NOVEL CANNABIGEROL DERIVATIVES

Abstract

The present invention relates to novel cannabigerol quinone derivatives of formula (I) wherein R is the carbon atom of a linear or branched group, represented by: aryl, alkenyl, alkynyl or alcoxycarbonil groups; or wherein R is the nitrogen atom of a linear or branched group, represented by: alkylamino, arylamino, alkenylamino or alkynylamino groups; or, alternatively, R represents a bond between 2 molecules of formula (I) forming a dimer. The invention also relates to the use of any of the compounds of formula (I) as medicaments in therapy, particularly for treating PPARg-related diseases due to their high PPARg agonistic effect lacking electrophilic (Nrf2 activation) and cytotoxic activities. This invention also provides pharmaceutical compositions comprising said compounds and method of treating diseases with said compounds.

##STR00001##

Claims

1. Compounds of Formula (I), or pharmaceutically acceptable salts thereof ##STR00028## wherein R is the carbon atom of a group, represented by: aryl, linear or branched alkenyl, linear or branched alkynyl, or linear or branched alkoxycarbonyl groups; or wherein R is the nitrogen atom of a group, represented by: linear or branched alkylamino, arylamino, linear or branched alkenylamino, or linear or branched alkynylamino groups; or, alternatively, R represents a bond between 2 molecules of formula (I) forming a dimer.

2. Compound according to claim 1 selected from: ##STR00029## 6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-methoxycarbonyl-[1,4]benzoquinone (II), ##STR00030## 6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-ethylamino-[1,4]benzoquinone (III), ##STR00031## 6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-pentylamino-[1,4]benzoquinone (IV), ##STR00032## 6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-isobutylamino-[1,4]benzoquinone (V), ##STR00033## 6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-butylamino-[1,4]benzoquinone (VI), ##STR00034## 6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-methylamino-[1,4]benzoquinone (VII), ##STR00035## 6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-isopropylamino-[1,4]benzoquinone (VIII), ##STR00036## 6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-benzylamino-[1,4]benzoquinone (IX), ##STR00037## 6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-(2,2-dimethyl-propylamino)-[1,4]benzoquinone (X), ##STR00038## 6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-(3-methyl-butylamino)-[1,4]benzoquinone (XI), and ##STR00039## 3,3′-bis((E)-3,7-dimethyl-octa-2,6-dienyl)-4,4′-dihydroxy-6,6′-dipentyl-1,1′-bi(cyclohexa-3,6-diene)-2,2′,5,5′-tetraone (XII).

3-10. (canceled)

11. Compound according to claim 1 which is ##STR00040## 6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-methoxycarbonyl-[1,4]benzoquinone (II).

12. Compound according to claim 1 which is ##STR00041## 6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-ethylamino-[1,4]benzoquinone (III).

13. Compound according to claim 1 which is ##STR00042## 6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-pentylamino-[1,4]benzoquinone (IV).

14. Compound according to claim 1 which is ##STR00043## 6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-isobutylamino-[1,4]benzoquinone (V).

15. Compound according to claim 1 which is ##STR00044## 6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-butylamino-[1,4]benzoquinone (VI).

16. Compound according to claim 1 which is ##STR00045## 6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-methylamino-[1,4]benzoquinone (VII).

17. Compound according to claim 1 which is ##STR00046## 6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-isopropylamino-[1,4]benzoquinone (VIII).

18. Compound according to claim 1 which is ##STR00047## 6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-benzylamino-[1,4]benzoquinone (IX).

19. Compound according to claim 1 which is ##STR00048## 6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-(2,2-dimethyl-propylamino)-[1,4]benzoquinone (X).

20. Compound according to claim 1 which is ##STR00049## 6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-(3-methyl-butylamino)-[1,4]benzoquinone (XI).

21. Compound according to claim 1 which is ##STR00050## 3,3′-bis((E)-3,7-dimethyl-octa-2,6-dienyl)-4,4′-dihydroxy-6,6′-dipentyl-1,1′-bi(cyclohexa-3,6-diene)-2,2′,5,5′-tetraone (XII).

22. A composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and at least one of a further active compound having additive or synergistic biological activity, a pharmaceutically inert ingredient, an excipient, or a carrier.

23. A method of treating a human or animal patient comprising administering an effective amount of a medicament comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof to the patient sufficient to ameliorate the symptoms of a disease.

24. The method of claim 23, wherein the disease is a PPARg mediated disease.

25. The method of claim 24, wherein the PPARg mediated disease is selected from: atherosclerosis, inflammatory bowel diseases, rheumatoid arthritis, liver fibrosis, nephropathy, psoriasis, skin wound healing, skin regeneration, pancreatitis, gastritis, neurodegenerative disorders, neuroinflammatory disorders, scleroderma, cancer, hypertension, obesity, or type II diabetes.

26. The method of claim 23, wherein the medicament further comprises at least one of a further active compound having additive or synergistic biological activity, a pharmaceutically inert ingredient, an excipient, or a carrier.

Description

DESCRIPTION OF FIGURES

[0077] The figures of the invention are briefly described below. An in deep explanation of each figure is included in every pertinent example.

Figures Abbreviations:

[0078] I: refers to CBG-Q. [0079] II: refers to compound of formula (II). [0080] III: refers to compound of formula (III). [0081] IV: refers to compound of formula (IV). [0082] V: refers to compound of formula (V). [0083] VI: refers to compound of formula (VI). [0084] VII: refers to compound of formula (VII). [0085] VIII: refers to compound of formula (VIII). [0086] IX: refers to compound of formula (IX). [0087] X: refers to compound of formula (X. [0088] XI: refers to compound of formula (XI). [0089] XII: refers to compound of formula (XII).

[0090] FIG. 1. PPARg Transactivation Assays in HEK-293 Cells

[0091] The concentration of the tested compound (M) is shown at the x-axis and the PPARg activation fold is shown at the y-axis. This figure shows the effect of CBG-Q or compound I versus the effect of compounds II-VI (FIG. 1A) and versus the effect of compounds VII-XII (FIG. 1B) on PPARg activity, ratifying that derivatives of CBG-Q (compound I), and specially compounds II, III, IV, V, VII, VIII, and XII, are being able to induce PPARg activation with higher efficiency than CBG-Q (compound I). The PPARγ full agonist Rosiglitazone (RZG) 1 μM was used as comparative control. Fold activation level was calculated, taking the control sample (−), without the presence of any PPARg agonist or activating agent, as reference. Data are expressed as mean±S.D. of at least three independent experiments.

[0092] FIG. 2. PPARg Transactivation Assays in Human Dermal Primary Fibroblasts.

[0093] The concentration of the tested compound (μM) is shown at the x-axis and the PPARg activation fold is shown at the y-axis. This figure shows the effect of CBG-Q (compound I) versus compounds II, III, IV, and V on PPARg activity, ratifying that those compounds II, III, IV, and V are being able to induce PPARg activation with higher efficiency than CBG-Q (compound I). The PPARγ full agonist Rosiglitazone (RZG) 1 μM was used as comparative control. Fold activation level was calculated, taking the control sample (−), without the presence of any PPARg agonist or activating agent, as reference. Data are expressed as mean±S.D. of at least three independent experiments.

[0094] FIG. 3. Cytotoxicity Activity.

[0095] The cell lines N2a (A), HT22 (B) and MO3.13 (C) cells were incubated for 24 h with the indicated doses of CBG-Q (Compound I) versus compounds II to XII, and cell viability was quantified by MTT assay. Results are shown as mean±S.D. from at least three independent experiments, and expressed as percentage of cell viability against the control sample (−), without the presence of any PPARg agonist or activating agent. Control was set as 100% and data were referred to that value. The results demonstrate that the cytotoxic activity associated to CBG-Q (compound I) is missing in all the CBG-Q derivatives in position 2 described in the present invention.

[0096] FIG. 4. Nrf2 Transcriptional Assays

[0097] HaCaT-ARE-Luc cells were incubated for 6 h with compounds CBG-Q compound I) and with compounds I to VI (A) or with compounds VII to XII (B) at the indicated concentrations, and protein lysates were prepared and analysed for luciferase activity. The pro-oxidant tert-Butylhydroquinone (tBHQ) at 20 μM, a compound that induces cellular oxidative stress, was used as positive control. Fold activation level was calculated, taking the control sample (−), without the presence of any PPARg agonist or activating agent, as reference. Data are expressed as mean±S.D. from at least three independent experiments. The results ratify that the reactive electrophilic activity associated to CBG-Q (compound I) is missing in all the compounds (derivatives in position 2) described in the present invention.

[0098] FIG. 5. Neuroprotective Activity.

[0099] N2a cells were pre-incubated for 1 h with compounds (II) to (V) and (XII) at the indicated concentrations. Then, cells were treated for 24 h with 5 mM glutamate to induce excitotoxicity, or cytotoxicity in neuronal cells induced by neurotransmitters. Cell viability was quantified by MTT assay. Results are shown as mean±S.D. from at least three independent experiments, and expressed as percentage of cell viability against the control sample (−), without the presence of any PPARg agonist or activating agent and with (−,+) or without (−,−) glutamate. Control was set as 100% and data were referred to that value.

[0100] FIG. 6. Compound (III) Alleviates EAE

[0101] C57BL/6 mice were immunized with MOG.sub.35-55 and their clinical score evaluated daily. Mice were treated daily with compound (III) (10 mg/kg) on day 6 post-immunization and the 21 following days. The graph shows the daily average clinical score (mean±SEM). Values are expressed as means±SEM for 10 animals per group.

[0102] FIG. 7. Effect of Compound (III) on Pro-Inflammatory Markers (EAE)

[0103] Gene expression of inflammatory markers including CCL2, IFNγ, INOS, TNFα, IL-1β and IL-17 in the spinal cord was down regulated in EAE+compound (III) (10 mg/kg) group compared with EAE+Vehicle mice. Expression levels were calculated using the 2.sup.−ΔΔCt method.

[0104] FIG. 8. Compound (XII) Alleviates EAE

[0105] C57BL/6 mice were immunized with MOG.sub.35-55 and their clinical score evaluated daily. Mice were treated daily with compound (XII) (5 mg/kg) on day 6 post-immunization and the 21 following days. The graph shows the daily average clinical score (mean±SEM). Values are expressed as means±SEM for 6 animals per group.

[0106] FIG. 9. Behavioral Score after 3NP Intoxication.

[0107] Mice were subjected to behavioral tests for determining their neurological status after the treatment with compounds I (10 mg/kg) (A), III (10 mg/kg) (B) and XII (10 mg/kg) (C). Hind limb clasping, Locomotor activity, Hind limb dystonia and Truncal Dystonia were rated from 0 to 2 based on severity: a score of 0 typically indicates normal function and 2 seriously affected. Values are expressed as means±SEM for 8 animals per group.

[0108] FIG. 10. Compound III Reduces the Expression on Inflammatory Marker mRNAs in the Striatum.

[0109] Gene expression of inflammatory markers including COX-2, TNFα, IL-6 and iNOS, was down regulated in 3NP+compound III (10 mg/kg) treated mice compared with 3NP+Vehicle mice. Expression levels were calculated using the 2.sup.−ΔΔCt method. Values are expressed as means±SEM for 6 animals per group.

[0110] FIG. 11. Compound XII Reduces the Expression on Inflammatory Marker mRNAs in the Striatum.

[0111] Gene expression of inflammatory markers including COX-2, TNFα, IL-6 and iNOS, was down regulated in 3NP+XII (10 mg/kg) treated mice compared with 3NP+Vehicle mice. Expression levels were calculated using the 2.sup.−ΔΔCt method. Values are expressed as means±SEM for 6 animals per group.

[0112] FIG. 12. Effect of Compound XII on Neurodegenerative Markers (3NP)

[0113] NeuN (neuronal marker), GFAP (astrocytes marker), and Iba1 (microglia marker) were detected by immunostaining in the coronal sections of striatum of mice treated with vehicle, 3NP+vehicle, 3NP+compound XII (10 mg/kg) and XII (10 mg/kg). Quantification of NeuN (A), GFAP (B) and Iba1 (C) positive cells in the mouse striatum. Total average number of neurons, astrocytes and microglia is shown. Values are expressed as means±SEM for 6 animals per group.

[0114] FIG. 13. Effect of Compound (III) on 6-OHDA-Induced Parkinson Symptomatology.

[0115] C57BL/6 mice were unilaterally injected intracerebroventricullarly with 6-hydroxydopamine (6-OHDA) or saline (control mice) and subjected to chronic intraperitoneal treatment with compound III (10 mg/ml) or vehicle (14 days), starting 16 h after the 6-OHDA injection. Motor coordination was evaluated by rotarod performance and motor activity was evaluated using a computer-aided actimeter. Values are expressed as means±SEM for 6 animals per group.

EXAMPLES

[0116] The examples of the present invention described below aim to illustrate its preferred embodiments without limiting its scope of protection.

Example 1. Chemical Synthesis and NMR Analysis

[0117] General Procedures for Compounds Derived from CBGA. Synthesis of Compounds (II) and (XII))

[0118] To a solution of CBGA (Cannabigerol acid) (360 mg, 0.80 mmol) in methanol (10 mL), dicyclohexylcarbodiimide (DCC) (331 mg, 1.6 mmol) and catalytic p-toluenesulfonic acid (ca. 10 mg) were added. After stirring for 40 min., the reaction was worked up by evaporation (Scheme 1). The residue was dissolved in toluene (ca 10 mL), and cooled (−18° C.) to precipitate the urea. After 1 h, the solution was filtered on a sintered glass filter, and the residue purified by flash chromatography of RP C-18 silica gel to afford 260 mg of (E)-methyl 3-(3,7-dimethylocta-2,6-dienyl)-2,4-dihydroxy-6-pentylbenzoate [colorless foam, yield: 70%].

[0119] .sup.1H NMR (CDCl.sub.3, 300 MHz) δ ppm 12.00 (bs, 1H), 6.25 (s, 1H), 5.27 (bt, J=6.5 Hz, 1H), 5.04 (bt, J=6.5 Hz, 1H), 3.90 (s, 3H), 3.41 (d, J=6.8 Hz, 1H), 2.05 (bm, 4H), 1.80 (bs, 3H), 1.66 (bs, 3H), 0.89 (t, J=6.0 Hz, 3H).

##STR00014##

Preparation Compound II

6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-metoxycarbonil-[1,4]benzoquinone

[0120] ##STR00015##

[0121] To a solution of 100 mg (0.27 mmol) of (E)-methyl 3-(3,7-dimethylocta-2,6-dienyl)-2,4-dihydroxy-6-pentylbenzoate in 4 mL EtOAc, SIBX (465 mg, 0.77 mmol, 3 mol equiv.) was added, and the reaction was refluxed for 1 h. After cooling and filtration over Celite, the filtrate was sequentially washed with sat. NaHCO.sub.3 and brine. After drying (Na.sub.2SO.sub.4) and evaporation, the residue was purified by column chromatography on silica gel (petroleum ether-CH2Cl2 8:5 as eluent) to afford 28 mg 6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-metoxycarbonill-[1,4]benzoquinone. [brown-colored solid, yield: 25%].

[0122] .sup.1H NMR (CDCl3, 300 MHz) δ ppm 6.95 (bs, 1H), 5.11 (bt, J=6.5 Hz, 1H), 5.04 (bt, J=6.5 Hz, 1H), 3.89 (s, 3H), 3.13 (d, J=6.5 Hz, 2H), 2.38 (m, 2H), 1.72 (bs, 3H), 1.65 (bs, 3H), 1.57 (bs, 3H), 0.89 (t. J=6.5 Hz, 3H).

Preparation Compound XII

3,3′-bis((E)-3,7-dimethylocta-2,6-dienyl)-4,4′-dihydroxy-6,6′-dipentyl-1,1′-bi(cyclohexa-3,6-diene)-2,2′,5,5′-tetraone

[0123] ##STR00016##

[0124] To a solution of cannabigerol (CBG) (500 mg, 0.16 mmol) in toluene (100 mL), NaH (95%, 150 mg, 0.48 mmol, 3 mol. equiv) was added, and the reaction was stirred vigorously leaving the flask open (Scheme 3). A violet color developed almost instantaneously, and after 12 h the reaction was worked up by acidification with 2N H.sub.2SO.sub.4 to pH 3, and partition between brine and EtOAc. The organic phase was dried (Na.sub.2SO.sub.4) and evaporated, and the residue was purified by gravity column chromatography on silica gel (petroleum ether-EtOAc 9:1 as eluant) to afford 120 mg 3,3′-bis((E)-3,7-dimethylocta-2,6-dienyl)-4,4′-dihydroxy-6,6′-dipentyl-1,1′-bi (cyclohexa-3,6-diene)-2,2′,5,5′-tetraone [brown dark gum, yield: 24%].

[0125] .sup.1H NMR (CDCl.sub.3, 300 MHz) δ ppm: 6.99 (bs, 2H), 5.10 (bt, J=6.5 Hz, 2H), 5.05 (bt, J=6.5 Hz, 2H) 3.13 (d, J=6.5 Hz, 4H), 1.71 (s, 6H), 1.65 (s, 6H), 1.57 (s, 6H), 0.81 (t, J=7.0 Hz,

Example 2. Chemical Synthesis and NMR Analysis

[0126] General Procedures for Compounds Derived from CBG. Synthesis of Compounds (III) to (XI))

[0127] Synthesis of CBG-Q (compound I) starting from CBG (Cannabigerol) was carried out by using tBuOK in toluene, at r.t., in the presence of air (Scheme 4)

##STR00017##

[0128] tBuOK (2.00 g, 17.824 mmol) was added to a solution of Cannabigerol (CBG) (2.00 g, 6.319 mmol) in toluene (400 mL), to give a purple-colored solution. The reaction mixture was stirred at r.t., in an air-opened round bottom flask, and conversion was monitored by TLC analysis (eluent: 10% EtOAc/hexanes) (Scheme 5). After 2 h, the reaction mixture was washed with HCl (5% aqueous solution, 300 mL) and the aqueous layer was extracted with EtOAc (100 mL). Combined organic layers were dried over Na.sub.2SO.sub.4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO.sub.2 (2 to 4% EtOAc/hexanes), to give 1.10 g of CBG-Q (compound I) [orange-colored solid, yield: 53%].

[0129] .sup.1H NMR (CDCl.sub.3, 300 MHz): δ 6.94 (s, —OH, 1H), 6.45 (s, 1H), 5.13 (br t, J=6.8 Hz, 1H), 5.04 (br t, J=6.8 Hz, 1H), 3.14 (s, J=6.8 Hz, 2H), 2.41 (t, J=7.8 Hz, 2H), 2.09-1.92 (m, 4H), 1.73 (br s, 3H), 1.57 (br s, 3H), ca. 1.52 (m, 2H), 1.38-1.17 (m, 4H), 0.89 (t, J=7.8 Hz, 3H).

[0130] Synthesis of derivatives substituted at position 2 with alkylamino, arylamino, alkenylamino or alkynylamino was accomplished by reacting CBG-Q (compound I) with a large excess of amine, at r.t., in an air-opened reaction system (Scheme 5)

##STR00018##

[0131] High conversion was achieved within several hours, to give spot to spot reactions. Solvent was concentrated off, and the crude residue was purified by reverse phase chromatography, to give products with purities about 95%.

Preparation of Compound III

6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-ethylamino-[1,4]benzoquinone

[0132] ##STR00019##

[0133] Ethylamine (5.2 mL, 70% solution in H.sub.2O, 65.403 mmol) was added to a solution of CBG-Q (compound I) (510 mg, 1.543 mmol) in EtOH (50 mL). The reaction mixture was stirred at r.t. for 2 h (Scheme 6). It was poured into H.sub.2O (120 mL), taken up to pH=2 with HCl (10% aqueous solution) and extracted with CH.sub.2Cl.sub.2 (2×80 mL). The organic layer was dried over Na.sub.2SO.sub.4 (anhydrous), filtered and concentrated. Crude residue was purified by reverse phase chromatography (30 to 100% CH.sub.3CN/H.sub.2O) to give 435 mg of 2-(3,7-dimethyl-octa-2,6-dienyl)-6-ethylamino-3-hydroxy-5-pentyl-[1,4]benzo-quinone [purple-colored solid, yield: 75%].

[0134] .sup.1H NMR (CDCl.sub.3, 300 MHz) δ ppm: 6.39 (bs, 1H), 5.09 (m, 2H), 3.54 (t, J=6.6 Hz, 2H), 3.05 (d, J=6.6 Hz, 2H), 2.49 (m, 2H), 1.99 (m, 4H), 1.72 (s, 3H), 1.64 (s, 3H), 1.57 (s, 3H), 1.44-1.22 (m, 9H), 0.88 (m, 3H).

Preparation Compound IV

6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-pentylamino-[1,4]benzoquinone

[0135] ##STR00020##

[0136] Amylamine (1.5 mL, 12.943 mmol) was added to a solution of compound CBG-Q (compound I) (109 mg, 0.330 mmol) in EtOH (10 mL). The reaction mixture was stirred at r.t. for 22 h (Scheme 7). It was poured into H.sub.2O (50 mL), taken up to pH=2 with HCl (10% aqueous solution) and extracted with CH.sub.2Cl.sub.2 (30 mL). The organic layer was dried over Na.sub.2SO.sub.4 (anhydrous), filtered and concentrated. Crude residue was purified by reverse phase chromatography (30 to 100% CH.sub.3CN/H.sub.2O) to give 88 mg of 2-(3,7-dimethyl-octa-2,6-dienyl)-3-hydroxy-5-pentyl-6-pentylamino-[1,4]benzoquinone [purple-colored solid, yield: 64%].

[0137] .sup.1H NMR (CDCl.sub.3, 300 MHz) δ ppm: 6.38 (bs, 1H), 5.13 (t, J=7.1 Hz, 1H), 5.05 (t, J=6.0 Hz, 1H), 3.47 (q, J=6.6 Hz, 2H), 3.06 (d, J=7.1 Hz, 2H), 2.49 (m, 2H), 2.08-1.93 (m, 4H), 1.72 (s, 3H), 1.65 (s, 3H), 1.57 (s, 3H), 1.42-1.28 (m, 12H), 0.91 (m, 6H).

Preparation Compound V

6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-isobutylamino[1,4]benzoquinone

[0138] ##STR00021##

[0139] Isobutylamine (1.3 mL, 13.082 mmol) was added to a solution of compound CBQ-G (compound I) (101 mg, 0.306 mmol) in EtOH (10 mL). The reaction mixture was stirred at r.t. for 8 h (Scheme 8). It was poured into H.sub.2O (50 mL), taken up to pH=2 with HCl (10% aqueous solution) and extracted with CH.sub.2Cl.sub.2 (30 mL). The organic layer was dried over Na.sub.2SO.sub.4 (anhydrous), filtered and concentrated. Crude residue was purified by reverse phase chromatography (30 to 100% CH.sub.3CN/H.sub.2O) to give 59 mg of 2-(3,7-dimethyl-octa-2,6-dienyl)-3-hydroxy-6-isobutylamino-5-pentyl-[1,4]benzoquinone [purple-colored solid, yield: 48%].

[0140] .sup.1H NMR (CDCl.sub.3, 250 MHz) δ ppm: 6.60 (bs, 1H), 5.11 (m, 2H), 3.28 (t, J=6.3 Hz, 2H), 3.06 (d, J=7.1 Hz, 2H), 2.49 (m, 2H), 2.07-1.84 (m, 4H), 1.72 (s, 3H), 1.65 (s, 3H), 1.57 (s, 3H), 1.41-1.27 (m, 7H), 1.02 (s, 3H), 0.98 (s, 3H), 0.89 (m, 3H).

Preparation Compound VI

6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-butylamino[1,4]benzoquinone

[0141] ##STR00022##

[0142] n-Butylamine (1.2 mL, 12.143 mmol) was added to a solution of compound CBG-Q (compound I) (102 mg, 0.309 mmol) in EtOH (12 mL). The reaction mixture was stirred at r.t. for 18 h (Scheme 9). It was poured into H.sub.2O (50 mL), taken up to pH=2 with HCl (10% aqueous solution) and extracted with CH.sub.2Cl.sub.2 (30 mL). The organic layer was dried over Na.sub.2SO.sub.4 (anhydrous), filtered and concentrated to obtain 190 mg of 2-butylamino-6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-[1,4]benzoquinone [purple-colored solid, yield: 98%].

[0143] .sup.1H NMR (CDCl.sub.3, 250 MHz) δ ppm: 6.50 (bs, 1H), 5.09 (m, 2H), 3.47 (q, J=7.1 Hz, 2H), 3.05 (d, J=7.1 Hz, 2H), 2.48 (m, 2H), 2.08-1.90 (m, 4H), 1.72 (s, 3H), 1.64 (s, 3H), 1.57 (s, 3H), 1.50-1.22 (m, 10H), 1.00-0.84 (m, 6H).

Preparation Compound VII

6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-methylamino-[1,4]benzoquinone

[0144] ##STR00023##

[0145] Methylamine (0.6 mL, 8 M solution in EtOH, 4.8 mmol) was added to a solution of compound CBG-Q (compound I) (102 mg, 0.309 mmol) in EtOH (10 mL). The reaction mixture was stirred at r.t. for 6 h (Scheme 10). It was poured into H.sub.2O (50 mL), taken up to pH=2 with HCl (10% aqueous solution) and extracted with CH.sub.2Cl.sub.2 (30 mL). The organic layer was dried over Na.sub.2SO.sub.4 (anhydrous), filtered and concentrated. Crude residue was purified by reverse phase chromatography (30 to 100% CH.sub.3CN/H.sub.2O) to give 23 mg of 2-(3,7-dimethyl-octa-2,6-dienyl)-3-hydroxy-6-methylamino-5-pentyl-[1,4] benzoquinone [purple-colored solid, yield: 20%].

[0146] .sup.1H NMR (CDCl.sub.3, 300 MHz) δ ppm: 6.48 (bs, 1H), 5.12 (t, J=6.6 Hz, 1H), 5.06 (t, J=6.6 Hz, 1H), 3.20 (d, J=6.0 Hz, 3H), 3.06 (d, J=7.1 Hz, 2H), 2.55 (t, J=7.1 Hz, 2H), 2.07-1.92 (m, 4H), 1.72 (s, 3H), 1.65 (s, 3H), 1.57 (s, 3H), 1.49-1.23 (m, 6H), 0.89 (m, 3H).

Preparation Compound VIII

6-(3,7-imethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-isopropylamino-[1,4]benzoquinone

[0147] ##STR00024##

[0148] Isopropylamine (1.0 mL, 11.639 mmol) was added to a solution of compound CBG-Q (compound I) (101 mg, 0.306 mmol) in EtOH (10 mL). The reaction mixture was stirred at r.t. for 18 h (Scheme 11). It was poured into H.sub.2O (50 mL), taken up to pH=2 with HCl (10% aqueous solution) and extracted with CH.sub.2Cl.sub.2 (30 mL). The organic layer was dried over Na.sub.2SO.sub.4 (anhydrous), filtered and concentrated. Crude residue was purified by reverse phase chromatography (30 to 100% CH.sub.3CN/H.sub.2O) to give 62 mg of 2-(3,7-dimethyl-octa-2,6-dienyl)-3-hydroxy-6-isopropylamino-5-pentyl-[1,4]benzoquinone [purple-colored solid, yield: 52%].

[0149] .sup.1H NMR (CDCl.sub.3, 300 MHz) δ ppm: 6.37 (s, 1H), 5.13 (t, J=6.6 Hz, 1H), 5.05 (t, J=6.6 Hz, 1H), 3.98 (m, 1H), 3.06 (d, J=7.1 Hz, 2H), 2.47 (m, 2H), 2.08-1.92 (m, 4H), 1.72 (s, 3H), 1.65 (s, 3H), 1.57 (s, 3H), 1.42-1.29 (m, 6H), 1.28 (s, 3H), 1.25 (s, 3H), 0.89 (m, 3H).

Preparation Compound IX

6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-benzylamino [1,4]benzoquinone

[0150] ##STR00025##

[0151] Benzylamine (1.3 mL, 11.913 mmol) was added to a solution of compound CBG-Q (compound I) (100 mg, 0.302 mmol) in EtOH (13 mL). The reaction mixture was stirred at r.t. for 18 h (Scheme 12). It was poured into H.sub.2O (50 mL), taken up to pH=2 with HCl (10% aqueous solution) and extracted with CH.sub.2Cl.sub.2 (30 mL). The organic layer was dried over Na.sub.2SO.sub.4 (anhydrous), filtered and concentrated. Crude residue was purified by reverse phase chromatography (30 to 100% CH.sub.3CN/H.sub.2O) to give 61 mg of 2-benzylamino-6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-[1,4] benzoquinone [purple-colored solid, yield: 46%].

[0152] .sup.1H NMR (CDCl.sub.3, 300 MHz) δ ppm: 7.43-7.27 (m, 5H), 6.80 (bs, 1H), 5.18-5.02 (m, 2H), 4.67 (d, J=5.5 Hz, 2H), 3.07 (d, J=6.6 Hz, 2H), 2.47 (t, J=7.7 Hz, 2H), 2.09-1.92 (m, 4H), 1.72 (s, 3H), 1.65 (m, 3H), 1.57 (s, 3H), 1.47-1.24 (m, 6H), 0.88 (m, 3H).

Preparation Compound X

6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-(2,2-dimethyl-propylamino)-[1,4]benzoquinone

[0153] ##STR00026##

[0154] Neopentylamine (1.4 mL, 12.063 mmol) was added to a solution of compound CBG-Q (compound I) (100 mg, 0.303 mmol) in EtOH (14 mL). The reaction mixture was stirred at r.t. for 18 h (Scheme 13). It was poured into H.sub.2O (50 mL), taken up to pH=2 with HCl (10% aqueous solution) and extracted with CH.sub.2Cl.sub.2 (30 mL). The organic layer was dried over Na.sub.2SO.sub.4 (anhydrous), filtered and concentrated. Crude residue was purified by reverse phase chromatography (30 to 100% CH.sub.3CN/H.sub.2O) to give 72 mg of 2-(3,7-dimethyl-octa-2,6-dienyl)-6-(2,2-dimethyl-propylamino)-3-hydroxy-5-pentyl[1,4] benzoquinone [purple-colored solid, yield: 65%].

[0155] .sup.1H NMR (CDCl.sub.3, 300 MHz) δ ppm: 6.62 (s, 1H), 5.14 (t, J=6.6 Hz, 1H), 5.05 (t, J=6.6 Hz, 1H), 3.27 (d, J=6.0 Hz, 2H), 3.07 (d, J=7.1 Hz, 2H), 2.50 (t, J=7.1 Hz, 2H), 2.09-1.92 (m, 4H), 1.72 (s, 3H), 1.65 (s, 3H), 1.57 (s, 3H), 1.47-1.25 (m, 6H), 1.02 (s, 9H), 0.90 (t, J=6.6 Hz, 3H).

Preparation Compound XI

6-(3,7-dimethyl-octa-2,6-dienyl)-5-hydroxy-3-pentyl-2-(3-methyl-butylamino)-[1,4]benzoquinone

[0156] ##STR00027##

[0157] Isopentylamine (1.4 mL, 11.886 mmol) was added to a solution of compound CBG-Q (compound I) (100 mg, 0.303 mmol) in EtOH (14 mL). The reaction mixture was stirred at r.t. for 18 h (Scheme 14). It was poured into H.sub.2O (50 mL), taken up to pH=2 with HCl (10% aqueous solution) and extracted with CH.sub.2Cl.sub.2 (30 mL). The organic layer was dried over Na.sub.2SO.sub.4 (anhydrous), filtered and concentrated. Crude residue was purified by reverse phase chromatography (30 to 100% CH.sub.3CN/H.sub.2O) to give 40 mg of 2-(3,7-dimethyl-octa-2,6-dienyl)-3-hydroxy-6-(3-methyl-butylamino)-5-pentyl-[1,4]benzoquinone [purple-colored solid, yield: 55%].

[0158] .sup.1H NMR (CDCl.sub.3, 300 MHz) δ ppm: 6.38 (bs, 1H), 5.09 (m, 2H), 3.50 (q, J=6.0 Hz, 2H), 3.06 (d, J=7.1 Hz, 2H), 2.51 (t, J=7.1 Hz, 2H), 2.11-1.92 (m, 4H), 1.72 (s, 3H), 1.65 (s, 3H), 1.57 (s, 3H), 1.48-1.24 (m, 7H), 0.96 (s, 3H), 0.94 (s, 3H), 0.89 (m, 3H).

[0159] In vitro assays

Example 2. PPARg Agonistic Activity

[0160] To investigate the biological activities of the novel compounds we performed PPARg transactivation assays in HEK-293 cells and human primary fibroblasts cells.

[0161] HEK293T cells and human primary fibroblasts cells were maintained at 37° C. in a humidified atmosphere containing 5% CO.sub.2 in DMEM supplemented with 10% fetal calf serum (FBS), and 1% (v/v) penicillin/streptomycin. Rosiglitazone was purchased from Cayman Chemical Company (Ann Arbor, Mich., USA). All other reagents were from Sigma Co (St Louis, Mo., USA). HEK293T cells (2×10.sup.3/well) (FIG. 1) or Human Dermal primary fibroblasts (5×10.sup.3/well) (FIG. 2) were seeded in BD Falcon™ White with Clear Bottom 96-well Microtest™ Optilux™ Plate for 24 hours. Afterwards, cells were transiently co-transfected with the expression vector GAL4-PPARγ and the luciferase reporter vector GAL4-luc using Roti©-Fect (Carl Roth, Karlsruhe, Germany) following the manufacturer's instructions. Twenty-four h post-transfection, cells were pretreated with increasing doses of the compounds for 6 hours. Then, the cells were lysed in 25 mM Tris-phosphate pH 7.8, 8 mM MgCl.sub.2, 1 mM DTT, 1% Triton X-100, and 7% glycerol. Luciferase activity was measured in the cell lysate using a TriStar LB 941 multimode microplate reader (Berthold) and following the instructions of the Luciferase Assay Kit (Promega, Madison, Wis., USA). Protein concentration was measured by the Bradford assay (Bio-Rad, Richmond, Calif., USA). The background obtained with the lysis buffer was subtracted in each experimental value and the specific transactivation expressed as a fold induction over untreated cells. All the experiments were repeated at least three times. The plasmids used were Gal4-hPPARgamma (plasmid name: pCMV-BD-hPPARg, made in Sinal Laboratory, Dept. of Pharmacology, Dalhousie University) and Gal4 luc reporter plasmid that includes five Gal4 DNA binding sites fused to the luciferase gene. The above assay is illustrated by FIG. 1 and FIG. 2 which shows the effect of CBG-Q (compound I) and derivatives on PPARg activity by means of a transactivation assay performed in cells transiently overexpressing PPARg in combination with a luciferase reporter gene (PPARg-GAL4/GAL4-LUC) and treated with the compounds for 6 hours. Data are given as means with deviation standard error bars of three replicates. A significant increase in luciferase activity was seen with quinone derivates as compared with untreated cells. This result confirms that compound II is significantly more potent than compound CBG-Q (compound I) to activate PPARg at the concentrations of 1 to 25 μM. Compounds III to XII increase PPARg transactivation in a concentration dependent manner, being III, IV, V and XII the most active compounds. In addition higher concentrations (25 and 50 μM) of these compounds are particularly potent to activate PPARg compared to CBG-Q (compound I). Rosiglitazone, a full PPARg agonist, increased more than 100 times the activity of PPARg at the concentration of 1 μM. In contrast the maximal induction of PPARg activity induced by 1 μM concentration of the compounds described in the present invention was never higher than 12 times (i.e. compound II) indicating that these novel compounds are PPARg modulator and not PPARg full agonists.

Example 3. Cytotoxicity Assays

[0162] Electrophilic quinones induce cytotoxicity and activate the Nrf2 pathway, a cellular sensor of reactive oxygen species generation. In FIG. 3 it is analyzed the induced cell death in three different types of cells (N2a, HT22 and MO3.13) by compounds CBG-Q (compound I) and compounds (II) to (XII).

[0163] Three cell lines, MO3.13, N2A and HT22 cells were maintained at 37° C. in a humidified atmosphere containing 5% CO.sub.2 in DMEM supplemented with 10% fetal calf serum (FBS), and 1% (v/v) penicillin/streptomycin. N2A, HT22 and MO3.13 cell viability was determined by the MTT assay. Briefly, cells were seeded at a density of 10.sup.4 cells/well in 96-well plates, 200 μl cell suspension per well, and cultured for 24 hours. Cells were then incubated with several concentrations of the compounds for 24 hours. After that, 100 μl of MTT (5 mg/ml) from a mixture solution of MTT: DMEM (1:2) was added to each well, and cells were incubated for 4 h at 37° C. in darkness. Then the reaction was stopped, supernatant removed and 100 μl of DMSO added to each well and incubated for 10 minutes in gentle shaking. Finally the absorbance was measured at 550 nm using a TriStar LB 941 (Berthold Technologies, GmbH & Co. KG). Control cells were set as 100% and data were referred to that value. The cell lines N2a (FIG. 3A), HT22 (FIG. 3B) and MO3.13 (FIG. 3C) cells were incubated for 24 h with the indicated doses of compounds CBG-Q (compound I) and compounds (II) to (XII), and cell viability was quantified by MTT assay. Results are shown as mean±S.D. from at least three independent experiments, and expressed as percentage of cell viability against the control sample (−). Control was set as 100% and data were referred to that value. The results demonstrate that the cytotoxic activity associated to CBG-Q (compound I) correlated with its ability to induce Nrf2 activation. In the same sense the lack of cytotoxic activity for compounds II to XII derivatives in position 2 of CBG-Q) described in the present invention, is correlated with their inability to activate Nrf2.

Example 4. Nrf2 Transcriptional Activity

[0164] To study the activity of the compounds on the Nrf2 pathway we generated the HaCaT-ARE-Luc cell line. Nqo1 ARE-Luc reporter plasmid and pPGK-Puro plasmid were co-transfected into HaCat cells using Lipofectamine© 2000 tranfection reagent (Life Technologies, Carlsbad, Ca, USA). Stable transformants were selected and maintained in RPMI 1640 containing 10% FBS, 1% penicillin-streptomycin and 10 μl/ml puromycin. HaCaT-ARE-Luc cells were incubated for 6 h with CBG-Q (compound I) and with compounds (II)-(VI) (A) or with compounds (VII)-(XII) (B) at the indicated concentrations, and protein lysates were prepared and analysed for luciferase activity as described in example 1. The prooxidant tert-Butylhydroquinone (tBHQ) at 20 μM was used as positive control. Fold activation level was calculated, taking the control sample (−) as reference (FIGS. 4A and 4B). Data are expressed as mean±S.D. from at least three independent experiments. The results ratify that the reactive electrophilic activity associated to CBG-Q (compound I) is missing in all the compounds (derivatives in position 2) described in the present invention.

Example 5. Neuroprotection Assays

[0165] Activation of the anti-inflammatory nuclear receptor PPARg plays an important role in neuroprotection and it is known that PPARg agonists prevent glutamate-induced cytotoxicity in neuronal cells.

[0166] Cultured N2A cells were pre-incubated with the compounds II, III, IV, V and XII at the indicated concentrations for 1 h and then treated with 5 mM glutamate to induce excitotoxicity during 24 h (FIG. 5). Cytotoxicity was determined by the MTT method as described in example 3. Results are shown as mean±S.D. from at least three independent experiments, and expressed as percentage of cell viability against the control sample (−). Control was set as 100% and data were referred to that value.

[0167] Those results show that compounds II, III, IV, V and XII, which are PPARg modulators, also protect neuronal cells from glutamate-induced apoptosis.

[0168] In Vivo Assays

Example 6. Induction of Experimental Autoimmune Encephalomyelitis (EAE)

[0169] PPARg modulators are of therapeutic use for neurodegenerative and inflammatory disorders and we have investigated the effects of two representative compounds of the present invention in three well-defined animal models of inflammation and neurodegeneration.

[0170] EAE was induced in female C57BL/6 mice at 6-8 weeks of age by subcutaneous immunization with myelin oligodendrocyte glycoprotein polypeptide (MOG.sub.35-55) (300 μg) and 200 μg of Mycobacterium tuberculosis (H37Ra Difco, Franklin Lakes, N.J., USA) in a 1:1 mix with incomplete Freund's adjuvant (CFA, Sigma-Aldrich, Madrid, Spain). On the same day and 2 days later, mice were injected intraperitoneally (ip) with 200 ng of pertussis toxin (Sigma-Aldrich, Madrid, Spain) in 0.1 ml PBS. Control animals (CFA) were inoculated with the same emulsion without MOG and they did not receive pertussis toxin. Treatment started at day 6 post-immunization (p.i.) and consisted in daily injections of compounds III (FIG. 6) and XII (FIG. 8) at the indicated doses or of the vehicle alone (DMSO/PBS) for the following 21 days. The mice were examined daily for clinical signs of EAE and disease scores were measured as follows: 0, no disease; 1, limp tail; 2, limp tail and hind limb weakness; 3, hind limb paralysis; 4, hind limb and front limb paralysis; 5, moribund and death. All animals were sacrificed 28 days (p.i.) for further analysis. Once sacrificed, animals were dissected and their spinal cords were rapidly removed and quickly frozen in RNAlater (Sigma-Aldric, Germany).

[0171] It is shown in FIG. 6 that compound III clearly attenuated the clinical manifestations of Experimental Autoimmune Encephalomyelitis (EAE) induced by subcutaneous immunization with (MOG.sub.35-55). Vehicle-treated mice developed a severe disease that peaked by day 16 post-injection (pi) reaching a score of 2.5 (maximal score is 3). In the mice that received compound III, the disease peaked on day 17 post-injection not reaching a score of 1,3 throughout the course of the experiment (day 6-day 28). The clinical symptoms in EAE correlated with the expression of the proinflammatory genes Ccl2, iNOs, TNFa, IFNg, IL-1b and IL-17 in the spinal cord of EAE mice that received the vehicle alone. By contrast, there was a significant decrease in all these parameters in the EAE mice that received compound III (FIG. 7). Moreover we show in FIG. 8 that compound XII also alleviated the clinical symptoms in EAE mice to the same extent than compound III confirming the anti-inflammatory activity of the compounds described in the present invention.

Example 7. Induction of Huntington's Disease (3NP Model)

[0172] The intoxication of mice with 3-Nitropropionic acid (3-NP), a potent irreversible inhibitor of mitochondrial complex II enzyme, leads to mitochondrial dysfunction and oxidative stress in animal models that results in a myriad of neurological, biochemical and histological effect that were reminiscent of some aspects of HD pathology. For example, 3NP-treated mice exhibited high scores in hindlimb clasping, dystonia, kyphosis and in the general locomotor activity compared to control animals.

[0173] Lesions of the striatum were induced with 3-NP in adult (16 week old; 30 g) male C57BL/6 mice (Harlan Ibérica, Barcelona, Spain). To this end, mice were subjected to seven intraperitoneal (i.p.) injections of 3NP (one injection each 12 hours) at a dose of 50 mg/kg (prepared in phosphate-buffered saline) for 3 days. These animals and their respective non-lesioned controls were used for pharmacological studies with compounds CBG-Q (compound I) and with compounds III and XII (FIG. 9). At least 6-8 animals were used per experimental group. Treatments consisted of four i.p. injections of the compounds at the indicated doses (one injection each 24 hours), or vehicle (DMSO 0.2%, BSA 5% in PBS) 30 min before the injections of 3NP. All animals were euthanized 12 hours after the last 3NP injection. Once euthanized, animals were dissected and their brains were rapidly removed. The right hemisphere was used to dissect the striatum, which was quickly frozen in RNAlater (Sigma-Aldrich, Germany) to analyzed inflammatory markers were by Real Time PCR. The left hemisphere was fixed in fresh 4% paraformaldehyde (in 0.1M phosphate buffered-saline) for 48 hours at 4° C. and embedded in paraffin wax for histological analysis. Mice were subjected to behavioral tests for determining their neurological status. We evaluated the general locomotor activity, the hindlimb clasping and dystonia, and the truncal dystonia. All behavioral tests were conducted prior to drug injections to avoid acute effects of the compounds under investigation.

[0174] FIG. 9 shows that CBG-Q (compound I) was unable to prevent the clinical symptoms induced by 3-NP intoxication but compounds III and XII clearly alleviates such symptomatology.

[0175] We also used the striatal parenchyma of 3NP-lesioned mice for analysis of some histological and molecular markers related to inflammation and neurodegeneration, which are affected in this experimental model. The expression of inflammatory enzymes COX-2 and iNOs was significantly up regulated in 3NP-lesioned mice in parallel to increased expression of proinflammatory cytokines TNFα and IL-6. Compounds III (FIG. 10) and XII (FIG. 11) attenuated the up-regulation of pro-inflammatory markers COX-2, iNOS, TNFα and IL-6 in the striatum of mice treated with 3NP.

[0176] In FIG. 12 it is shown that the striatal parenchyma of these 3NP-lesioned animals showed an important degree of neuronal death that was confirmed by NeuN immunohistochemistry, which proved a reduction of more than 50% in the immunolabelling for this neuronal marker in the striatal parenchyma. The loss of neurons was accompanied by a notable decrease in GFAP.sup.+ cells (astrogliosis) and an increased expression of Iba-1.sup.+ cells (reactive microgliosis). Compound XII originated a preservation of striatal neurons against 3NP toxicity as revealed by NeuN staining. Moreover the treatment with Compound XII counteracted the lost of GFAP.sup.+ cells induced by 3NP and prevented the induction of reactive microgliosis (Iba-1.sup.+ cells).

Example 8. Induction of Parkinson's Disease (6-OHDA Model)

[0177] Compound III was also of therapeutic use in a murine model of Parkinson disease (PD).

[0178] C57BL/6 mice pretreated intracerebroventricularly (i.c.v.) were anesthetized with an intraperitoneal (i.p.) injection of 200 mg/kg of 2,2,2-tribromoethanol (Sigma-Aldrich) and placed in a stereotaxic frame with a mouse adapter (David Kopf Instruments, Tujunga, Calif., USA). Using a Hamilton syringe (Hamilton, Bonaduz, Switzerland), 4 μL of 6-OHDA-HBr solution (5 μg/μL) in 0.02% ascorbic acid (SigmaAldrich) were injected in the left striatum in two deposits at the following stereotaxic coordinates (mm from bregma): AP, +0.65; L, −2.0; V1, −4 and V2, −3.5, targeting the dorsolateral striatum. After the injection, the skin was sutured and the animals were removed from the stereotaxic instrument and placed on a heating pad for 30 min. The mice were subjected to chronic intraperitoneal treatment with compound III (10 mg/ml) or vehicle (14 days), starting 16 h after the 6-OHDA injection. Motor coordination was evaluated in the rotarod test (Ugo Basile, Rome, Italy) at crescent speed. Each day, mice had a 1 min training session in the immobile rod. If the mouse fell from the rotarod during the training session, it was placed back. Then the performance of the mice was tested in 5 min sessions every 20 min. Thus, the speed of the rod was turned on up to 40 rpm for five minutes. The latency to fall off the rod was measured on consecutive days in lesioned mice following the compound III administration or vehicle control. Motor activity (ambulatory activity, mean velocity, resting time, fast movements and number of rearings) was evaluated using a computer-aided actimeter (FIG. 13).

[0179] The FIG. 13 shows that the appearance of motor symptoms that resemble human PD (changes in ambulatory activity, mean velocity, resting time, fast movement, number of rearing and rotarod performance) produced with 6-hydroxydopamine (6OHDA) were almost completely suppressed by the treatment with compound III.

Example 9. Histological Analysis (Example 7)

[0180] Brains from 3NP model were fixed in 4% paraformaldehyde and 5-μm-thick sections for immunohistochemical analysis of NeuN (FIG. 12A), a marker of neurons, GFAP (FIG. 12B), a marker of astrocytes and Iba-1 (FIG. 12C), a marker of microglial cells. For immunohistochemistry sections were incubated overnight at 4° C. with: (i) monoclonal anti-mouse NeuN antibody (Millipore, Mass., USA) used at 1/100; (ii) monoclonal anti-mouse Iba-1 antibody (Millipore, Mass., USA) used at 1/50, (iii) monoclonal anti-mouse GFAP antibody (Santa Cruz Biotechnology, CA, USA) used at 1/50. After incubation with the corresponding primary antibody, sections were washed in 0.1 M PBS and incubated O/N at 4° with Goat anti-mouse (Millipore, Mass., USA) secondary antibody. Reaction was revealed with diaminobenzidine. Negative control sections were obtained using the same protocol with omission of the primary antibody. All sections for each immunohistochemical procedure were processed at the same time and under the same conditions. A Leica DM2500 microscope and a Leica DFC 420C camera were used for slide observation and photography, and all image processing was done using ImageJ, the software developed and freely distributed by the US National Institutes of Health (Bethesda. Md., USA).

Example 10. Real-Time Quantitative PCR Used in the Invention (Examples 6 and 7)

[0181] Total RNA was isolated from striata (3NP model) or spinal cord (EAE model) using RNeasy Lipid Tissue Mini Kit (Qiagen, GmbH). The total amount of RNA extracted was quantitated by spectrometry at 260 nm and its purity from the ratio between the absorbance values at 260 and 280 nm. Genomic DNA was removed to eliminate DNA contamination. Single-stranded complementary DNA was synthesized from up to 1 μg of total RNA (pool from at least 3 animals per group) using iScript™ cDNA Synthesis Kit (Bio-Rad, Hercules, Calif., USA). The reaction mixture was kept frozen at −20° C. until enzymatic amplification. The iQ™ SYBR Green Supermix (Bio-Rad) was used to quantify mRNA levels for COX-2, TNF-α, IL-6, IL-17, IL-1β, IFN-γ, CCL-2 or iNOS depending on disease's model. Real-time PCR was performed using a CFX96 Real-Time PCR Detection System (Bio-Rad). The GAPDH housekeeping gene was used to standardize the mRNA expression levels in every sample. Expression levels were calculated using the 2.sub.−ΔΔCt method. Sequences of oligonucleotide primers are given in Table 2.

TABLE-US-00002 TABLE 2 List of mouse primer sequences used in quantitative Polymerase Chain Reaction. Genes Forward Reverse IL-6 5′-GAACAACGATGATGCACTTGC-3′ 5′-TCCAGGTAGCTATGGTACTCC-3′ IL-1β 5′-CTCCACCTCAATGGACAGAA-3′ 5′-GCCGTCTTTCATTACACAGG-3′ Ccl2 5′-GGGCCTGCTGTTCACAGTT-3′ 5′-CCAGCCTACTCATTGGGAT-3′ IFNγ 5′-CTCAAGTGGCATAGATGTGGAAG-3′ 5′-GCTGGACCTGTGGGTTGTTGA-3′ IL-17 5′-CCTCAGACTACCTCAACCGTTC-3′ 5′-TTCATGTGGTGGTCCAGCTTTC-3′ iNOS 5′-AACGGAGAACGTTGGATTTG-3′ 5′-CAGCACAAGGGGTTTTCTTC-3′ COX-2 5′-TGAGCAACTATTCCAAACCAGC-3 5′-GCACGTAGTCTTCGATCACTATC-3 TNFα 5′-AGAGGCACTCCCCCAAAAGA-3′ 5′-CGATCACCCCGAAGTTCCCATT-3′ GAPDH 5′-TGGCAAAGTGGAGATTGTTGCC-3′ 5′-AAGATGGTGATGGGCTTCCCG-3′

[0182] The present results substantiate the therapeutic use of the compounds described in the present inventions, particularly compounds II, III, IV, V and XII in neurodegenerative diseases and traumatic brain disorders where neuroinflammation and neurotoxicity play a significant role. In addition the compounds of the invention are particularly suitable as PPARg agonists particularly for treating inflammatory diseases (see Table 1 of the state of the art), metabolic diseases and type II diabetes.

REFERENCES

[0183] Ahmadian M, Suh J M, Hah N, Liddle C, Atkins A R, Downes M, Evans RM. PPARγ signaling and metabolism: the good, the bad and the future. 2013. Nat Med. 19:557-66 [0184] Barish G D, Narkar V A, Evans R M. 2006. PPARδ: a dagger in the heart of the metabolic syndrome. J Clin Invest. 116:590-597 [0185] Bernardo, A., Minghetti, L., 2008. Regulation of Glial Cell Functions by PPAR-gamma natural and Synthetic Agonists. PPAR Res. 2008, 864140. [0186] Bolton J L, Trush M A, Penning T M, Dryhurst G, Monks TJ. Role of quinones in toxicology. 2000. Chem Res Toxicol. 3:135-60. [0187] Burstein S. 2005. PPAR-gamma: a nuclear receptor with affinity for cannabinoids. Life Sci. 77:1674-84. [0188] Ciudin A, Hernandez C, Simó R. 2012. Update on cardiovascular safety of PPARgamma agonists and relevance to medicinal chemistry and clinical pharmacology. Curr Top Med Chem. 12: 585-604. [0189] Doshi L S, Brahma M K, Bahirat U A, Dixit A V, Nemmani K V. 2012. Discovery and development of selective PPAR gamma modulators as safe and effective antidiabetic agents. Expert Opin Investig Drugs. 19:489-512. [0190] Fievet C, Fruchart J C, Staels B, 2006. PPAR alpha and PPAR gamma dual agonists for the treatment of type2 diabetes and the metabolicsyndrome. Curr. Opin. Pharmacol. 6: 606-614. [0191] Gelman, L., Feige, J. N., Desvergne, B., 2007. Molecular basis of selective PPARgamma modulation for the treatment of type 2 diabetes. Biochim. Biophys. Acta 1771: 1094-1107. [0192] Granja A G, Carrillo-Salinas F, Pagani A, Gómez-Cañas M, Negri R, Navarrete C, Mecha M, Mestre L, Fiebich B L, Cantarero I, Calzado M A, Bellido M L, Fernandez-Ruiz J, Appendino G, Guaza C, Muñoz E. 2012. A cannabigerol quinone alleviates neuroinflammation in a chronic model of multiple sclerosis. J Neuroimmune Pharmacol. 4:1002-16 [0193] Kostadinova R, Wahli W, Michalik L. 2005. PPARs in diseases: control mechanisms of inflammation. Curr Med Chem. 12: 2995-3009 [0194] Lehmann J M, Moore L B, Smith-Oliver T A, Wilkison W O, Willson T M, Kliewer S A. 1995. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 270:12953-6. [0195] Liu J, Li H, Burstein S H, Zurier R B, Chen J D, 2003. Activation and binding of peroxisome proliferator-activated receptor gamma by synthetic cannabinoid ajulemic acid. Mol. Pharmacol. 63: 983-992. [0196] Monks T J, Jones D C. 2002. The metabolism and toxicity of quinones, quinonimines, quinone methides, and quinone-thioethers. Curr Drug Metab. 4:425-38. [0197] Na H K, Surh Y J. 2013. Oncogenic potential of Nrf2 and its principal target protein heme oxygenase-1. Free Radic Biol Med. 67:353-365 [0198] O'Sullivan S E. 2007. Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol. 152:576-82. [0199] Poulsen L, Siersbaek M, Mandrup S. PPARs: fatty acid sensors controlling metabolism. 2012. Semin Cell Dev Biol. 23:631-639. [0200] Rosen E D, MacDougald O A. 2006. Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol. 7:885-96. [0201] Singh, J. Petter, R. C. Baillie, T. A. Whitty, A. 2011. The resurgence of covalent drugs. Nat. Rev. Drug Discov. 10: 307-17 [0202] Solis L M, Behrens C, Dong W, Suraokar M, Ozburn N C, Moran C A, Corvalan A H, Biswal S, Swisher S G, Bekele B N, Minna J D, Stewart D J, Wistuba I I. 2010. Nrf2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features. Clin Cancer Res. 16:3743-53 [0203] M. B. Sporn, K. T. Liby. 2012. NRF2 and cancer: the good, the bad and the importance of context. Nat. Rev. Cancer. 12: 564-57 [0204] Stienstra R, Duval C, Muller M, Kersten S, 2007. PPARs, obesity, and inflammation. PPAR Res. 95974. [0205] Sun Y, Bennett A. 2007. Cannabinoids: A New Group of Agonists of PPARs. PPAR Res. 23513. [0206] Széles, L., Töröcsik, D., Nagy, L., 2007. PPARgamma in immunity and inflammation: cell types and diseases. Biochim. Biophys. Acta 1771: 1014-1030. [0207] Tachibana K, Yamasaki D, Ishimoto K, Doi T. 2008. The Role of PPARs in Cancer. PPAR Res. 102737. [0208] Tontonoz P, Spiegelman B M. 2008. Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem. 77: 289-312. [0209] Vanden Berghe W, Vermeulen L, Delerive P, DeBosscher K Staels B, Haegeman G. 2003. A paradigm for gene regulation: inflammation, NF-kB and PPAR. Adv. Exp. Med. Biol. 544:181-196. [0210] Vivacell Biotechnology España, S. L. 2011. Cannabinoid quinone derivatives. WO 2011117429 A1.