JPH02256678A - New morphine derivative - Google Patents

Abstract

NEW MATERIAL:A morphine derivative shown by formula I (R1 is H or lower alkanoyl; R2 is lower alkanoyl; R3 is cyclopropylmethyl or aryl) aH an acid addition salt. EXAMPLE:A compound shown by formula II. USE:A drug useful as an analgesic, having strongly analgesic action, narcotic antagonism, low drug dependence and being expected to have nonnarcotic properties. PREPARATION:As shown in the reaction formula, cyclopropylmorphine shown by formula IV is obtained from a compound shown by formula III by Gates and Motzka method and then reacted with a R2SH by light extension method to give a compound shown by formula I wherein R3 is cyclopropylmethyl group.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to -reduction charge (I) (wherein R1 is a hydrogen atom or a lower alkanoyl group, NR2
represents a lower alkanoyl group, and R3 represents a cyclopropylmethyl group or an allyl group. ) A novel 6β-thiomorphine derivative represented by: - The compound represented by Toriyo (I) has strong analgesic effects, narcotic antagonistic effects, and extremely low drug dependence, making it a powerful analgesic that is expected to be non-narcotic. It is a powerful substance as a medicine.

[Problems to be solved by the conventional technology/invention Comorphine is a compound known as the main component of opium alkaloids, and is widely used as an anesthetic and analgesic. However, it has the problem of easily causing morphine addiction.

Furthermore, naloxone represented by the formula (n), which is known to have a narcotic antagonistic effect like the compound of the present invention, has a weak analgesic effect and is not very suitable as an analgesic. Therefore, it has been desired to develop a drug that has strong analgesic activity, narcotic antagonism, and less drug dependence.

As a result of intensive research aimed at solving these problems, the present inventors discovered that the compound represented by (I) exhibits an analgesic activity five times or more that of morphine, and has a narcotic antagonistic effect. , led to the present invention.

Means for Solving the Problem] That is, the present invention provides a novel 6
The present invention provides β-thiomorphine derivatives.

Among the 6β-thiomorphine derivatives of the present invention, those in which R3 is a cyclopropylmethyl group are derived from normorphine represented by the formula (III), for example, as shown in the formula below.
es and Montzka's method [M, Gates, T.
,A,Montzka;J,Med,Chem,,7,
127. (1964) to obtain cyclopropylmethylnormorphine of formula (V), which was then processed by the Mitsunobu method [0, Mitsunobu:5YnthesiS
t 1981+ 1 by reacting R2SH (R2 is the same as above).

Further, when R3 is an allyl group, for example, normorphine represented by the formula (nl) is reacted with allyl bromide and potassium carbonate in a polar solvent, preferably dimethylformamide to obtain N-allylnormorphine, which is then purified by Mitsunobu. It can be obtained by reacting R2SH (R2 is the same as above) according to the method.

The lower alkanoyl group in R1 and R2 of the compound of the present invention includes those having 2 to 7 carbon atoms, and preferably, for example, an acetyl group, propio(III) (IV) (V) (in the formula R1 and R2 (means the same as in the previous term) Furthermore, the compound represented by -replacement (I) can be converted into an acid addition salt if necessary. The acids in acid addition salts are:
When used for medical purposes, there are no particular limitations as long as the acid is a medically acceptable acid addition acid. Specifically, citric acid,
Organic acids such as fumaric acid, maleic acid, tartaric acid, or hydrochloric acid,
Examples include mineral acids such as hydrobromic acid, nitric acid, and sulfuric acid.

The compounds of the present invention can be used as
As a result of measuring its analgesic activity using a radiant heat stimulation method using a mouse, it was found to have an analgesic activity approximately 5 to 6 times stronger than morphine. Furthermore, while morphine has almost no analgesic activity remaining 3 hours after administration, the compound of the present invention still exhibits significant analgesic activity and is excellent in durability. Furthermore, the compound of the present invention has an excellent analgesic effect via the mono-receptor and an analgesic action at the μ-receptor as a result of studies using electrical stimulation specimens of the marginal wall of isolated guinea pig ileum pieces. It has been shown that it is excellent as a medicine.

[Example code] Next, the present invention will be specifically explained with reference to Examples.

Example 1 6.35 ml of diisopropyl azodicarboxylate was added dropwise to a solution 801 of anhydrous tetrahydrofuran containing 8.48 g of triphenylphosphine at 0° C. under a nitrogen stream, and the mixture was stirred for 30 minutes under water cooling. Then, under water cooling, 3.41 thioacetic acid and Gat
Cyclopropylmethylnormorphine synthesized from normorphine by the method of Es and Montzka5. O
A suspension of g of anhydrous tetrahydrofuran was added dropwise thereto, and the mixture was stirred for 4 hours. Thereafter, tetrahydrofuran was distilled off, and the resulting residue was purified by silica gel column chromatography to obtain 3.9 g of colorless crystals of 6β-acetylthio-N-cyclopropylmethylnormorphine (yield: 66.2%).
and 1.0 g (yield 15.3%) of 3-acetyl=6β-acetylthio-N-cyclopropylmethylnormorphine were obtained. Dissolve 2.0 g of 6β-acetylthio N-cyclopropylmethylnormorphine in tetrahydrofuran,
Hydrogen chloride gas is introduced, tetrahydrofuran is distilled off, and the residue is crystallized from ether, resulting in a melting point of 192-19
1.9 g of colorless crystals of hydrochloride [formula (■)] at 4° C. were obtained.

Light intensity [α co-259.9° (B20, C=0.
297) Elemental analysis value C2□H25NO3S・HCΩ (molecular weight 419.989) CHN Theoretical value (%): B2.92 6.24 3.
34 actual measurement ff1 (%): G2.72 G, 1
8 3.14 Example 2 1.0 g of 6β-acetylthio-N-cyclopropylmethylnormorphine obtained in Example 1 is dissolved by adding 21 ml of acetic anhydride, and the mixture is stirred at room temperature for 1 hour. Thereafter, ether was added and hydrogen chloride gas was introduced to obtain 0.9 g of 3-acetyl-6β-acetylthio-N-cyclopropylmethylnormorphine hydrochloride [formula 2] as colorless crystals. It gradually decomposed at a melting point of 200°C or higher.

20- Light intensity [α co -260.2° (H20NC=0.
327) Elemental analysis value C24H27NO4S@HCΩ (molecular weight 462-007) CHN Theoretical value (%): 62.39 B, 11 3
．． 03 Actual measurement value (%): Ei2.12 Ei,
25 2.87 Also, 3-acetyl- obtained in Example 1
6β-acetylthio-N-cyclopropylmethylnormorphine was converted into a hydrochloride by dissolving it in ether and introducing hydrogen chloride gas, and the same physical properties were also obtained.

Example 3 From 1.4 g of N-allylnormorphine, 3-acetyl-6 was prepared in the same manner as in Example 1 and Example 2.
β-acetylthio-N-allylnormorphine hydrochloride [
Formula (■)] 0.9 g was obtained. The melting point was 207-210°C.

Light intensity [α co -272.8° (H20+C=0.
171) Elemental analysis value C23H25N04S11HCp (molecular weight 485.996) CHN Theoretical value (%): 59.28 5.84 3.
00 Actual value (%): 59.33 6.0?
2.96 Example 4 1.6 g of 6β-a7,000-ruthio N-cyclopropylmethylnormorphine obtained in Example 1 was processed into 50 ml of 0°2N potassium hydroxide-ethanol, and heated for 30 minutes at room temperature under a nitrogen stream. Stir. The reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with chloroform. The extract is dehydrated and concentrated under reduced pressure to obtain 6β-mercapto-N-cyclopropylmethylnormorphine. This product is reacted with 1.4 mj of triethylamine and 0.88 ml of propionyl chloride in chloroform. After 2 hours, the reaction solution was washed with saturated hydrogen carbonate solution, saturated brine, dehydrated, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3% methanol-chloroform) to give 3-propionyl- 1.2 g of 6β-propionylthio-cyclopropylmethylnormorphine was obtained. (Mass spectrometry (m/z): 453 (M)) A hydrochloride [formula (IX)] was obtained by a conventional method.

Melting point = 202-206°C Light intensity [α] -252,88° - (MeOH, C = 0.200) Example 5 Using inbutyl chloride in place of propionyl chloride in Example 4, 3- Isobutyryl-6β
-Inbutyrylthio-cyclopropylmethylnormorphine hydrochloride [formula (X)] was obtained in a yield of 75%. The melting point is 2
The temperature was 10-215°C.

and Hl Light intensity [αco -262.62' (MeOH, C=0.198) Example 6 Analgesic test using radiant heat stimulation method Using 4-week-old mice (Slc: ddY1 male), 7 mice per group, The compound of the present invention and morphine hydrochloride were each subcutaneously injected, and 1 hour later, radiant heat stimulation [A, G, HAYE]
S, M, J, 5HEEHAN, M, B, TYER8;B
rj t, J, Pharmacol, v 9L 11
1-115. The analgesic test was performed by reference L987. That is, when the mouse's tail was irradiated with a strong light beam, the time it took for the mouse to wag its tail was measured, and this was taken as the pain threshold. The results are shown in Figure 1.

Compound (V[) and compound (■) are both 0°03
A dose-dependent analgesic effect was observed within the dose range of ~1.0-g/kg. The effect is 1.0gg for both the same compounds.
/kg was statistically significant.

[: p<O, ot, Dunnett's t-te
On the other hand, morphine hydrochloride used as a control drug showed a significant analgesic effect at doses of 3.2 mg/kg or more.

Example 7 Marginal wall electrical stimulation test of isolated guinea pig ileum piece Koster
Litz and Waterfield's method [H.
KO8TERLITZ, A.

A, WATERFIELD; Annu, Rev.

Pharmacol, 15+ 29-47. (19
[75)], the effects of the compounds were investigated using smooth muscle contraction caused by electrical stimulation (0.1 Hz) of the marginal wall of isolated guinea pig ileum pieces as an index.

The results are shown in Table 1.

The numerical values in Table 1 are based on the method of Arunlakshana and 5chiid [0, ARUNLAKSHANA
,H,0,5CHILD;Brlt,J,Pharma
ccl, t 14, 48-58, (1959), and expressed as the average Hanato standard deviation value of 5 examples of each compound.

Table 1 Morphine hydrochloride 7.32±0.13 8.45±0.13 (1
,03±0.09) Compound (VI @ [01) 8.38±0.08 7.75±0.12 (0,!
13 ±0.09) Compound (■ΦHCI) 9,O1±0.16 7.80±0.13 (0,8
4±o,ti)E,1. Debeer: Fed, Pro.
c,, see LfL412.1959] Table 2 Antipruritic effect of acetic acid writhing method in mice Example 8 Analgesic effect of acetic acid writhing method 5 Mice (S 1 c: ddy, male), 1
Using a group of 7 animals, as a compound of the present invention and a control compound,
Morphine hydrochloride and pentazocine were each subcutaneously administered, and 30 minutes later, 0.6% acetic acid was administered at 0.1 per mouse log.
ml was administered intraperitoneally, and 10 minutes later, the number of writhing was measured for 10 minutes. The ED father's value was displayed second. [Acetic acid rising method is R0Koster+M, Anderson
and

[Brief explanation of drawings]

FIG. 1 shows the results of an analgesic test using the radiant heat stimulation method in mice for the compound of the present invention and morphine hydrochloride. Procedural amendment (method) Engraving of drawings (no changes in content) Fig. 1 Analgesic test using radiant heat stimulation method in mice (average of 7 cases each ±S.E.) Tomiie: p<o. 01 (Dunnett's test) 1990 4
Patent Application No. 329086, dated February 2, 1999, 2, Title of the invention: New Morphine Derivatives 3, Relationship with the person making the amendment: Patent applicant: Chugai Pharmaceutical Co., Ltd., 5-5-1 Ukima, Kita-ku, Tokyo (331) March 13, 1990 (Delivery date: March 20, 1990) (Note) Document address and contact address: 171) Shimaku Kukada, 3-41-8 Takada, Toshima-ku, Tokyo 5° Drawing subject to correction 6゜Amendment details: “Engraving of the drawing originally attached to the application, as shown in the attached sheet (no change in content)”

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 is a hydrogen atom or a lower alkanoyl group,
R_2 represents a lower alkanoyl group, and R_3 represents a cyclopropylmethyl group or an allyl group. ) and its pharmaceutically acceptable acid addition salts.