acids for the Treatment of Neurodegenerative Diseases

Abstract

The present invention concerns novel derivatives of 1-phenylalkanecarboxylic acids, pharmaceutical compositions thereof, a process for their preparation and their use for the treatment and/or prevention of neurodegenerative diseases such as Alzheimer' s disease.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of general formula (I):

wherein:

• B is H or the side chain of an alpha-amino acid;
• R and R₁ are the same and are a linear or branched C₁-C₄ alkyl; or they form a 3 to 6 carbon atoms ring with the carbon atom to which they are linked;
• R₂ is H, CF₃, OCF₃ or a halogen selected from the group of F, Cl, Br, I, preferably fluorine.
• Ar is phenyl substituted with one or more groups R₃ wherein R₃ represents:
  • halogen as previously defined; CF₃; C₃-C₈ cycloalkyl optionally substituted with one or more C₁-C₄ alkyl and/or oxo groups; CH═CH₂; NO₂; CH₂OH; CN; methylenedioxy; ethylenedioxy;
  • phenyl optionally substituted with one or more of the following groups: halogen as previously defined; CF₃, OCF₃, OH; linear or branched C₁-C₄ alkyl; a saturated heterocycle with at least 4 carbon atoms and at least 1 heteroatom; C₃-C₈ cycloalkyl optionally substituted with one or more linear or branched C₁-C₄ alkyl groups, CF₃ and/or OH;
  • OR₄ or NHCOR₄ wherein R₄ is CF₃, linear or branched C₂-C₆ alkenyl or alkynyl; benzyl; phenyl optionally substituted with one or more of the following groups: halogen as previously defined, CF₃, OCF₃, OH, linear or branched C₁-C₄ alkyl; a saturated heterocycle with at least 4 carbon atoms and at least 1 heteroatom; C₃-C₈ cycloalkyl optionally substituted with one or more linear or branched C₁-C₄ alkyl groups, CF₃ and/or OH;
  • SR₅, SO₂R₅ or COR₅ wherein R₅ is linear or branched C₁-C₆ alkyl;or Ar is a heterocycle selected from the group consisting of pyrrole, pyrazole, furan, thiophene, indole, isoindole, benzofuran, benzothiophene, imidazole, oxazole, isoxazole, thiazole, benzoimidazole, benzoxazole, benzothiazole, pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, dibenzofuran, dibenzothiophene, thianthrene, carbazole, pyridazine, cinnoline, phthalazine, 1,5-naphthiridine, 1,3-dioxole, 1,3-benzodioxole, said heterocycle being optionally substituted with one or more groups R₃ as defined above.

Amides of an alpha-amino acid representative of the invention are preferably selected from the group of glycinamide, alanylamide, serinamide, and valinamide, even more preferably in the levo form.

The preferred amide is glycinamide (H₂NCH₂CONH₂).

A first group of preferred compounds is that in which:

• B is H;
• R and R₁ form a 3 carbon atoms ring;
• R₂ is fluorine;
• Ar is phenyl as defined above.

A second group of preferred compounds is that in which:

• B is H;
• R and R₁ are both methyl;
• R₂ is fluorine;
• Ar is phenyl as defined above.

A third group of preferred compounds is that in which:

• B is H;
• R and R₁ form a 3 carbon atoms ring;
• R₂ is fluorine;
• Ar is a heterocycle as defined above.

A fourth group of preferred compounds is that in which:

• B is H;
• R and R₁ are both methyl;
• R₂ is fluorine;
• Ar is a heterocycle as defined above.

The invention also includes the enantiomers, metal and organic salts and other esters pharmaceutically acceptable.

A further object of the present invention is the use of the aforementioned compounds for the therapeutical treatment and/or prevention of neurodegenerative diseases connected with an increased production of the neurotoxic peptide Aβ₄₂, such as Alzheimer's disease.

Still a further object of the invention are solid or liquid pharmaceutical compositions, preferably for the oral use, comprising at least one compound of formula (I) in admixture with pharmaceutically acceptable excipients and/or vehicles, for example those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A.

The compounds of general formula (I) can be prepared according to methods known literature by conversion of an acid of formula (II)

in which R, R₁, R₂, and Ar are as defined above, into the corresponding acyl chloride, followed by reaction with the amide of the suitable alpha-amino acid.

Alternatively, said compounds can be prepared by direct reaction of the acid of formula (II) with the amide of the suitable alpha-amino acid in the presence of coupling agents such as dycyclohexylcarbodiimide (DCC), polymer supported-DCC, or N,N′carbonyldiimidazole or treating a corresponding ester with the compound formed in situ by reacting trimethylaluminium and the amide of a suitable alpha-amino acid.

The acids of formula (II) can be prepared as described in the co-pending International application No. PCT/EP2004/001596.

EXAMPLES

The following Example illustrates the invention in a more detail.

Preparation of the Glycinamide of the 1-[2-Fluoro-4′-[[4-(Trifluoromethyl)-Cyclohexyl]oxy]-1,1 ′-Biphenyl-4-yl]-Cyclopropanecarboxylic Acid

Preparation of the 1-(2-Fluoro-4′-Hydroxy-Biphenyl-4-yl)-Cyclopropanecarboxylic Acid

To a solution of K₂CO₃ (447 mg, 3.2 mmoles) in dioxane (30 ml) and water (3 ml), 250 mg of 1-(4-bromo-3-fluoro-phenyl)-cyclopropanecarboxylic acid (1.0 mmole) and 265 mg of hydroxyphenylboronic acid (1.9 mmoles) are added under stirring. Under nitrogen atmosphere, 39 mg of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (PdCl₂-DPPF) are added. The resulting mixture is heated at 65° C. for one hour, then the reaction is quenched by adding a 10% w/v HCl solution.

Extractions with ethyl acetate, washings with water and brine and evaporation afford the crude product, which is crystallized from ethyl acetate/hexane, to give the 1-(2-fluoro-4′-hydroxy-biphenyl-4-yl)-cyclopropanecarboxylic acid. Yield: 85%.

Preparation of the 1-[2-Fluoro-4′-(4-Trifluoromethyl-Cyclohexyloxy)-Biphenyl-4-yl] -Cyclopropanecarboxylic Acid

Diethyl azodicarboxylate (370 μL, 2.4 mmoles) is added to a solution of 200 mg of 1-(2-fluoro-4′-hydroxy-biphenyl-4-yl)-cyclopropanecarboxylic acid (0.8 mmoles), triphenyl phosphine (623 mg, 2.4 mmoles) and 4-trifluoromethyl cyclohexanol (400 mg, 2.4 mmoles) in dry THF (3 mL) at 0° C. under nitrogen atmosphere. The resulting clear orange solution is left under stirring overnight, then quenched with water and extracted with ethyl acetate. The organic phase is washed with 10% w/v HCl solution, dried on Na₂SO₄ and evaporated. Purification by chromatography on silica gel by eluting with methylene chloride:methanol 98:2 v/v furnishes 1-[2-fluoro-4′-(4-trifluoromethyl-cyclohexyloxy)-biphenyl-4-yl]-cyclopropanecarboxylic acid as a white solid.

Yield: 26%.

HPLC purity (254 nm): 98%

Preparation of the Glycinamide of the 1-[2-Fluoro-4′-(4-Trifluoromethyl-Cyclohexyloxy)-Biphenyl-4-yl] -Cyclopropanecarboxylic Acid

Oxalyl chloride (530 μL, 6.0 mmoles) is added dropwise to a solution of 1-[2-fluoro-4′-(4-trifluoromethyl-cyclohexyloxy)-biphenyl-4-yl]-cyclopropane carboxylic acid (480 mg, 1.0 mmoles) in 5 ml of methylene chloride, under nitrogen. The resulting solution is stirred at room temperature for 2 hours, then evaporated to dryness and redissolved in methylene chloride. A suspension of glycinamide hydrochloride (133 mg. 1.3 mmoles) and triethylamine (3 ml) in 5 ml of methylene chloride is added to the solution and the resulting mixture is stirred for 2 hours at room temperature. After addition of water, the organic phase is washed with a 2N K₂CO₃ solution and brine, dried on Na₂SO₄ and evaporated. The solid obtained is purified by chromatography. After recrystallization from ethyl acetate/petroleum ether a white solid is obtained.

• HPLC purity (254 nm): 98%.
• ESI⁺): 479.2 (MH⁺).
• ¹H NMR(CDCl₃): 7.47 (dd, 2H); 7.43 (dd, 1H); 7.25 (dd, 1H); 7.19 (dd, 1H); 6.97 (dd, 2H); 6.05 (t, 1H); 5.94 (s, 1H); 5.34 (s, 1H); 4.23 (m, 1H); 3.88 (d, 2H); 2.35-2.25 (m, 2H); 2.15-2.01 (m, 3H); 1.64 (m, 2H); 1.48 (dd, 4H); 1.14 (m, 2H).Legend: dd=doublet of doublets; t=triplet; d=doublet; s=singlet; m multiplet.

Claims

1. A compound of the general formula (I):

2. The compound as claimed in claim 1, wherein B is H.

3. The compound as claimed in claim 1, wherein B is H; R and R1 form a 3 carbon atoms ring; R2 is fluorine; and Ar is phenyl as defined in claim 1.

4. The compound as claimed in claim 1, wherein B is H; R R1 are both CH3; R2 is fluorine; and Ar is phenyl as defined in claim 1.

5. The compound as claimed in claim 1, wherein B is H; R and R1 form a 3 carbon atom ring; R2 is fluorine; and Ar is a heterocycle as defined in claim 1.

6. The compound as claimed in claim 1, wherein B is H; R and R1 are both CH3; R2 is fluorine; Ar is a heterocycle as defined in claim 1.

7. The compound as claimed in claim 1 as a medicament.

8. The pharmaceutical composition containing a compound of formula (I) as claimed in claim 1 in admixture with pharmaceutically acceptable vehicles and/or excipients.

9. The pharmaceutical composition as claimed in claim 8, for oral administration.

10. A method of using a compound of formula (I) as claimed in claim 1, for the preparation of a medicament for the treatment of neurodegenerative diseases connected with an increased production of neurotoxic peptide Aβ42.

11. The method of using the compounds of formula (I) as claimed in claim 10, for the treatment of Alzheimer's disease.