New Kaurane analogues, their preparation and therapeutically uses

Abstract

Synthesis of novel kaurane analogues , their preparation, and their uses in cardiac protection against ischemia, hypertrophy and chemotherapy induced cardiomyopathy as well as cerebral ischemia.

##STR00001## Wherein R.sup.1: formyl, carboxylic acid (carboxyl), salt of carboxylic acid R.sup.2: oxygen, C-16 ketone to hydroxyl

Claims

1. kuarane analogue compounds of formula 1 of the following structures and its pharmaceutically acceptable salts. ##STR00008## Wherein R.sup.1: formyl, carboxylic acid (carboxyl), salt of carboxylic acid R.sup.2: oxygen, C-16 ketone to hydroxyl

2. A process producing compounds of claim 1.

3. A method of use compounds of claim 1 in manufactures of medicaments for treatment of cardiac diseases.

4. The said cardiac diseases in claim 3 are cardiac ischemia, cardiac hypertrophy, cardiomyopathy and heart failure.

5. The said cardiac diseases in claim 3 are cardiac toxicities induced by chemo-therapeutic medicine or other medicine.

6. The said chemo-therapeutic medicine said in claim 5 are anthracyclines including doxorubicin, epirubicin, daunorubicin and aclarubicin, 5, The said cardiac diseases in claim 3 is cardiac arrhythmia.

6. A method of use compounds of claim 1 in manufactures of medicaments for treatment of cerebral ischemia diseases.

7. The said of cerebral ischemia diseases in claim 6 are cerebral stroke and ischemic neuro-degenerative diseases.

8. A method of claim 3,wherein, the said medicaments are pharmaceutical preparations including: solid dose forms, gel, suppository, liquid or lyophilizes powder for injections, ointment or patches for topic use and aerosol or dry powders for lung inhalation or nasal.

9. The method of claim 1, wherein, the said pharmaceutical acceptable salts are hydrochloride, hydrobromide, sulphate, hydrogen sulphate, dihydrogen phosphate, methanesulphonate, bromide, methyl sulphate, acetate, oxalate, maleate, fumarate, succinate, 2-naphthalene-sulphonate, glyconate, gluconate, citrate, tartaric, lactic, pyruvic isethionate, benzenesulphonate or para-toluenesulphonate.

Description

DETAILS OF INVENTION

[0007] The object of the invention is to provide a simple synthetic method to obtain novel kauranes compounds. It is also an object of the invention to exhibit kaurene compounds in protecting activity against cardiac and cerebral ischemia, hypertrophy and cardiomyopathy and chemotherapy induced cardiac toxicity.

[0008] According to the invention, the said kaurene compounds have a general structure as in formula (I):

##STR00002## [0009] Wherein [0010] R.sup.1: formyl, carboxylic acid, salt of carboxylic acid [0011] R.sup.2: C-16 ketone to hydroxyl

[0012] Synthesized novel analogues of kaurane, modifications at C-15 and C-16 positions resulted a potential application. All the synthesized new analogues of kauranes have shown very good protective activity against drugs induced cardiotoxicity.

##STR00003##

Reagents and conditions: (i) HCHO, NaOH, EtOH, 65 C; (ii) NaOCl, NaClO.sub.2, TEMPO, KBr, ACN, 10 C; (iii) NaOCl, AcOH, rt; (iv) NaOCl, NaClO.sub.2, TEMPO, KBr, ACN, 10 C.

[0013] Pharmacological Activity

[0014] This invention disclosed that among the synthesized new kaurane analogues, compounds 1 and 2 have shown maximum protective activity against Doxorubicin-induced cardiotoxicity. Further, we have showed that the synthesized compounds (1-4) co-treatment prevented Doxorubicin-induced cardiac dysfunctions in vivo.

TABLE-US-00001 TABLE 1 The LC.sub.50 of DOX after co-treated with compounds of formula 1 95% Confidence Group LC.sub.50/(μM) interval/(μM) DOX 51.56 42.49-62.58 DOX + 1 66.62 58.04-76.46 DOX + 2 92.61  72.27-118.70 DOX + 3 74.83 60.38-92.73 DOX + 4 83.04 76.91-89.67

[0015] This invention disclosed that in cardiac toxicity animal induced by other drugs used for chemotherapy, such as anthracyclines, including, epirubicin, daunorubicin and aclarubicin, treatments of compound 1 and 2 showed Signiant beneficial effects in term of function and pathology is a widely used chemotherapy medicine with cardiotoxicity.

[0016] This invention also disclosed that in cardiac ischemia animal model by coronary ligation, compound 1 and compound 2 significantly increased the cardiac contractility and reduced the area of infraction and increased number of micro-blood vessels in comparison of control. In addition, compound 1 and 2 also reduced the occurrence of arrhythmia induced by acute ischemia. This invention disclosed that compound 1 and 2 can increased the function of failing heart due to acute coronary ligation.

[0017] Furthermore, in an embodiment of this invention, a chronic cardiac hypertrophy and heart failure animal was induced by TAC (Thoracic aorta constriction) . The animal was treated with compound 1 and 2 for consecutive 4 weeks after the surgery. The cardiac contractility was significantly enhanced in treated group in comparing of control animals. In histo- pathology, there were significant reduction of size of cardiomyocytes, reduced number of myofibroblasts, reduced interstitial collagen deposition in treatment animals in comparing to control.

[0018] In other embodiment, this invention disclosed that in a drug induced diabetes animal model, cardiomyopathy was developed after 4 weeks. However, the cardiac inflammatory changes were diminished after treatment of compound 1 and 2 for 2 weeks.

[0019] This invention disclosed that compound 1 and 2 can be used for treatment of ischemic heart diseases, heart failure, hypertrophy cardiac remolding and cardiomyopathy and arrhythmia.

[0020] This invention disclosed that in a cerebral ischemia animal model, treatments of compound 1 and 2 significantly reduced the area of infraction and improved the movement and behavers in comparison of control.

[0021] This invention disclosed that other compounds of formula 1 also showed similar beneficial effects as noted above.

EXAMPLES

Example 1 ,

[0022] Synthesis of compounds 1 and 2

[0023] To a stirred solution of compound B (500 mg, 1.42 mmol) in acetonitrile (25 mL), added NaClO.sub.2 (1.42 mmol), KBr (30 mol%) and NaOCl (1.42 mmol) at 10° C. Finally charged TEMPO (10 mol%) and allowed to stir the reaction mixture for 1 h. Monitored the reaction progress using thin layer chromatography. Upon completion added water (15 mL) and adjusted the pH of the reaction medium to neutral using dilute HCl(0.01M). Extracted the products in to organic layer (ethylacetate), dried and removed the solvent by distillation under vacuum. The crude products (both acid and aldehyde derivatives) were purified by column chromatography (silica gel-100-200 mesh) eluted with ethylacetate/n-hexane.

[0024] Synthesis of compound 3

[0025] Charged NaOCl (1.14 mmol) in to a stirring solution of compound B (400 mg, 1.14 mmol) in acetic acid (7 mL) at room temperature. Monitored the reaction progress using thin layer chromatography. Upon completion, quenched the reaction by adding water. Extracted the product in to organic layer (ethylacetate), dried and removed the solvent by rotary evaporation under vacuum. The crude product was purified by column chromatography (silica gel-100-200 mesh) eluted with ethylacetate/n-hexane.

[0026] Synthesis of compound 4

[0027] To a stirred solution of compound 3 (300 mg, 0.86 mmol)in acetonitrile (10 mL), added NaClO.sub.2 (0.86 mmol), KBr (30 mol%) and NaOCl (0.86 mmol) at 10° C. Finally charged TEMPO (10 mol%) and allowed to stir the reaction mixture for 1 h. Monitored the reaction progress using thin layer chromatography. Upon completion added water (15 mL) and adjusted the pH of the reaction medium to neutral using dilute HCl (0.01 M). Extracted the products in to organic layer (ethylacetate), dried in sodium sulphate and removed the solvent by distillation under vacuum. The crude products (both acid and aldehyde derivatives) were purified by column chromatography (silica gel-100-200 mesh) eluted with ethylacetate/n-hexane.

Examples 2

[0028] Structure analysis

[0029] (4R, 4aS, 7S, 8R, 9S, 11aS, 11lbS)-8-hydroxy-4, 9, 11b-trimethyltetradecahydro-6a, 9-methanocyclohepta[a]naphthalene-4,7-dicarboxylic acid (1)

##STR00004##

[0030] Yield: 312 mg, 60%; .sup.1H NMR δ .sub.H (400 MHz, MeOD) 4.11 (1 H, d, J5.0), 2.90 (1 H, d, J3.8), 2.08 (2 H, dd, J21.6, 14.5), 1.92 (1 H, dd, J27.7, 13.9), 1.83-1.55 (7 H, m), 1.39 (1 H, d, J14.2), 1.29 (1 H, s), 1.24-1.19 (1 H, m), 1.17 (3 H, s), 1.13-1.04 (2 H, m), 1.02 (1 H, d, J4.1), 0.99 (3 H, s), 0.96 (1 H, s), 0.93 (3 H, s), 0.89 (1 H, d, J4.3); .sup.13C NMR δ .sub.c (100 MHz, MeOD) 181.63, 179.73, 84.33, 58.88, 58.45, 57.00, 55.33, 46.43, 44.59, 42.22, 40.94, 39.45, 39.17, 37.74, 34.22, 29.55, 25.16, 22.70, 20.65, 20.07, 13.25; HRMS (ESI) exact calculated mass for [M-1] (C.sub.21H.sub.32O.sub.5) requires m/z 363.2249, found m/z 363.2208.

[0031] (4R, 4aS, 7S, 8R, 9S, 11aS, 11bS)-7-formyl-8-hydroxy-4, 9, llb-trimethyltetradecahydro-6a, 9-methanocyclohepta[a]naphthalene-4-carboxylic acid (2)

##STR00005##

[0032] Yield: 149mg, 60%; .sup.1H NMR δ .sub.H (400 MHz, CDCl.sub.3) 9.93 (1 H, d, J2.6), 4.23 (1 H, d, J4.8), 2.93-2.86 (1 H, m), 2.15 (1 H, d, J 13.4), 1.94 (1 H, dt, J 13.9, 3.6), 1.80 (4 H, dd, J 15.0, 12.1), 1.43-1.35 (2 H, m), 1.23 (4 H, d, J2.6), 1.22(1 H, s), 1.18(1 H, s), 1.15(1 H, d, J2.8), 1.05 (3 H, dd, J13.0, 4.3), 0.98 (3 H, s), 0.96 (3 H, s), 0.93 (1 H, d, J4.2), 0.90 (1 H, d, J4.3), 0.88 - 0.84 (1 H, m); .sup.13C NMR δ .sub.c (100 MHz, CDCl.sub.3) 204.37, 183.82, 78.52, 61.92, 57.39, 56.86, 54.02, 46.63, 43.71, 41.34, 39.52, 38.68, 37.82, 35.91, 33.13, 28.88, 24.69, 21.65, 19.75, 18.79, 13.13; HRMS (ESI) exact calculated mass for [M-1] (C.sub.21H.sub.32O.sub.4) requires m/z 347.2300, found m/z 363.2331.

[0033] (4R, 4aS, 7R, 9S, 11aS, 11bS)-7-(hydroxymethyl)-4, 9, 11b-trimethyl-8-oxotetradecahydro-6a, 9-methanocyclohepta[a]naphthalene-4-carboxylic acid (3)

##STR00006##

[0034] Yield: 354 mg, 89%; .sup.1H NMR δ .sub.H (400 MHz, CDC1.sub.3) 3.92 (1 H, dd, 10.7, 5.4), 3.68 (1 H, dd, J10.5, 9.1), 2.56-2.50 (1 H, m), 2.18 (1 H, d, J 13.4), 1.89(1 H, dd, J8.7, 4.7), 1.85-1.78 (2 H, m), 1.77-1.69 (3 H, m), 1.67-1.61 (1 H, m), 1.44 (2 H, dd, J12.8, 5.5), 1.36-1.29 (2 H, m), 1.26 (3 H, s), 1.23-1.16 (3 H, m), 1.05 (1 H, dd, J 13.5, 4.2), 0.99 (3 H, s), 0.98 -0.87 (2 H, m), 0.84 (3 H, s); .sup.13C NMR δ .sub.c (100 MHz, CDC1.sub.3) 226.46, 183.44, 60.52, 57.26, 57.00, 53.04, 52.51, 48.66, 43.74, 40.72, 39.78, 38.59, 37.82, 37.19, 35.32, 29.14, 21.67, 19.94, 19.75, 18.94, 13.53; HRMS (ESI) exact calculated mass for [M+Na] (C.sub.21H.sub.32O.sub.4) requires m/z 371.2198, found m/z 371.2131.

[0035] (4R, 4aS, 7S, 9S, 11aS, 11bS)-4, 9, 11b-trimethyl-8-oxotetradecahydro-6a, 9-methanocyclohepta[a]naphthalene-4, 7-dicarboxylic acid (4)

##STR00007##

[0036] Yield: 232 mg, 78%; .sup.1H NMR δ .sub.H (400 MHz, CDC1.sub.3) 9.73 (1 H, d, J25.7), 2.68-2.62 (1 H, m), 2.18 (2 H, dd, J12.0, 2.2), 1.96(1 H, d, J13.6), 1.91-1.81 (2 H, m), 1.80-1.71 (3 H, m), 1.62-1.32(7 H, m), 1.28 (3 H, s), 1.20(1 H, d, J 11.5), 1.14(3 H, d, J6.2), 1.04(1 H, td, J13.6, 4.4), 0.94-0.85 (1 H, m), 0.63 (3 H, s); .sup.13C NMR δ .sub.c (101 MHz, CDC1.sub.3) 209.72 (s), 188.52 (s), 183.69 (s), 79.61 (s), 59.01 (s), 57.61 (s), 52.75 (s), 50.16 (s), 48.99 (s), 48.57 (s), 43.68 (s), 40.32 (s), 38.67 (s), 38.60 (s), 37.49 (s), 29.11 (s), 21.93 (s), 21.28 (s), 20.29 (s), 19.20 (s), 15.77 (s); HRMS (ESI) exact calculated mass for [M-1] (C.sub.21H.sub.30O.sub.4) requires m/z 345.2144, found m/z 345.2154.