JPS61271275A - Morphinan derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] This invention relates to morphinan derivatives including morphine.

[Disclosure of the Invention] This invention is based on the formula (■): [wherein X and Y are each hydrogen, or - together -0-1 R8 is optionally substituted with 1 to 3 alkyl] (wherein the substituents have up to a total of 3 carbon atoms (-f4'')), Schiff [J propylmethyl or 3-furylmethyl, R7 is hydrogen, carbon number 1
alkyl having ~10 atoms, cycloalkyl having 5 or 6 carbon atoms, optionally substituted with phenyl, or optionally having substituents 4 to 12 carbon atoms;
phenylalkyl, rt. is hydrogen, alkyl having 1 to 10 carbon atoms, or phenyl, R4 is hydrogen, OH, NR6R7, NHCOR, NHSo
, R', or NHCOOR", R6 and R7 are each independently hydrogen or alkyl having 1 to 3 carbon atoms, R is alkyl having 1 to 6 carbon atoms, phenyl, or -A-COOR", A is alkylene or alkenylene each having 2 to 4 carbon atoms, R' is alkyl having 1 to 6 carbon atoms, or phenyl, R'' is methyl or ethyl, where R3 is in the alpha position, R4 is in the β position, R4 is in the α position if R3 is in the β position, or R3 and R4 together are O or CH, and R6 is hydrogen or methyl.

However, when x+y is -0-1, R7 is hydrogen, R4 is an α-OI-I group, and R8 and R5 are hydrogen, R3 is a group other than cyclopropylmethyl and allyl, and R2, R3, R
When 4 and R5 are both hydrogen, R2 is a group other than cyclopropylmethyl] A free base or acid addition salt of a compound represented by the following, and when those compounds have a free 01-1 group, A physiologically hydrolysable, pharmaceutically acceptable free base or acid addition salt of the ester compound is provided.

The compounds of this invention exist in the form of free bases or acid addition salts, which can be obtained in conventional manner from the free base, and vice versa.

Representative examples of acid addition salts are hydrochloride, hydrobromide, acidic maleate and acidic malonate.

The compounds shown in this invention can be manufactured according to the following methods.

(a) Formula (Ia): (In the formula, R8° represents cyclopropylmethyl or 3-)lylmethyl) In order to produce a compound represented by formula (■):, the compound of formula (■): was brominated. To create a furan ring by dehydrobrominating a compound having a bromine atom in at least the 5-position and further debrominating the product, or (b) to produce a compound represented by formula (Ib): Formula (X): [wherein Z and Zo represent alkyl having 1 to 3 carbon atoms, or taken together (ct-rt)t or (CH
z) represents a] The ketal group of the compound represented by is hydrolyzed to form an oxo group, or (c) formula (Ic): (wherein R is alkyl having 1 to IO carbon atoms or (representing phenyl), a compound of formula (I'): is reacted with an organometallic compound having an R5 group, or (d) a compound of formula (Id): is produced. (e) Formula (Is): (wherein R4'' is N Re It t, NHC] t, N
In order to produce a compound represented by the formula (!゛)
The corresponding 6-
An amino compound is prepared and, if desired, the N atom of the resulting compound is alkylated or acylated, or (r) a compound of formula (I) is prepared in order to produce a compound of formula (1). Either the oxo group is reduced to a hydroxyl group, or (g) formula (I
g): To produce a compound represented by formula (XII): or (h) to produce a compound represented by formula (1h): by hydrogenolysis reaction, formula ( XII [): The mino compound is optionally alkylated or acylated, or [wherein R5'' is allyl optionally substituted with 1 to 3 alkyl groups (wherein the substituents are the total number of carbon atoms to prepare a compound of formula (XIV):
``To react with a compound represented by Or (k)
To prepare a compound of formula (I) in which R and R3 together represent CUt, a compound of formula (I) in which R3 and R4 together represent O is converted into (C8I46)3P=C
H, or (1) free 0 [(formula with group ・
In order to prepare physiologically hydrolysable pharmaceutically acceptable esters of compounds of formula (I), such compounds of formula (1) are combined with a suitable acid, or a reactive derivative of the acid. or (m) R4 is N Ra
R? (Here, R6 and R7 have the same meanings as above, but any one of R8 and R7 is hydrogen, NH
COR, NHSO, R', or N1-I C0OR”
In order to produce a compound of formula (I) in which R4 is a group other than is hydrogen or NHt) are alkylated or acylated, respectively.

In this case, in each of the above formulas, the arrangement of the bond connecting the Y group at the 5th position and the 13th position is the same as in formula (1), and R1-R6 and X and Y Unless otherwise specified, the definition of is the same as the description given in formula (1) above.

In the above formulas and their explanations and specific examples, as well as in the intermediates and final products shown, for example, in each formula up to formula (1'), the chiral carbon atom is in the same configuration as in the natural morphinan system (levorotatory). That is, the 9th position is R, the 13th position is R, and the 14th position is S.

The invention also encompasses the compound of formula (1), for example in the form of a mixture with its epimer, for example as a racemic mixture.

Examples of substituents on the phenyl ring include halogen having an atomic number of 9 to 53, cr', hydroxyl, nitro, alkyl having 1 to 3 carbon atoms, and 1 to 3 carbon atoms.
alkoxy, or NRaRb, where Ra and Rb are independently hydrogen or alkyl of 1 to 3 carbon atoms.

Monosubstitution is preferred.

In the above formula, preferably RI is cyclopropylmethyl, and/or R is alkyl, especially methyl or ethyl, and/or R1 is cycloalkyl, especially cyclohexyl, and/or
or R2 is optionally substituted phenyl (e.g., phenyl or p-Ho-phenyl), and/or R3 is hydrogen, alkyl having 1 to 4 g carbon atoms, or phenyl, and/or R4 is hydroxyl, or hydrogen. , especially hydroxyl,
and/or R2 and R4 are together 0 or CHt;
and/or R6 is hydrogen.

Conveniently, R3 and R4 are both 0. Conveniently, both X and Y are H.

When R4 is OH, it is preferably at the α position.

All reactions can be carried out by conventional methods, or can be carried out according to the examples described below. As mentioned above, the reaction (a
) is carried out in three steps, first bromination, e.g. with Brt in glacial acetic acid, then bromination in an alkaline medium (e.g. Na
OH solution) and finally introduced (e.g. at positions 1 and 7 during the first step bromination reaction).
Note that any remaining Br atoms can be removed by a reduction reaction. This removal by a reductive reaction can be carried out, for example, by hydrogenation in the presence of Pd/C.

Reaction (b) can be carried out by a method of hydrolysis in an acidic medium (eg, HCρ solution).

Reaction (e) can be carried out, for example, by reacting with an organolithium compound in ether.

The reduction reactions (d) and (g) can be carried out by methods normally used for hydrogenation reactions of double bonds, such as hydrogenation using Pd/C as a catalyst. Reaction (e) is known as a reductive amination reaction. Hydrogenation can be carried out using boron derivatives, such as NaCN BN2 as reducing agent in the presence of ammonium acetate. Subsequently, the optional alkylation or acylation reaction and reaction (m) are carried out by known methods, for example using alkyl halides or acid halides in the presence of a base, for example the method described in Example 9. It can be implemented in the same way.

Reaction to reduce oxo group to hydroxyl group (reaction r
) can be carried out by a method known as a reduction reaction, for example, using NaBH as a reducing agent.

Benzyl group elimination reaction of the compound of formula (XIII) (reaction h
) can be carried out in the usual manner, for example by hydrogenation with Pd/C. Any subsequent reactions can be carried out by the method described in reaction (e).

Reaction (i) is a conventional reaction for alkylating secondary or tertiary amines.

The ether cleavage reaction of reaction (j) is l-113r, B
This can be done by using conventional reagents such as Br+ or pyridine hydrochloride.

Reaction (k) can be carried out by the conventional method known as the Wittig reaction.

The acylation reaction of reaction (1) can be carried out by a conventional method, for example, a method using an acid halide in the presence of a base.

The starting compound (reaction a) represented by formula (■) can be produced, for example, according to the following reaction formula.

(IV) (V) (V) The production (reaction a') of the compound of formula (II)
A compound of formula R, CH2-9-S-CH! A reaction (Diels,
Alder reaction).

The ring-opening reaction of the furan ring (simultaneously changing the position of the S atom) (reaction b') can be carried out, for example, by reaction with HB r.

Ring-opening reaction of S ring for the purpose of producing a compound of formula (V) (
Reaction c') can be achieved, for example, by a reduction reaction with Li in liquid ammonia, which simultaneously achieves saturation of the double bonds and reduction of the oxo groups.

Reaction for eliminating the SH group from the compound of formula (V) (reaction d'
) can be carried out using Raney nickel in methanol, for example.

Finally, the 6-hydroxyl group of the compound of formula (VI) is
For example, this can be converted into an oxo group by the usual method of reaction with oxalyl dichloride and dimethyl sulfoxide (reaction e').

The compound of formula (■) (1'tt is phenyl) can be obtained by reaction with Raney nickel in methanol, and the compound of formula (1'
It can be produced directly from the compound of 11).

The starting compound of formula (X) (reaction b) can be prepared from the compound of formula (■) according to the reaction scheme below.

#e (X) Compounds of formula (■) can be obtained by conventional reactions in which the 4-hydroxyl group is etherified, for example with halogenated benzenes in the presence of a base and copper (reaction f')
.

The thus obtained compound of formula (■) can be converted into a ketal group by the usual method of acting on the 6-oxo group with alcohol or glycol (reaction g').

1. Finally, the 4-phenoxy group of the thus obtained compound of formula (IX) is eliminated by carrying out a reduction reaction using Na in liquid ammonia, for example (reaction h').

The starting compounds of formula (XI) and formula (■) can be obtained by dehydrating a compound of formula (I c) or formula (I f), respectively. This dehydration reaction is
It can be carried out in the usual manner, for example by heating in an acidic medium (eg HCQ solution) or in pyridine hydrochloride. In this way, a mixture of 5,6- and 6,7-didehydro compounds is produced.

The starting compound represented by formula (XI[) is obtained by reacting the 6-oxo group of the compound group of formula (I゛) with benzylamine to create a corresponding benzylimine compound, and the compound thus obtained. can be obtained by further reacting with a Grignard reaction represented by the formula R3°MgX, followed by hydrolysis.

The starting compound represented by formula (XIV) is a corresponding N-methyl compound [These N-methyl compounds can be prepared by a method similar to that of the compound of formula (1) shown in this invention]
(using, for example, chloroformic acid vinyl ester or cyanogen bromide).

In the above reaction, formula (1) in which R8 and R4 are different
are obtained, they always have (6
α-R8,6β-R4) and (6α-R4,6β-R
,) exist as isomer mixtures, and these can be prepared by the usual methods,
For example, it can be separated by chromatography.

Reaction (c) for producing a starting material of formula (XIII)
) and in the Grignard reaction, (6α-0H16β-
R3') or (6α-N Ht, 6β-R3') compounds are respectively preferentially produced.

This invention includes the compounds of formulas (1) to (XTV) themselves.

With respect to the individual starting materials, unless the method of preparation is specifically stated, the material is known or can be prepared by conventional methods analogous to those of the examples.

Compounds of formula (II) are known. These compounds can be made from thebaine. This invention also
Provided is a method for making a compound of formula (1), wherein R3 and R6 are together oxygen. The reaction includes any of the following steps in any order.

(i) Substituting the 17-methyl group of thebaine with an R, group.

(ii) CH! An Rt group is introduced at the 14th position.

(iii) If appropriate, a demethylation reaction is carried out to convert the methoxy groups in the 3- and 6-positions into hydroxyl and keto groups, respectively.

(iv) If desired, the oxygen bridge between the 4 and 5 positions is removed.

The term "thebaine" includes all alkaloids of the thebaine series. These reactions may optionally be performed, for example reactions (a) to (Ill) and (ao) to (b')
One or more steps may be performed along the lines described above, and for example step (1ii) may include a dislocation. It is also possible to carry out further reactions, for example from one intermediate to another and from I compounds of formula (I) to other compounds, by customary methods.

[Example] Next, the present invention will be specifically explained with reference to Examples. The examples are merely illustrative of the invention and are not intended to limit the scope of the invention. .

In Example 1, temperatures are uncorrected values and are expressed in degrees Celsius. Maleic acid ester is the same as maleate.

Example 1 17-cyclopropyl medilu 4,5α-epoxy-3
-methoxy-14β-ethylmorphinan-6-one (a
) 6.14-Endo-etheno-6,7,8,14-tetrahydro-7-thia-8α-methyl-N-cyclopropylmethylnortebaine N-cyclopropylmethylnortepain 46.49 (0
, 132 mol) and S-ethylethanethiosulfinate 17.69 (0,128 mol) in toluene + 000
1 under reflux for 1 hour, cooled, and washed twice with water. The organic layer was dried with NatsO*, concentrated, and the residue was purified on silica gel with methylene chloride/metal/a thick NH3 (99
, 51510, 1) (7) Apply flash chromatography using a mixed solution.

The title compound is isolated as pale yellow crystals.

(b) 48% of the compound 40.69 (0,099 mol) obtained with N-cyclopropylmethyl-5,14-ethano-17α-methyl-18-thianortepain (la)
Upon addition to 150 x f2 of hydrobromic acid and stirring at room temperature, the starting material is completely dissolved. Immediately after the reaction product begins to crystallize, 60 mQ of methanol is added and stirred at 0°C for 1 hour. The hydrobromide salt of the title compound is filtered off and washed with methanol/ether. M, P,: 256-25
8℃.

(c) N-Cyclopropylmethyl-4,6α-dihydroxy-14β-(1-mercapto)ethyl-3-methoxymorphinan In 1.8 f2 of liquid ammonia, at -45°C, 4.5% lithium was added.
31? (0.62 mol) is dissolved, and to this deep blue solution is added a normal solution of compound 2259 (56.7 mmol) obtained in (1b) in 500% tetrahydrofuran.

After 20 minutes at −40° C., the solution is decomposed by adding solid ammonium chloride, the ammonia is distilled off, the residue is taken up in water and extracted three times with ether. After drying the organic layer, concentrate
Flash chromatography with a mixture of ethyl acetate/hexane (1:4 to 1:2) gives the title compound as a colorless oil.

(d) N-cyclopropylmethyl-14β-ethyl-
130 g of 4,6α-dihydroxy-3-methoxymorphinan Raney nickel was added to 1.5σ of methanol, and while stirring vigorously, the compound 13 obtained in (lc) was added.
．． 49 (33,3 mmol) of methanol 250z (2
Add the solution rapidly. After 15 minutes, the reaction mixture is filtered and concentrated by evaporation. The residue is taken up in dichloromethane, dried over l'J ay S Oa and concentrated by evaporation to give the title compound as a pale red foam.

(e) N-cyclopropylmethyl-14β-ethyl-
4-Hydroxy-3-methoxymorphinan-6-one Oxalyl chloride 4.35i12 (50.4 mmol) was added to 500 mmol of methylene chloride at -60°C, and this was dissolved in DMSO.
7,2112 (100,7 mmol) of methylene chloride 8
5. Mix with the shochu solution. Compound 179 obtained in (1d)
(45.8 mmol) of methylene chloride in 100x (l) was added to this at -78°C and after 5 minutes at -78°C, an additional 32x (2 (229 mmol) of triethylamine was added to -6
Add to this at 0° to 50°C.

After gradually warming the reaction mixture to room temperature and adding water, the mixture is extracted three times with methylene chloride. After drying the organic layer,
Evaporate and concentrate with ethyl acetate/hexane (l:3 to l:1)
Flash chromatography on a mixture of gives the title compound as a colorless oil.

(f) Compound 14.69 (39.6 mmol) obtained from 17-cyclopropylmethyl-4.5α-epoxy-3-methoxy-14β-ethylmorphinan-6-one (le) was mixed with 430 J of glacial acetic acid! In addition to 12, a solution of Brtl 9.09 (119 mmol) in glacial acetic acid 200x (7) was added dropwise over 30 minutes to this while stirring at room temperature.90
After a few minutes, the reaction mixture was concentrated by evaporation and the residue was taken up in methylene chloride IQ and dissolved in 300 ml of 1N NaOH solution.
The methylene chloride layer was separated and washed with water and a small amount of lO% tartaric acid solution (pH 7).
) L,, after drying with NatSOa, concentrate. The residue was dissolved in 170 inches of glacial acetic acid and 130 mN of water! and 10% P
After addition of d/C39, the mixture is hydrogenated for 15 hours at room temperature and 1 atm. Pd/C was filtered off, glacial acetic acid was distilled off, and the residue was taken up in water/2N-N a I CO3 solution.
This is extracted three times with methylene chloride. The organic layer is Na
* After drying on S04, concentration and flash chromatography with a mixture of ethyl acetate/hexane (1:5) give the title compound as colorless crystals.

Example 2 17-cyclopropylmethyl-4.5α-epoxy-1
4β-Ediyl-3-hydroxymorphinan-6-one Compound 3.259 (8.9 mmol) of Example 1 and pyridine hydrochloride 109 were heated at 190° C. for 3 hours, cooled, collected in water, and diluted with concentrated aqueous ammonia. The mixture is made basic and extracted three times with methylene chloride. Ethyl acetate/hexane (1
: By performing flash chromatography on a mixture of 5), the title compound is obtained as colorless crystals. Recrystallization from ether/pentane gives analytically pure product.

M, P: 157-158°C.

Example 3 14β-benzyl-17-cyclopropylmethyl-4°5α-epoxy-3-methoxymorphinan-6-one (
a) 6,14-x nodo-etheno-6,,7,8,14
-tetrahydro-7-thia-8α-phenyl-N-cyclopropylmethylnortepain N-cyclopropylmethylnonoshiteno<IsoAnA9(
0.z 5 mol) and S-pendylphenylmethanediosulfinate (21 g (0.08 mol)) in toluene 50 mol).
Heat to reflux in 1Q for 1 hour. The reaction mixture is concentrated by distillation, mixed with water and extracted three times with ether. The ether layer is dried and evaporated leaving colorless crystals. Washing this with a small amount of ether gives the title compound.

M, P,: l118-150°C.

(b) N-cyclopropylmethyl-3-methoxy-4-
Hydroxy-14β-benzylmorphinan-6-one (
Compound 209 (42.3 mmol) obtained in 3a) and Raney nickel 2009 are heated under reflux in methanol 1.3ρ for 4 hours, then 70 g of Raney nickel is added and heated for an additional 3 hours. Filter off the Raney nickel and wash well with methanol.

The combined methanol layers are concentrated and the residue is taken up in ether, dried over NatsO4 and concentrated to give a colorless oil. Flash chromatography on silica gel with a mixture of ethyl acetate/hexane (1:8) gives the title compound as colorless crystals. M, P: 122-124°C.

(c) +4β-benzyl-17-cyclopropylmedyru-4,5α-epoxy-3-methoxymorphinan-6-
2.2 g (5.1 mmol) of the compound obtained with (3b)
was added to 70x (l) of glacial acetic acid, and this was added to Br-2,459 (
15.

3 mmol) of glacial acetic acid 30xQ solution at room temperature.
After stirring for an hour, concentrate by evaporation. The residue was taken up in methylene chloride and diluted with 1N-NaOH solution 1001 while cooling with water.
Separate the organic layer, shake with water, and add 10% tartaric acid until pH 6.

The organic layer was dried over NaeSO4, concentrated, and 200 ml of a mixture of water/glacial acetic acid (1:I) was added to the residue, followed by 4.2 g of sodium acetate and 10% Pd/CO,7
59 is added and the mixture is hydrogenated at room temperature and 3 atm.

The reaction mixture is filtered and concentrated, the residue is taken up in methylene chloride and washed with 2N sodium hydroxide solution. Dry the organic layer and concentrate to give a pale yellow oil. Flash chromatography of this with a mixture of ether/hexane (1:3) gives the title compound as a colorless oil.

Example 4 14β-benzyl-17-cyclopropylmethyl-4,
5α-Epoxy-3-hydroxymorphinan-6-one 12.5 g of pyridine hydrochloride and 5.2 g of the compound of Example 3
9 (12 mmol) were mixed at room temperature and 16
Heat to 0°C. After 1 hour, 12.5 g of pyridine hydrochloride was added, and the mixture was heated at 160°C for an additional hour. After cooling, the mixture was taken into ice water and made alkaline with concentrated ammonia water.
Extract three times with methylene chloride. The organic layer is dried over NatSO4, concentrated by evaporation and flash chromatographed on silica gel with a mixture of ethyl acetate/hexane (1:3). The title compound is isolated as unreacted starting material and a colorless oil. The title compound is converted to the hydrochloride salt with an ether/ethanol/HCρ mixture. M, P, +260℃.

Example 5 N-cyclopropylmethyl-14β-benzyl-3-methoxymorphinan-6-one (a) N-cyclopropylmethyl-14β-benzyl-3-methoxy-4-phenoxymorphinan-6-one Example 8.99 (19 mmol) of the compound obtained in (3b), bromobenzene 5aQ (48 mmol) and 1G038.09C (58 mmol) were dissolved in 100 yen of pyridine, and 2.0 g of copper powder was added. Heat at 140° C. for 16 hours under an argon atmosphere. Ice water was added to the dark colored reaction mixture, and this liquid was extracted three times with ether. The organic layer is dried over NatSO4 and then concentrated by evaporation to give the title compound as a dark oil. This product is used without further purification in the reaction to produce the compound described below.

(b) Compound 9.29 (18 mmol) obtained with N-cyclopropylmethyl-14β-benzyl-3-methoxy-4-phenoxy-6,6-ethylenedioxy-morphinan (5a)
Ethylene glycol 30y ((0,54 mol) and p
-k I+j ding-'/fu 11/+'/
# * Blasphemy ÷ klMsQ A a (
Q n S (11 mol) is heated to reflux in benzene IQ for 4 hours with a water separator. The reaction mixture was reduced to 2N
- Washing once each with caustic soda solution and water, drying the organic layer over NatSO4 and then concentrating to give the title compound as a dark brown oil. This product is used without further purification in the reaction to produce the compound described below.

(c) N-cyclopropylmethyl-14β-benzyl-3-methoxy-6,6-ethylenedioxy-morphinan - (5
A solution of 9.7 g (17.6 mmol) of the compound obtained in b) in 250 aC of toluene was added dropwise, and then sodium 2
．． 59 (lO9 mmol) is added to this.

The reaction mixture is stirred at -55 to -35°C for 4 hours, then solid ammonium chloride is added to the liquid to decompose and the ammonia is distilled off. Dry the ether layer with NatSo4,
Concentration and flash chromatography give the title compound as colorless crystals. [α
)3=-28,8° (CH301-1).

(d) Compound 5,89 (12,6 mmol) obtained with N-cyclopropylmethyl-14β-benzyl-3-methoxymorphinan-6-one (5c) was heated in I N-HCl2750 liquor for 4 hours. After refluxing and cooling, mix with ice/concentrated ammonia water and dilute with ether for 30 minutes.
Extract times. The title compound is obtained by drying and concentrating the organic layer, followed by recrystallization from ether. M,P
, :t 65-167°C.

Example 6 N-cyclopropylmethyl-14β-benzyl-3-hydroxymorphinan-6-one 1.65 LiI (4 mmol) of the compound of Example 5 and 8.69 pyridine hydrochloride were heated at 180°C, and after 1 hour. , add 8.69 g of pyridine hydrochloride and raise the temperature to 18 ml for another hour.
Keep at 0℃. Add water/aqueous ammonia to the reaction mixture,
Extract three times with methylene chloride. The organic layers are combined, dried, concentrated and subjected to furan chromatography (ethyl acetate/hexane, 1:8) to give the hydrochloride of the title compound. M, P,: 290°C
, M, P, (1-tBr salt)〉280°C. [α)to(
Free base)--69,6° (CH, 014) Example 7! 7-cyclopropyl mediru 4.5α-epoxy-1
4β-Ethyl-3,6α-dihydroquine-6β-methylmorphinan Compound 635m9 (1.8 mmol) of Example 2 was heated at 0°C.
100×f7 of ether and then a solution of 1.6 M methyllithium in ether (14 mQc 22.4 mmol) is added thereto. The reaction mixture is gradually warmed to room temperature and after 4 hours is decomposed by adding 10% ammonium chloride solution and extracted three times with methylene chloride. The organic layer is washed with concentrated aqueous ammonia, dried over Na2SO4, and concentrated.

Flash chromatography with an ethyl acetate/hexane (1:5) mixture gives the title compound as colorless crystals together with unreacted starting material. Recrystallization from ether/hexane gives the analytically inline title compound. M, P, 199-200°C0 Example 8! 7-cyclobrobylmethyl-6α-amino-4゜5α
-Epoxy-3°-hydroxy-14β-ethylmorphinan, and 17-cyclopropylmethyl-6β-amino-4,5α
N a CN B H5
A solution of 260 mmol (4.13 mmol) in methanol is added dropwise. After stirring for 17 hours at room temperature, the reaction mixture is adjusted to 1) H1 with concentrated hydrochloric acid and concentrated by evaporation. The residue is taken up in water, adjusted to pl-18 with 2N caustic soda and extracted three times with methylene chloride. Organic layer with NatsO
After drying at
Concentrated ammonium (98:2:0°2~90:10:0.
Flash chromatography on a mixture of 5) gives the two title compounds (6B-isomer elutes first, then 6α-isomer).

Example 9 17-cyclopropylmethyl-4,5α-epoxy-1
4β-ethyl-3-hydroxy-6β-[trans-3
-(Methoxycarbonyl)acrylamide 13 selhinantetrahydrofuran 10zQ solution 10mQ and K.

426+ g (1 mmol) of the hydrochloride salt of the β-isomer of Example 8 in a mixture of 3600 shoulder 9 (4.35 mmol) of CO
was added at room temperature, and then, with stirring, 136 m9 (1.1 mmol) of fumaric acid monomethyl chloride was added to this with stirring.
of tetrahydrofuran 10zQ solution is gradually added.

After 30 minutes, the reaction mixture is extracted three times with ethyl acetate, the organic layer is dried over Na2SO4 and concentrated by evaporation.

The hydrochloride salt of the title compound is obtained by subjecting the residue to flash chromatography (methylene chloride/methanol/concentrated aqueous ammonia 99:1:0.1) and crystallizing the hydrochloride salt from ethanol. M, P,: >300°C
0 By the same method, 17 was obtained from the 6α-isomer of Example 8.
-cyclopropylmethyl-4,5α-epoxy-14β
-Ethyl-droxy-6α [trans-3-(methoxycarbonyl)acrylamide]morphinan is produced. M, P: 233-236°C.

Example 1O N-cyclopropylmethyl-14β-ethyl-3°6α
-dihydroxy-6β-methylmorphinan N-cyclopropylmethyl-14β-ethyl-3-hydroxymorphinan-6-one [prepared from the compound of example (1e) by a method analogous to examples 5 and 6]1. 1y(3
, 25 mmol) to 130 x g of ether at 0°C,
1.6M-methyllithium ether solution 24.4 t
x (lc39 mmol) is added to this. The reaction mixture was gradually warmed to room temperature and stirred for 4 hours, then mixed with 10% ammonium chloride solution lOmQ and plucked with 3N HCl2.
Make H1 acidic. It is then made basic again with concentrated aqueous ammonia and extracted twice with ether. Nat the ether layer
After drying with SO+, concentrating and flash chromatography (methylene chloride/methanol/aqueous ammonia 98%).
2.0.2) to obtain the acidic malonate of the title compound. M, P: 183-184°C.

Example 1t N-cyclopropylmethyl-14β-ethyl-3hydroxy-6α-methylmorphinan (a) N-cyclopropylmethyl-14β-ethyl-
6α-Hydroxy-3-methoxy-6β-methylmorphinan N-cyclopropylmethyl-14β-ethyl-3-methoxymorphinan-6-one [prepared from the compound of Example (le) by a method analogous to Example 5] 0.769(
2.16 mmol) was added to 100 heads of ether at 0°C,
While stirring, add 16.3zc of a 1.6M ethereal solution of methyllithium.

The reaction mixture was gradually warmed to room temperature and after 3 hours, lO%
Decompose by adding 1011ρ of ammonium chloride solution. The ether layer is separated, dried over NatSO4, and concentrated to yield the title compound as a pale yellow oil. This product is used without further purification in the reaction to produce the compound described below.

(b) 0.89 (2,16 mmol) of the compound obtained with N-cyclopropylmethyl-5,6-(and 6°7-)didehydro-14β-ethyl-3-hydroxy-〇-methylmorphinan (lla) and pyridine hydrochloride 47 are heated to 180°C, and further pyridine hydrochloride 49 is added thereto over a period of 1.5 hours. After 4.5 hours, cool, add ice/aqueous ammonia and extract the mixture three times with ether. Dry and concentrate the organic layer to obtain a green-brown oil. This is chromatographed on silica gel (methylene chloride/methanol 98:2 to 95:5) to give a colorless oil.

The ratio of the two 5,6- and 6,7-didehydro forms is 5
:1.

(c) N-cyclopropylmethyl-14β-ethyl-
0.459 (1.33 mmol) of the compound obtained with 3-hydroxy-〇α-methylmorphinan (llb) was dissolved in 50 ml of glacial acetic acid and 2511.12 of water, and the pA
/('IInw)n'JaLhnchee r1stylenr'IL
Q@rT-7-E Hydrogenate for 15 hours. The reaction mixture is filtered and concentrated by evaporation, the residue is taken up in water 710% aqueous ammonia and extracted three times with ether. After drying the organic layer, it was concentrated and chromatographed on silica gel (
Methylene chloride/methanol/concentrated ammonia water 96:4:
0.2) gives the title compound as a colorless oil. This is crystallized as acidic maleate.

M, P,: 203-204°C Example 12 N-cyclopropylmethyl-4,5α-epoxy-14
β-ethyl-3,6β-dihydroxymorphinan, and N-cyclopropylmethyl-4,5α-epoxy-14
β-Ethyl-3,6α-dihydroxymorphinan 0.92 g (2,6 mmol) of the compound of Example 2 was dissolved in ethanol loOm (7) and 51 g (0,1
3 mmol) and stirred at room temperature for 4 hours. water 30
The reaction mixture was decomposed by adding sake and stirring for 30 minutes, the ethanol was distilled off, and the remaining aqueous layer was first mixed with water/
The mixture is made acidic by adding 3N-HCQ, and then made alkaline again with concentrated aqueous ammonia. The precipitated crystals are collected by filtration and recrystallized from ether to obtain the 6α-hydroxy isomer. M
, P,: 299°C (hydrochloride). Chromatography of the mother liquor on silica gel (methylene chloride/methanol/aqueous ammonia 96:4:0.2) gives the 6β-hydroxy isomer as a colorless oil. M, P,: 182~
184°C (acidic maleate).

Example 13 N-cyclopropylmethyl-14β-ethyl-6β-hydroxy-3-methoxymorphinan, and N-cyclopropylmethyl-14β-ethyl-6α-hydroxy-
3-Methoxymorphinan N-cyclopropylmethyl 14β-ether-3-methoxy2 (starting compound 10.9 59<2.7 mmol) was dissolved in 70 liters of ethanol, and NaBH. 0.5 3g
(0.14 mol) is added and the mixture is stirred at room temperature for 3 hours. The reaction mixture is decomposed by adding 20 rx (l) of water and stirring for 30 minutes. The ethanol is distilled off and the residue is extracted three times with methylene chloride. The organic layer is dried and concentrated to give a colorless oil. This is chromatographed on silica gel (methylene chloride/methanol/aqueous ammonia 99:1:0.H) to separate the two title compounds. Both compounds are isolated as colorless oils.

Example I4 14β-benzyl-N-cyclopropyl medyl-6β-hydroxy-3-methoxymorphinan, and 14β-
Benzyl-N-fucloprobylmethyl-6α-hydroxy-3-methoxymorphinan The above title compound is prepared from the compound of Example 5 by a method analogous to Example I3.

Example 15 14β-benzyl-N-cyclopropylmethyl-3.

6β-dihydroxymorphinan 6β-hydroxy isomer of Example 14 0.59 (1.

2 mmol) with 3.5 g of pyridine hydrochloride at 180
Heat to ℃. Pyridine hydrochloride 2 every 1.5 hours.

Add 59 each. After adding a total of 8.5 g of pyridine hydrochloride over a total of 4.5 hours, 10% aqueous ammonia is added and the mixture is extracted three times with ether.

The combined ether layers were dried, concentrated, and then chromatographed on silica gel (methylene chloride/methanol/
a aqueous ammonia 95:5:0.25) to obtain the title compound. M. P. :>280°C (hydrochloride).

Example 16 14β-benzyl-N-cyclopropylmethyl-3-hydroxy2 (a) 14β-benzyl-N-cyclopropylmethyl-
5,6-(and 6,7-)didehydro-3-hydroxymorphinan 6α-hydroxy isomer of Example 14 0.89 (1.

92 mol) and pyridine hydrochloride 69 are heated to 180° C., and 6 g of pyridine hydrochloride is added every 1.5 hours. After adding a total of 18 g of pyridine hydrochloride for a total of 5 hours, water/concentrated aqueous ammonia is added to the mixture, which is extracted three times with ether. After drying and concentration of the combined organic layers, chromatography on silica gel (methylene chloride/methanol/aqueous ammonia 99:I:0.1) yields the title compound as a colorless oil.

(b) 14β-benzyl-N-cyclopropylmethyl-
0.579 (1.48 mmol) of the compound obtained from 3-hydroxymorphinan (a) was dissolved in 60 mQ of glacial acetic acid and 30 mQ of water, and then 0.4 g of Pd/C (10%) was added thereto. and the mixture is hydrogenated for 15 hours at room temperature and 3-4 atm. After filtering the reaction mixture, it is concentrated, mixed with water/aqueous ammonia and extracted three times with ether. The organic layer is dried, concentrated and chromatographed on silica gel (methylene chloride/methanol/conc. aqueous ammonia 98:2:0.2) to give the title compound as a colorless oil. M. P. :>
280°C (hydrochloride).

Compounds of formula (1) (R9=cyclopropyl medyl, R3-hydrogen) not shown below were prepared from the corresponding starting compounds by methods similar to those of the above examples.
(In the table, malonate indicates acidic malonate.) Example 45 N-cyclopropylmethyl-14β-benzyl-3-hydroxy-6-methylene-morphinan NaH 760 mg
Wash with dry pentane. DMSO6xQ is added to this and the mixture is heated at 80°C for 30 minutes and then cooled to 0°C.

63g of methyltriphenylphosphonium bromide in DMSO
12ml and add this to the above solution. 15
After min, DMS of N-cyclopropylmethyl-14β-benzyl-3-hydroxymorphinan-6-one 19
O6112 solution was added to this at room temperature and the reaction mixture was heated to 60
Stir at ℃ for 12 hours. A solution of ice and 10% NH,CC is added until pH 7, then the solution is extracted three times with ether. Evaporate the solvent and add ethyl acetate/hexane (1:
The title compound is obtained by flash chromatography on the mixture of 8). Crystallizes as the hydrochloride salt from acetone. M, P: 212°C.

The compound of formula (1) has pharmacological activity and is therefore useful as a medicine.

These compounds have in particular morphine antagonist activity or mixed morphine agonistic and morphine antagonist activity.

Morphine antagonist activity was demonstrated by the test shown below. Female or male rats or mice weighing 20-25 g are used for this test.

Thirty minutes before the treatment, mice are secured in special Plexigiass tubes, allowing free movement with only the tail protruding from the tube. Using a high-density light, heat point stimulation is applied 35 mm from the root to the cranial side of the tail. The response is shown as a tail waggle. The latency (time from stimulus to onset of response) is measured 30 and 15 minutes before intracerebrovascular application of the test substance. Morphine is injected subcutaneously (5,6 m9/kg) 2 minutes after test substance administration. This dose is sufficient to cause an analgesic effect in 80-100% of mice (prolonging latency by 75% or more). Latency times are measured again 30 minutes after morphine administration (32 minutes after test substance administration). The compounds reduce the analgesic activity of morphine at about 0.5 to about 30 tng/g/p/o administration.

Morphine agonistic activity can be determined, for example, in the Arthritis Pain Test [
A.W. Pricio et al., European Journal of Pharmacology (Eur.

J, Pharmacol, ), vol. 31, 207-
Based on the test method described on page 15 (197.5)], this is evidenced by the analgesic activity.

Generally, compounds of formula (1) are morphine antagonists, but morphine agonist activity can be significantly increased by appropriate selection of substituent R4. For example, in formula (1), R is cyclopropylmethyl and R4
Compounds in which is the NHCO-A-GOOR' group exhibit significant analgesic activity.

In general, morphine agonists 17 rupine antagonists have a 0.5 to 30
Oral administration of m9/9 shows analgesic activity.

Due to their analgesic activity, these substances have application in the treatment of pain due to various causes.

Also, compounds of formula (1) having morphine antagonistic activity, especially compounds in formula (1) in which R4 is 1-1 or OH, or compounds in which R3 and R4 together form a 0 or CHI bridge. stimulates the secretion of luteinizing hormone (LH). This LH stimulating effect occurs, for example, from 15 minutes to 3 hours (for example, 1 hour) after administration of the test substance.
It can be determined by measuring the serum LH concentration of adult male rats subsequently acquired by radioimmunoassay. In this test, the compound was approximately 1-30 yg/kg
It shows activity when administered orally. Compounds of formula (I) in which R3 is phenyl exhibit particularly strong LH-stimulating effects.

Therefore, these compounds are opiate agonists/
Useful as an antagonist, especially R4
Compounds in which H or OH, or R1 and R4 taken together to form a bridge, are useful as luteinizing hormone stimulators. Those compounds are
Indications requiring luteinizing hormone stimulating activity, such as anovulatory syndrome, amenorrhea, infertility, idiopathic hypogonadotropic hypogonadism, secondary hypothalamic hypogonadism, Coleman syndrome, delayed puberty , hypothalamic LH, such as menstrual disorders in adolescence, and neurogenic incoherence, etc.
Applies to indications based on RH dysfunction. If possessing opiate antagonist activity, the compounds may be used in obesity, drug addiction, alcoholism, ataxia, hexagenic and endotoxic shock, cognitive disorders such as Alzheimer's disease, and immune system deficiency diseases, etc. .

Indications associated with LH stimulatory effects are preferred indications.

The compound of Example 6 is a preferred compound.

For all these indications, the precise dosage will, of course, vary depending on the compound used, the mode of administration, and the treatment desired.

Generally, it is about 0.2 to about 3(
Satisfactory results are obtained by administering a dose of JMg/kg. The dosage range encompasses the vi/kg range for test animals and humans, and also encompasses all modes of administration.

The daily dosage applied to large mammals is from about 1019 to about forty of the compound, e.g.
2 to 4 unit dosage forms containing ~50 mg per day.
It is conveniently administered in divided doses or in sustained release form.

The suitable daily dosage for a particular compound will depend on a number of factors, but will vary depending on the standard drug for the indication, e.g.
Naltrexone (naH) in the indication of LH stimulatory action
determined by relative potency to standard drugs such as rexone (rexone).

The compound of Example 6 was administered to adult male rats at a dose of 5 or 6 mg/
In the above-mentioned test C experiment, in which the serum LH concentration was orally administered at a dose of 9% to 90% after administration, and the serum LH concentration increased 1 hour after administration, the increase value was approximately 80%.
The waste was 9/IIQ (the control value was approximately 30JI9/1tQ).
). The standard drug naltrexone caused an increase in serum LH levels of approximately 70 mg/xQ.

In another experiment performed using the compound of Example 4, serum values determined in a similar manner were 9 (p.

o,) at 50 mg/rpQ, 3, 2 m9/kg (
p, o, ) at 54 locations/9.10 xg/&9(p, o
) is 68mg/kg, 32mg/kg is 75mg/k
qc control was 34m9/9). In addition, using the compound of Example 4, 32 m9/kqcp was obtained in the same manner.

In another experiment performed at a dose of 0, ), the serum L H concentration reached 148 mg/kg (9 to control value 44 H/kg).

The standard drug naltrexone rose to 93o/9 at the same dose.

Therefore, it was found that the compounds of Example 4 and Example 6 can be administered in the same or lower amounts than the conveniently used naltrexone.

The applicable dosage for large mammals is about 10 to 30 doses per day.
Shoulder 9.

In addition, the compound of Example 27 is acetamol (E
In the above-mentioned analgesic test for arthritis pain, in which D 50174 R9/ni9, p, o,) was compared as a control, EDs
o IH/kg (p, o, ). Based on this result, it was found that the compound of Example 27 was administered at a lower dose than paraacetamol in large mammals.

The compounds of this invention can be administered in free base form or in the form of pharmaceutically acceptable acid addition salts. Such salts can be made in conventional manner and have the same level of activity as the free base form. The invention also provides a pharmaceutical composition comprising a compound of the invention in free base form or in the form of a pharmaceutically acceptable acid addition salt, together with a pharmaceutical carrier or diluent. Such compositions can be formulated by conventional methods.

These compounds can be administered by any conventional route of administration, in particular enterally, preferably orally, e.g. in the form of tablets or capsules, or parenterally, e.g. as an injectable solution or It can be administered in the form of a suspension.

The present invention also provides a compound represented by formula (1) in the form of a free base or a pharmaceutically acceptable acid addition salt for pharmaceutical use, particularly for anovulatory syndrome, amenorrhea, infertility,
idiopathic hypogonadotropic hypogonadism, secondary hypothalamic hypogonadism, Coleman syndrome, delayed puberty, such as menstrual disorders in puberty, neurogenic incoherence, obesity,
drug dependence, alcoholism, ataxia, pachycardia or endotoxic shock, cognitive impairments such as Alzheimer's disease,
and for use as a medicine for immune system deficiency diseases, etc.

In one group of compounds, R1 is hydrogen or has 1-1 carbon atoms.
0 alkyl, phenyl or phenylalkyl having 7 to 12 carbon atoms, R3 and R4 have the same meanings as above, provided that R5 and R4 together are CHt, the free base of the group of compounds; or in the form of an acid addition salt.

In the first group of compounds, R, is allyl with optional substituents.

In the second group of compounds, R2 is cyclopropylmethyl.

In the third group of compounds, R1 is 3-furylmethyl.

In the fourth group of compounds, R1 is .

In the fifth group of compounds, Rt is alkyl.

In the sixth group of compounds, R7 is cycloalkyl.

In the seventh group of compounds, R7 is optionally substituted phenyl.

In the eighth group of compounds, R7 is optionally substituted phenylalkyl.

In group 9 of compounds, R3 is H.

In group 10 of compounds, N R3 is alkyl.

In Group 11 of compounds, R3 is phenyl.

In group 12 of compounds, R4 is H.

In the third group of compounds, R4 is OI-[.

In group 14 of compounds, R4 is NRaR7.

In group 15 of compounds, R4 is NC0r.

In group 16 of compounds, R4 is N1-15O2R'.

In group 17 of compounds, R4 is NH-COOR''.

In group 18 of compounds, R3 is in the alpha position.

In group 19 of compounds, R3 is in the β position.

In group 20 of compounds, R3 and R4 are O.

In Group 21 of compounds, R3 and R4 are CH.

In group 22 of compounds, R6 is CHs.

In Group 23 of compounds, R6 is ■].

Claims (1)

[Claims] 1. Formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, X and Y are each hydrogen, or together -O-, R_1 is the desired allyl optionally substituted by 1 to 3 alkyl (wherein the substituents have a total of up to 3 carbon atoms), cyclopropylmethyl or 3-furylmethyl, R_2 is hydrogen, 1 carbon atom ~10 alkyl, cycloalkyl having 5 or 6 carbon atoms, phenyl optionally having a substituent, or having 7 to 12 carbon atoms optionally having a substituent phenylalkyl, R_3 is hydrogen, alkyl having 1 to 10 carbon atoms, or phenyl, R_4 is hydrogen, OH, NR_6R_7, NHCOR, N
HSO_2R', or NHCOOR'', R_6 and R_7 are each independently hydrogen or alkyl having 1 to 3 carbon atoms, R is alkyl having 1 to 6 carbon atoms, phenyl, or -A-COOR'', A are alkylene or alkenylene each having 2 to 4 carbon atoms, R' is alkyl having 1 to 6 carbon atoms, or phenyl, R'' is methyl or ethyl, where if R_3 is in the alpha position, R_4 is β position, R_3 is β
, then R_4 is α, or R_3 and R_4 together are =O or =CH_2 and R
_5 is hydrogen or methyl. However, X+Y is -O-, R_2 is hydrogen, R_4 is α-OH group, R_3 and R_
When 5 is hydrogen, R_1 is a group other than cyclopropylmethyl and allyl, and when R_2, R_3, R_4 and R_5 are all hydrogen, R_1 is a group other than cyclopropylmethyl. Free bases or acid addition salts of the compounds represented by the following: and, when those compounds have a free 0H group, free bases or acid addition salts of physiologically hydrolyzable, pharmaceutically acceptable ester compounds thereof. 2, R_2 is hydrogen, alkyl having 1 to 10 carbon atoms,
Phenyl or phenylalkyl having 7 to 12 carbon atoms, R_3 and R_4 have the same meanings as in claim 1, except when R_3 and R_4 together represent CH2 A free base or acid addition salt of a compound according to claim 1. 3. The free base or acid addition salt of the compound according to claim 1, wherein R_1 is cyclopropylmethyl. 4. A compound according to claim 1 consisting of N-cyclopropylmethyl-14β-benzyl-3-hydroxymorphinan-6-one in the form of the free base or acid addition salt. 5. A method for producing the effect of an opiate antagonist/agonist, which comprises administering to a subject in need of treatment an effective amount of a compound according to claim 1 in order to produce the effect of an opiate antagonist/agonist. 6. A method for stimulating the secretion of luteinizing hormone, which comprises administering to a subject in need of treatment an effective amount of the compound according to claim 1 in order to stimulate the secretion of luteinizing hormone. 7. Anovulation syndrome, amenorrhea, infertility, idiopathic hypogonadotropic hypogonadism, secondary hypothalamic hypogonadism, Coleman syndrome, delayed puberty, menstrual disorders, anorexia nervosa, obesity For the treatment of drug addiction, alcoholism, movement disorders, cardiac and endotoxic shock, cognitive disorders such as Alzheimer's disease, or immune system modulation, the claims are directed to a subject in need of treatment. A method of treating a subject as described above comprising administering an effective amount of a compound according to paragraph 1. 8. A pharmaceutical composition comprising a free base or pharmaceutically acceptable acid addition salt form of a compound according to claim 1 together with a pharmaceutical carrier or diluent. 9. Formulas (III), (IV), (V), (VI) listed below
, (VII), (VIII), (IX) or (X): ▲ Formula,
There are chemical formulas, tables, etc. ▼ (III) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (V) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VI) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VII) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VIII) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IX) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (X ) (In the formula, each substituent has the same meaning as described in claim 1, and the arrangement of the chiral carbon atoms at the 5th, 9th, and 13th positions is the same as in thebaine.) Compound. 10. Formula (X I ), (XIII), or (XIV): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (X I ) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (XIII) ▲ Mathematical formulas, chemical formulas, tables, etc. There are compounds shown as ▼(XIV).