TERPINEOL AND PREPARATION METHOD AND APPLICATION THEREOF

Abstract

The present invention discloses a terpinenol compound as well as its preparation method and application. The structure of such terpinenol compound is as shown in Formula (I) or (II). In Formula (I), R is independently selected from C.sub.12-C.sub.16 alkyl, NR.sup.1R.sup.2, SR.sup.3 or OR.sup.4; R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from C.sub.1-C.sub.6 alkyl or NO.sub.2; the C.sub.1-C.sub.6 alkyl can be substituted by OH; Alternatively, the R.sup.1 and R.sup.2 form a five-member ring or six-member ring in together with N used to link up them; the five-member or six-member ring may contain one O or CO. As indicated by results of activity test, such terpinenol compound has satisfactory effect in prevention of asthma, inflammation and pulmonary artery hypertension, which also has high pharmaceutical significance.

##STR00001##

Claims

1-9. (canceled)

10. A terpinenol compound, characterized in that its structure is as shown in Formula (I): ##STR00045## wherein R is one of the following functional groups: ##STR00046## and wherein, refers to link location.

11. The method for preparation of terpinenol compound according to claim 10, characterized in that it comprises the following steps: (1) obtaining the esterified intermediate through reaction between the -terpinenol and bromoacetyl bromide in the dichloromethane under the action of pyridine; (2) obtaining the terpinenol compound through substitution reaction between the esterified intermediate as obtained in Step (1) and nucleophilic reagent in the acetonitrile under the action of inorganic base; wherein the nucleophilic reagent is in one of the following structural groups: ##STR00047##

12. The method of using the terpinenol compound according to claim 10 in the pharmaceutical field, characterized in that the terpinenol compound is used to prepare anti-asthma drug; wherein the anti-asthma drug is used for bronchial dilation.

13. The method of using the terpinenol compound according to claim 10 in the pharmaceutical field, characterized in that the terpinenol compound is used to prepare anti-inflammatory drug.

14. The method of using the terpinenol compound according to claim 10 in the pharmaceutical field, characterized in that the terpinenol compound is used to prepare the drug used for therapy or alleviation of pulmonary hypertension.

Description

SPECIFIC EMBODIMENTS OF THE INVENTION

Embodiment 1

[0034] -terpinenol (4 mmol) taken by precise weighing was dissolved in 10 ml dichloromethane, and (6 mmol) pyridine was added, then myristoyl chloride (6 mmol) was added subjecting to ice bathing for reaction for 8 hours at room temperature to obtain the final product 2a (3.74 mmol, yield rate of 93.5%). Product structure is as follows:

##STR00005##

Embodiment 2

[0035] -terpinenol (4 mmol) taken by precise weighing was dissolved in 10 ml dichloromethane, and (6 mmol) pyridine was added, then Octadecanoyl chloride (6 mmol) was added subjecting to ice bathing for reaction for 8 hours at room temperature to obtain the final product 2b (3.86 mmol, yield rate of 96.5%).

##STR00006##

Embodiment 3-12

[0036] (1) 1.85 g (10 mmol) -terpinenol was taken by weighing, and was put into 50 ml round-bottom flask; 30 ml dichloromethane and 1.91 ml (20 mmol) pyridine were further added, then 2.09 ml (20 mmol) bromoacetyl bromide was added subjecting to ice bathing for reaction at room temperature for 7 hours to obtain intermediate 3 (5.9 mmol, yield rate of 48.2%).

[0037] Reaction equation is stated as follows:

##STR00007##

[0038] (2) Intermediate 3 (274 mg, 1 mmol) was dissolved in 10 mL acetonitrile, and potassium carbonate (276.4 mg, 2 mmol) and intermediate 4 (2 mmol) were added at room temperature to obtain product 5; structure and yield rate of intermediate 4 were as shown in Table 1.

TABLE-US-00001 TABLE 1 Substrate in Embodiment 3-12 and Results Embodiment Intermediate 3 Yield Yield Coefficient 3 [00008] 0.765 mmol 76.5% 4 [00009] 0.842 mmol 84.2% 5 [00010] 0.748 mmol 74.8% 6 [00011] 0.914 mmol 91.4% 7 [00012] 0.839 mmol 83.9% 8 [00013] 0.812 mmol 81.2% 9 [00014] 0.828 mmol 82.8% 10 [00015] 0.87 mmol 87% 11 [00016] 0.873 mmol 87.3% 12 [00017] 0.635 mmol 63.5%

Embodiment 13

[0039] -terpinenol (400 mg) was added into 10 mL methanol, and Pd/C (40 mg) was further added for agitation in the hydrogen environment for 8 hours. Colorless oily substance 6 (38 mg, 93.5%) was obtained through separation. Reaction equation is as follows:

##STR00018##

[0040] Data on structural characteristics of some compounds is as follows:

##STR00019##

[0041] 1H NMR (500 MHz, CDCl.sub.3): 5.37 (s, 1H), 2.25-2.16 (m, 2H), 2.07-1.90 (m, 4H), 1.89-1.76 (m, 2H), 1.64 (s, 3H), 1.61-1.52 (m, 2H), 1.43 (s, 3H), 1.41 (s, 3H), 1.25 (s, 21H), 0.91-0.82 (m, 3H).

##STR00020##

[0042] 1H NMR (500 MHz, CDCl.sub.3): 5.36 (dd, J=8.3, 6.9 Hz, 1H), 2.20 (t, J=7.5 Hz, 2H), 2.08-1.91 (m, 4H), 1.88-1.75 (m, 2H), 1.64 (s, 3H), 1.58-1.53 (m, 2H), 1.44 (s, 3H), 1.41 (s, 3H), 1.34-1.19 (m, 29H), 0.88 (t, J=7.0 Hz, 3H).

##STR00021##

[0043] 1H NMR (500 MHz, CDCl.sub.3): 5.38 (d, J=2.0 Hz, 1H), 3.62-3.58 (m, 2H), 3.24 (s, 2H), 2.73-2.69 (m, 2H), 2.44 (s, 3H), 2.13-1.93 (m, 4H), 1.89-1.76 (m, 2H), 1.66 (s, 3H), 1.49 (s, 3H), 1.46 (s, 3H), 1.32 (tt, J=10.4, 5.3 Hz, 1H).

##STR00022##

[0044] 1H NMR (500 MHz, CDCl.sub.3): 5.38 (dd, J=3.1, 1.7 Hz, 1H), 3.78 (dd, J=8.3, 3.6 Hz, 4H), 3.13 (d, J=1.3 Hz, 2H), 2.64-2.56 (m, 4H), 2.12-1.92 (m, 4H), 1.89-1.76 (m, 2H), 1.66 (s, 3H), 1.48 (s, 3H), 1.45 (s, 3H), 1.36-1.26 (m, 1H).

##STR00023##

[0045] 1H NMR (500 MHz, CDCl.sub.3): 5.36 (s, 1H), 3.75 (s, 2H), 2.13-1.94 (m, 4H), 1.92-1.76 (m, 2H), 1.64 (s, 3H), 1.45 (s, 3H), 1.36 (s, 3H), 1.33 (qd, J=12.3, 5.6 Hz, 1H).

##STR00024##

[0046] 1H NMR (500 MHz, CDCl.sub.3): 5.38 (dd, J=2.9, 1.5 Hz, 1H), 3.23 (s, 2H), 2.67 (q, J=7.3 Hz, 4H), 2.10-1.93 (m, 4H), 1.88-1.76 (m, 2H), 1.65 (s, 3H), 1.47 (s, 3H), 1.44 (s, 3H), 1.35-1.25 (m, 1H), 1.08 (td, J=7.2, 4.1 Hz, 6H).

##STR00025##

[0047] 1H NMR (500 MHz, CDCl.sub.3): 5.37-5.34 (m, 1H), 3.75 (t, J=5.6 Hz, 2H), 3.18 (s, 2H), 2.81 (t, J=5.5 Hz, 2H), 2.09-1.94 (m, 4H), 1.86-1.76 (m, 2H), 1.63 (s, 3H), 1.45 (s, 3H), 1.43 (s, 3H), 1.35-1.25 (m, 1H);

##STR00026##

[0048] 1H NMR (500 MHz, CDCl.sub.3): 5.33 (t, J=8.9 Hz, 1H), 3.24 (s, 2H), 2.87 (t, J=6.1 Hz, 4H), 2.48 (t, J=6.1 Hz, 4H), 2.09-1.89 (m, 4H), 1.86-1.73 (m, 2H), 1.63 (s, 3H), 1.46 (s, 3H), 1.43 (s, 3H), 1.34-1.25 (m, 1H);

##STR00027##

[0049] 1H NMR (500 MHz, CDCl.sub.3): 5.35 (d, J=2.1 Hz, 1H), 3.73-3.66 (m, 1H), 3.11 (s, 2H), 2.81 (td, J=8.9, 3.8 Hz, 2H), 2.38-2.30 (m, 2H), 2.10-1.88 (m, 4H), 1.85-1.74 (m, 2H), 1.68-1.58 (m, 6H), 1.45 (s, 3H), 1.42 (s, 3H), 1.33-1.26 (m, 1H);

##STR00028##

[0050] 1H NMR (500 MHz, CDCl.sub.3): 5.35 (s, 1H), 3.81 (s, 1H), 3.71 (d, J=11.0 Hz, 1H), 3.60 3.46 (m, 1H), 3.27-3.15 (m, 2H), 2.85-2.77 (m, 1H), 2.68 (dd, J=14.0, 8.4 Hz, 1H), 2.09 1.90 (m, 4H), 1.86-1.75 (m, 2H), 1.63 (s, 3H), 1.45 (s, 3H), 1.43 (s, 3H), 1.33-1.25 (m, 1H);

##STR00029##

[0051] 1H NMR (500 MHz, CDCl.sub.3): 5.42-5.33 (m, 1H), 3.06 (d, J=1.2 Hz, 2H), 2.55-2.43 (m, 4H), 2.10-1.89 (m, 4H), 1.86-1.71 (m, 2H), 1.62 (s, 3H), 1.59 (dd, J=11.3, 5.7 Hz, 4H), 1.43 (d, J=5.8 Hz, 3H), 1.42-1.37 (m, 5H), 1.27 (ddd, J=24.4, 12.2, 5.7 Hz, 1H);

##STR00030##

[0052] 1H NMR (500 MHz, CDCl.sub.3): 5.33 (s, 1H), 3.56-3.54 (m, 1H), 3.11 (s, 2H), 2.81 (td, J=8.9, 3.8 Hz, 2H), 2.38-2.30 (m, 2H), 2.10-1.88 (m, 4H), 1.85-1.74 (m, 2H), 1.68-1.58 (m, 6H), 1.45 (s, 3H), 1.42 (s, 3H), 1.33-1.26 (m, 1H);

##STR00031##

[0053] 1H NMR (500 MHz, CDCl.sub.3): 1.75 (ddd, J=16.6, 10.2, 4.5 Hz, 4H), 1.43-1.42 (m, 1H), 1.29-1.17 (m, 2H), 1.13 (s, 6H), 1.07-0.96 (m, 2H), 0.89 (dd, J=12.0, 2.9 Hz, 1H), 0.85 (d, J=6.5 Hz, 3H).

Bronchiectasis and Anti-Inflammation Experiment

[0054] Method: Isolated tracheal strip was fabricated, and was placed in the in-vitro tracheal experiment device; 100 L acetylcholine chloride was added following tension adjustment and balancing to make the trachea extract, and the tension of trachea was increased. Once the tension was increased to the maximum value, and became balanced, corresponding trial drug was fed to inhibit extraction of the trachea; isometric muscle tension variation curve was recorded, and diastolic rate of smooth muscle was calculated. Diastolic rate=(tension after radiographytension after dosing)/(tension after radiography)*100%.

[0055] Rat asthma model was established, and proceeded with blunt dissection of trachea following the last feeding of drug for trachea alveolar washing. Bronchi alveolar lavage fluid (BALF) was collected, and total number of nucleated cells were counted. Results were as shown in Table 2.

TABLE-US-00002 TABLE 2 Relaxation rate % Inflammatory Group 0.75 mmol/L 1.25 mmol/L cell ( 10.sup.8/L) Blank R 7.73 4.81 13.59 9.14 85.50 18.70.sup.## group Model 182.50 24.52.sup. group Amino- 43.67 10.20.sup. 56.70 9.26.sup. phylline A.sup.a H 14.62 4.24* * 21.57 7.04* * .sup. B.sup.a CH.sub.3 34.35 14.72 47.72 15.94 C.sup.a CH.sub.2CH.sub.3 18.18 6.26* * 23.22 4.39* * .sup. N.sup.a CH.sub.2CH.sub.2CH.sub.3 21.20 9.24* * 25.47 8.69* * ISO.sup.a [00032] 19.88 8.82* * 22.79 8.27* * .sup. TR.sup.a [00033] 25.49 6.53* 28.02 8.83* * -T 28.40 16.13.sup. 38.35 13.62.sup. 113.00 21.27.sup.# A (CH.sub.2).sub.12CH.sub.3 17.56 2.89* *.sup. 16.55 14.47* * 139.50 31.24.sup. B (CH.sub.2).sub.16CH.sub.3 15.4 9.83* * 10.63 13.77* * 134.50 25.27.sup. C [00034] 50.24 7.30.sup. 76.85 7.70* *.sup. 77.50 68.81.sup.## D [00035] 36.60 13.79.sup. 59.35 14.66.sup. 110.5 16.21.sup.## E [00036] 17.13 6.98* * 10.84 4.46* * 139.50 20.71.sup. F [00037] 42.33 10.45.sup. 46.71 3.56* .sup. 101.50 14.68.sup.# G [00038] 48.29 9.36.sup. 81.09 10.15* *.sup. 76.00 18.15.sup.## H [00039] 20.85 7.55* *.sup. 43.81 10.16*.sup. 123.00 17.23.sup.# J [00040] 35.17 13.87.sup. 71.53 15.45.sup. 99.50 21.23.sup.## K [00041] 34.84 19.74 65.29 13.43.sup. 104.50 13.25.sup.## L [00042] 42.49 6.14.sup. 52.21 6.98.sup. 110.50 16.18.sup.## M [00043] 27.74 2.08*.sup. 61.01 5.07.sup. 97.50 13.11.sup.## N [00044] 27.16 14.10* 41.28 13.17*.sup. 140.00 26.21.sup. With regard to several compounds in preferred embodiments of .sup.aCN 103922927 A, formula for computation of diastolic rate has been improved to some extent; meanwhile, as there exists certain difference to testing results of different batches, data on diastolic rate is also varied. refers to substitution position; compound N is product structure. **refers to P<0.01 as compared with -terpinenol group; *refer to P<0.05 as compared with -terpinenol group; .sup.refers to P<0.01 as compared with blank group; .sup.refers to P<0.05 as compared with blank group. As compared with model group, .sup.#P<0.05, .sup.##P<0.01

[0056] Various compound groups can increase the diastolic rate of trachea smooth muscle, and inhibit inflammation under different dosage. On this account, it can be used to cure inflammation incurred by asthma, chronic obstructive pulmonary diseases and various other diseases, such as arthritis, rheumatoid arthritis, bronchitis, allergic rhinitis and allergic dermatitis.

Impact on Monocrotaline Incurred Pulmonary Hypertension to Rats

[0057] Method: Rat PAH model was established, and normal saline was fed to contrast group with volume equivalent to that for injection. Drug for interference was fed 2 days after radiography. 200 mg/Kg per compound was fed on daily basis. Normal saline was used with equivalent volume for lavage to the contrast group and model group respectively. Right ventricular systolic pressure of rat was measured by means of Right cardiac catheterization at anesthesia state on the 30th day. Results were as shown in Table 3.

TABLE-US-00003 TABLE 3 Right Ventricular Systolic Pressure of Different Groups (x s) n RVSP (mmHg) Normal group 10 .sup.21.08 2.13.sup.# Model group 8 43.78 2.14.sup.# -terpinenol group 8 33.03 2.22.sup. A 8 35.07 2.81 B 10 36.08 2.01 C 8 .sup.22.33 1.03.sup.## D 8 32.04 1.12.sup. E 8 35.53 3.02 F 8 .sup.23.35 1.04.sup.## G 8 .sup.21.08 1.31.sup.# H 8 30.33 2.03.sup. J 8 27.06 1.17.sup. K 8 31.13 2.03.sup. L 8 .sup.25.36 1.17.sup.# M 8 33.36 2.05.sup. N 8 32.56 2.82.sup.

[0058] As compared with model group, P<0.05, P<0.01; as compared with -terpinenol group #P<0.05, ##P<0.01.

[0059] As indicated by testing results, various compounds can provide certain protection for monocrotaline incurred rat pulmonary artery hypertension. Furthermore, they can improve hemodynamic indicators, reduce right ventricular systolic pressure, alleviate right ventricular load, reduce right heart hypertrophy indicators, and alleviate pulmonary vascular remodeling.