JPH04273880A - Dihydromorphine derivative - Google Patents

Abstract

PURPOSE:To provide a new compound having agonistic action against opioid receptor and useful as an analgesic having decreased side effects. CONSTITUTION:A compound of formula I (R<1> is H or 2-5C alkanoyl; R<2> is 2-5C alkanoyl), e.g. 6beta-acetylthio-17-cyclopropylmethyl-4, 5-epoxymorphinan-3-ol. The compound of formula I can be produced by reacting a compound of formula II with a carbothio S-acid of formula R<2>-SH in an inert organic solvent (e.g. THF) using triphenyl phosphine and an azodicarboxylic acid diester at 0 deg.C to ordinary temperature.

Description

[Detailed description of the invention]

0001

[Industrial Field of Application] The present invention provides compounds of the general formula (I) which have excellent analgesic effects and reduce undesirable side effects.

0
002]

[Case 2]

The present invention relates to novel dihydromorphine derivatives represented by the formula (wherein R1 and R2 have the same meanings as below) and non-toxic acid addition salts thereof.

0004

[Prior Art] In order for an analgesic to exhibit an analgesic effect,
Must bind to opioid receptors (opioid receptors). To date, opioid receptors include μ, κ,
It has been confirmed that there are four subtypes: δ and σ. It has also been discovered that these receptors exist not only in the brain but also in other parts of the body, such as the intestinal tract and the vas deferens.

[0005] Mu receptor agonists are generally said to have strong analgesic effects and the ability to eliminate fear of pain, discomfort, and the like. In addition, κ receptor agonists have strong analgesic effects, but they also have unpleasant psychoactive effects (dysphoria).
c/psychotomimetic) and are associated with undesirable side effects such as movement disorders [Tren
ds in pharmacological science
ence, 11, 70 (1990) and J. Ame
r. Med. Assoc. , 259(9) 1362
(1988)].

As a compound structurally similar to the compound of the present invention, JP-A No. 2-256678 discloses a compound having the general formula (
A)

[0007]

[Chemical formula 3]

The compounds represented by the formula (wherein Ra1 represents a hydrogen atom or a lower alkanoyl group, Ra2 represents a lower alkanoyl group, and Ra3 represents a cyclopropylmethyl group or an allyl group) and their acid addition salts are Disclosed. It is also specified that the compound represented by the general formula (A) has an excellent analgesic effect via the κ receptor and an antagonistic effect at the μ receptor.

[0009]

[Object of the present invention] The present inventor has conducted extensive research in order to find an analgesic drug mediated by μ receptors (i.e., μ receptor agonist) that exhibits excellent analgesic effects without undesirable side effects. As a result, they discovered a μ receptor agonist that is 10 times more effective than morphine, and completed the present invention.

The difference in chemical structure between the compound of the present invention and the compound described in JP-A-2-256678 is that C
All that matters is the presence or absence of a double bond at the 7-C8 position. However, the difference in action is greater than the difference in structure. That is, although the compound of the present invention acts as an agonist on μ receptors and has no effect on κ receptors, the compound described in JP-A-2-256678 acts as an agonist on μ receptors. Shows antagonistic effects on the body,
It acts as an agonist for κ receptors. This difference in effect is completely unexpected.

[0011]

DISCLOSURE OF THE INVENTION The present invention provides general formula (I)

0012

[C4]

(In the formula, R1 is a hydrogen atom or a carbon number of 2
~5 alkanoyl group, R2 has 2 to 5 carbon atoms
represents an alkanoyl group. ) and its non-toxic acid addition salts.

In the general formula (I), the alkanoyl group having 2 to 5 carbon atoms represented by R1 and R2 includes acetyl group, propionyl group, butyryl group, valeryl group and isomers thereof. Both groups are preferred, but
A more preferred group is an acetyl group.

Among the compounds of the present invention represented by general formula (I),
Typical examples are 6β-acetylthio-17-cyclopropylmethyl-4,5-epoxymorphinan-3-ol and 3-acetoxy-6β-acetylthio-17.
-cyclopropylmethyl-4,5-epoxymorphinan, and their non-toxic acid addition salts.

The compound of the present invention represented by general formula (I) is
If desired, it is converted into an acid addition salt by a known method. Preferably, the acid addition salt is non-toxic and water soluble. Suitable acid addition salts include, for example, inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, nitrates, or acetates, lactates, tartrates, benzoates. Examples include organic acid salts such as acid salts, citrates, methanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, isethionates, glucuronates, and gluconates.

The compound of the present invention represented by general formula (I) is
It can be produced according to the reaction scheme shown below.

[0018]

[C5]

(In the formula, R1a is a hydrogen atom or a carbon number of 2
~5 alkanoyl group, R1b has 2 to 5 carbon atoms
represents an alkanoyl group. However, when R1a represents an alkanoyl group, R1a and R2 represent the same group. )

Step (a) is a Mitsunobu reaction in which triphenylphosphine or tributylphosphine and azodicarboxylic acid diester (
diisopropyl azodicarboxylate, dimethyl azodicarboxylate, etc.) and a carbothio S-acid represented by the formula: R2-SH at 0°C to room temperature. The product is a compound in which R1a represents a hydrogen atom and R
1a is obtained as a mixture of compounds representing an alkanoyl group.

Step (b) is an acylation reaction, which is carried out by reacting the corresponding acid halide or acid anhydride in the presence of a tertiary amine in a suitable inert organic solvent or without a solvent.

The compound of formula (II) is described in J. Med. Ch
em. , 30(6), 1040-1044 (1987)
It is a known compound described in .

Furthermore, the compound of the present invention represented by the general formula (I) in which R1 represents a hydrogen atom is represented by the general formula (III)

[
0024

[C6]

The compound represented by the formula (wherein R2 has the same meaning as above) was prepared using boron tribromide in an inert organic solvent (chloroform, methylene chloride, etc.) at 0°C.
It can also be produced by reacting nearby.

The compound represented by the general formula (III) has 1
Same as step (a) using 7-cyclopropylmethyl-4,5-epoxy-3-methoxymorphinan-6α-ol (which can be easily produced from known compounds using known methods) as the starting material. It can be manufactured as follows.

The reaction product can be purified by conventional purification means, such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate,
It can be purified by thin layer chromatography, column chromatography, washing, recrystallization, or other methods. Purification may be performed for each reaction or after completion of several reactions.

The compounds of the present invention represented by the general formula (I) and their non-toxic acid addition salts had agonist activity towards the μ receptor. This agonist activity has an inhibitory effect on muscle contraction caused by electrical stimulation of the longitudinal muscles of the guinea pig ileum (Annu. Rev. Pharmaco
l. , 15, 29-47 (1975)).

A part of the results are shown in FIG. The IC50 value of the compound of the present invention produced in Example 1 was 2.82 nM. The IC50 value of morphine hydrochloride used as a control was 4.
Since it was 5.8 nM, it means that the compound of Example 1 has about 16 times more agonist activity against the μ receptor than morphine.

[0030] Furthermore, this contraction inhibition is weakened by naloxone, which is an antagonist of μ receptors, but the pattern is different from that of morphine, indicating that the compounds of the present invention act on μ receptors different from that of morphine. it is conceivable that.

Furthermore, since the compound of the present invention did not show any effect on the contraction caused by electrical stimulation of the rabbit vas deferens, which is rich in κ receptors, it is presumed that it does not have an agonist effect on κ receptors. Ru.

The compounds of the present invention represented by the general formula (I) and their non-toxic acid addition salts have agonist activity against μ receptors, and therefore are effective analgesics (for example, for post-operative pain and cancer-induced pain). It is thought to be useful for treating pain, etc.). Moreover, since the compound of the present invention does not act on κ receptors, it is an excellent analgesic without undesirable side effects such as unpleasant mental effects or movement disorders.

In order to use the compound of the present invention represented by general formula (I), its non-toxic acid addition salt, or its hydrate for the above purpose, it is usually administered systemically or locally, orally or parenterally. It is administered in the form of

The dosage varies depending on age, symptoms, therapeutic effects, administration method, treatment time, etc., but it is usually administered orally or parenterally once to several times a day in the range of 100 μg to 100 mg per adult. Administered orally.

When administering the compound of the present invention, solid compositions, liquid compositions, and other compositions for oral administration, injections for parenteral administration, external preparations, suppositories, etc. can also be used. .

[0036]

EXAMPLES The present invention will be explained in detail with reference to Examples below, but the present invention is not limited thereto. Example 1 6β-acetylthio-17-cyclopropylmethyl-4
, 5-epoxymorphinan-3-ol synthesis

00
37]

[C7]

Diisopropyl azodicarboxylate (0.83 ml) was added to a solution of triphenylphosphine (1.4 g) in tetrahydrofuran (15 ml) under a nitrogen atmosphere.
After dropping at ℃, the mixture was stirred for 30 minutes. Next, 17-cyclopropylmethyl-4,5-epoxymorphinan-4,6α-diol (J.Med.C
hem. , 30(6), 1040-1044 (1987
A tetrahydrofuran solution (5 ml) of 154 mg) prepared by the method described in
Add thioacetic acid (H3 CCOSH, 0.4 ml),
Stir for 24 hours. Add ethanol to the reaction mixture,
After concentration under reduced pressure, the residue was extracted with a mixture of ethyl acetate and hydrochloric acid, and the aqueous layer was adjusted to pH 8 with sodium hydrogen carbonate and extracted with chloroform. The chloroform extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, chloroform:methanol = 30:1),
The title compound (107 mg) having the following physical properties was obtained. Melting point: 212-213°C; Optical rotation: [α]D -102.68 (c=0.50, chloroform, 28°C); Mass (m/z): 385 (M+).

Example 2 Synthesis of 3-acetoxy-6β-acetylthio-17-cyclopropylmethyl-4,5-epoxymorphinan

[
0040

[Chemical formula 8]

3-hydroxy compound (produced in Example 1,
A mixture of 50 mg), acetic anhydride (5 ml) and a catalytic amount of pyridine was stirred at 90°C for 3 hours. Water was added to the reaction mixture, the pH was adjusted to 9 with 28% aqueous ammonia, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, chloroform:methanol = 30:1) to obtain the title compound (55.4 mg) having the following physical properties. IR (chloroform solution): ν 2920, 1760
, 1670, 1430 cm-1; Mass (m/z): 427 (M+), 384, 55
.

Example 3 6β-acetylthio-17-cyclopropylmethyl-4
, Separate synthesis method of 5-epoxymorphinan-3-ol

[0043]

[Chemical formula 9]

6β-acetylthio-17-cyclopropylmethyl-4,5-epoxy-3-methoxymorphinan (17-cyclopropylmethyl-4,5-epoxy-
1 produced in the same manner as in Example 1 using 3-methoxymorphinan-6α-ol as the starting material.
．． A chloroform solution (20 ml) of 738 g) was added dropwise to a mixture of boron tribromide (1M methylene chloride solution, 36.7 ml) and chloroform (30 ml) over 2 minutes under ice cooling, and then stirred at room temperature for 20 minutes. The reaction mixture was poured into ice water, and the aqueous layer was adjusted to pH 9 with 28% aqueous ammonia.
The mixture was extracted with chloroform. The extract was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, chloroform:methanol = 20:1) to obtain the title compound (780 mg) having the same physical properties as the compound obtained in the example.
) was obtained.

[Brief explanation of the drawing]

FIG. 1 is a graph showing the inhibitory effects of the compound of the present invention and morphine hydrochloride on muscle contraction caused by electrical stimulation of the guinea pig ileum slave muscle.

Claims (1)

[Claims] Claim 1: General formula (I): (wherein, R1 represents a hydrogen atom or an alkanoyl group having 2 to 5 carbon atoms, and R2 represents an alkanoyl group having 2 to 5 carbon atoms.) compound, or its non-toxic acid addition salt.