WO2014157437A1 - Propellane derivative - Google Patents

Abstract

A propellane derivative represented by general formula (I) (wherein R¹ represents a hydrogen atom, a C_1-6 alkyl group, a cycloalkylalkyl group (wherein the number of carbon atoms in a cycloalkyl moiety is 3 to 6 and the number of carbon atoms in an alkylene moiety is 1 to 5), an aralkyl group (wherein the number of carbon atoms in an aryl moiety is 6 to 10 and the number of carbon atoms in an alkylene moiety is 1 to 5) or the like; R² represents a hydroxy group, a C_1-6 alkoxy group or the like; V represents CH or N; W, X, Y and Z independently represent CR³ or N, wherein a case in which each of W, X, Y and Z represents N is excluded, and W, X, Y and Z may be the same as or different from one another when each of at least two of W, X, Y and Z represents CR³; and R³ represents a hydrogen atom, a halogen atom, a nitro group, a C_1-6 alkyl group or the like), a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound, or a solvate of the compound or the tautomer, stereoisomer or pharmaceutically acceptable salt, which can be used as an analgesic agent or the like.

Description

Properan derivatives

The present invention relates to a propeller derivative having an opioid δ receptor agonistic action.

Three types of opioid receptors, μ, δ, and κ, are known, and morphine that exhibits a strong affinity for μ receptors has long been used as an analgesic. Although the analgesic action of morphine is powerful, it is known to cause adverse events such as dependence formation, respiratory depression, and constipation through the μ receptor.
On the other hand, δ receptors also have analgesic effects, but δ receptor agonists are known not to participate in adverse events seen in morphine.
Therefore, it is considered that an agonist selective for the δ receptor may be an analgesic superior to morphine, and research on its creation has been actively conducted. It has also been reported that δ receptor agonists can become anxiolytics and antidepressants (Non-Patent Documents 1 to 7).
However, no δ receptor agonist has yet been approved as a therapeutic or prophylactic agent.
In Patent Document 1, the following formula (A),

It is described that the compound represented by the formula has an opioid δ receptor agonistic action.

Further, in Non-Patent Document 8, the following formula (B),

In this report, the compound has a higher affinity for the mu receptor than for the delta receptor.

On the other hand, as an opioid receptor agonist having a propeller skeleton, Non-Patent Document 9 discloses that the following formula (C),

In the above structural formula, when R ³ is phenethyl, the compound has a high affinity for the μ receptor, and when 2- (furan-3-yl) ethyl is used, the κ receptor has a high affinity.
In addition, in Patent Document 2 and Non-Patent Document 10, the present inventors provide the following formula (D),

However, it has been reported that this compound has a low affinity for the δ receptor and a high affinity for the κ receptor.

The compounds represented by the above formulas (C) and (D) are structurally different from the compounds of the present invention in which a bicyclic nitrogen-containing heterocycle such as quinoline is condensed to the propeller skeleton represented by the following general formula (I). There is a clear difference.

On the other hand, as an opioid receptor agonist / antagonist in which a bicyclic nitrogen-containing heterocycle is condensed to a propeller skeleton, claim 1 of Patent Document 3 includes the following general formula (E),

(Wherein R is H or C _1-10 alkyl, etc., X is H, OH or C _1-6 alkoxy, etc., Y part is benzene etc. condensed with a 5-6 membered aromatic heterocycle)
The compound represented by these is described.

However, the compound specifically described in this patent has the general formula (E) in which the Y moiety is only indole or N-methylindole, and the propeller skeleton represented by the following general formula (I) has a quinoline ring. There is no description of the compound of the present invention in which a bicyclic nitrogen-containing heterocyclic ring such as naphthylidine ring or quinoxaline ring is condensed, and there is a description that these compounds have high affinity for the μ receptor.

WO 2008/001859 JP2008-179556 Chinese Patent Publication 101402636

An object of the present invention is to provide a propeller derivative represented by the following general formula (I), a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate of the compound, and a solvate thereof. The object is to provide analgesics, anxiolytics and antidepressants contained as ingredients.

That is, the present invention includes the following general formula (I):

Wherein R ¹ is (a) hydrogen, (b) C _1-6 alkyl, (c) C _6-10 aryl, (d) C _2-6 alkenyl, (e) cycloalkylalkyl (of the cycloalkyl moiety The number of carbon atoms is 3 to 6, the number of carbon atoms in the alkylene portion is 1 to 5.), (f) Aralkyl (the number of carbon atoms in the aryl portion is 6 to 10, and the number of carbon atoms in the alkylene portion is 1 to 5. ), (G) C _3-6 cycloalkyl or (h) heteroarylalkyl (wherein heteroaryl contains 1 to 4 heteroatoms selected from N, O and S as ring members and is a carbon atom of an alkylene moiety) The number represents 1-5.)
Where (b) C _1-6 alkyl of R ¹
(E) alkylene and cycloalkyl moieties of cycloalkylalkyl (wherein the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms),
(F) an alkylene moiety of aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and (h) a heteroarylalkyl (heteroaryl is derived from N, O and S) An alkylene moiety comprising 1 to 4 selected heteroatoms as ring-constituting atoms, and the alkylene moiety having 1 to 5 carbon atoms)
_1-6 halogens, hydroxy, C _1-6 alkoxy, C _6-10 aryloxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, carboxyl and alkoxycarbonyl (the number of carbon atoms in the alkoxy moiety is _1-6 )) May be substituted with at least one substituent selected from
And (c) C _6-10 aryl of R ¹
(F) an aryl moiety of aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and (h) a heteroarylalkyl (heteroaryl is derived from N, O and S) A heteroaryl moiety comprising 1 to 4 selected heteroatoms as ring member atoms, and the alkylene moiety having 1 to 5 carbon atoms).
C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkanoyloxy, hydroxy, alkoxycarbonyl (the alkoxy moiety has 1 to 6 carbon atoms), carbamoyl, alkylcarbamoyl (the alkyl moiety has 1 carbon atom) 6)), dialkylcarbamoyl (the alkyl part has 1 to 6 carbon atoms), halogen, nitro, cyano, C _1-6 alkyl substituted with 1 to 3 halogens, 1 to 3 halogens Substituted C _1-6 alkoxy, phenyl, heteroaryl (including 1 to 4 heteroatoms selected from N, O and S as ring members), phenoxy, phenylalkyl (the number of carbon atoms of alkyl is 1 to 3), optionally substituted with at least one substituent selected from methylenedioxy and NR ⁴ R ⁵ ,
Wherein R ⁴ and R ⁵ are each independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, C _1-6 alkanoyl, or alkoxycarbonyl (the number of carbon atoms in the alkoxy moiety) 1 to 6)), or R ⁴ and R ⁵ may contain a hetero atom selected from N, O and S together with the N atom to which they are bonded. A 7-membered ring may be formed,
R ² is hydrogen, hydroxy, halogen, cyano, carbamoyl, C _1-6 alkoxy, C _6-10 aryloxy, C _1-6 alkanoyloxy, nitro, amino, C _1-8 alkylamino, aralkylamino (of the aryl moiety) The number of carbon atoms is 6 to 10, the number of carbon atoms of the alkylene moiety is 1 to 5.) or acylamino (the number of carbon atoms of the acyl moiety is 2 to 6);
V represents CH or N;
W, X, Y and Z each independently represent CR ³ or N.
However, W, X, Y and Z are not N at the same time, and when two or more of W, X, Y and Z are CR ³ , these may be the same or different.
R ³ is hydrogen, halogen, nitro, C _1-6 alkyl, hydroxy, C _1-6 alkoxy, C _1-6 alkyl substituted with 1 to 3 halogens, hydroxy substituted C _1-6 alkyl, to three halogen substituted _{C 1-6} alkoxy, hydroxy substituted _{C 1-6 alkoxy, C 1-6 C 1-6} alkyl alkoxy-substituted phenyl, cyano, isothiocyanato, ^SR 6, _{^{SOR 6, SO 2 R 6,}} (CH 2) r COOR 6, SO 2 NR 7 R 8, CONR 7 R 8, (CH 2) r NR 7 R 8 or ^{_{(CH 2) r N (R}} 7) COR 8 Or two R ³ bonded to adjacent carbons together represent methylenedioxy,
Here, R ⁶ represents hydrogen or C _1-6 alkyl,
R ⁷ and R ⁸ each independently represent hydrogen, C _1-6 alkyl or cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms). ,
R represents an integer of 0 to 5. )

Or a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound or a solvate thereof.

The present invention also relates to a pharmaceutical comprising the propellane derivative represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof. .
The present invention also includes a propellane derivative represented by the above general formula (I), a tautomer, stereoisomer, pharmaceutically acceptable salt thereof or solvate thereof as an active ingredient. It is related with the pharmaceutical composition to contain.
The present invention also includes a propellane derivative represented by the above general formula (I), a tautomer, stereoisomer, pharmaceutically acceptable salt thereof or solvate thereof as an active ingredient. It relates to analgesics containing.
The present invention also includes a propellane derivative represented by the above general formula (I), a tautomer, stereoisomer, pharmaceutically acceptable salt thereof or solvate thereof as an active ingredient. It relates to the anxiolytic drug contained.
Furthermore, the present invention provides a propeller derivative represented by the above general formula (I), a tautomer, stereoisomer, pharmaceutically acceptable salt of the compound or a solvate thereof as an active ingredient. As an antidepressant.

Next, the present invention will be described in more detail.
Among the propeller derivatives represented by the above general formula (I), tautomers, stereoisomers, pharmaceutically acceptable salts or solvates thereof, the following are preferable. It is done.
(1)
R ¹ is hydrogen, C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has carbon atoms 6 to 10 and the alkylene moiety has 1 to 5 carbon atoms.) The propeller derivative represented by the above general formula (I), a tautomer, stereoisomer or pharmaceutically acceptable compound thereof Salts or solvates thereof.
(2)
R ¹ is C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms). 10 wherein the alkylene moiety has from 1 to 5 carbon atoms, wherein the alkyl moiety is substituted by either hydroxy, _1-6 halogen, or C _1-6 alkoxy. A propellane derivative represented by I), a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound or a solvate thereof.
(3)
A propellane derivative represented by the above general formula (I), wherein R ² is hydroxy, C _1-6 alkoxy, C _1-6 alkanoyloxy, or carbamoyl, or the propellane derivative described in (1) or (2) above, A tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
(4)
The propeller derivative represented by the above general formula (I), wherein R ² is hydroxy or C _1-6 alkoxy, or the propeller derivative described in the above (1) or (2), a tautomer or stereoisomer of the compound Or a pharmaceutically acceptable salt thereof or a solvate thereof.
(5)
The propeller derivative represented by the above general formula (I) in which V is CH, or the propeller derivative described in the above (1) to (4), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof Salts or solvates thereof.
(6)
W, X, Y and Z are the same or different and CR ³ is the propeller derivative represented by the above general formula (I), or the propeller derivative described in the above (1) to (5), a tautomer of the compound, A stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
(7)
W, X, Y and Z are the same or different and are selected from CH, C—C _1-6 alkyl, C-halogen, C-hydroxy and C—C _1-6 alkoxy; Or a propeller derivative described in (1) to (5) above, a tautomer, stereoisomer, pharmaceutically acceptable salt of the compound, or a solvate thereof.
(8)
A propellane derivative represented by the above general formula (I) wherein W, X, Y and Z are CH, or a propeller derivative described in the above (1) to (5), a tautomer, a stereoisomer of the compound, Or a pharmaceutically acceptable salt thereof or a solvate thereof.
(9)
R ¹ is hydrogen, C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has carbon atoms 6 to 10 and the alkylene moiety has 1 to 5 carbon atoms.)
R ² is hydroxy or C _1-6 alkoxy, and
V, W, X, Y and Z are the propeller derivatives represented by the above general formula (I), wherein the compound is a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or their Solvate.
(10)
R ¹ is hydrogen, C _1-6 alkyl or aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms);
R ² is hydroxy or C _1-6 alkoxy, and
V, W, X, Y and Z are the propeller derivatives represented by the above general formula (I), wherein the compound is a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or their Solvate.
(11)
R ¹ is hydrogen, C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has carbon atoms 6 to 10 and the alkylene moiety has 1 to 5 carbon atoms.)
R ² is C _1-6 alkoxy and
V, W, X, Y and Z are the propeller derivatives represented by the above general formula (I), wherein the compound is a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or their Solvate.
(12)
R ¹ is C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms). 10 wherein the alkylene moiety has from 1 to 5 carbon atoms, and the alkyl moiety is substituted by either hydroxy, _1-6 halogen, or C _1-6 alkoxy;
R ² is hydroxy, C _1-6 alkoxy, C _1-6 alkanoyloxy, or carbamoyl;
V is CH,
W, X, Y, and Z are the same or different and CR ³ is a propellan derivative represented by the above general formula (I), a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound, or Their solvates.
(13)
R ¹ is C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms). 10 wherein the alkylene moiety has from 1 to 5 carbon atoms, and the alkyl moiety is substituted by either hydroxy, _1-6 halogen, or C _1-6 alkoxy;
R ² is hydroxy, C _1-6 alkoxy, C _1-6 alkanoyloxy, or carbamoyl;
V is CH,
W, X, Y and Z are the same or different and are selected from CH, C—C _1-6 alkyl, C-halogen, C-hydroxy and C—C _1-6 alkoxy; Or a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
(14)
R ¹ is C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms). 10 wherein the alkylene moiety has from 1 to 5 carbon atoms, and the alkyl moiety is substituted by either hydroxy, _1-6 halogen, or C _1-6 alkoxy;
R ² is hydroxy, C _1-6 alkoxy, C _1-6 alkanoyloxy, or carbamoyl;
V is CH,
A propellane derivative represented by the above general formula (I) wherein W, X, Y and Z are CH, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof; object.
(15)
R ¹ is C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms). 10 wherein the alkylene moiety has from 1 to 5 carbon atoms, and the alkyl moiety is substituted by either hydroxy, _1-6 halogen, or C _1-6 alkoxy;
R ² is hydroxy or C _1-6 alkoxy,
V is CH,
W, X, Y, and Z are the same or different and CR ³ is a propellan derivative represented by the above general formula (I), a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound, or Their solvates.
(16)
R ¹ is C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms). 10 wherein the alkylene moiety has from 1 to 5 carbon atoms, and the alkyl moiety is substituted by either hydroxy, _1-6 halogen, or C _1-6 alkoxy;
R ² is hydroxy or C _1-6 alkoxy,
V is CH,
W, X, Y and Z are the same or different and are selected from CH, C—C _1-6 alkyl, C-halogen, C-hydroxy and C—C _1-6 alkoxy; Or a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
(17)
R ¹ is C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms). 10 wherein the alkylene moiety has from 1 to 5 carbon atoms, and the alkyl moiety is substituted by either hydroxy, _1-6 halogen, or C _1-6 alkoxy;
R ² is hydroxy or C _1-6 alkoxy,
V is CH,
A propellane derivative represented by the above general formula (I) wherein W, X, Y and Z are CH, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof; object.
(18)
R ¹ is cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and the alkyl moiety is hydroxy, 1 to 6 halogens, Or substituted by either C _1-6 alkoxy,
R ² is hydroxy, C _1-6 alkoxy, C _1-6 alkanoyloxy, or carbamoyl;
V is CH,
W, X, Y, and Z are the same or different and CR ³ is a propellan derivative represented by the above general formula (I), a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound, or Their solvates.
(19)
R ¹ is cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and the alkyl moiety is hydroxy, 1 to 6 halogens, Or substituted by either C _1-6 alkoxy,
R ² is hydroxy, C _1-6 alkoxy, C _1-6 alkanoyloxy, or carbamoyl;
V is CH,
W, X, Y and Z are the same or different and are selected from CH, C—C _1-6 alkyl, C-halogen, C-hydroxy and C—C _1-6 alkoxy; Or a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
(20)
R ¹ is cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and the alkyl moiety is hydroxy, 1 to 6 halogens, Or substituted by either C _1-6 alkoxy,
R ² is hydroxy, C _1-6 alkoxy, C _1-6 alkanoyloxy, or carbamoyl;
V is CH,
A propellane derivative represented by the above general formula (I) wherein W, X, Y and Z are CH, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof; object.
(21)
R ¹ is cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and the alkyl moiety is hydroxy, 1 to 6 halogens, Or substituted by either C _1-6 alkoxy,
R ² is hydroxy or C _1-6 alkoxy,
V is CH,
W, X, Y, and Z are the same or different and CR ³ is a propellan derivative represented by the above general formula (I), a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound, or Their solvates.
(22)
R ¹ is cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and the alkyl moiety is hydroxy, 1 to 6 halogens, Or substituted by either C _1-6 alkoxy,
R ² is hydroxy or C _1-6 alkoxy,
V is CH,
W, X, Y and Z are the same or different and are selected from CH, C—C _1-6 alkyl, C-halogen, C-hydroxy and C—C _1-6 alkoxy; Or a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
(23)
R ¹ is cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and the alkyl moiety is hydroxy, 1 to 6 halogens, Or substituted by either C _1-6 alkoxy,
R ² is hydroxy or C _1-6 alkoxy,
V is CH,
A propellane derivative represented by the above general formula (I) wherein W, X, Y and Z are CH, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof; object.

In this patent,
C _1-6 alkyl includes methyl, ethyl, propyl, i-propyl, butyl, t-butyl, pentyl, neopentyl, hexyl and the like.
C _1-6 alkyl substituted with 1 to 3 halogens includes 2-chloroethyl, 2-fluoroethyl, 3-fluoropropyl, 2,2-difluoroethyl, trifluoromethyl or 3,3,3-trimethyl Examples include fluoropropyl.
Examples of C _2-6 alkenyl include 2-propenyl and 3-methyl-2-butenyl.
Cycloalkylalkyl (wherein the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms) is substituted with C _3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl Methyl, ethyl and the like.
Aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms) includes a benzyl group or a phenethyl group.
C _3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
C _6-10 aryl includes phenyl or naphthyl.
Examples of heteroaryl (including 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms) include pyridyl, furyl, imidazolyl, pyrimidinyl, pyrazinyl and thiazolyl.
Heteroarylalkyl (heteroaryl contains 1 to 4 heteroatoms selected from N, O and S as ring members, and the alkylene moiety has 1 to 5 carbon atoms) includes (pyridine-2- Yl) methyl, (pyridin-3-yl) methyl, (pyridin-4-yl) methyl, (furan-2-yl) methyl, (furan-3-yl) methyl, (imidazol-2-yl) methyl, Imidazol-4-yl) methyl, (imidazol-5-yl) methyl, (thiazol-2-yl) methyl, (thiazol-4-yl) methyl, (thiazol-5-yl) methyl, 2- (pyridin-2) -Yl) ethyl, 2- (pyridin-3-yl) ethyl, 2- (pyrazol-1-yl) ethyl, 2- (thiophen-2-yl) ethyl, or 2- (thiophene-3) Yl) ethyl, and the like.

Examples of C _1-6 alkanoyl include acetyl and propionyl.
_{Examples of} C _1-6 alkoxy include methoxy, ethoxy, propoxy and the like.
Examples of C _1-6 alkanoyloxy include acetoxy and the like.
Examples of alkoxycarbonyl (the number of carbon atoms in the alkoxy moiety is 1 to 6) include methoxycarbonyl and ethoxycarbonyl.
Examples of the halogen include fluorine, chlorine, bromine and the like.
Examples of C _1-6 alkoxy substituted with 1 to 3 halogens include fluoromethoxy and trifluoromethoxy.
Examples of phenylalkyl (the number of carbon atoms in the alkylene moiety is 1 to 3) include benzyl and the like.
_{Examples of} C _6-10 aryloxy include phenoxy.
_{Examples of} C _1-8 alkylamino include methylamino and ethylamino.
Examples of aralkylamino (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms) include benzylamino and the like.
Examples of acylamino (acyl moiety has 2 to 6 carbon atoms) include acetylamino and the like.
Examples of the alkylcarbamoyl (the alkyl moiety has 1 to 6 carbon atoms) include ethylcarbamoyl and the like.
Examples of the dialkylcarbamoyl (the alkyl moiety has 1 to 6 carbon atoms) include diethylcarbamoyl and the like.
Examples of the C _1-6 alkyl substituted with hydroxy include 2-hydroxyethyl and the like.
Examples of the C _1-6 alkoxy substituted with hydroxy include 2-hydroxyethoxy and the like.
The 4- to 7-membered ring in which R ⁴ , R ⁵ and the N atom are combined and may further contain a heteroatom selected from N, O and S includes a piperidine ring, a piperazine ring or a morpholine ring. Can be mentioned.

In the propeller derivatives represented by the above general formula (I), tautomers, stereoisomers or pharmaceutically acceptable salts of the compounds, the pharmaceutically acceptable salt is preferably an acid addition. Examples of the acid addition salt include salts with organic acids or inorganic acids such as hydrochloride, sulfate, fumaric acid, oxalate, methanesulfonate, camphorsulfonate, and the like.

In the propeller derivatives represented by the above general formula (I), tautomers, stereoisomers, pharmaceutically acceptable salts or solvates thereof, the stereoisomers include cis, trans Examples include isomers, racemates and optically active substances.
In the propeller derivatives represented by the above general formula (I), tautomers, stereoisomers, or pharmaceutically acceptable salts of the compounds or solvates thereof, the solvates are the present invention. Or a pharmaceutically acceptable solvate thereof, including hydrates.

Next, a method for producing a propellane derivative represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof is shown below.

(Production method 1)
When the propeller derivative represented by the above general formula (I), R ¹ is cyclopropylmethyl, R ² is C _1-6 alkoxy or hydroxy, and V is CH:

(Wherein R ²⁰ represents C _1-6 alkoxy, and W, X, Y, and Z are as defined above.)

First Step The compound (c) of the present invention is synthesized from the compound (a) by any of the following methods. Compound (a) as a starting material is synthesized by a known method (J. Org. Chem., 2008, 73, 8093 and Bioorg. Med. Chem. Lett., 2011, 21, 4104) and a method analogous thereto.
Method a :
A method of reacting compound (a) with compound (b) in the presence of an acid such as methanesulfonic acid in a solvent such as ethanol.
Method b :
A method of reacting compound (a) with compound (a) in the presence of a base such as potassium hydroxide in a solvent such as ethanol-water.

Second Step The compound (d) of the present invention in which R ^{2 in the} general formula (I) is hydroxy is synthesized from the compound (c) by either the following method or a method analogous thereto.
A method of reacting boron tribromide in a solvent such as dichloromethane,
Method of causing alkanethiol such as 1-dodecanethiol to act in the presence of a base such as potassium t-butoxide in a solvent such as N, N-dimethylformamide (DMF) Method of heating in the presence of pyridinium hydrochloride

(Production method 2)
In Propellane derivative represented by the general formula (I), when the ^R 1, ^{R 2} is _{C 1-6} alkoxy or hydroxy ^{R 1} is other than cyclopropylmethyl, V is CH:
Method A :

(In the formula, R ¹⁰ other than cyclopropylmethyl represents R ¹ , R ²⁰ represents C _1-6 alkoxy, and W, X, Y and Z are the same as above.)

The first step compound (e) is prepared by a known de-N-alkylation method (Bioorg. Med. Chem. Lett., 2010, 20) comprising the reaction of compound (a) with chloroformate and subsequent decarbamate reaction. , 6302 etc.) or a method analogous thereto.

Second Step The compound (f) of the present invention is synthesized from the compound (e) according to the method described in the first step of production method 1.

Third Step The compound (c-1) of the present invention is synthesized from the compound (f) by a normal N-alkylation reaction, a reductive amination reaction, or a reduction reaction with lithium aluminum hydride followed by amidation. .

Fourth Step The compound (d-1) of the present invention is synthesized from the compound (c-1) according to the method described in the second step of Production Method 1.

Method B :

(In the formula, R ¹⁰ other than cyclopropylmethyl represents R ¹ , R ²⁰ represents C _1-6 alkoxy, and W, X, Y and Z are the same as above.)

The first step compound (h) is synthesized from the compound (g) by the method described in the first step in Method A of Production Method 2 or a method using diethyl azodicarboxylate (Synthetic Communications, 1995, 25, 829, etc.). The Compound (g) as a starting material is synthesized by a known method (J. Org. Chem., 2008, 73, 8093 and Bioorg. Med. Chem. Lett., 2011, 21, 4104) and a method analogous thereto.

The second step compound (i) is synthesized from compound (h) according to the method described in the third step in Method A of Production Method 2.

The third step compound (a-1) is synthesized by reacting compound (i) with a mineral acid such as hydrochloric acid in a solvent such as tetrahydrofuran (THF) or methanol. As the acid, a Lewis acid may be used instead of the mineral acid.

Using the methods described in the first and second steps of the fourth and fifth step production method 1, the compounds (c-1) and (d-1) of the present invention are synthesized, respectively.

(Production method 3)
When the propeller derivative represented by the above general formula (I) is R ² is hydrogen, cyano or CONH ₂ , and V is CH:

(Wherein R ²¹ represents hydrogen, cyano or CONH ₂ , and R ¹ , W, X, Y and Z are the same as described above.)

The compound (k) of the present invention in which R ^{2 in the} general formula (I) is hydrogen, cyano or CONH ₂ is obtained from the compound (j) using the method described in the first step of production method 1 and a method analogous thereto. Can be synthesized. The starting material (j) is synthesized from the compound (l) by any of the following methods.

When R ²¹ is hydrogen:

(Wherein R ²⁰ represents C _1-6 alkoxy, and R ¹ is as defined above.)

Compound (m) from the first step compound (l) [synthesized by the method described in J. Org. Chem., 2008, 73, 8093 and Bioorg. Med. Chem. Lett., 2011, 21, 4104] The conversion to is carried out by a method in which an alkanethiol such as 1-dodecanethiol is allowed to act in the presence of a base such as potassium t-butoxide in a solvent such as DMF and the like.

The conversion from the second step compound (m) to compound (n) is carried out by trifluoromethanesulfonylation reaction using N-phenylbis (trifluoromethanesulfonimide) or trifluoromethanesulfonic anhydride.

The conversion from the third step compound (n) to the compound (o) is performed by a reduction reaction under a palladium catalyst (such as the method described in Tetrahedron Letters, 2010, 51, 2359).

The conversion from the fourth step compound (o) to the compound (j-1) is performed according to the method described in the third step in Method B of Production Method 2 and a method analogous thereto.

(2) When R ² = cyano, CONH ₂

(In the formula, R ¹ is the same as above.)

The first step compound (p) is synthesized from the compound (n) by a cyanation reaction under a palladium catalyst.

The conversion from the second step compound (p) to the compound (j-2) is performed according to the method described in the third step in Method B of Production Method 2 and a method analogous thereto.

The third step compound (j-3) is synthesized from the compound (j-2) using a usual hydrolysis reaction in addition to the method shown in the above reaction formula.

(Production Method 4)
When the propeller derivative represented by the above general formula (I) is R ² is amino and V is CH:

(Wherein CBz represents a benzyloxycarbonyl group, and R ¹ , W, X, Y and Z are the same as above).

The first step compound (q) is carried out by a cross-coupling reaction between compound (n) and benzophenone imine in the presence of a palladium catalyst, followed by an acid hydrolysis reaction.

The second step compound (r) is synthesized by reacting compound (q) with benzyl chloroformate in the presence of a base such as triethylamine in a solvent such as dichloromethane.

The third step compound (s) is synthesized by one of the methods described in the first step of production method 1 or a method analogous thereto.

Fourth Step Conversion of the compound (s) of the present invention into the compound (t) is carried out by catalytic hydrogenation using palladium-carbon or the like, or acid treatment using hydrogen bromide / acetic acid or the like.

(Production method 5)
In the case of the propeller derivative represented by the above general formula (I), R ² is C _1-6 alkoxy or hydroxy, and V is N:

(Wherein R ²⁰ represents C _1-6 alkoxy, and R ¹ , W, X, Y and Z are the same as defined above.)

The compound (x) of the present invention can be obtained from the compound (a-2) to the compound (a) according to the method shown in the above reaction route (method according to the reaction route described in J. Med. Chem. 1991, 34, 1715). It is synthesized via u) and the inventive compound (w).

Other compounds included in the general formula (I) can also be produced by a combination of the above synthesis methods and the methods described in Examples below.

Next, the results of pharmacological experiments will be described.
As described in Table 1 of Example 12 below, the propeller derivatives represented by the above general formula (I), tautomers, stereoisomers, or pharmaceutically acceptable salts of the compounds or their solvents The sum exhibited selective affinity for the opioid δ receptor in tests for binding affinity for μ, δ and κ opioid receptors.
As described in Table 2 of Example 13 below, the propeller derivatives represented by the above general formula (I), tautomers, stereoisomers, or pharmaceutically acceptable salts of the compounds or their solvents In the opioid receptor functional test, the Japanese product was found to have excellent agonist activity for the δ receptor.

Therefore, the propeller derivatives represented by the above general formula (I), tautomers, stereoisomers, or pharmaceutically acceptable salts of the compounds or solvates thereof prevent acute pain and chronic pain. It can be used as a prophylactic and therapeutic agent for pain treatment in accompanying diseases, rheumatoid arthritis, osteoarthritis, cancer pain with strong pain such as bone tumor, diabetic neuropathic pain, postherpetic neuralgia, visceral pain, etc. it can.
In addition, the propeller derivatives represented by the above general formula (I), tautomers, stereoisomers, pharmaceutically acceptable salts or solvates thereof, such as depression, panic disorder, Drugs for anxiety, stress disorders (PTSD, acute stress disorder), and other mental disorders with anxiety (antidepressants, anxiolytics, etc.) include urinary incontinence, myocardial ischemia, hypertension, Parkinson's disease It can be used as a prophylactic and therapeutic drug.

The propeller derivatives represented by the above general formula (I), tautomers, stereoisomers or pharmaceutically acceptable salts of the compounds or solvates thereof are administered orally to humans or not It can be administered by an appropriate administration method such as oral administration. It can also be used in combination with other analgesics.
For formulation, it can be produced into a dosage form such as a tablet, granule, powder, capsule, suspension, injection, suppository and the like by a conventional method in the technical field of formulation.
For these preparations, for example, in the case of tablets, usual excipients, disintegrants, binders, lubricants, pigments and the like are used. Here, as the excipient, lactose, D-mannitol, crystalline cellulose, glucose and the like are used, as the disintegrant, starch, carboxymethylcellulose calcium (CMC-Ca), etc., as the lubricant, magnesium stearate, Examples of binders include talc and the like, and hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP), and the like. Solvents, stabilizers, solubilizers, suspending agents, emulsifiers, soothing agents, buffers, preservatives and the like are used for the preparation of injections.
In general, for adults, the active ingredient is the propeller derivative represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound or a pharmaceutically acceptable salt thereof. The solvate is administered at 0.1 μg to 1 g / day, preferably 0.001 to 200 mg / day for injection, and 1 μg to 10 g / day, preferably 0.01 to 2000 mg / day for oral administration. However, it can be increased or decreased depending on age, symptoms, etc.
Next, although a reference example and an example are given and the present invention is explained still in detail, the present invention is not limited to these.

(6aR, 11aS) -15- (Cyclopropylmethyl) -8-methoxy-11,12-dihydro-6H-6a, 11a- (ethanoiminomethano) indeno [2,1-b] acridine (2)

Compound 1 (61.1 mg, 0.188 mmol) [compound described in J. Org. Chem. 2008, 73, 8093. and Bioorg. Med. Chem. Lett., 2011, 21, 4104.] under an argon atmosphere After dissolving in ethanol (10 mL), 2-aminobenzaldehyde (91.0 mg, 0.751 mmol) and methanesulfonic acid (48.7 μL, 0.751 mmol) were added, and the mixture was refluxed for 12 hours. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by preparative TLC to give the title compound 2 (27.0 mg, 35%) as a yellow oil.

¹ H NMR (300 MHz, CDCl ₃ ): δ 0.01-0.09 (m, 2H), 0.42-0.52 (m, 2H), 0.74-0.89 (m, 1H), 1.70-1.86 (m, 1H), 1.93-2.04 (m, 1H), 2.07-2.25 (m, 2H), 2.27-2.69 (m, 5H), 2.80 (d, J = 15.2Hz, 1H), 2.97 (d, J = 15.2Hz, 1H), 3.08 ( d, J = 17.0Hz, 1H), 3.20-3.36 (m, 1H), 3.24 (d, J = 9.9Hz, 1H), 3.79 (s, 3H), 6.69 (dd, J = 2.4,8.1Hz, 1H ), 6.77 (d, J = 2.4Hz, 1H), 7.12 (d, J = 8.1Hz, 1H), 7.40-7.47 (m, 1H), 7.57-7.64 (m, 1H), 7.68-7.73 (m, 1H), 7.84 (s, 1H), 7.97 (d, J = 8.3Hz, 1H).

(6aR, 11aS) -15- (cyclopropylmethyl) -11,12-dihydro-6H-6a, 11a- (ethanoiminomethano) indeno [2,1-b] acridin-8-ol (3)

Pyridinium hydrochloride (624 mg, 5.40 mmol) was added to compound 2 (27.0 mg, 0.0658 mmol), and the mixture was stirred at 180 ° C. for 2 hours. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by preparative TLC to give the title compound 3 (20.7 mg, 79%) as a colorless oil. Further, this compound was treated with a 15% hydrogen chloride / methanol solution to obtain a hydrochloride.

(Free base)
¹ H NMR (300 MHz, CDCl ₃ ): δ 0.01-0.09 (m, 2H), 0.39-0.53 (m, 2H), 0.72-0.88 (m, 1H), 1.68-1.82 (m, 1H), 1.92-2.03 (m, 1H), 2.05-2.28 (m, 4H), 2.54-2.66 (m, 2H), 2.72 (d, J = 15.3Hz, 1H), 2.85 (d, J = 15.3Hz, 1H), 3.06- 3.22 (m, 3H), 3.50 (d, J = 17.7Hz, 1H), 6.60 (dd, J = 2.2,8.0Hz, 1H), 6.84 (d, J = 2.2Hz, 1H), 7.00 (d, J = 8.0Hz, 1H), 7.42-7.49 (m, 1H), 7.57-7.65 (m, 1H), 7.69-7.75 (m, 1H), 7.91 (s, 1H), 8.10 (d, J = 8.5Hz, 1H).

(6aR, 11aS) -8-Methoxy-15-methyl-11,12-dihydro-6H-6a, 11a- (ethanoiminomethano) indeno [2,1-b] acridine (5)

According to the method described in Example 1, compound 4 (83.5 mg, 0.293 mmol) [J. Org. Chem. 2008, 73, 8093. and Bioorg. Med. Chem. Lett., 2011, 21, 4104. The title compound 5 (37.9 mg, 35%) was obtained as a white amorphous using the described compound].

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.69-2.10 (m, 2H), 2.13-2.29 (m, 3H), 2.17 (s, 3H), 2.30-2.50 (m, 2H), 2.79 (d, J = 15.3Hz, 1H), 2.94 (d, J = 15.3Hz, 1H), 3.02-3.12 (m, 1H), 3.19 (d, J = 17.7Hz, 1H), 3.30 (d, J = 17.7Hz, 1H) ), 3.79 (s, 3H), 6.69 (dd, J = 2.5, 8.1Hz, 1H), 6.77 (d, J = 2.5Hz, 1H), 7.13 (d, J = 8.1Hz, 1H), 7.40-7.47 (m, 1H), 7.57-7.64 (m, 1H), 7.67-7.72 (m, 1H), 7.82 (s, 1H), 7.97 (d, J = 8.4Hz, 1H).

(6aR, 11aS) -15-methyl-11,12-dihydro-6H-6a, 11a- (ethanoiminomethano) indeno [2,1-b] acridin-8-ol (6)

According to the method described in Example 2, compound 5 (37.9 mg, 0.102 mmol) was used to give the title compound 6 (24.3 mg, 67%) and its hydrochloride as a white amorphous.
(Free base)
¹ H NMR (300 MHz, CDCl ₃ ): δ 1.70-1.84 (m, 1H), 1.92-2.04 (m, 1H), 2.12-2.29 (m, 2H), 2.20 (s, 3H), 2.37-2.55 (m , 2H), 2.75 (d, J = 15.2Hz, 1H), 2.84 (d, J = 15.2Hz, 1H), 3.08-3.21 (m, 3H), 3.43 (d, J = 17.8Hz, 1H), 6.61 (dd, J = 2.2,8.0Hz, 1H), 6.81 (d, J = 2.2Hz, 1H), 7.01 (d, J = 8.0Hz, 1H), 7.43-7.50 (m, 1H), 7.59-7.66 ( m, 1H), 7.70-7.76 (m, 1H), 7.91 (s, 1H), 8.08 (d, J = 8.5Hz, 1H).

(Reference Example 1)

(4aR, 9aR) -6-methoxy-4,9-dihydro-1H-4a, 9a- (ethanoiminomethano) fluoren-3 (2H) -one (7)

Compound 1 (1.89 g, 5.81 mmol) was dissolved in dichloromethane (10 mL) under an argon atmosphere, and 2,2,2-trichloroethyl chloroformate (1.6 mL, 11.6 mmol) and potassium carbonate (2.4 g) were dissolved. 17.4 mmol) and stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was dissolved in acetic acid (10 mL) without purification, zinc powder (1.92 g, 29.32 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution and 25% aqueous ammonia solution were added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to obtain the title compound 7 (1.26 g, 79%) as a white amorphous.

(6aR, 11aS) -8-Methoxy-11,12-dihydro-6H-6a, 11a- (ethanoiminomethano) indeno [2,1-b] acridine (8)

Under an argon atmosphere, compound 7 (329 mg, 1.21 mmol) was dissolved in ethanol (10 mL), 2-aminobenzaldehyde (588 mg, 4.85 mmol) and methanesulfonic acid (315 μL, 4.85 mmol) were added, and 6.5. Reflux for hours. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain a mixture (379 mg, 88%) of the title compound 8 and its positional isomer as a white amorphous substance.

1-(((6aR, 11aS) -8-methoxy-11,12-dihydro-6H-6a, 11a- (ethanoiminomethano) indeno [2,1-b] acridin-15-yl) methyl) cyclopropanol ( 9)

Under an argon atmosphere, a mixture of Compound 8 and its regioisomer (113 mg, 0.316 mmol) was dissolved in DMF (10 mL), and 1-acetoxycyclopropanecarboxylic acid (228 mg, 1.58 mmol), 1-ethyl-3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (303 mg, 1.58 mmol) and dimethylaminopyridine (193 mg, 1.58 mmol) were added and stirred for 5 hours. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain a colorless oily substance (180 mg).
Lithium aluminum hydride (120 mg, 3.16 mmol) was suspended in THF (3.2 mL), concentrated sulfuric acid (84.2 μl, 1.58 mmol) was added dropwise at 0 ° C., and the mixture was stirred at 0 ° C. for 15 minutes. A colorless oily substance (180 mg) obtained above in THF (6 mL) solution was added dropwise at 0 ° C. and stirred for 30 minutes, then warmed to room temperature and stirred for 1 hour. A 25% aqueous ammonia solution (10 mL) was added, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Water was added and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by preparative TLC to give the title compound 9 (29.1 mg, 22%) as a white amorphous.

¹ H NMR (300 MHz, CDCl ₃ ): δ 0.29-0.38 (m, 2H), 0.75-0.84 (m, 2H), 1.69-1.82 (m, 1H), 1.94-2.06 (m, 1H), 2.37-2.50 (m, 1H), 2.39 (d, J = 2.1Hz, 1H), 2.47 (d, J = 11.8Hz, 1H), 2.53-2.63 (m, 1H), 2.57 (d, J = 11.5Hz, 1H) , 2.86 (d, J = 15.4Hz, 1H), 2.98 (d, J = 15.4Hz, 1H), 3.06-3.35 (m, 3H), 3.19 (d, J = 17.3Hz, 1H), 3.30 (d, J = 17.3Hz, 1H), 3.78-3.83 (m, 1H), 3.79 (s, 3H), 6.71 (dd, J = 2.5, 8.1Hz, 1H), 6.77 (d, J = 2.5Hz, 1H), 7.13 (d, J = 8.1Hz, 1H), 7.41-7.49 (m, 1H), 7.58-7.66 (m, 1H), 7.69-7.74 (m, 1H), 7.84 (s, 1H), 7.98 (d, J = 8.4Hz, 1H).

(6aR, 11aS) -15-((1-hydroxycyclopropyl) methyl) -11,12-dihydro-6H-6a, 11a- (ethanoiminomethano) indeno [2,1-b] acridin-8-ol ( 10)

According to the method described in Example 2, compound 9 (29.1 mg, 0.0682 mmol) was used to give the title compound 10 (22 mg, 78%) and its hydrochloride as a colorless oil.
(Free base)
¹ H NMR (300 MHz, CDCl ₃ ): δ 0.26-0.40 (m, 2H), 0.71-0.86 (m, 2H), 1.65-1.77 (m, 1H), 1.91-2.03 (m, 1H), 2.25-2.39 (m, 4H), 2.60-2.71 (m, 2H), 2.78 (d, J = 15.5Hz, 1H), 2.89 (d, J = 15.5Hz, 1H), 3.10-3.21 (m, 3H), 3.37 ( d, J = 17.4Hz, 1H), 6.63 (dd, J = 2.2,8.0Hz, 1H), 6.81 (d, J = 2.2Hz, 1H), 7.00 (d, J = 8.0Hz, 1H), 7.43- 7.51 (m, 1H), 7.58-7.67 (m, 1H), 7.71-7.77 (m, 1H), 7.92 (s, 1H), 8.10 (d, J = 8.5Hz, 1H).

(6aR, 11aS) -15-benzyl-8-methoxy-11,12-dihydro-6H-6a, 11a- (ethanoiminomethano) indeno [2,1-b] acridine (11)

Under an argon atmosphere, a mixture of compound 8 and its regioisomer (98.7 mg, 0.277 mmol) was dissolved in DMF (2 mL), benzyl bromide (98.7 μL, 0.831 mmol) and potassium carbonate (153 mg, 1. 11 mmol) was added and stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography and preparative TLC to give the title compound 11 (21.8 mg, 18%) as a white amorphous.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.69-1.81 (m, 1H), 1.91-2.03 (m, 1H), 2.21-2.38 (m, 3H), 2.39-2.51 (m, 1H), 2.75 (d , J = 15.2Hz, 1H), 2.95 (d, J = 15.0Hz, 1H), 2.99 (d, J = 17.2Hz, 1H), 3.15-3.49 (m, 2H), 3.25 (d, J = 8.6Hz , 1H), 3.39 (d, J = 6.5Hz, 1H), 3.79 (s, 3H), 6.69 (dd, J = 2.4, 8.1Hz, 1H), 6.77 (d, J = 2.4Hz, 1H), 7.12 (d, J = 8.1Hz, 1H), 7.21-7.34 (m, 5H), 7.35-7.40 (m, 1H), 7.41-7.48 (m, 1H), 7.57-7.65 (m, 1H), 7.69-7.74 (m, 1H), 7.82 (s, 1H), 7.98 (d, J = 8.5Hz, 1H).

(6aR, 11aS) -15-benzyl-11,12-dihydro-6H-6a, 11a- (ethanoiminomethano) indeno [2,1-b] acridin-8-ol (12)

According to the method described in Example 2, Compound 11 (21.8 mg, 0.0488 mmol) was used to give the title compound 12 (7.6 mg, 36%) and its hydrochloride as a white amorphous.
(Free base)
¹ H NMR (300 MHz, CDCl ₃ ): δ 1.37-1.84 (m, 3H), 1.93-2.04 (m, 1H), 2.18 (d, J = 11.4Hz, 1H), 2.35 (d, J = 11.4Hz, 1H), 2.45-2.56 (m, 1H), 2.70-2.83 (m, 2H), 3.02 (d, J = 17.8Hz, 1H), 3.12-3.26 (m, 2H), 3.29-3.47 (m, 2H) , 6.61 (dd, J = 2.2,8.0Hz, 1H), 6.82 (d, J = 2.2Hz, 1H), 7.02 (d, J = 8.0Hz, 1H), 7.22-7.34 (m, 5H), 7.44- 7.51 (m, 1H), 7.59-7.67 (m, 1H), 7.72-7.78 (m, 1H), 7.90 (s, 1H), 8.08 (d, J = 8.4Hz, 1H).

(Reference Example 2)

1-((6aR, 11aS) -8-methoxy-11,12-dihydro-6H-6a, 11a- (ethanoiminomethano) indeno [2,1-b] acridin-15-yl) -2-phenylethanone (13)

Under an argon atmosphere, a mixture of compound 8 and its regioisomer (99.0 mg, 0.278 mmol) was dissolved in dichloromethane (3 mL), phenylacetyl chloride (73.5 μl, 0.556 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Stir. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by preparative TLC to give the title compound 13 (44.6 mg, 34%) as a colorless oil.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.80-2.07 (m, 2H), 2.63 (s, 0.5H), 2.75 (s, 0.5H), 2.85 (d, J = 16.8Hz, 1H), 2.92 3.10 (m, 4H), 3.18-3.28 (m, 2H), 3.31-3.40 (m, 1H), 3.44-3.59 (m, 2H), 3.70-3.83 (m, 0.5H), 3.77 (s, 1.5H ), 3.79 (s, 1.5H), 4.13 (d, J = 13.5Hz, 0.5H), 6.62-6.74 (m, 2H), 6.84 (d, J = 8.2Hz, 1H), 6.93 (d, J = 7.8Hz, 0.5H), 7.01-7.07 (m, 1.5H), 7.11-7.21 (m, 2H), 7.24-7.38 (m, 1H), 7.43-7.51 (m, 1H), 7.59-7.67 (m, 1H), 7.70-7.78 (m, 1.5H) (brs, 0.5H), 7.96-8.04 (m, 1H).

(6aR, 11aS) -8-methoxy-15-phenethyl-11,12-dihydro-6H-6a, 11a- (ethanoiminomethano) indeno [2,1-b] acridine (14)

Lithium aluminum hydride (21.4 mg, 0.564 mmol) was suspended in THF (5 mL), and a solution of compound 13 (44.6 mg, 0.0940 mmol) in THF (5 mL) was added dropwise at 0 ° C. at 0 ° C. The mixture was warmed to room temperature and stirred for 1 hour. Ethyl acetate (5 mL) and saturated aqueous sodium sulfate solution (0.1 mL) were added at 0 ° C., the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by preparative TLC to give the title compound 14 (34.5 mg, 80%) as a yellow oil.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.67-1.80 (m, 1H), 1.91-2.02 (m, 1H), 2.26-2.57 (m, 6H), 2.68-2.84 (m, 3H), 2.93 (d , J = 15.2Hz, 1H), 3.05 (d, J = 17.3Hz, 1H), 3.14-3.32 (m, 3H), 3.79 (s, 3H), 6.70 (dd, J = 2.4,8.1Hz, 1H) , 6.77 (d, J = 2.4Hz, 1H), 7.09-7.28 (m, 6H), 7.41-7.48 (m, 1H), 7.57-7.64 (m, 1H), 7.68-7.74 (m, 1H), 7.80 (s, 1H), 7.98 (d, J = 8.4Hz, 1H).

(6aR, 11aS) -15-phenethyl-11,12-dihydro-6H-6a, 11a- (ethanoiminomethano) indeno [2,1-b] acridin-8-ol (15)

According to the method described in Example 2, compound 14 (34.5 mg, 0.0749 mmol) was used to give the title compound 15 (26.8 mg, 80%) and its hydrochloride as a colorless oil.
(Free base)
¹ H NMR (300 MHz, CDCl ₃ ): δ 1.66-1.80 (m, 1H), 1.94-2.04 (m, 1H), 2.16-2.29 (m, 2H), 2.39-2.63 (m, 4H), 2.66-2.79 (m, 3H), 2.86 (d, J = 15.4Hz, 1H), 3.04-3.23 (m, 3H), 3.41 (d, J = 17.7Hz, 1H), 6.62 (dd, J = 2.3,8.0Hz, 1H), 6.87 (d, J = 2.3Hz, 1H), 7.02 (d, J = 8.0Hz, 1H), 7.12-7.29 (m, 5H), 7.44-7.52 (m, 1H), 7.59-7.67 (m , 1H), 7.72-7.78 (m, 1H), 7.89 (s, 1H), 8.12 (d, J = 8.4Hz, 1H).

Opioid receptor binding test

The binding affinity of the compounds of the present invention for μ, δ and κ opioid receptors was examined.
Method: Mouse cerebrum and guinea pig cerebellar membrane fraction were prepared according to the previous report (J. Biol. Chem. 2001 276: 15409-15414.). [ ³ H] DAMGO (μ opioid receptor), [ ³ H] DPDPE (δ opioid receptor), and [ ³ H] U69,593 (κ opioid receptor) were used as radioligands for each opioid receptor. The murine cerebral membrane fraction was used for the assay of μ and δ receptors, and the guinea pig cerebellar membrane fraction was used for the assay of κ receptor. For non-specific binding, μ: DAMGO, δ: DPDPE, and κ: U69,593 were each used at 1 μM. Each receptor membrane fraction is reacted with the radioligand and various concentrations of the specimen for a predetermined time. After the B / F separation, the amount of radioactivity remaining on the filter is measured with a liquid scintillation counter, and the binding inhibition rate of the test compound ( IC ₅₀ value) was calculated. The Ki value was calculated from the obtained IC ₅₀ value using the following formula.
Ki = IC ₅₀ / (1 + L / Kd)
L: Concentration of radioligand used Kd: Kd value of radioligand
Further, the δ-receptor selectivity in the opioid receptor was determined by calculating the ratio (μ / δ or κ / δ) between the Ki value for μ or κ and the Ki value for δ.

DAMGO:
[D-Ala ² , N-MePhe ⁴ , Gly-Ol] enkephalin
DPDPE:
[D-Pen ² , D-Pen ⁵ ] enkephalin
U69,593:
(+)-(5α, 7α, 8β) -N-methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro [4.5] dec-8-yl] benzeneacetamide

As shown in Table 1, the compounds of the present invention showed selective affinity for the opioid δ receptor.

Opioid receptor function test

The functional activity of the compounds of the present invention against μ, δ and κ opioid receptors was examined.
Method: A cell membrane fraction was prepared using CHO cells (catalog number and accession number are listed below) stably expressing human opioids μ, δ, and κ receptors. A reaction solution (50 mM [Tris (hydroxymethyl) aminomethane] -HCl pH 7.4, 5 mM MgCl ₂ , 1 mM EGTA, 100 mM NaCl) containing a cell membrane fraction, each test compound, 30 μM GDP and 100 pM [ ³⁵ S] GTPγS; The reaction was performed for 2 hours. After B / F separation, the amount of radioactivity remaining on the filter was measured with a microplate scintillation counter, and a dose-response curve of the test compound was determined in the concentration range of 10 ⁻¹¹ to 10 ⁻⁶ M to determine the activity (EC ₅₀ value). ) And maximum response (Emax value). Nonspecific binding was determined by the coexistence of non-radioactive 10 μM GTPγS. DAMGO (μ), DPDPE (δ), and U-69,593 (κ) were used as standard opioid receptor drugs.

CHO: Chinese hamster ovary
GDP: guanosine-5'-diphosphate
GTP: guanosine-5'-triphosphate

Catalog number and accession number μ: Catalog No. CT6605, accession No. NM_000914
δ: Catalog No.CT6607, accession No.NM_000911.2
κ: Catalog No.CT6606, accession No.NM_000912
(ChanTest Corporation)

As shown in Table 2, it was confirmed that the compounds of the present invention have potent agonist activity against the opioid δ receptor.

Claims (29)

1. The following general formula (I),
   

   

   Wherein R ¹ is (a) hydrogen, (b) C _1-6 alkyl, (c) C _6-10 aryl, (d) C _2-6 alkenyl, (e) cycloalkylalkyl (of the cycloalkyl moiety The number of carbon atoms is 3 to 6, the number of carbon atoms in the alkylene portion is 1 to 5.), (f) Aralkyl (the number of carbon atoms in the aryl portion is 6 to 10, and the number of carbon atoms in the alkylene portion is 1 to 5. ), (G) C _3-6 cycloalkyl or (h) heteroarylalkyl (wherein heteroaryl contains 1 to 4 heteroatoms selected from N, O and S as ring members and is a carbon atom of an alkylene moiety) The number represents 1-5.)
   Where (b) C _1-6 alkyl of R ¹
   (E) alkylene and cycloalkyl moieties of cycloalkylalkyl (wherein the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms),
   (F) an alkylene moiety of aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and (h) a heteroarylalkyl (heteroaryl is derived from N, O and S) An alkylene moiety comprising 1 to 4 selected heteroatoms as ring-constituting atoms, and the alkylene moiety having 1 to 5 carbon atoms)
   _1-6 halogens, hydroxy, C _1-6 alkoxy, C _6-10 aryloxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, carboxyl and alkoxycarbonyl (the number of carbon atoms in the alkoxy moiety is _1-6 )) May be substituted with at least one substituent selected from
   And (c) C _6-10 aryl of R ¹
   (F) an aryl moiety of aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and (h) a heteroarylalkyl (heteroaryl is derived from N, O and S) A heteroaryl moiety comprising 1 to 4 selected heteroatoms as ring member atoms, and the alkylene moiety having 1 to 5 carbon atoms).
   C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkanoyloxy, hydroxy, alkoxycarbonyl (the alkoxy moiety has 1 to 6 carbon atoms), carbamoyl, alkylcarbamoyl (the alkyl moiety has 1 carbon atom) 6)), dialkylcarbamoyl (the alkyl part has 1 to 6 carbon atoms), halogen, nitro, cyano, C _1-6 alkyl substituted with 1 to 3 halogens, 1 to 3 halogens Substituted C _1-6 alkoxy, phenyl, heteroaryl (including 1 to 4 heteroatoms selected from N, O and S as ring members), phenoxy, phenylalkyl (the number of carbon atoms of alkyl is 1 to 3), optionally substituted with at least one substituent selected from methylenedioxy and NR ⁴ R ⁵ ,
   Wherein R ⁴ and R ⁵ are each independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, C _1-6 alkanoyl, or alkoxycarbonyl (the number of carbon atoms in the alkoxy moiety) 1 to 6)), or R ⁴ and R ⁵ may contain a hetero atom selected from N, O and S together with the N atom to which they are bonded. A 7-membered ring may be formed,
   R ² is hydrogen, hydroxy, halogen, cyano, carbamoyl, C _1-6 alkoxy, C _6-10 aryloxy, C _1-6 alkanoyloxy, nitro, amino, C _1-8 alkylamino, aralkylamino (of the aryl moiety) The number of carbon atoms is 6 to 10, the number of carbon atoms of the alkylene moiety is 1 to 5.) or acylamino (the number of carbon atoms of the acyl moiety is 2 to 6);
   V represents CH or N;
   W, X, Y and Z each independently represent CR ³ or N.
   However, W, X, Y and Z are not N at the same time, and when two or more of W, X, Y and Z are CR ³ , these may be the same or different.
   R ³ is hydrogen, halogen, nitro, C _1-6 alkyl, hydroxy, C _1-6 alkoxy, C _1-6 alkyl substituted with 1 to 3 halogens, hydroxy substituted C _1-6 alkyl, to three halogen substituted _{C 1-6} alkoxy, hydroxy substituted _{C 1-6 alkoxy, C 1-6 C 1-6} alkyl alkoxy-substituted phenyl, cyano, isothiocyanato, ^SR 6, _{^{SOR 6, SO 2 R 6,}} (CH 2) r COOR 6, SO 2 NR 7 R 8, CONR 7 R 8, (CH 2) r NR 7 R 8 or ^{_{(CH 2) r N (R}} 7) COR 8 Or two R ³ bonded to adjacent carbons together represent methylenedioxy,
   Here, R ⁶ represents hydrogen or C _1-6 alkyl,
   R ⁷ and R ⁸ each independently represent hydrogen, C _1-6 alkyl or cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms). ,
   R represents an integer of 0 to 5. )
   Or a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
2. R ¹ is hydrogen, C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has carbon atoms The propeller derivative according to claim 1, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. Solvates.
3. R ¹ is C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms). 10 wherein the number of carbon atoms of the alkylene moiety is from 1 to 5. The alkyl moiety is substituted by either hydroxy, _1-6 halogens, or C _1-6 alkoxy. Or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof.
4. The propeller derivative according to claims 1 to 3, wherein R ² is hydroxy, C _1-6 alkoxy, C _1-6 alkanoyloxy, or carbamoyl, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof. Salts or solvates thereof.
5. The propeller derivative according to claims 1 to 3, wherein R ² is hydroxy or C _1-6 alkoxy, a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
6. 6. The propeller derivative according to claim 1, wherein V is CH, a tautomer, stereoisomer, pharmaceutically acceptable salt of the compound or a solvate thereof.
7. W, X, Y and Z are the same or different and CR ³ and the propellane derivative according to claim 1, tautomer, stereoisomer, pharmaceutically acceptable salt thereof or solvent thereof Japanese products.
8. The W-, X-, Y- and Z are the same or different and are selected from CH, C—C _1-6 alkyl, C-halogen, C-hydroxy and C—C _1-6 alkoxy. Or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof.
9. W, X, Y and Z are CH, The propeller derivative according to claims 1 to 6, a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof of the compound.
10. R ¹ is hydrogen, C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has carbon atoms 6 to 10 and the alkylene moiety has 1 to 5 carbon atoms.)
    R ² is hydroxy or C _1-6 alkoxy, and
    The propeller derivative according to claim 1, wherein V, W, X, Y and Z are CH, a tautomer, stereoisomer, pharmaceutically acceptable salt of the compound or a solvate thereof.
11. R ¹ is hydrogen, C _1-6 alkyl or aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms);
    R ² is hydroxy or C _1-6 alkoxy, and
    The propeller derivative according to claim 1, wherein V, W, X, Y and Z are CH, a tautomer, stereoisomer, pharmaceutically acceptable salt of the compound or a solvate thereof.
12. R ¹ is hydrogen, C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has carbon atoms 6 to 10 and the alkylene moiety has 1 to 5 carbon atoms.)
    R ² is C _1-6 alkoxy and
    The propeller derivative according to claim 1, wherein V, W, X, Y and Z are CH, a tautomer, stereoisomer, pharmaceutically acceptable salt of the compound or a solvate thereof.
13. R ¹ is C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms). 10 wherein the alkylene moiety has from 1 to 5 carbon atoms, and the alkyl moiety is substituted by either hydroxy, _1-6 halogen, or C _1-6 alkoxy;
    R ² is hydroxy, C _1-6 alkoxy, C _1-6 alkanoyloxy, or carbamoyl;
    V is CH,
    2. The propeller derivative according to claim 1, wherein W, X, Y and Z are the same or different and CR ³ , a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof .
14. R ¹ is C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms). 10 wherein the alkylene moiety has from 1 to 5 carbon atoms, and the alkyl moiety is substituted by either hydroxy, _1-6 halogen, or C _1-6 alkoxy;
    R ² is hydroxy, C _1-6 alkoxy, C _1-6 alkanoyloxy, or carbamoyl;
    V is CH,
    2. The propeller according to claim 1, wherein W, X, Y and Z are the same or different and are selected from CH, C—C _1-6 alkyl, C-halogen, C-hydroxy and C—C _1-6 alkoxy. Derivatives, tautomers, stereoisomers, or pharmaceutically acceptable salts of the compounds, or solvates thereof.
15. R ¹ is C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms). 10 wherein the alkylene moiety has from 1 to 5 carbon atoms, and the alkyl moiety is substituted by either hydroxy, _1-6 halogen, or C _1-6 alkoxy;
    R ² is hydroxy, C _1-6 alkoxy, C _1-6 alkanoyloxy, or carbamoyl;
    V is CH,
    The propellane derivative according to claim 1, wherein W, X, Y and Z are CH, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
16. R ¹ is C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms). 10 wherein the alkylene moiety has from 1 to 5 carbon atoms, and the alkyl moiety is substituted by either hydroxy, _1-6 halogen, or C _1-6 alkoxy;
    R ² is hydroxy or C _1-6 alkoxy,
    V is CH,
    2. The propeller derivative according to claim 1, wherein W, X, Y and Z are the same or different and CR ³ , a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof .
17. R ¹ is C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms). 10 wherein the alkylene moiety has from 1 to 5 carbon atoms, and the alkyl moiety is substituted by either hydroxy, _1-6 halogen, or C _1-6 alkoxy;
    R ² is hydroxy or C _1-6 alkoxy,
    V is CH,
    2. The propeller according to claim 1, wherein W, X, Y and Z are the same or different and are selected from CH, C—C _1-6 alkyl, C-halogen, C-hydroxy and C—C _1-6 alkoxy. Derivatives, tautomers, stereoisomers, or pharmaceutically acceptable salts of the compounds, or solvates thereof.
18. R ¹ is C _1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms). 10 wherein the alkylene moiety has from 1 to 5 carbon atoms, and the alkyl moiety is substituted by either hydroxy, _1-6 halogen, or C _1-6 alkoxy;
    R ² is hydroxy or C _1-6 alkoxy,
    V is CH,
    The propellane derivative according to claim 1, wherein W, X, Y and Z are CH, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
19. R ¹ is cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and the alkyl moiety is hydroxy, 1 to 6 halogens, Or substituted by either C _1-6 alkoxy,
    R ² is hydroxy, C _1-6 alkoxy, C _1-6 alkanoyloxy, or carbamoyl;
    V is CH,
    2. The propeller derivative according to claim 1, wherein W, X, Y and Z are the same or different and CR ³ , a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof .
20. R ¹ is cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and the alkyl moiety is hydroxy, 1 to 6 halogens, Or substituted by either C _1-6 alkoxy,
    R ² is hydroxy, C _1-6 alkoxy, C _1-6 alkanoyloxy, or carbamoyl;
    V is CH,
    2. The propeller according to claim 1, wherein W, X, Y and Z are the same or different and are selected from CH, C—C _1-6 alkyl, C-halogen, C-hydroxy and C—C _1-6 alkoxy. Derivatives, tautomers, stereoisomers, or pharmaceutically acceptable salts of the compounds, or solvates thereof.
21. R ¹ is cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and the alkyl moiety is hydroxy, 1 to 6 halogens, Or substituted by either C _1-6 alkoxy,
    R ² is hydroxy, C _1-6 alkoxy, C _1-6 alkanoyloxy, or carbamoyl;
    V is CH,
    The propellane derivative according to claim 1, wherein W, X, Y and Z are CH, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
22. R ¹ is cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and the alkyl moiety is hydroxy, 1 to 6 halogens, Or substituted by either C _1-6 alkoxy,
    R ² is hydroxy or C _1-6 alkoxy,
    V is CH,
    2. The propeller derivative according to claim 1, wherein W, X, Y and Z are the same or different and CR ³ , a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof .
23. R ¹ is cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and the alkyl moiety is hydroxy, 1 to 6 halogens, Or substituted by either C _1-6 alkoxy,
    R ² is hydroxy or C _1-6 alkoxy,
    V is CH,
    2. The propeller according to claim 1, wherein W, X, Y and Z are the same or different and are selected from CH, C—C _1-6 alkyl, C-halogen, C-hydroxy and C—C _1-6 alkoxy. Derivatives, tautomers, stereoisomers, or pharmaceutically acceptable salts of the compounds, or solvates thereof.
24. R ¹ is cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and the alkyl moiety is hydroxy, 1 to 6 halogens, Or substituted by either C _1-6 alkoxy,
    R ² is hydroxy or C _1-6 alkoxy,
    V is CH,
    The propellane derivative according to claim 1, wherein W, X, Y and Z are CH, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
25. A medicament comprising the propelleran derivative according to any one of claims 1 to 24, a tautomer, stereoisomer, pharmaceutically acceptable salt of the compound, or a solvate thereof.
26. A pharmaceutical comprising the propellane derivative according to any one of claims 1 to 24, a tautomer, stereoisomer, pharmaceutically acceptable salt thereof or solvate thereof as an active ingredient. Composition.
27. An analgesic comprising, as an active ingredient, the propellane derivative according to any one of claims 1 to 24, a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof of the compound. medicine.
28. An antiperme comprising the propeller derivative according to any one of claims 1 to 24, a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof as an active ingredient. Anxiety medication.
29. An antiperme comprising the propeller derivative according to any one of claims 1 to 24, a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate thereof as an active ingredient. Depressant.