JPH1171350A - Hydroxypiperidine compound and agent thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having MIP-α/RANTES receptor antagonism, and useful for preventing and treating diseases such as allergic diseases, inflammatory diseases and multiple sclerosis. SOLUTION: This new compound is shown by formula I [X<1> and Y<1> are each a (halogen-substituted) phenyl or pyridyl; R<1> is a (halogenated) 1-6C alkyl or the like], e.g. 1-(t-butoxycarbonyl)piperidin-4-yl N- 5-[4-(4-chlorophenyl)-4- hydroxypiperidino]-2,2-diphenylpentyl}carbamate. The compound of formula I is obtained by conventional alkylation of the amino group between a compound of formula II (L<1> is an eliminable group) and a compound of formula III. This new compound is useful for preventing and treating, in particular, such diseases as bronchial asthma, atopic dermatitis, allergic rhinitis, arteriosclerosis, arthrorheumatism, and nephritis.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a MIP-1α / R
It has an ANTES receptor antagonistic activity and is used for the prevention of drugs, especially allergic diseases (eg, bronchial asthma, atopic dermatitis, etc.), inflammatory diseases (eg, arteriosclerosis, rheumatoid arthritis, etc.), multiple sclerosis, etc. The present invention relates to a novel compound useful for treatment and an agent thereof.

[0002]

2. Description of the Related Art Chemokines are a group of cytokines that regulate the chemotaxis of leukocytes, and are involved in the progression and exacerbation of the disease state in the acute and chronic phases of inflammation together with other cytokines. This has been revealed in recent years. RANT among chemokines
ES (Regulated on activation, normal T expressed
and secreted) and MIP-1α (Macrophage infla
mmatory protein-1α) belongs to the so-called CC chemokines, mainly acting on lymphocytes, monocytes, eosinophils, and basophils to increase the migration activity, as well as degranulation and various inflammatory mediators. It is known to have a direct leukocyte activating action such as release (Clinical Immunotherapy Vol. 4, pp. 1-8, 1995). Among them, RANTES gene expression increased in synovial fluid of rheumatic patients (Clinical & Experimental Immunology Vol. 101, 398, 1995 and Lancet 343, 547, 1994) and in atherosclerotic lesions. Has been observed. In addition, it has been reported that administration of MIP-1α antibody to mice delayed the onset of arthritis and further ameliorated the symptoms (The Journal of Japan).
American Society for Clinical Investigation, Vol. 95, p. 2868, 1995
Year). However, antibodies are generally high polymers and are known to have problems with oral absorbability and stability.

The MIP-1α / RANTES receptor is MI
P-1α, RANTES or MCP-3 (monocyte
Common receptors for chemokines such as chemoattractant protein-3 (named CCR1; Nature Medicine, Vol. 2, 1174)
P. 1996). As the above CCR1 receptor antagonist, RANTE has already been used.
Peptide-type antagonists to S and the like are known [Journal of Biological Chemistry, 271: 10
512-10527, 1996], but it is known that peptide-type antagonists have problems such as oral absorption and stability. In addition, eosinophils and basophils have been revealed to be involved in the onset, progression, and exacerbation of various allergic diseases and inflammatory diseases by aggregation and activation at sites of inflammation. Inhibiting the action is thought to lead to the prevention and treatment of immune system diseases such as bronchial asthma, atopic dermatitis, arteriosclerosis and rheumatoid arthritis (Clinical Immunotherapy, Chapter 4
Vol. 1-8, 1995). However, there are no reports of such inhibitors at present.

[0004]

SUMMARY OF THE INVENTION MIP-1α / RAN
TES receptor antagonist, and RANTES or MI
There is a demand for the development of a new drug having an excellent clinical effect for preventing and treating diseases caused by P-1α.

[0005]

As a result of various studies, the present inventors have found that equation (1)

Embedded image [Wherein X ¹ and Y ¹ are the same or different,
Each represents a phenyl group or a pyridyl group which may be substituted with a halogen atom, and R ¹ represents a C _1-6 alkyl group which may be halogenated;

Embedded image (Wherein R ² represents a hydrogen atom, C _1-6 alkoxy-carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, a nicotinoyl group optionally substituted with a halogen atom, or Represents an isonicotinoyl group which may be substituted with a halogen atom). A compound represented by the formula (2):

Embedded image Wherein X ² and Y ² are the same or different,
A phenyl group or a pyridyl group each of which may be substituted with a halogen atom, and R ³ represents a C _1-6 alkyl group which may be substituted with a hydroxy group,

Embedded image (Wherein, R ⁴ is (1) hydroxy, C _1-6 alkyl - carbonyloxy and a C _1-6 alkyl group optionally having a substituent selected from pyridyl, substituted with (2) a halogen atom or pyrrolidinyl A C _1-6 alkoxy group which may be substituted, (3) a pyridyl group which may have a substituent or (4) a phenyl group which may have a substituent.) Is shown. However, when R ³ is propyl or butyl substituted with a hydroxy group, it represents a phenyl group or a pyridyl group in which at least one of X ² and Y ² is substituted with a halogen atom. A compound represented by the formula (3):

Embedded image Wherein X ³ and Y ³ are the same or different,
A phenyl group or a pyridyl group each of which may be substituted with a halogen atom,

Embedded image Is - (CH ₂₎ n- (where n indicates an integer of 1 to 3) or _{- (CH 2) m-CH} = indicates (m represents an integer of 0 to 2), R ⁵ is a hydrogen atom or a C _1-6 alkoxy-
Indicates a carbonyl group. A compound represented by the formula (4):

Embedded image Wherein X ⁴ and Y ⁴ are the same or different,
A phenyl group or a pyridyl group each of which may be substituted with a halogen atom, wherein R ⁶ is a C _1-6 alkyl group,
A piperidino group substituted with nicotinoyl or isonicotinoyl which may be substituted with a halogen atom,
It represents a pyridyl group which may have a substituent or a piperidino group substituted by a C _1-6 alkoxy-carbonyl. However, when R ⁶ is a methyl group, at least one of X ⁴ and Y ⁴ represents a phenyl group substituted with a halogen atom, or both represent a pyridyl group. And a compound represented by the formula (5)

Embedded image Wherein X ⁵ and Y ⁵ are the same or different,
A phenyl group or a pyridyl group, each of which may be substituted with a halogen atom, wherein ring A is a halogen atom, an oxo group, a C _1-6 alkyl group which may be halogenated, or a C ₁ group which may be halogenated; _It may be substituted with a _-6 alkoxy group. ] Or a salt thereof for the first time, and a compound represented by the formula

Embedded image [In the formula, X and Y are the same or different and each represents a phenyl group or a pyridyl group which may be substituted with a halogen atom. Unexpectedly excellent MIP-1α / RANTES based on the specific chemical structure of the group represented by
It has a receptor antagonistic effect and has a clinically superior preventive and therapeutic effect on diseases caused by MIP-1α and / or RANTES.
Based on these, the present invention has been completed.

That is, the present invention relates to (1) a compound (I)
Or a salt thereof, (2) compound (II) or a salt thereof,
(3) Compound (III) or a salt thereof, (4) Compound (I
V) or a salt thereof, (5) Compound (V) or a salt thereof,
(6) a pharmaceutical composition comprising the compound according to any of the above (1) to (5) or a salt thereof, (7)
MIP-1α / RANTE containing the compound or salt thereof according to any of the above (1) to (5)
S receptor antagonist, and formula (8)

Embedded image [Wherein the symbols have the same meanings as described above. And NH ₂ R ³ wherein R ³ is as defined above. Wherein the compound is reacted in the presence of a base.

The term "halogen atom" used in the present specification includes, for example, fluorine, chlorine, bromine and iodine. As used herein, the term "C
Examples of " _1-6 alkyl" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. In the above formulas (I) to (VI), X, X ¹ , X ² ,
X ³ , X ⁴ , X ⁵ , Y, Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ each represent “a phenyl group or a pyridyl group each of which may be substituted with a halogen atom”. As the “halogen atom”, fluorine or chlorine is preferably used.
The "phenyl group optionally substituted with a halogen atom"
Examples thereof include a phenyl group which may have 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) as a substituent, and a preferred specific example is, for example, phenyl , 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,5-difluorophenyl and the like. Among them, phenyl or 4-fluorophenyl is preferably used. The “pyridyl group optionally substituted with a halogen atom” includes, for example, a pyridyl group optionally having one or two halogen atoms (eg, fluorine, chlorine, bromine or iodine) as a substituent. And an unsubstituted pyridyl group (for example, 2-pyridyl, 3-pyridyl or 4-pyridyl) is preferable, and among them, 2-pyridyl and the like are preferably used.
^{X, X 1, X 2,} X 3, X 4, X 5, Y, Y 1, Y 2, Y 3, Y
^4, and as preferably Y ⁵ phenyl, 4-fluorophenyl or 2-pyridyl and the like. X ¹ and Y ¹ are preferably both phenyl, and preferably X ² and Y ² are both phenyl, one is phenyl and the other is 2-pyridyl,
When one is phenyl and the other is 4-fluorophenyl, both are 2-pyridyl, one is 2-pyridyl and the other is 4-fluorophenyl or both are 4-fluorophenyl, and X ³ and Y ³ are preferably ,
X ⁴ and Y ⁴
Are preferably phenyl, one is phenyl and the other is 2-pyridyl, one is phenyl and the other is 4-
Fluorophenyl, both 2-pyridyl, one is 2-
Pyridyl, the other being 4-fluorophenyl or both 4
And X ⁵ and Y ⁵ are preferably both phenyl.

In the above formula (I), R ¹ is an optionally halogenated C _1-6 alkyl group or a group represented by the formula

Embedded image (Wherein R ² represents a hydrogen atom, a C _1-6 alkoxy-carbonyl, a C _1-6 alkyl-carbamoyl, a nicotinoyl group optionally substituted with a halogen atom, or an isonicotinoyl group optionally substituted with a halogen atom. )).

The "optionally halogenated C _1-6 alkyl group" for R ¹ includes, for example, 1 to 3
C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl) which may have halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) Butyl, pentyl, hexyl, etc.) and the like.
Methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-chloroethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl , 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl and the like can give. Among them, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-chloroethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-triethyl Optionally halogenated C such as fluoropropyl and isopropyl
_{A 1-3} alkyl group and the like are preferable, and 2-chloroethyl and the like are particularly preferable.

In the above formula (I), R ² is substituted with a hydrogen atom, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbamoyl, a nicotinoyl group optionally substituted with a halogen atom or a halogen atom. Represents an optionally substituted isonicotinoyl group. “C _1-6 alkoxy- represented by R ²
As "carbonyl", for example, methoxycarbonyl,
Examples include ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl and the like, with tert-butoxycarbonyl being preferred. The “C _1-6 alkyl-carbamoyl” represented by R ² includes, for example, mono-C _1-6 alkyl-carbamoyl such as methylcarbamoyl and ethylcarbamoyl, or di-C _1-6 such as dimethylcarbamoyl and diethylcarbamoyl. Examples thereof include alkyl-carbamoyl and the like, and among them, ethylcarbamoyl and the like are preferable. Examples of the “nicotinoyl group optionally substituted with a halogen atom represented by R ² ” include 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine,
A nicotinoyl group which may be substituted with iodine, etc., and a nicotinoyl group is preferable. Examples of the “isonicotinoyl group optionally substituted with a halogen atom” represented by R ² include one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
And an isonicotinoyl group which may be substituted, and an isonicotinoyl group is preferable. As R ² , a hydrogen atom, tert-butoxycarbonyl, ethylcarbamoyl or nicotinoyl group is preferably used. R ¹ is 2-chloroethyl,

Embedded image And the like are preferably used.

In the above formula (II), R ³ is a C _1-6 alkyl group which may be substituted by a hydroxy group,

Embedded image Wherein R ⁴ is (1) C _1-6 alkyl which may be substituted by hydroxy, C _1-6 alkyl-carbonyloxy or pyridyl.
_1-6 alkyl group, (2) C _1-6 alkoxy group optionally substituted with a halogen atom or pyrrolidinyl, (3) pyridyl group optionally having a substituent, or (4) having a substituent Represents a phenyl group which may be substituted. ] Is shown. Examples of the “C _1-6 alkyl group _optionally substituted with a hydroxy group” for R ³ include methyl, ethyl, propyl, butyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxy Butyl and the like, among which methyl, 3-hydroxypropyl and the like are preferably used. In the “C _1-6 alkyl group optionally substituted with hydroxy, C _1-6 alkyl-carbonyloxy or pyridyl” for R ⁴ , “hydroxy, C ₁ -alkyl” which the C _1-6 alkyl group has as a substituent _-6 alkyl - carbonyloxy or pyridyl "may have three to 1 the same or different and each substitutable position of C _1-6 alkyl groups. R ^{4 represents} a C 5 optionally substituted by hydroxy, C _1-6 alkyl-carbonyloxy or pyridyl.
_{In the} “ _1-6 alkyl group”, examples of the “C _1-6 alkyl-carbonyloxy” that the C _1-6 alkyl group has as a substituent include, for example, acetoxy, ethylcarbonyloxy,
Examples thereof include propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, and tert-butylcarbonyloxy, and among them, acetoxy is preferably used. “Hydroxy, C _{1-6 represented} by R ⁴
In the “C _1-6 alkyl group optionally substituted with alkyl-carbonyloxy or pyridyl”, examples of the pyridyl that the C _1-6 alkyl group has as a substituent include 2
Examples thereof include -pyridyl, 3-pyridyl and 4-pyridyl, and 2-pyridyl is preferably used. R ⁴
"Pyridyl group optionally having substituent (s)"
Is a pyridyl group optionally having 1 to 3, preferably 1 to 2 substituents at substitutable positions on the ring (eg, 2
-Pyridyl, 3-pyridyl, 4-pyridyl), and examples of the substituent include (i) a halogen atom, (ii)
An optionally halogenated C _1-6 alkyl group, (ii.
i) an optionally halogenated C _1-6 alkoxy group,
(Iv) a C _1-3 alkylenedioxy group, (v) a cyano group, and (vi) a hydroxy group. The “optionally halogenated C _1-6 alkyl group” includes
The same as those exemplified in the above-mentioned “C _1-6 alkyl group which may be halogenated for R ¹ ” and the like are used. As the “optionally halogenated C _1-6 alkoxy group”, for example, a lower alkoxy group optionally having 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) For example, C _1-6 such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
Alkoxy group and the like), and specific examples thereof include
For example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2-chloroethoxy, 2,2,2-
Trifluroethoxy, n-propoxy, isopropoxy, n-butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy,
Hexyloxy and the like. As the "C _1-3 alkylenedioxy group", for example, methylenedioxy,
Examples include ethylenedioxy and propylenedioxy. Preferred examples of the “pyridyl group optionally having substituent (s)” for R ⁴ include an unsubstituted pyridyl group (particularly, 3-pyridyl and 4-pyridyl).
The “optionally substituted phenyl group” for R ⁴ includes, for example, a phenyl group optionally having 1 to 3 substituents at substitutable positions on the ring. As the substituent, those similar to the above-mentioned examples of the substituent of the “pyridyl group optionally having substituent (s)” and the like are used. Preferred examples of the “phenyl group which may have a substituent” include an unsubstituted phenyl group.

R ⁴ is preferably hydroxymethyl, acetoxymethyl, 2-chloroethoxy, 2- (pyrrolidin-1-yl) ethoxy, pyridyl (especially 3-
Pyridyl, 4-pyridyl) or phenyl. R ³ is preferably methyl, hydroxypropyl, hydroxymethyl,

Embedded image And so on.

In the above formula (III),

Embedded image Represents a single bond or a double bond. In the above formula (III), Q
The - indicates a _{(CH 2) m-CH =} (m denotes an integer of 0 to 2) - (CH ₂₎ n-(where n indicates an integer of 1 to 3) or. n is preferably 1 and m is preferably 0. In the above formula (III), R ⁵ represents a hydrogen atom or a C _1-6 alkoxy-carbonyl group. As the “C _1-6 alkoxy-carbonyl group”,
For example, those similar to the “C _1-6 alkoxy-carbonyl group” exemplified for the above R ² can be mentioned.
-Butoxycarbonyl is preferably used. R ⁵ is preferably a hydrogen atom or tert-butoxycarbonyl.

In the above formula (IV), R ⁶ is a C _1-6 alkyl group, a nicotinoyl optionally substituted with a halogen atom or a piperidino group substituted with isonicotinoyl optionally substituted with a halogen atom, a substituent A pyridyl group or a piperidino group substituted by a C _1-6 alkoxy-carbonyl which may have As the “C _1-6 alkyl group” represented by R ⁶ , for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Examples thereof include sec-butyl, tert-butyl, pentyl, and hexyl. Of these, methyl is preferred. Examples of the “nicotinoyl group optionally substituted by a halogen atom or piperidino group substituted by isonicotinoyl optionally substituted by a halogen atom” include, for example, 1 to 3 halogen atoms at substitutable positions on a ring. Atoms (for example,
Fluorine, chlorine, bromine, iodine, etc.) and a piperidino group having 1 to 2 nicotinoyl groups or isonicotinoyl groups which may be substituted, and specifically,

Embedded image And so on. The `` pyridyl group optionally having substituent (s) '' is a substituent at a substitutable position on the ring 1 to 3
And preferably a pyridyl group which may have 1 to 2 substituents such as (i) a halogen atom, (ii) an optionally halogenated C _1-6 alkyl group, ( iii) an optionally halogenated C _1-6 alkoxy group, (iv) a C _1-3 alkylenedioxy group,
(V) a cyano group, and (vi) a hydroxy group. The “piperidino group substituted by C _1-6 alkoxy-carbonyl” includes, for example, C _1-6 alkoxy-carbonyl (eg, acetoxy, ethoxycarbonyl, propoxycarbonyl, etc.) at a substitutable position on the ring. And a piperidino group having two or more substituents. R ⁶ is preferably methyl, 3-pyridyl,
Ethoxycarbonyl-piperidino,

Embedded image And so on.

In the above formula (V), the substituent on the ring A is a halogen atom, an oxo group, an optionally halogenated C
_1-6 alkyl group or C _1-6 which may be halogenated
Shows an alkoxy group. One or two of these substituents may be substituted at substitutable positions on the ring A. “Optionally halogenated C _1-6 represented as a substituent on ring A
Examples of the “alkyl group” include the same groups as those exemplified as the “ _optionally halogenated C _1-6 alkyl group” for R ¹ . “Optionally halogenated C” represented as a substituent on ring A
Examples of the “ _1-6 alkoxy group” include, for example, “optionally halogenated C _1-6 ” described as the “substituent” of the “pyridyl group optionally having substituent (s)” for R ^4.
Examples are the same as those exemplified as the "alkoxy group". As the ring A, for example,

Embedded image And the like are preferably used.

Specific examples of preferred compounds include, for example, 1- (tert-butoxycarbonyl) piperidin-4-yl
N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) carbamate, piperidin-4-yl N- (5- (4- (4-chlorophenyl)- Four-
(Hydroxypiperidino) -2,2-diphenylpentyl) carbamate, 1- (N-ethylcarbamoyl) piperidine-4
-Yl N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) carbamate, 1- (nicotinoyl) piperidin-4-yl N- (5- (4
-(4-chlorophenyl) -4-hydroxypiperidino) -2,2
-Diphenylpentyl) amino carbamate, 1- (5- (4
-(4-chlorophenyl) -4-hydroxypiperidino) -2,2
-Diphenylpentyl) -3- (1- (2-chloroethyloxycarbonyl) piperidin-4-yl) urea, 1- (5- (4-
(4-chlorophenyl) -4-hydroxypiperidino) -2,2-
Diphenylpentyl) -3- (1- (acetoxyacetyl)
Piperidin-4-yl) urea, 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) -3- (1- (nicotinoyl) piperidin-4- Ill)
Urea, 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) -3- (1- (isonicotinoyl) piperidin-4-yl) urea, 1- (Five-
(4- (4-chlorophenyl) -4-hydroxypiperidino)-
2,2-diphenylpentyl) -3- (1- (benzoyl) piperidin-4-yl) urea, 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2- Diphenylpentyl) -3- (1- (2-hydroxyacetyl) piperidin-4-yl) urea, 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenyl Pentyl) -3- (1-
(2-pyrrolidin-1-yl) ethyloxycarbonyl)
Piperidin-4-yl) urea, N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) nicotinamide, 2-chloroethyl (5- (4-
(4-chlorophenyl) -4-hydroxypiperidino) -2,2-
Diphenylpentylamino) carbamate, 1- (5- (4-
(4-chlorophenyl) -4-hydroxypiperidino) -2,2-
Diphenylpentyl) -4,5-dihydro-2-oxazolone,
2- (1- (t-butoxycarbonyl) piperidin-4-yl)-
N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) acetamide, 2- (1-
(T-butoxycarbonyl) piperidine-4-ylidene) -N-
(5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) acetamide, N- (5- (4
-(4-chlorophenyl) -4-hydroxypiperidino) -2,2
-Diphenylpentyl) -2- (piperidin-4-yl) acetamide;

N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) -2- (piperidin-4-ylidene) acetamide, 1- (5- ( 4- (4-chlorophenyl) -4-hydroxypiperidino) -2-phenyl
-2- (2-pyridyl) pentyl) -3- (3-hydroxypropyl) urea, 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2-phenyl-2- ( 2-pyridyl) pentyl) -3- (1- (nicotinoyl) piperidin-4-yl) urea, 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2-phenyl-2 -(2-pyridyl) pentyl)
-3- (1- (Isonicotinoyl-4-yl) urea, 1- (5-
(4- (4-chlorophenyl) -4-hydroxypiperidino)-
2-phenyl-2- (2-pyridyl) pentyl) -3- (1-((3-
Pyridyl) acetyl) piperidin-4-yl) urea, 1-
(5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2-phenyl-2- (2-pyridyl) pentyl) -3- (1-
((4-pyridyl) acetyl) piperidin-4-yl) urea, N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2-phenyl-2- (2-pyridyl) pentyl ) -1
-(Nicotinoyl) piperidinecarboxamide, N- (5-
(4- (4-chlorophenyl) -4-hydroxypiperidino)-
2-phenyl-2- (2-pyridyl) pentyl) -1- (isonicotinoyl) piperidinecarboxamide, 1- (5- (4- (4-
(Chlorophenyl) -4-hydroxypiperidino) -2,2-di (2-pyridyl) pentyl) -3- (3-hydroxypropyl) urea, 1- (5- (4- (4-chlorophenyl) -4- Hydroxypiperidino) -2,2-di (2-pyridyl) pentyl)-
3- (1- (nicotinoyl) piperidin-4-yl) urea, 1
-(5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-di (2-pyridyl) pentyl) -3- (1- (isonicotinoyl-4-yl) urea, 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-di (2-pyridyl) pentyl) -3- (1-((3-pyridyl) acetyl) piperidine-4- Yl) urea, 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-di (2-pyridyl) pentyl) -3- (1-((4-pyridyl) Acetyl) piperidin-4-yl) urea;

N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-di (2-pyridyl) pentyl)-
1- (nicotinoyl) piperidinecarboxamide, N- (5-
(4- (4-chlorophenyl) -4-hydroxypiperidino)-
2,2-di (2-pyridyl) pentyl) -1- (isonicotinoyl) piperidinecarboxamide, N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-di (2 -Pyridyl) pentyl) acetamide, 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-bis (4-fluorophenyl) pentyl) -3- (3-hydroxypropyl ) Urea, 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-bis (4-fluorophenyl)
Pentyl) -3- (1- (nicotinoyl) piperidin-4-yl) urea, 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-bis (4-fluoro Phenyl)
Pentyl) -3- (1- (isonicotinoyl-4-yl) urea, 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-bis (4-fluorophenyl) Pentyl) -3- (1-((3-pyridyl) acetyl) piperidine-4-
Yl) urea, 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-bis (4-fluorophenyl) pentyl) -3- (1-((4-pyridyl ) Acetyl) piperidin-4-yl) urea, N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-bis (4-fluorophenyl) pentyl) -1- ( Nicotinoyl) piperidinecarboxamide, N- (5- (4- (4-chlorophenyl) -4
-Hydroxypiperidino) -2,2-bis (4-fluorophenyl) pentyl) -1- (isonicotinoyl) piperidinecarboxamide, N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-bis (4-fluorophenyl) pentyl) acetamide, 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2- (4-fluorophenyl) -2- ( 2-pyridyl) pentyl) -3- (3-hydroxypropyl) urea, 1- (5- (4- (4-chlorophenyl) -4
-Hydroxypiperidino) -2- (4-fluorophenyl) -2
-(2-pyridyl) pentyl) -3- (1- (nicotinoyl) piperidin-4-yl) urea, 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2- ( 4-fluorophenyl) -2- (2-pyridyl) pentyl) -3- (1- (isonicotinoyl-4-yl) urea,

1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2- (4-fluorophenyl) -2- (2-
Pyridyl) pentyl) -3- (1-((3-pyridyl) acetyl) piperidin-4-yl) urea, 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2- (4-fluorophenyl) -2- (2-pyridyl) pentyl) -3- (1-
((4-pyridyl) acetyl) piperidin-4-yl) urea, N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2- (4-fluorophenyl) -2- ( 2-pyridyl) pentyl) -1- (nicotinoyl) piperidinecarboxamide, N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2- (4-fluorophenyl) -2- (2 -Pyridyl) pentyl) -1- (isonicotinoyl) piperidinecarboxamide, N- (5- (4- (4-chlorophenyl) -4
-Hydroxypiperidino) -2- (4-fluorophenyl) -2
-(2-pyridyl) pentyl) acetamide, 1- (5- (4- (4
-Chlorophenyl) -4-hydroxypiperidino) -2- (4-
(Fluorophenyl) -2-phenylpentyl) -3- (3-hydroxypropyl) urea, 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2- (4-fluorophenyl) -2-phenylpentyl) -3- (1- (nicotinoyl) piperidin-4-yl) urea, 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2- (4- Fluorophenyl) -2-phenylpentyl) -3- (1- (isonicotinoyl-4-yl) urea, 1- (5- (4- (4-chlorophenyl)-
4-hydroxypiperidino) -2- (4-fluorophenyl)-
2-phenylpentyl) -3- (1-((3-pyridyl) acetyl) piperidin-4-yl) urea,

1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2- (4-fluorophenyl) -2-phenylpentyl) -3- (1-((4-pyridyl) ) Acetyl) piperidin-4-yl) urea, N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2- (4-fluorophenyl) -2-phenylpentyl) -1- (Nicotinoyl) piperidinecarboxamide, N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2- (4-fluorophenyl) -2-phenylpentyl) -1- (isonicotinoyl) piperidinecarboxamide Or N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2- (4-fluorophenyl) -2phenylpentyl) acetamide or a salt thereof. The above compound is a free form,
Any of salts, hydrates and the like may be used. Compound (I) or a salt thereof (hereinafter simply referred to as compound (I)), compound (II) or a salt thereof (hereinafter simply referred to as compound (II)), compound (III) or a salt thereof (hereinafter referred to as Compound (III)), Compound (IV) or a salt thereof (hereinafter simply referred to as Compound (IV)) and Compound (V) or a salt thereof (hereinafter simply referred to as Compound (V)) Although various production methods are conceivable, typical examples are shown below. In the following description of the production method, the starting compound and the reaction product may form a salt that does not hinder the reaction.

Manufacturing method-1

Embedded image (In the above formula, L ¹ to L ⁵ represent a leaving group, and other symbols have the same meanings as described above.) The reaction is a conventional amino group alkylation reaction [for example, ORGANIC Organic Group Preparations (ORGANIC). FUNCTIONAL GROUP PREPARATIONS)
Second edition, ACADEMIC PRESS, IN
C.) described method]. As the leaving groups L ¹ to L ⁵ , a halogen atom (preferably chloro, bromo, iodo), a methanesulfonyloxy group, p-
Examples thereof include a toluenesulfonyloxy group and a benzenesulfonyloxy group. The reaction is carried out by stirring at room temperature to 100 ° C (preferably room temperature to 50 ° C) for 0.5 to 1 day in an inert solvent. Usually 1 to 3 equivalents of base are added, but this is not necessary. Alcohol solvents, ether solvents, halogen solvents, aromatic solvents, acetonitrile, N, N-
Dimethylformylamide (DMF), acetone, methyl ethyl ketone, dimethylsulfoxide and the like can be used alone or in combination. Among them, acetonitrile, DMF, acetone, ethanol and the like are preferable.

Examples of the base include: 1) a strong base, for example, a hydride of an alkali metal or an alkaline earth metal (eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), an alkali metal or alkali Earth metal amides (eg, lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethylsilazide, sodium hexamethylsilazide, potassium hexamethylsilazide, etc.), alkali metal or alkaline earth metal lower (C _1-4) alkoxide (e.g., sodium methoxide, sodium ethoxide, potassium t- butoxide) and the like; 2) inorganic bases such as alkali metal or alkaline earth metal hydroxides (e.g., water Sodium oxide, potassium hydroxide Lithium hydroxide, barium hydroxide, etc.), alkali metal or alkaline earth metal carbonates (eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal or alkaline earth metal bicarbonates (eg, hydrogen carbonate) Sodium, potassium bicarbonate, etc.)
3) organic bases and the like, for example, triethylamine, diisopropylethylamine, N-methylmorpholine,
-Dimethylaminopyridine, DBU (1,8-diazabicyclo [5.4.0] -7-undecene), DBN
Amines such as (1,5-diazabicyclo [4.3.0] non-5-ene) or pyridine, imidazole,
And basic heterocyclic compounds such as 2,6-lutidine. Compound (I), compound (II), compound (III), compound (IV) and compound (V) obtained by the above production method are subjected to hydrolysis, halogenation, oxidation, reduction, alkylation, General organic synthesis reactions such as acylation reaction and ring formation reaction can further lead to the object of the present invention. As a separate production method of compound (I), compound (II), compound (III), compound (IV) and compound (V), for example, when the compound has a carbonyl in the molecule, the following compound having a hydroxyl group is obtained by a Grignard reaction or the like. Can be led.

Manufacturing method-2

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image (In the formula, M represents a metal used in a so-called Grignard reaction such as lithium, sodium, and bromomagnesium,
Other symbols are as defined above. The Grignard reaction is carried out by reacting a compound (VII) or a compound (VI
I) ′, compound (VII) ″, compound (VII) ″ ″ or compound (VII) ″ ″ in an ether solvent at room temperature to 8 ° C.
The reaction is carried out at 0 ° C (preferably 30 to 60 ° C) for 1 to 24 hours. The reaction is preferably carried out under deoxygenated / anhydrous conditions, and sometimes it is preferable to coexist with anhydrous cerium chloride (catalytic amount to 2 equivalents, preferably 1 equivalent).

In the case where the ketone represented by the compound (X) or the compound (X ″ ″) is converted into an alcohol, a metal hydride (eg, lithium aluminum hydride, sodium borohydride, borohydride) Lithium, sodium cyanoborohydride, diborane, dibutylaluminum hydride, etc.) in an inert solvent. Examples of the inert solvent include ether solvents (eg, ethyl ether, tetrahydrofuran, dioxane, etc.), alcohol solvents (eg, methanol, ethanol, tert-butanol, etc.), toluene, hexane and the like. The metal hydride is used in an amount of 1 to 20 equivalents, more preferably 3 to 12 equivalents, and the reaction temperature is from -70 ° C to 100 ° C. The preferred reaction temperature and reaction time vary depending on the reducing agent used, but in the case of a metal hydride, 0 ° C to 30 ° C and 30 minutes to 18 hours are appropriate.

In the compounds (I) to (IV), -COOR ¹ , -CONHR ³ ,

Embedded image The acyl group represented by and -COR ⁶ can be exchanged for another acyl group directly or through a hydrolysis reaction. The hydrolysis reaction includes an alkali hydrolysis reaction and an acid hydrolysis reaction. In the case of the “alkali hydrolysis reaction”, the compound is dissolved in a solvent (eg, water, alcohols, ethers alone or a mixture of two or more of these). ), An alkali (for example, a hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or barium hydroxide). As the solvent, a mixed solvent of water and methanol is preferable. As the alkali, sodium hydroxide is preferable. The amount of the alkali used is about 2 to 1 based on the compound.
00 equivalents, preferably about 5 to 10 equivalents. The reaction temperature is about 10 ° C to 120 ° C, preferably about 50 ° C to 120 ° C. The reaction time is about 5 minutes to 100 hours, preferably about 10 to 50 hours. As a preferred reaction example, the solvent is a mixed solvent of water and methanol, the reaction temperature is about 50 ° C. to 120 ° C., and the reaction time is about 10 to 50 hours. The “acid hydrolysis reaction” is carried out by adding a compound in water or acetic acid in the presence of an excess amount of a mineral acid (eg, hydrochloric acid, sulfuric acid, phosphoric acid, etc.) at room temperature to 120 ° C. for 0.5 hour.
What is necessary is just to heat and stir for 18 hours. It is preferably carried out at room temperature to 100 ° C. in the presence of dilute hydrochloric acid alone or in the presence of acetic acid. The above acyl group can be converted into another acyl group by the acylation reaction described below after the hydrolysis reaction.

Production method-3

Embedded image (In the above formula, each symbol has the same meaning as described above.) The acylation reaction is carried out by a known method [for example, Organic Functional Group Preparations (ORGANI
C FUNCTIONAL GROUP PREPARATIONS) Second Edition, Method described in ACADEMIC PRESS, INC.]. For example, compound (I),
When producing compound (III) and compound (IV),
Compound (XII) is reacted with 1 to 5 equivalents, preferably 1 to 3 equivalents, of the corresponding reactive derivative of an organic acid in an inert solvent at a reaction temperature of -20 ° C to 50 ° C (preferably 0 ° C to room temperature), The reaction is carried out for a reaction time of 5 minutes to 100 hours. Inert solvents include ether solvents, halogen solvents, aromatic solvents, acetonitrile,
N, N-dimethylformylamide (DMF), acetone, methyl ethyl ketone, dimethyl sulfoxide (DM
SO), water or the like can be used alone or as a mixture thereof. Among them, acetonitrile, dichloromethane, chloroform and the like are preferable. The reaction may proceed more smoothly by coexistence of 1 to 10 equivalents, preferably 1 to 3 equivalents of a base. As the base, both inorganic bases and organic bases are effective. Examples of inorganic bases include hydroxides, hydrides, carbonates, bicarbonates, and organic acid salts of alkali metals and alkaline earth metals, among which potassium carbonate, sodium carbonate, sodium hydroxide, and hydroxides. Potassium, sodium bicarbonate and potassium bicarbonate are preferred. Tertiary amines such as triethylamine are preferred as the organic base. Examples of the reactive derivative include an acid anhydride, an acid halide (for example, acid chloride and acid bromide), and an active ester. Among them, an acid halide is preferable.

When acylating from a carboxylic acid, 1 to 1.5 equivalents of a carboxylic acid and a dehydrating condensing agent (1 to 1.5 equivalents) such as dicyclohexylcarbodiimide (DCC) are used in an inert solvent (for example, , A halogen-based solvent, acetonitrile) at room temperature for 0.5 to 24 hours. When producing the compound (II) the corresponding isocyanate (OCN-R ³ (R ³ is as defined above.)), Isothiocyanate (SCN-R
³ (R ³ has the same meaning as described above)) in an inert solvent (eg, a halogen-based solvent, acetonitrile, etc.) at an reaction temperature of −20 ° C. to 50 ° C.
(Preferably from 0 ° C. to room temperature), and a reaction time of 5 minutes to 1
The reaction is performed for 00 hours. Occasionally, 1 to 10 equivalents of an organic base such as triethylamine are used in order to promote the reaction. In addition, the compound (I
I) can also be produced by the following exchange reaction (Production method 4).

Manufacturing method-4

Embedded image (In the formula, each symbol has the same meaning as described above.) In the reaction, an equivalent or excess amine (NH ₂ R ³ (R ³ has the same meaning as described above)) and compound (XIII) are mixed with acetonitrile and DMF. The reaction proceeds at room temperature to 50 ° C. for 1 to 24 hours in the presence of 1 to 10 equivalents of an inorganic base (eg, potassium carbonate, sodium carbonate, etc.) in an inert solvent such as water.

The above "Production method-1" and "Production method-2"
Can be synthesized by combining known synthesis methods in the literature. For example, the following compound used in the above “Production method-1” can be easily obtained or synthesized,

Embedded image Can be produced from the corresponding ketone body in the same manner as in the above "Production method-2". Starting compound (VII),
Compound (VII) ', Compound (VII)'', Compound (VII)'''
And compound (VII) ″ ″ can be synthesized by a method known per se, and examples thereof include the following scheme-1.

Scheme-1

Embedded image (Wherein J ¹ represents cyano, carboxyl, lower (C _1-3 ) alkoxycarbonyl, formyl, etc., and J ² represents a group convertible to a leaving group (for example, cyano, carboxyl, lower (C _1-3) ) Alkoxycarbonyl, protected hydroxyl group, etc.), L ′ has the same meaning as L above, and other symbols have the same meanings as above.) Compound (XX) in an equivalent to excess amount of compound (XXI), compound (XX) ) ′ To an equivalent or excess of compound (XXI), compound (XX) ″ to an equivalent or an excess of compound (XXI), compound (X
X) An equivalent or excess of compound (XXI) and / or an excess of compound (XXI) with respect to compound (XXI) '''' can be arbitrarily selected from ether solvents, DMF, DMSO, alcohol solvents, acetonitrile, acetone and the like. In an inert solvent alone or in a mixed solvent system in the presence of a catalytic amount or an excess of a base (usually 1 to 3 equivalents) at -20 ° C to 120 ° C for 5 minutes to 24 hours to give compound (XXII) and compound (XX), respectively. XXII) ′, compound (XXII) ″, compound (XXII) ″ ″ and compound (XXII) ″ ″. Compound (XXII), compound (XXII) ′, compound (XXII) ″, compound (XXII) ″ ″ and compound (XXI)
I) "" is the compound (XX), the compound (XX) ', the compound (XX) ", the compound (XX)""and the compound (XX)"", respectively.
Of acrylonitrile and acrylic acid lower alkyl ester (2 to 10 equivalents) in the presence of a base catalyst.

Examples of the base include: 1) a strong base, for example, a hydride of an alkali metal or an alkaline earth metal (eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), alkali metal or alkali Earth metal amides (eg, lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethylsilazide, sodium hexamethylsilazide, potassium hexamethylsilazide, etc.), alkali metal or alkaline earth metal (C _1-4 ) alkoxides (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.); 2) inorganic bases, for example, hydroxides of alkali metals or alkaline earth metals (eg, water Sodium oxide, potassium hydroxide Lithium hydroxide, barium hydroxide, etc.), alkali metal or alkaline earth metal carbonates (eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal or alkaline earth metal bicarbonates (eg, hydrogen carbonate) Sodium, potassium bicarbonate, etc.)
3) organic bases and the like, for example, triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, DBU (1,8-diazabicyclo [5.4.0] -7-undecene), DBN (1,5
Amines such as -diazabicyclo [4.3.0] non-5-ene) or pyridine, imidazole, 2,6-
And basic heterocyclic compounds such as lutidine.

Compound (XXII), compound (XXII) ′, compound (XXII) ″, compound (XXII) ″ ″ and compound (XXI)
I) '''' is a combination of known organic synthesis reactions such as hydrolysis, halogenation, oxidation, reduction, alkylation, acylation, and ring formation. Each compound (VI
I), compound (VII) ′, compound (VII) ″, compound (VI
It is possible to lead to I) ″ ″ and compound (VII) ″ ″. Examples of the reaction include the following production methods. Method 1

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image Method 2

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image (In the formula, L ″ has the same meaning as L, and the other symbols have the same meanings as above.) Compound (XXV) to compound (XXV) ″ ″ and compound (XXIX) to compound (XXIX) Examples of the reduction reaction for '''' include a method using a metal hydride or the like or a catalytic reduction method. In the catalytic reduction method, a catalytic amount of a metal catalyst such as Raney nickel, platinum oxide, metallic palladium or palladium-carbon and an inert solvent (for example, an alcoholic solvent) are used at room temperature to 100 ° C. and a hydrogen pressure of 1 atm.
It is obtained by reacting at atmospheric pressure for 1 to 48 hours.

The reduction reaction with a metal hydride can be carried out by a metal hydride (for example, lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, diborane, dibutylaluminum hydride, etc.) or a metal (for example, The reaction is easily achieved by using zinc, iron, sodium, potassium or the like) in an inert solvent. Examples of the inert solvent include ether solvents (eg, ethyl ether, tetrahydrofuran, dioxane, etc.), alcohol solvents (eg, methanol, ethanol, tert-butanol, etc.), toluene and hexane. Preferred metal hydrides include lithium aluminum hydride. The metal hydride is used in an amount of 4 to 20 equivalents, more preferably 6 to 12 equivalents, and the reaction temperature is from -70 ° C to 100 ° C. The preferred reaction temperature depends on the reducing agent used, but is suitably from 30 ° C to 70 ° C. The reaction time is between 30 minutes and 18 hours. It is also possible to selectively reduce only the cyano group or only the ester group. Conversion of a hydroxyl group to a leaving group,
Alternatively, the conversion of amino groups and the like are described in the literature [for example, Comprehensive Organic Transformation VHS Publishers (Comprehensiv
e Organic Transformations, VCH Publishers Inc.)]
It can be performed according to the method described. Compound (XXVI
Compound (XXVIII) to compound (XXVIII) "" can be derived from I) to compound (XXVII) "" by a known Wittig reaction. The reaction is carried out in an inert solvent (alcohol-based solvent, ether-based solvent, etc.) using 1 equivalent to an excess of Wittig reagent (eg, ethyl triphenylphosphoranylidene acetate, ethyl diethylphosphonoacetate) if necessary. It is obtained by reacting at -20 ° C to 60 ° C for 5 minutes to 18 hours in the presence of a base.
Examples of the base include 1) a strong base such as sodium hydride and potassium t-butoxide; 2) an inorganic base (for example, a hydroxide of an alkali metal or an alkaline earth metal (eg, sodium hydroxide, potassium hydroxide, water Lithium oxide, barium hydroxide, etc.), alkali metal or alkaline earth metal carbonate (eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal or alkaline earth metal bicarbonate (eg, sodium bicarbonate) , Potassium bicarbonate, etc.); 3) organic bases (eg, amines such as triethylamine and DBU).

When the double bond is reduced, the above-mentioned catalytic reduction method can be used. Compound (XXIII) to compound (XXIII) "" which is one of the starting materials can be synthesized from arylacetonitrile, diarylketone, or the like by a method known per se (for example, synthesis, page 172, 1977). In each of the above-mentioned reactions and each reaction of the synthesis of the starting compound, when the starting compound has an amino group, a carboxyl group or a hydroxyl group as a substituent, a protecting group generally used in peptide chemistry or the like is introduced into these groups. The target compound can be obtained by removing the protecting group as necessary after the reaction. Examples of the amino-protecting group include, for example, C
_1-6 alkyl-carbonyl group (eg, formyl, acetyl, ethylcarbonyl, etc.), C _1-6 alkyloxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.), benzoyl group, C _7-10 aralkyl-carbonyl group (eg, Examples thereof include a C _7-14 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl), a trityl group, a phthaloyl group, and an N, N-dimethylaminomethylene group. These groups have one to three halogen atoms (eg, fluorine, chlorine,
Bromine and iodine), a nitro group and the like.

Examples of the carboxyl-protecting group include a C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, etc.), a phenyl group, a trityl group, a silyl group (eg, , Trimethylsilyl, tert-butyldimethylsilyl, etc.). These groups have one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C
_It may be substituted with a _1-6 alkyl-carbonyl group (eg, formyl, acetyl, propionyl, butylcarbonyl, etc.), nitro group and the like. As the protecting group for the hydroxyl group, for example, a C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, butyl, tert-
Butyl, etc.), phenyl group, C _7-10 aralkyl group (eg,
Benzyl, etc.), formyl, C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl, etc.), benzoyl group, C _7-10 aralkyl-carbonyl group (eg, benzyl carbonyl, etc.), tetrahydropyranyl group, tetrahydrofuranyl group , A silyl group (eg, trimethylsilyl, te
rt-butyldimethylsilyl and the like).
These groups include one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), a C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, etc.), a phenyl group, a C _{7- 10 It} may be substituted by an aralkyl group (eg, benzyl and the like), a nitro group and the like. As a method for removing these protecting groups, a method known per se or a method analogous thereto is used. For example, acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride And a method using palladium acetate or the like.

The salts of the compounds (I) to (V) include, for example, salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and basic or acidic amino acids. And the like. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt. Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and the like. Preferred examples of salts with inorganic acids include:
For example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like can be mentioned. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like. Preferable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, and preferable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, and the like. Can be Among them, pharmaceutically acceptable salts are preferable, and examples thereof include, when the compound has a basic functional group, inorganic salts such as hydrochloride, sulfate, phosphate, and hydrobromide; Or organic salts such as acetate, maleate, fumarate, succinate, methanesulfonate, p-toluenesulfonate, citrate, tartrate, etc. For example, inorganic salts, ammonium salts and the like of alkali metal salts (such as sodium salt and potassium salt) or alkaline earth metal salts (such as calcium salt and magnesium salt) can be mentioned. Compound (I) to compound (V) or a salt thereof can be prepared by a known method, for example, solvent extraction, liquid conversion, phase transfer,
Isolation by crystallization, recrystallization, chromatography, etc.
It can be purified. The compounds (I) to (V) or salts thereof of the present invention can be isolated and purified by the same known means as described above.
It may be used as a raw material in the next step as a reaction mixture without isolation. Compound (I) to compound (V) or a salt thereof is an optical isomer, a stereoisomer,
When it contains a regioisomer or a rotamer, these are also contained as the compound of the present invention, and each can be obtained as a single product by a synthesis method and a separation method known per se. For example, when the compound of the present invention has an optical isomer, the optical isomer resolved from the compound is also included in the present invention. The optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by optically resolving the final racemic mixture according to a conventional method. As the optical resolution method, a method known per se, for example,
The following fractional recrystallization method, chiral column method, diastereomer method and the like are used. 1) Fractional recrystallization method A method in which a salt is formed between a racemate and an optically active compound, which is separated by a fractional recrystallization method and, if desired, undergoes a neutralization step to obtain a free optical isomer. 2) Chiral column method A method in which a racemate or a salt thereof is applied to a column for separation of optical isomers (chiral column) to be separated. For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation), and water, various buffers (eg, phosphate buffer, etc.), organic solvents (eg, ethanol, The optical isomers are separated by developing a solution of methanol or acetonitrile alone or as a mixture. For example, in the case of gas chromatography, CP-Chirasil-De
Separation is performed using a chiral column such as XCB (manufactured by GL Sciences). 3) Diastereomer method A racemic mixture is made into a diastereomer mixture by a chemical reaction with an optically active reagent, and the mixture is converted into a single substance by a usual separation means (eg, fractional recrystallization, chromatography, etc.). And then separating optically active reagent sites by a chemical treatment such as a hydrolysis reaction to obtain optical isomers. For example, when the compound of the present invention has a hydroxyl group or a primary or secondary amino group in the molecule, the compound and an optically active organic acid (eg, MPTA [α-methoxy-α- (trifluoromethyl) phenylacetic acid]),
(-)-Menthoxyacetic acid or the like) to give a diastereomer of an ester form or an amide form, respectively. On the other hand, when the compound of the present invention has a carboxylic acid group, an amide or ester diastereomer can be obtained by subjecting the compound to an optically active amine or alcohol reagent for a condensation reaction. The separated diastereomer is converted to the optical isomer of the original compound by subjecting it to acid hydrolysis or basic hydrolysis reaction.

The compound (I) to compound (V) of the present invention or a salt thereof can be used as it is or according to a method known per se, by mixing a pharmacologically acceptable carrier with a pharmaceutical composition, for example, a tablet (sugar-coated tablet, film) Orally or parenterally (eg, topical, rectal, intravenous, etc.) as powders, granules, capsules, (including soft capsules), liquids, injections, suppositories, sustained release agents, etc. ) Can be safely administered. The content of compound (I) to compound (V) or a salt thereof in the preparation of the present invention is 0.1 to 100% by weight of the whole preparation, respectively. The dosage varies depending on the administration subject, administration route, disease and the like. For example, as a therapeutic agent for viral encephalitis, an adult (60 kg) is administered orally as an active ingredient (compound (I), compound (II) ), Compound (III), compound (IV) or compound (V), or a salt thereof) in an amount of about 0.1 to 500 mg, preferably about 1 to 10 mg.
0 mg, more preferably about 5 to 100 mg, can be administered once or several times a day.
Pharmaceutically acceptable carriers that may be used in the production of the preparation of the present invention include various organic or inorganic carrier substances commonly used as preparation materials, such as excipients, lubricants, and binders in solid preparations. Agents, disintegrants; solvents in liquid preparations, solubilizers, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can also be used. As an excipient, for example, lactose,
White sugar, D-mannitol, starch, corn starch,
Examples include crystalline cellulose and light anhydrous silicic acid. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.

As the binder, for example, crystalline cellulose,
Examples include sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, and sodium carboxymethylcellulose. Disintegrators include, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Examples of the dissolution aid include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. As a suspending agent, for example, stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride,
Surfactants such as glyceryl monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like. Examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Examples of the soothing agent include benzyl alcohol and the like. As preservatives, for example, paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol,
Dehydroacetic acid, sorbic acid and the like. Examples of the antioxidant include sulfite and ascorbic acid.

The drug containing the hydroxypiperidino compound of the present invention and a pharmaceutically acceptable salt thereof has excellent MIP-1α / RANTES receptor antagonism, and thus can be used in mammals (eg, humans and dogs). , Cats, cows, horses,
Various viral or infectious diseases of rats, mice, monkeys, etc. (eg, acute viral encephalitis, acute bacterial meningitis, Helicobacter pylori infection, pneumonia, hepatitis A, hepatitis B, C) Hepatitis, herpes simplex virus infection, varicella-zoster virus infection, AIDS infection, influenza infection, invasive staphylococcal infection, tuberculosis, etc., tumor (eg, bladder cancer, breast cancer, cervical cancer, chronic) Lymphocytic leukemia, chronic myeloid leukemia,
Colorectal cancer, multiple myeloma, malignant myeloma, prostate cancer, lung cancer, gastric cancer, Hodgkin's disease, etc., allergic diseases (eg, bronchial asthma, atopic dermatitis, allergic rhinitis, etc.), inflammatory diseases ( For example, arteriosclerosis, arteriosclerosis that develops after heart transplantation, (chronic) rheumatoid arthritis,
Nephritis), diabetic diseases (eg, diabetes, diabetic nephropathy, diabetic complications, diabetic retinopathy, diabetic microangiopathy, etc.), central diseases (eg, Alzheimer's disease, epilepsy, fever, pain, Dementia, etc.), hyperlipidemia, hypercholesterolemia, thrombocytopenia due to dialysis, spinal cord injury, osteoporosis, ulcerative colitis, peptic ulcer, sepsis (shock), reperfusion injury in lung and heart, unstable narrowing Heart disease, transient ischemic attack, valvular heart disease, rejection after organ transplantation, restenosis after angioplasty, systemic lupus erythematosus, multiple sclerosis, renal failure, endometriosis, pulmonary fibrosis, It is useful for prevention and treatment of adult respiratory arrest syndrome and the like, and particularly useful for prevention and treatment of allergic diseases, inflammatory diseases, and multiple sclerosis. MIP-1α / RANTES of the present invention
Compounds used as receptor antagonists have low toxicity and few side effects. Acute toxicity by oral administration in rats is 1
00 mg / kg or more.

[0040]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention further includes the following reference examples,
The present invention will be described in detail with reference to Examples, Formulation Examples and Experimental Examples, which are merely examples, do not limit the present invention, and may be changed without departing from the scope of the present invention. In this specification, “room temperature” indicates 0 to 30 ° C., and anhydrous magnesium sulfate or anhydrous sodium sulfate was used for drying an organic solvent in the following Reference Examples and Examples. % Means percent by weight unless otherwise specified. Abbreviations used in other texts have the following meanings. s: singlet d: doublet t: triplet q: quartet m: multiplet br: broad (j): coupling constant (coupling) Hertz) CDCl ₃ : deuterated chloroform IPE: isopropyl ether THF: tetrahydrofuran DMF: N, N-dimethylformylamide DMSO: dimethyl sulfoxide ¹ H-NMR: proton nuclear magnetic resonance (normally measured in a free form, there is a conformational isomer) In the case, only the main peak was described.) DMEM: Dulbecco's modified Eagle's medium Dulbecco's transformation Eagle's medium PBS: phosphate buffered saline

[0041]

【Example】

Reference Example 1 1-tert-butoxycarbonyl-4-hydroxypiperidine 1-tert-butoxycarbonyl-4-piperidone (6.0 g) was dissolved in ethanol (60 ml), and sodium borohydride (0.45 g) was added at 0 ° C. Then, the mixture was stirred at room temperature for 16 hours. After acidifying the reaction solution with acetic acid, ethyl acetate (120
ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (6.1 g) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.35-1.57 (2H, m), 1.46 (9
H, s), 1.78-1.94 (2H, m), 2.42 (1H, br), 2.95
-3.08 (2H, m), 3.79-3.90 (3H, m). Reference Example 2 2- [1- (t-butoxycarbonyl) piperidin-4-yl] acetic acid described in J. Chem. Soc. PERKIN TRANS.I, 641 (1995).
2- [1- (t-butoxycarbonyl) piperidin-4-yl]
A 1 N aqueous sodium hydroxide solution (96 ml) was added to an ethanol solution (100 ml) of ethyl acetate (20 g), and the mixture was added at room temperature.
Stirred for 8 hours. The reaction solution was concentrated under reduced pressure, adjusted to pH 3 by adding 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate / hexane to give the title compound (15.4
g) was obtained. Melting point 95-96 ℃

Reference Example 3 2- [1- (t-butoxycarbonyl) piperidine-4-ylidene] acetic acid 2- [N- (t- The title compound was obtained in the same manner as in Reference Example 1 using butoxycarbonyl) piperidine-4-ylidene] ethyl acetate. Recrystallization solvent Ethyl acetate / hexane Melting point 133-134 ℃

Reference Example 4 Ethyl 4-cyano-4,4-diphenyl-1-butanol ethyl 4-cyano-4,4-diphenylbutyrate (44.0
g) was dissolved in THF (440 ml) and lithium tetrahydroborate (3.9 g) was carefully added at 0 ° C.
The mixture was heated to room temperature and stirred for 2 days. The reaction solution was poured into cold 1 N hydrochloric acid (440 ml) and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and eluted with ethyl acetate-hexane (1: 2) to give the title compound (34.
6 g) were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.62-1.76 (2H, m), 2.47-2.55
(2H, m), 3.69 (2H, t), 7.28-7.42 (10H, m).

Reference Example 5 1-Bromo-4-cyano-4,4-diphenylbutane Triphenylphosphine (27.5 g) was suspended in acetonitrile (100 ml), cooled to 0 ° C., and brominated (5.2).
ml) was added dropwise. After completion of the dropwise addition, 4-cyano-4,4-
A solution of diphenyl-1-butanol (25.1 g) in acetonitrile (40 ml) was added at 0 ° C. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure, ether was added to the residue, and triphenylphosphine oxide was filtered off. The filtrate was washed with saturated saline, dried, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluted with ether, and crystallized from IPE to obtain the title compound (25.6 g). ¹ H-NMR (CDCl ₃ ) δ: 1.93-2.07 (2H, m), 2.527-2.6
1 (2H, m), 3.44 (2H, t), 7.26-7.42 (10H, m).

Reference Example 6 4- (4-chlorophenyl) -1- (4-cyano-4,
4-Diphenylbutyl) -4-hydroxypiperidine 1-bromo-4-cyano-4,4-diphenylbutane (22.0 g) was dissolved in acetonitrile (500 ml), and 4- (4-chlorophenyl) -4-hydroxypiperidine was dissolved. (17.8 g), potassium iodide (1.2 g) and potassium carbonate (29 g) were added. After stirring at room temperature for 16 hours, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate.
It was washed with pure water. The organic layer was washed with saturated brine, dried, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and eluted with ethyl acetate to give the title compound (3) as an amorphous powder.
1.4 g) were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.60-1.83 (5H, m), 2.06 (2
H, dt), 2.30-2.49 (6H, m), 2.71 (2H, br d),
7.27-7.45 (14H, m).

Reference Example 7 1-amino-5- [4- (4-chlorophenyl) -4-
[Hydroxypiperidino] -2,2-diphenylpentane 4- (4-chlorophenyl) -1- (4-cyano-4,
4-Diphenylbutyl) -4-hydroxypiperidine (31.3 g) was added to a saturated ammonia-ethanol solution (5.
00 ml), and Raney cobalt catalyst (20 g) was added. The mixture was stirred at 70 ° C. for 8 hours under a hydrogen pressure of 5 atm.
The solvent was distilled off under reduced pressure, and the residue was crystallized from ethyl acetate to obtain the title compound (17.8 g). Melting point 116-117 ° C

Reference Example 8 Phenyl N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] carbamate 1-amino-5- [4- (4-chlorophenyl) ) -4-Hydroxypiperidino] -2,2-diphenylpentane (22.5 g) in THF
(250 ml), triethylamine (3.5 ml) and phenyl chlorocarbonate (6.6 ml) were added at room temperature, and the mixture was stirred for 2 hours. The reaction solution was washed with a mixture of 1 N sodium hydroxide and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel chromatography, eluted with ethyl acetate, and crystallized from IPE / ethyl ether to give the title compound (15.5 g). 138-140 ℃

Reference Example 9 1- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3- [1- (trifluoroacetyl) piperidine-4- Il] urea phenyl N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] carbamate (22.8 g) and 4-amino-1-trifluoroacetylpiperidine hydrochloride The salt (14.0 g) was stirred in DMF (250 ml) and potassium carbonate (13.8 g) was added at room temperature. After stirring for 16 hours, the mixture was poured into pure water (500 ml) and extracted with ethyl acetate (500 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel chromatography, eluted with ethyl acetate, and crystallized from IPE / ether to give the title compound (20.1 g). Melting point 192-193 ℃

Reference Example 10 1- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3- (piperidine-4-
Yl) urea 1- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-diphenylpentyl] -3- [1- (trifluoroacetyl) piperidin-4-yl] urea (2.35 g) to T
Dissolve in HF (10.5 ml) and add 0.5N sodium hydroxide (1
0.5 ml) and stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was crystallized from ethyl acetate / ethyl ether to give the title compound (1.92
g) was obtained. Melting point 194-196 ℃

Reference Example 11 Phenyl N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2-phenyl-2- (2-pyridyl) pentyl) carbamate 5- (4- (4 -Chlorophenyl) -4-hydroxypiperidino) -2-
Phenyl-2- (2-pyridyl) pentylamine (9 g) was added to THF (90
ml), and triethylamine (1.4 ml) and phenyl chlorocarbonate (2.5 ml) were added at room temperature and stirred for 3 hours. The reaction solution was diluted with ethyl acetate, and washed with a 1 N aqueous sodium hydroxide solution. The organic layer was washed with saturated saline, dried and concentrated. The residue was subjected to silica gel chromatography and eluted with ethyl acetate-methanol (19: 1) to give the title compound (4.4 g) as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.12-1.44 (2H,
m), 1.57-1.83 (3H, m), 1.
95-2.15 (2H, m), 2.20-2.45
(6H, m), 2.61-2.76 (2H,
m), 3.97-4.18 (2H, m), 6.
20 (1H, t, J = 5.6 Hz), 6.94
−7.42 (16H, m), 7.60 (1H,
dt, J = 1.8, 7.7 Hz), 8.59
(1H, d, J = 4.4 Hz).

Reference Example 12 Bis (4-fluorophenyl) acetonitrile 4-Fluorobenzaldehyde (31.5 ml) was added to an aqueous solution (350 ml) of sodium bisulfite (37.6 g) at 40 ° C. Two
After stirring for an hour, ether (175 ml) was added to the reaction solution,
An aqueous solution (35 ml) of sodium cyanide (15.4 g) was added at 0 ° C, and the mixture was stirred at room temperature for 16 hours. The reaction solution was extracted with ether, and the extract was washed with saturated saline, dried and concentrated. The mixture of the residue and fluorobenzene (74.6 ml) was
At 75 ° C was added to sulfuric acid (75 ml). After stirring for 1 hour, the reaction solution was poured into ice water, extracted with ethyl acetate, and the extract was washed with saturated saline, dried and concentrated. The obtained residue was crystallized from hexane to give the title compound (36.6 g). ¹ H-NMR (CDCl ₃ ) δ: 5.12 (1H, s), 7.01-7.12 (4H,
m), 7.26-7.37 (4H, m).

Reference Example 13 Ethyl 4-cyano-4,4-bis (4-fluorophenyl) butyrate Bis (4-fluorophenyl) acetonitrile (34.4 g) was dissolved in isopropyl alcohol (500 ml), and ethyl acrylate (21.2 g) was added. ml) and 1,8-diazabicyclo [5,4,0] -7-undecene (3 ml) and heated under reflux for 5 hours. The reaction solution was concentrated, the residue was dissolved in ethyl acetate, washed with 1N hydrochloric acid and saturated saline, dried and concentrated. The residue was subjected to silica gel chromatography, and hexane-ethyl acetate (4:
Elution was carried out in 1) to obtain the title compound (44.6 g) as an oil. _{^{1 HNMR (CDCl 3) δ:}} 1.24 (3H, t, J = 7.2Hz), 2.38-2.44
(2H, m), 2.65-2.75 (2H, m), 4.11 (2H, q, J = 7.2H
z), 7.02-7.12 (4H, m), 7.32-7.40 (4H, m).

Reference Example 14 5-bromo-2,2-bis (4-fluorophenyl) butyronitrile Ethyl 4-cyano-4,4-bis (4-fluorophenyl) butyrate (24.7 g) obtained in Reference Example 13. Was dissolved in THF (250 ml), lithium borohydride (2.0 g) was added at 0 ° C., and the mixture was stirred at room temperature for 16 hours. The reaction solution was cooled to 0 ° C., and after excessive lithium borohydride was decomposed with 1 N hydrochloric acid, extracted with ethyl acetate. The extract was washed with saturated saline, dried and concentrated. The residue was subjected to silica gel chromatography and eluted with hexane-ethyl acetate (2: 1). The obtained oil was dissolved in acetonitrile (30 ml) and added to a solution of a mixture of triphenylphosphine (20.1 g) and bromine (3.8 ml) in acetonitrile (73 ml). The reaction solution was stirred at room temperature for 1 hour and concentrated. After the residue was diluted with ether, insolubles were removed by filtration. The filtrate was concentrated, and the residue was subjected to silica gel chromatography and eluted with hexane-ethyl acetate (4: 1) to give the title compound (23.4 g) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.92-2.06 (2H, m), 2.47-2.58 (2
H, m), 3.45 (2H, t, J = 6.1Hz), 7.01-7.13 (4H, m),
7.29-7.40 (4H, m).

Reference Example 15 4- (4-Chlorophenyl) -1- (4-cyano-4,4-bis (4-fluorophenyl) butyl) -4-hydroxypiperidine 2,2-bis (4-fluorophenyl) butyronitrile (17.5 g) was added to acetonitrile (200 m
l), 4- (4-chlorophenyl) -4-hydroxypiperidine (12.7 g), potassium carbonate (20.7 g), and potassium iodide (0.83 g) were added. After stirring the reaction solution at 65 ° C. for 16 hours,
The mixture was poured into cold water and extracted with ethyl acetate. The extract was washed with saturated saline, dried and concentrated. The residue was subjected to silica gel chromatography and eluted with hexane-ethyl acetate (1: 1). The obtained oil was crystallized from hexane to give the title compound (16.3 g). 124-125 ° C

Reference Example 16 1-Amino-5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-bis (4-fluorophenyl) pentane (4-chlorophenyl) -1- (4-cyano-
4,4-bis (4-fluorophenyl) butyl) -4-hydroxypiperidine (16 g) in 10% -ammonia-ethanol solution (15
0 ml), and Raney cobalt catalyst (25 g) was added. Two
The mixture was stirred at 50 ° C. under 0 atm of hydrogen for 4 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was crystallized from isopropyl ether to give the title compound (13.8 g). 113-115 ° C

Reference Example 17 Phenyl N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-bis (4-fluorophenyl) pentyl] carbamate 1-amino-5- [4- (4-chlorophenyl) -4
-Hydroxypiperidino] -2,2-bis (4-fluorophenyl) pentane (7.3 g) was dissolved in THF (75 ml), and triethylamine (1.0 ml) and phenyl chlorocarbonate (1.9 ml) were added at room temperature. The mixture was stirred for 3 hours. The reaction solution was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was washed with saturated saline, dried and concentrated. The obtained residue was subjected to silica gel chromatography and eluted with ethyl acetate-hexane (1: 1). The obtained oil was crystallized from isopropyl ether to give the title compound (4.4 g). Melting point 129-132 ° C

Reference Example 18 (4-fluorophenyl) phenylacetonitrile Mandelonitrile (26.6 g) and fluorobenzene (74.6 m
The mixture of l) was added to sulfuric acid (75 ml) at 0-10 ° C. After the dropwise addition, the reaction solution was stirred for 1 hour and poured into ice water. After extraction with ethyl acetate, the extract was washed with saturated saline, dried and concentrated. The residue was subjected to silica gel chromatography and eluted with ethyl acetate-hexane (4: 1) to give the title compound (32.2 g) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 5.13 (1H, s), 7.07 (2H, t, J = 8.
6Hz), 7.37-7.52 (7H, m).

Reference Example 19 Ethyl 4-cyano-4- (4-fluorophenyl) -4-phenylbutyrate (31.7 g) of (4-fluorophenyl) phenylacetonitrile (31.7 g) obtained in Reference Example 18 was replaced with isopropyl alcohol ( 500 ml) and dissolved in ethyl acrylate (21.2 m
l) and 1,8-diazabicyclo [5,4,0] -7-undecene (3 ml) were added, and the mixture was reacted under reflux for 5 hours. The reaction solution was concentrated, the residue was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated saline, dried and concentrated. The residue was subjected to silica gel chromatography and eluted with hexane-ethyl acetate (7: 1) to give the title compound (25.5 g) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7.2Hz), 2.39-2.4
8 (2H, m), 2.68-2.77 (2H, m), 4.10 (2H, q, J = 7.2H
z), 7.06 (2H, t, J = 8.6Hz), 7.28-7.40 (7H, m).

Reference Example 20 4-cyano-4- (4-fluorophenyl) -4-phenylbutanol 4-cyano-4- (4-fluorophenyl) -4- obtained in Reference Example 19
Ethyl phenylbutyrate (25.5 g) was dissolved in THF (250 ml),
Lithium borohydride (2.1 g) was added at
Stirred for 6 hours. The reaction solution was cooled to 0 ° C., and after excessive lithium borohydride was decomposed with 1 N hydrochloric acid, extracted with ethyl acetate. The extract was washed with saturated saline, dried and concentrated. The obtained residue was subjected to silica gel chromatography and eluted with hexane-ethyl acetate (3: 1) to give the title compound (15.8 g) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.50 (1H, br), 1.59-1.77 (2H,
m), 2.44-2.53 (2H, m), 3.69 (2H, t, J = 6.0Hz), 7.04
(2H, t, J = 8.6Hz), 7.28-7.40 (7H, m).

Reference Example 21 5-Bromo-2- (4-fluorophenyl) -2-phenylbutyronitrile 4-cyano-4- (4-fluorophenyl) -4- obtained in Reference Example 20
Phenylbutanol (15.6 g) in acetonitrile (25 ml)
Was dissolved. Triphenylphosphine (20.1 g) was added to the reaction solution.
Solution of bromine (3.8 ml) and acetonitrile (58 ml)
And stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, the residue was diluted with ether, and unnecessary substances were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with hexane-ethyl acetate (4: 1).
The title compound (16.8 g) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.92-2.06 (2H, m), 2.50-2.59 (2
H, m), 3.44 (2H, t, J = 6.2Hz), 7.06 (2H, t, J = 8.6H
z), 7.31-7.41 (7H, m).

Reference Example 22 4- (4-chlorophenyl) -1- (4-cyano-4- (4-fluorophenyl) -4-phenylbutyl) -4-hydroxypiperidine 5-bromopiperidine obtained in Reference Example 21 -2- (4-fluorophenyl) -2-
Phenylbutyronitrile (10.0 g) was added to acetonitrile (100
ml), and 4- (4-chlorophenyl) -4-hydroxypiperidine (7.6 g), potassium carbonate (12.4 g), and potassium iodide (0.5 g) were added. The reaction was stirred at 65 ° C. for 24 hours. The reaction solution was poured into cold water and extracted with ethyl acetate. The extract was washed with saturated saline, dried and concentrated. The obtained residue was subjected to silica gel chromatography to give hexane-
Elution was performed with ethyl acetate (1: 1). The obtained oil was crystallized from hexane to give the title compound (10.9 g). 135-136 ° C

Reference Example 23 1-amino-5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2- (4-fluorophenyl) -2-phenylpentane -(4-chlorophenyl) -1- (4-cyano-4
-(4-Fluorophenyl) -4-phenylbutyl) -4-hydroxypiperidine (10 g) in 10% -ammonia-ethanol solution
(150 ml), and Raney cobalt catalyst (15 g) was added. The reaction was stirred at 50 ° C. under 20 atm of hydrogen for 4 hours.
The catalyst was removed by filtration, and the filtrate was concentrated. The residue was crystallized from isopropyl ether to give the title compound (7.9 g). Melting point 94-96 ℃

Reference Example 24 Phenyl N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2- (4-fluorophenyl) -2-phenylpentyl] carbamate Obtained in Reference Example 23 , 1-amino-5- [4- (4-chlorophenyl) -4
-Hydroxypiperidino] -2- (4-fluorophenyl) -2-phenylpentane (4.7 g) was dissolved in THF (100 ml), and triethylamine (0.7 ml) and phenyl chlorocarbonate (1.3 ml) were brought to room temperature. And stirred for 3 hours. The reaction solution was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was washed with saturated saline, dried and concentrated. The residue was subjected to silica gel chromatography and eluted with ethyl acetate-hexane (4: 1). The obtained oil was crystallized from isopropyl ether to give the title compound (3.1 g). 142-144 ° C

Reference Example 25 (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-
(Il) cyanide dibenzosuberyl chloride (22.9 g) in toluene (250 ml)
And copper cyanide (10.5 g) was added thereto, followed by stirring under reflux for 3 hours. After cooling to room temperature, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated saline, dried and concentrated. The obtained residue was subjected to silica gel chromatography, eluted with ethyl acetate, the solvent was distilled off under reduced pressure, and the residue was crystallized from hexane to obtain the title compound (13.8 g). ¹ H-NMR (CDCl ₃ ) δ: 3.17-3.41 (4H, m), 5.48 (1H,
s), 7.14-7.28 (6H, m), 7.45-7.28 (2H, m).

Reference Example 26 Ethyl 3- (5-cyano-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) propionate (10,11-dihydro-ethyl) obtained in Reference Example 25. 5H-Dibenzo [a, d] cyclohepten-5-yl) cyanide (14.3 g) was dissolved in isopropyl alcohol (150 ml), and ethyl acrylate (9.2 m
l), 1,8-diazabicyclo [5,4,0] -7-undecene (1.5 ml)
Was added and reacted under reflux for 16 hours. The solvent is distilled off under reduced pressure,
The residue was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated saline, dried and concentrated. The obtained residue was subjected to silica gel chromatography and eluted with hexane-ethyl acetate (9: 1) to give the title compound (25.5 g) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.1Hz), 2.26-2.3
5 (2H, m), 2.76-2.85 (2H, m), 2.94-3.10 (2H, m), 3.
32-3.51 (2H, m), 4.01 (2H, q, J = 7.1Hz), 7.12-7.29
(6H, m), 7.92-8.00 (2H, m).

Reference Example 27 (5- (3-Hydroxypropyl) -10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) cyanide Ethyl -10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) propionate
(16.7 g) was dissolved in THF (150 ml), lithium borohydride (1.4 g) was added at 0 ° C, and the mixture was stirred at room temperature for 16 hours. The reaction solution was cooled to 0 ° C., and after excessive lithium borohydride was decomposed with 1 N hydrochloric acid, extracted with ethyl acetate. The extract was washed with saturated saline, dried and concentrated. The obtained residue was subjected to silica gel chromatography and eluted with hexane-ethyl acetate (7: 3) to give the title compound (14) as an oil.
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.41-1.58 (2H, m), 1.98 (1H, b
r), 2.42-2.62 (2H, m), 2.96-3.09 (2H, m), 3.30-3.47
(2H, m), 3.57 (2H, t, J = 6.2Hz), 7.05-7.28 (6H, m),
7.91-8.00 (2H, m).

Reference Example 28 (5- (3-bromopropyl) -10,11-dihydro-5H-dibenzo
[a, d] cyclohepten-5-yl) cyanide (5- (3-hydroxypropyl) -10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) cyanide obtained in Reference Example 27 (13.8 g) was dissolved in acetonitrile (25 ml) and added to an acetonitrile solution (50 ml) of a mixture of triphenylphosphine (13.8 g) and bromine (2.6 ml). After stirring at room temperature for 1 hour, the reaction solution was concentrated, the residue was diluted with ether, and the insoluble matter was removed by filtration. The filtrate was concentrated, and the residue was subjected to silica gel chromatography and eluted with hexane-ethyl acetate (4: 1) to give the title compound (16 g) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.73-1.88 (2H, m), 2.47-2.60 (2
H, m), 2.94-3.12 (2H, m), 3.28-3.49 (4H, m), 7.11-
7.28 (6H, m), 7.89-7.99 (2H, m).

Reference Example 29 (5- (3- (4- (4-chlorophenyl) -4-hydroxypiperidino) propyl) -10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl ) Cyanide (5- (3-bromopropyl) -10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) cyanide obtained in Reference Example 28
(16 g) was dissolved in acetonitrile (150 ml), and 4- (4-chlorophenyl) -4-hydroxypiperidine (12 g), potassium carbonate (13.1 g), and potassium iodide (0.8 g) were added. The reaction solution was stirred at 65 ° C. for 32 hours, cooled to room temperature, poured into cold water, and extracted with ethyl acetate-THF (9: 1). The extract was washed with saturated saline, dried and concentrated. The residue was subjected to silica gel chromatography and eluted with ethyl acetate. The obtained oil was crystallized from ethyl acetate-ether to give the title compound.
(17.1 g) was obtained. 127-129 ° C

Reference Example 30 1- (3- (5- (aminomethyl) -10,11-dihydro-5H-dibenzo
(a, d) cyclohepten-5-yl) propyl) -4- (4-chlorophenyl) -4-hydroxypiperidine (5- (3- (4- (4-chlorophenyl) -4- Hydroxypiperidino) propyl) -10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) cyanide (16.4 g)
It was dissolved in a 0% -ammonia-ethanol solution (160 ml), and Raney cobalt catalyst (25 g) was added. The reaction was stirred at 50 ° C. under 20 atm of hydrogen for 3 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (16.6) as an amorphous powder.
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.08-1.63 (7H, m), 1.87-2.23 (8
H, m), 2.63-2.75 (2H, m), 3.00 (4H, s), 3.30 (2H,
s), 7.02-7.16 (4H, m), 7.20-7.34 (4H, m), 7.39 (2
H, d, J = 8.4Hz), 7.57 (2H, d, J = 8.0Hz).

Reference Example 31 N- (5- (3- (4- (4-chlorophenyl) -4-hydroxypiperidino) propyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5- Yl) methyl) acetamide 1- (3- (5- (aminomethyl) -10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) propyl) -4- obtained in Reference Example 30 (4-chlorophenyl) -4-hydroxypiperidine (0.
47 g) was dissolved in THF (5 ml) and triethylamine (0.14 m
l) and acetyl chloride (0.07 ml) were added at room temperature and stirred for 1 hour. The reaction solution was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was washed with saturated saline, dried and concentrated. The residue was subjected to silica gel chromatography and eluted with ethyl acetate-methanol (7: 3), and the obtained oil was crystallized from ethyl acetate-ether to give the title compound (0.42 g)
I got 152-153 ° C

Reference Example 32 Phenyl N- (5- (3- (4- (4-chlorophenyl) -4-hydroxypiperidino) propyl-10,11-dihydro-5H-dibenzo
[a, d] cyclohepten-5-yl) methyl) carbamate 1- (3- (5- (aminomethyl) -10,11-dihydro-5H-dibenzo [a, d] cycloheptene- obtained in Reference Example 30) 5-yl) propyl) -4- (4-chlorophenyl) -4-hydroxypiperidine (1
1.8 g) in THF (120 ml) and triethylamine (1.7
ml) and phenyl chlorocarbonate (3.2 ml) were added at room temperature and stirred for 1 hour. The reaction solution was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was washed with saturated saline, dried and concentrated. The obtained residue was subjected to silica gel chromatography and eluted with ethyl acetate-methanol (19: 1) to give the title compound (16 g) as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.09-1.26 (2H, m), 1.55-1.62 (2
H, m), 1.72 (1H, br), 1.93-2.07 (2H, m), 2.10-2.36
(6H, m), 2.41-2.59 (2H, m), 3.07 (4H, s), 4.02 (2H,
d, J = 5.9Hz), 4.70-4.81 (1H, m), 6.91 (2H, d, J = 7.
3Hz), 7.05-7.41 (13H, m), 7.65 (2H, d, J = 8.0Hz).

Reference Example 33 1- (5- (3- (4- (4-chlorophenyl) -4-hydroxypiperidino) propyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5- Yl) methyl) -3- (3-hydroxypropyl) urea 1- (3- (5- (aminomethyl) -10,11-dihydro-5H-dibenzo [a, d] cycloheptene- obtained in Reference Example 30 5-yl) propyl) -4- (4-chlorophenyl) -4-hydroxypiperidine (0.
Using the title compound (0.4 g) in the same manner as in Reference Example 9.
3 g) was obtained. Melting point 148-150 ° C (crystallization solvent: ethyl acetate-ether)

Reference Example 34 1- (5- (3- (4- (4-chlorophenyl) -4-hydroxypiperidino) propyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5- Yl) methyl) -3- (1- (isonicotinoyl) piperidine) urea dihydrochloride obtained in Reference Example 30, 1- (3- (5- (aminomethyl) -10,11-dihydro-5H-dibenzo [a , d] Cyclohepten-5-yl) propyl) -4- (4-chlorophenyl) -4-hydroxypiperidine (0.
Using 59 g), 1- (5- (3- (4- (4-
(Chlorophenyl) -4-hydroxypiperidino) propyl-1
An amorphous powder of 0,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) methyl) -3- (1- (isonicotinoyl) piperidine) urea was obtained. Then, the title compound (0.30 g) was obtained as the hydrochloride as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 0.95-1.26 (4H, m), 1.56-1.67 (2
H, m), 1.70-2.08 (5H, m), 2.12-2.27 (6H, m), 2.45-
2.57 (2H, m), 2.76-3.12 (6H, m), 3.48-3.72 (2H, m),
3.85-3.93 (3H, m), 4.05-4.14 (1H, m), 4.43-4.53
(1H, m), 7.03-7.32 (10H, m), 7.40 (2H, d, J = 8.8H
z), 7.60 (2H, d, J = 8.0Hz), 8.83-8.66 (2H, m).

Reference Example 35 N- (1-benzyl-4-piperidyl) -9H-xanthene 9-carboxamide Xanthene 9-carboxylic acid (11.3 g) was dissolved in DMF (150 ml), and 4-amino-1-benzyl was added. Piperidine (9.5 g), triethylamine (14 ml), diethyl cyanophosphate (7.5 ml) at 0 ° C
And stirred at room temperature for 2 hours. The reaction solution was poured into cold water, and the precipitate was collected by filtration. It was again dissolved in THF, dried over anhydrous sodium sulfate, and then subjected to silica gel chromatography, and eluted with ethyl acetate-THF (9: 1). The solvent was distilled off under reduced pressure, and the obtained crystalline residue was washed with hexane to obtain the title compound (15.2 g). 213-214 ° C

Reference Example 36 N- (4-Piperidyl) -9H-xanthene 9-carboxamide N- (1-benzyl-4-piperidyl) -9H-xanthene 9-carboxamide (0.8 g) obtained in Reference Example 35 was added. The residue was dissolved in THF (10 ml), 1-chloroethyl chloroformate (0.26 ml) was added at room temperature, and the mixture was refluxed for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained crystalline residue was dissolved again in methanol (10 ml) and refluxed for 3 hours. After cooling to 0 ° C., the mixture was made basic with a 1N aqueous sodium hydroxide solution and extracted with ethyl acetate-THF. The extract was washed with saturated saline, dried and concentrated. The obtained crystalline residue was washed with ethyl acetate to give the title compound (0.53 g). Melting point 252-255 ° C

Reference Example 37 N- (1-Isonicotinoyl-4-piperidyl) -9H-xanthen-
9-carboxamide obtained in Reference Example 36, N- (4-piperidyl) -9H-xanthene-9-
Carboxamide (0.93 g) was dissolved in DMF (25 ml), and triethylamine (1.26 ml) and isonicotinoyl chloride hydrochloride (0.64 g) were added at room temperature, followed by stirring for 1 hour.
The reaction solution was diluted with pure water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel chromatography, and eluted with ethyl acetate-methanol (9: 1). The solvent was distilled off under reduced pressure, and the obtained crystalline residue was washed with ethyl acetate-ether (2: 1) to give the title compound (0.
67 g) were obtained. 248-249 ° C

Reference Example 38 N- (1- (2-methyl-1-propen-3-yl) -4-piperidyl) -9H
-Xanthen-9-carboxamide obtained in Reference Example 36, N- (4-piperidyl) -9H-xanthene-9-
Carboxamide (0.93 g) was dissolved in DMF (25 ml), and potassium carbonate (0.93 g), 3-chloro-2-methyl-1-propene (0.29 ml), and potassium iodide (0.05 g) were added at room temperature. And stirred for 3 hours. The reaction solution was poured into pure water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel chromatography and eluted with ethyl acetate. The solvent was distilled off under reduced pressure, and the obtained crystalline residue was washed with ethyl acetate-ether (1: 1) to give the title compound (0.75%).
g) was obtained. 174-176 ° C

Reference Example 39 1-benzyl-1-methyl-4-((9H-xanthen-9-ylcarbonyl) amino) piperidinium iodide N- (1-benzyl-4-piperidyl)-obtained in Reference Example 35 9H-xanthene-9-carboxamide (0.80 g) in THF (25 ml)
Was dissolved at 60 ° C., and methyl iodide (0.25 ml) was added.
The mixture was stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration to give the title compound (0.37 g). 156-158 ℃

Example 1 1- (tert-butoxycarbonyl) piperidin-4-yl N-
(5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) carbamate

Embedded image 1- (tert-Butoxycarbonyl) -4-hydroxypiperidine (3.02 g) was dissolved in DMF (30 ml), 1,1'-carbonyldiimidazole (2.92 g) was added, and the mixture was stirred for 5 hours. 1-amino-5- [4- (4-chlorophenyl) -4 was added to the reaction solution.
-Hydroxypiperidino] -2,2-diphenylpentane (6.74 g) was added, and the mixture was further stirred at room temperature for 16 hours. The obtained solution was diluted with ethyl acetate and washed with saturated saline. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel chromatography and eluted with ethyl acetate to obtain the title compound (2.83 g) as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.47 (3H, m), 1.44 (9
H, s), 1.58-1.89 (6H, m), 1.96-2.13 (4H, m),
2.23-2.37 (4H, m), 2.65 (2H, brd, J = 7.4Hz), 3.
03-3.18 (2H, m), 3.56-3.75 (2H, m), 3.92 (2H, m
d, J = 6.0Hz), 4.33-4.42 (1H, m), 4.64-4.79 (1
H, m), 7.16-7.37 (12H, m), 7.42 (2H, d, J = 8.4H
z).

Example 2 Piperidin-4-yl N- (5- (4- (4-chlorophenyl)-
4-hydroxypiperidino) -2,2-diphenylpentyl)
Carbamate

Embedded image 1- (tert-butoxycarbonyl) piperidin-4-yl N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) carbamate obtained in Example 1 (2.00 g) in ethyl acetate (10 ml)
4N hydrochloric acid-ethyl acetate solution (10 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate (50 ml).
0 ml). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain the title compound (1.68 g) as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.21-1.52 (4H, m), 1.58-1.6
9 (2H, m), 1.77-1.89 (4H, m), 1.95-2.18 (4H,
m), 2.22-2.38 (4H, m), 2.54-2.72 (4H, m), 2.9
2-3.05 (2H, m), 3.92 (2H, d, J = 6.2Hz), 4.35-4.
44 (1H, m), 4.53-4.72 (1H, m), 7.16-7.37 (12
H, m), 7.42 (2H, d, J = 8.4Hz).

Example 3 1- (N-ethylcarbamoyl) piperidin-4-yl N- (5
-(4- (4-chlorophenyl) -4-hydroxypiperidino)
-2,2-Diphenylpentyl) carbamate

Embedded image Piperidin-4-yl N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) carbamate (0.45 g) obtained in Example 2 was added to THF (10 ml)
And ethyl isocyanate (63 μl) was added thereto, followed by stirring at room temperature for 16 hours. The obtained solution was diluted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was subjected to silica gel chromatography and subjected to ethyl acetate-
Elution with methanol (4: 1) gave the title compound (0.35 g) as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.17 3H, t, J = 7.0Hz), 1.22-
1.88 (12H, m), 2.03-2.22 (4H, m), 2.30-2.53
(4H, m), 2.64-2.81 (2H, m), 3.02-3.30 (4H,
m), 3.49-3.67 (2H, m), 3.92 (2H, d, J = 6.0Hz),
4.34-4.53 (2H, m), 4.65-4.80 (1H, m), 7.15-7.3
7 (12H, m), 7.43 (2H, d, J = 8.8Hz).

Example 4 1- (nicotinoyl) piperidin-4-yl N- (5- (4- (4
-Chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) carbamate

Embedded image Piperidin-4-yl N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) carbamate (0.45 g) obtained in Example 2 and triethylamine (0.26 nicotinic acid chloride hydrochloride (0.16 g) was added, and the mixture was stirred at room temperature for 3 hours. The obtained solution was diluted with ethyl acetate, washed with 1 N sodium hydroxide and saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was subjected to silica gel chromatography and eluted with ethyl acetate-methanol (7: 3) to obtain the title compound (0.42 g) as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.39 (4H, m), 1.42-2.1
7 (10H, m), 2.24-2.41 (4H, m), 2.57-2.71 (2H,
m), 3.16-3.64 (2H, m), 3.93 (2H, d, J = 6.1H
z), 4.01 (1H, br), 4.37 (1H, br), 4.87 (1H, br)
br), 7.15-7.45 (15H, m), 7.71-7.77 (1H, m),
8.60-8.66 (2H, m).

Example 5-1 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) -3- (1- (2-chloroethyloxycarbonyl) ) Piperidin-4-yl) urea

Embedded image 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) -3- (piperidine-4-
Il) urea (2.88 g) and triethylamine (0.84 ml)
Was dissolved in THF (50 ml), 2-chloroethyl chlorocarbonate (0.57 ml) was added, and the mixture was stirred at room temperature for 2 hours. The obtained solution was diluted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure,
The obtained residue was subjected to silica gel chromatography, and eluted with ethyl acetate-methanol (4: 1). The obtained oil was crystallized from ethyl acetate-diethyl ether to give the title compound (2.32 g). 223-226 ° C

In the same manner as in Example 5-1, 5-2 to 5-5 were synthesized. Example 5-2 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) -3- (1- (acetoxyacetyl) piperidin-4-yl) Urea

Embedded image Crystallization solvent Ethyl acetate-ether Melting point 168-172 ℃

Example 5-3 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) -3- (1- (nicotinoyl) piperidine-4- Ill) urea

Embedded image Crystallizing solvent Ethyl acetate-ether Melting point 196-198 ° C

Example 5-4 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) -3- (1- (isonicotinoyl) piperidine-4- Ill) urea

Embedded image Crystallization solvent Ether-IPE Melting point 174-176 ℃

Example 5-5 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) -3- (1- (benzoyl) piperidine-4- Ill) urea

Embedded image Crystallizing solvent Ether Melting point 214-216 ℃

Example 6 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) -3- (1- (2-hydroxyacetyl) piperidine-4 -Il) Urea

Embedded image 1- (5- (4- (4-chlorophenyl) -4- obtained in Example 5-2
Hydroxypiperidino) -2,2-diphenylpentyl) -3-
(1- (Acetoxyacetyl) piperidin-4-yl) urea (0.39 g) was dissolved in methanol (3 ml), 1N sodium hydroxide (1 ml) was added, and the mixture was stirred at room temperature for 3 hours.
The obtained solution was diluted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was subjected to silica gel chromatography and eluted with ethyl acetate-methanol (7: 3) to obtain the title compound (0.19 g) as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.02-1.39 (4H, m), 1.61-2.1
7 (10H, m), 2.22-2.39 (4H, m), 2.57-2.84 (3H,
m), 2.91-3.06 (1H, m), 3.37-3.57 (2H, m), 3.
64 (1H, br), 3.82-4.07 (4H, m), 4.11 (2H,
s), 4.43 1H, brd, J = 13.4Hz), 7.13-7.47 (14H,
m).

Example 7 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) -3- (1- (2-pyrrolidin-1-yl) Ethyloxycarbonyl) piperidine-4-
Ill) urea

Embedded image 1- (5- (4- (4-chlorophenyl) -4- obtained in Example 5-1
Hydroxypiperidino) -2,2-diphenylpentyl) -3-
(1- (2-chloroethyloxycarbonyl) piperidine-4
-Yl) urea (0.51 g) was dissolved in DMF (5 ml), and pyrrolidine (0.25 ml) was added in the presence of sodium iodide (0.01 g), followed by stirring at 60 ° C for 48 hours. The obtained solution was diluted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was subjected to silica gel chromatography and eluted with ethyl acetate-methanol (7: 3). The obtained oil was crystallized from diethyl ether-IPE to give the title compound (0.24 g). Melting point 169-172 ℃

Example 8-1 N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) nicotinamide dihydrochloride

Embedded image 1-Amino-5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentane (0.67 g) and triethylamine (0.42 ml) are dissolved in THF (10 ml) and nicotine Acid chloride hydrochloride (0.30 g) was added, and the mixture was stirred at room temperature for 16 hours. After diluting the obtained solution with ethyl acetate, 1
The extract was washed with normal sodium hydroxide and saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was subjected to silica gel chromatography and eluted with ethyl acetate-methanol (7: 3). The obtained oil was treated with 4N hydrogen chloride-ethyl acetate solution to obtain the title compound (0.57 g. ¹ H-NMR (CDCl ₃ ) δ: 1.32-1.47 (2H, m), 1.60-1.7
2 (2H, m), 1.95-2.24 (5H, m), 2.34-2.58 (4H,
m), 2.67-2.82 (2H, m), 4.20 (2H, d, J = 5.9Hz),
5.85 (1H, br), 7.14-7.42 (15H, m), 7.90-7.98
(1H, m), 8.62-8.69 (2H, m).

8-2 was synthesized in the same manner as in Example 8-1. Example 8-2 2-Chloroethyl (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentylamino) carbamate

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.38 (2H, m), 1.57-1.7
9 (2H, m), 2.00-2.38 (9H, m), 2,60-2.77 (2H,
m), 3.60 (2H, t, J = 5.6Hz), 3.94 (2H, d, J = 5.9H)
z), 4.25 (2H, t, J = 5.6Hz), 4.50-4.62 (1H, m),
7.13-7.38 (12H, m), 7.43 (2H, d, J = 8.6Hz).

Example 9 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) -4,5-dihydro-2-oxazolone

Embedded image 2-chloroethyl (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentylamino) carbamate (0.56 g) obtained in Example 8-2 was added to THF (10
ml), potassium t-butoxide (0.22 g) was added, and the mixture was stirred at room temperature for 1 hour. The obtained solution was diluted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was subjected to silica gel chromatography and eluted with ethyl acetate. The obtained oil was crystallized from diethyl ether to give the title compound (0.33 g). 210-212 ° C

Example 10-1 2- (1- (t-butoxycarbonyl) piperidin-4-yl)-
N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) acetamide

Embedded image 2- [1- (t-butoxycarbonyl) piperidin-4-yl]
Triethylamine (0.31 ml) was added to a solution of acetic acid (0.60 g) in THF (6 ml), the mixture was cooled to −10 ° C., and a solution of pivaloyl chloride (0.28 ml) in THF (2 ml) was added dropwise. The reaction solution was stirred at 0 ° C for 20 minutes, cooled to -10 ° C, and 1-amino-5- (4-
(4-chlorophenyl) -4-hydroxypiperidino) -2,2-
A THF solution (4 ml) of diphenylpentane (1.0 g) was added dropwise. After stirring the reaction solution at 0 ° C. for 30 minutes, ethyl acetate was added,
Washed with saturated aqueous sodium bicarbonate and water. The organic layer was dried, concentrated under reduced pressure, applied to an alumina column, and eluted with ethyl acetate / hexane (1: 1) to obtain the title compound (1.18 g) as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 0.85-1.74 (11H, m), 1.44 (9
H, s), 1.76-2.14 (5H, m), 2.20-2.38 (4H, m),
2.54-2.74 (4H, m), 3.90-4.20 (4H, m), 4.94-5.0
6 (1H, m), 7.10-7.45 (14H, m). 10-2 was synthesized in the same manner as in Example 10-1.

Example 10-2 2- (1- (t-butoxycarbonyl) piperidine-4-ylidene) -N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2, 2-diphenylpentyl) acetamide

Embedded image ¹ H-NMR (CDCl ₃ 3) δ: 1.08-1.40 (2H, m), 1.46 (9
H, s), 1.56-2.40 (13H, m), 2.56-2.86 (4H, m),
3.32-3.50 (4H, m), 3.98-4.10 (2H, m), 4.92-5.
04 (1H, m), 5.39 (1H, s), 7.15-7.45 (14H,
m).

Example 11-1 N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) -2- (piperidine-4-
Ill) acetamide dihydrochloride

Embedded image 2- (1- (t-butoxycarbonyl) piperidin-4-yl)-
N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) acetamide (0.30
A 4N hydrogen chloride-ethanol solution (2 ml) was added to an ethanol solution (5 ml) of g), and the mixture was stirred at 40 ° C. for 10 minutes. The reaction solution was concentrated under reduced pressure to obtain the title compound (0.25 g) as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 0.8-1.4 (4H, m), 1.4-2.8 (13
H, m), 2.2-2.4 (4H, m), 2.4-2.7 (4H, m), 2.8-
3.0 (2H, m), 3.99 (2H, d), 4.9-5.1 (1H, m),
7.1-7.5 (14H, m). 11-2 was synthesized in the same manner as in Example 11-1.

Example 11-2 N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2,2-diphenylpentyl) -2- (piperidine-4-
Ilidene) acetamide dihydrochloride

Embedded image ¹ H-NMR (CDCl ₃ ) δ: 1.2-1.4 (2H, m), 1.5-1.8 (2
H, m), 1.9-2.5 (12H, m), 2.5-2.9 (8H, m), 3.9-
4.1 (2H, m), 4.9-5.1 (1H, m), 5.33 (1H, s),
7.1-7.5 (14H, m).

Example 12-1 N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino)
2-phenyl-2- (2-pyridyl) pentyl) -1- (ethoxycarbonyl) piperidine-4-carboxamide dihydrochloride

Embedded image 5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2-
Phenyl-2- (2-pyridyl) pentylamine (0.45 g) in DMF
(5 ml), 1-ethoxycarbonyl-4-piperidinecarboxylic acid (0.20 g), triethylamine (0.28 ml), diethyl cyanophosphate (0.14 ml) were added at 0 ° C., and the mixture was added at room temperature.
Stir for 1 hour. The reaction solution was poured into cold water, and the precipitate was collected by filtration. After dissolving in ethyl acetate again, washed with saturated saline,
It was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate-methanol (4: 1). After evaporating the solvent under reduced pressure, the residue was converted into a hydrochloride and crystallized from ethyl acetate to give the title compound (0.44 g). 143-145 ° C

Example 12-2 N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino)
2-phenyl-2- (2-pyridyl) pentyl) -1- (isonicotinoyl) piperidine-4-carboxamide trihydrochloride

Embedded image 5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2-
Using phenyl-2- (2-pyridyl) pentylamine (0.45 g), the title compound (0.45 g) was obtained as an amorphous powder in the same manner as in Example 12-1. ¹ H-NMR (CDCl ₃ ) δ: 1.30-2.03 (10H, m), 2.12-2.62
(8H, m), 2.73-3.04 (4H, m), 3.47-3.95 (3H, m), 4.1
4-4.30 (1H, m), 4.40-4.62 (1H, m), 7.05-7.47 (13H,
m), 7.60-7.70 (1H, m), 8.57 (1H, d, J = 4.4Hz), 8.66
(2H, d, J = 5.9Hz).

Example 12-3 N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino)
-2,2-bis (4-fluorophenyl) pentyl) -1- (isonicotinoyl) piperidine-4-carboxamide dihydrochloride

Embedded image 1-amino-5- [4- (4-chlorophenyl) -4 obtained in Reference Example 16
Using -hydroxypiperidino] -2,2-bis (4-fluorophenyl) pentane (0.49 g), the title compound (0.70 g) was obtained in the same manner as in Example 12-1. 160-162 ° C

Example 12-4 N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino)
2- (4-fluorophenyl) -2-phenylpentyl) -1- (isonicotinoyl) piperidine-4-carboxamide dihydrochloride

Embedded image 1-amino-5- [4- (4-chlorophenyl) -4 obtained in Reference Example 23
Using -hydroxypiperidino] -2- (4-fluorophenyl) -2-phenylpentane (0.47 g) as the amorphous powder in the same manner as in Example 12-1, the title compound (0.57 g) I got ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.41 (2H, m), 1.49-2.23 (1
2H, m), 2.20-2.47 (4H, m), 2.63-3.06 (4H, m), 3.54
-3.65 (1H, m) 3.90-4.04 (2H, m), 4.57-4.63 (1H, m),
5.17 (1H, br), 7.00 (2H, t, J = 8.3Hz), 7.11-7.35
(11H, m), 7.42 (2H, d, J = 8.8Hz), 8.66 (2H, d, J = 5.8
Hz).

Example 13-1 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino)
2-phenyl-2- (2-pyridyl) pentyl) -3- (3-hydroxypropyl) urea dihydrochloride

Embedded image Phenyl N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2-phenyl-2- (2-pyridyl) pentyl) carbamate (0.57 g) obtained in Reference Example 11 was added to DMF. (6 ml), 3-hydroxypropylamine (0.15 ml) and potassium carbonate (0.28 g) were added at room temperature, and the mixture was stirred for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and eluted with ethyl acetate-methanol (7: 3). After evaporating the solvent under reduced pressure, the residue was dissolved in THF, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The title compound (0.42 g) was obtained as an amorphous powder as a hydrochloride. ¹ H-NMR (CDCl ₃ ) δ: 1.30-1.57 (4H, m), 1.63-1.85 (3
H, m), 2.10-2.37 (4H, m), 2.43-2.63 (4H, m), 2.78-
2.93 (2H, m), 3.17-3.26 (2H, m), 3.44-3.55 (2H, m),
3.70-3.82 (1H, m), 3.85-4.13 (2H, m), 4.78 (1H, b
r), 5.38 (1H, br), 7.05-7.37 (9H, m), 7.44 (2H, d,
J = 8.0Hz), 7.53-7.62 (1H, m), 8,51-8,56 (1H, m).

Example 13-2 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino)
-2-phenyl-2- (2-pyridyl) pentyl) -3- (1- (nicotinoyl) piperidin-4-yl) urea trihydrochloride

Embedded image Using phenyl N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2-phenyl-2- (2-pyridyl) pentyl) carbamate (0.57 g) obtained in Reference Example 11. Example 13-1
The title compound (0.38
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.05-1.57 (4H, m), 1.62-1.75 (2
H, m), 1.80-2.35 (9H, m), 2.40-2.78 (4H, m), 2.82
(2H, br), 3.03 (2H, br), 3.76 (2H, br), 3.95 (2H, br)
d, J = 6.2Hz), 4.55 (2H, br), 5.47 (1H, br), 7.07-7.
46 (12H, m), 7.59 (1H, dt J = 1.8, 7.7Hz), 7.73 (1H,
td, J = 1.8, 7.7Hz), 8.53-8.57 (1H, m), 8.61-8.65
(2H, m).

Example 13-3 1- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino)
2-phenyl-2- (2-pyridyl) pentyl) -3- (1- (isonicotinoyl) piperidin-4-yl) urea trihydrochloride

Embedded image Using phenyl N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino) -2-phenyl-2- (2-pyridyl) pentyl) carbamate (0.57 g) obtained in Reference Example 11. Example 13-1
The title compound (0.52
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.45 (4H, m), 1.55 -1.97
(4H, m), 2.04-2.28 (4H, m), 2.37-3.56 (4H, m), 2.7
2-3.15 (4H, m), 3.64-3.75 (1H, m), 3.91-3.98 (2H,
m), 4.42-4.57 (2H, m), 4.68 (1H, br), 5.47 (1H, b
r), 7.08-7.32 (11H, m), 7.43 (2H, d, J = 8.7Hz), 7.6
2 (1H, dt, J = 1.8, 7.8Hz), 8.50-8.55 (1H, m), 8.67
(2H, d, J = 6.0Hz).

Example 13-4 1- (5- [4- (4-chlorophenyl) -4-hydroxypiperidino]
-2,2-bis (4-fluorophenyl) pentyl) -3- (1- (isonicotinoyl) piperidin-4-yl) urea dihydrochloride

Embedded image Using phenyl N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-bis (4-fluorophenyl) pentyl] carbamate (0.60 g) obtained in Reference Example 17 ,Example
The title compound as an amorphous powder in the same manner as 13-1
(0.72 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.03-1.42 (4H, m), 1.63-1.97 (4
H, m), 2.03-2.38 (4H, m), 2.41-2.80 (4H, m), 2.76-
3.10 (4H, m), 3.42-3.58 (1H, m), 3.66-3.88 (4H, m),
4.43-4.62 (3H, m), 6.93 (4H, d, J = 8.6Hz), 7.10-7.
23 (6H, m), 7.29 (2H, d, J = 10.2Hz), 7.43 (2H, d, J
= 8.8Hz), 8.65 (2H, d, J = 5.9Hz).

Example 13-5 1- (5- [4- (4-chlorophenyl) -4-hydroxypiperidino]
-2,2-bis (4-fluorophenyl) pentyl) -3- (3-hydroxypropyl) urea

Embedded image Using phenyl N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2,2-bis (4-fluorophenyl) pentyl] carbamate (0.60 g) obtained in Reference Example 17 ,Example
The title compound (0.31 g) was obtained in the same manner as in 13-1. 128-131 ° C

Example 13-6 1- (5- [4- (4-chlorophenyl) -4-hydroxypiperidino]
-2,2-bis (4-fluorophenyl) pentyl) -3- (1- (nicotinoyl) piperidin-4-yl) urea

Embedded image Phenyl N- [5- [4- (4-chlorophenyl)-obtained in Reference Example 17
Example 13-1 using 4-hydroxypiperidino] -2,2-bis (4-fluorophenyl) pentyl] carbamate (0.60 g)
The title compound (0.60 g) was obtained in the same manner as described above. Melting point 185-188 ° C

Example 13-7 1- (5- [4- (4-chlorophenyl) -4-hydroxypiperidino]
-2- (4-fluorophenyl) -2-phenylpentyl) -3- (1-
(Isonicotinoyl) piperidin-4-yl) urea dihydrochloride

Embedded image Phenyl N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2- (4-fluorophenyl) obtained in Reference Example 24
[2-Phenylpentyl] carbamate (0.59 g) was used to obtain the title compound (0.71 g) as an amorphous powder in the same manner as in Example 13-1. ¹ H-NMR (CDCl ₃ ) δ: 1.05-1.43 (4H,
m), 1.63-1.95 (4H, m),
2.12-2.78 (8H, m), 2.82-3.
15 (4H, br), 3.42-3.58 (1
H, m), 3.73 (2H, br), 3.8
9 (2H, d, J = 6.0 Hz), 4.38−
4.55 (1H, m), 4.63 (2H, b
r), 6.96 (2H, d, J = 8.6H)
z), 7.12-7.37 (11H, m),
7.43 (2H, d, J = 8.8 Hz);
65 (2H, d, J = 6.0 Hz).

Example 13-8 1- (5- [4- (4-Chlorophenyl) -4-hydroxypiperidino] -2- (4-fluorophenyl) -2-phenylpentyl) -3- (3- (Hydroxypropyl) urea hydrochloride

Embedded image Phenyl N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2- (4-fluorophenyl) obtained in Reference Example 24
[2-Phenylpentyl] carbamate (0.59 g) was used to obtain the title compound (0.43 g) as an amorphous powder in the same manner as in Example 13-1. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (2H, br), 1.51-1.86 (6H,
m), 1.98-2.18 (4H, m), 2.30-2.43 (4H, m), 2.64-2.75
(2H, m), 3.20-3.30 (2H, m), 3.58 (2H, t, J = 5.5H
z), 3.91 (2H, d, J = 5.9Hz), 4.13 (1H, br), 4.40-4.4
7 (1H, m), 6.98 (2H, d, J = 8.6Hz), 7.11-7.35 (9H,
m), 7.43 (2H, d, J = 8.8Hz).

Example 13-9 1- (5- [4- (4-chlorophenyl) -4-hydroxypiperidino]
-2- (4-fluorophenyl) -2-phenylpentyl) -3- (1-
(Nicotinoyl) piperidin-4-yl) urea dihydrochloride

Embedded image Phenyl N- [5- [4- (4-chlorophenyl) -4-hydroxypiperidino] -2- (4-fluorophenyl) obtained in Reference Example 24
[2-Phenylpentyl] carbamate (0.59 g) was used to obtain the title compound (0.34 g) as an amorphous powder in the same manner as in Example 13-1. ¹ H-NMR (CDCl ₃ ) δ: 1.33 (4H, br), 1.63-1.78 (2H,
m), 1.81-2.02 (3H, m), 2.05-2.36 (4H, m), 2.40-2.60
(4H, m), 2.73-2.87 (2H, m), 3.00 (2H, br), 3.74 (2
H, br), 3.87 (2H, d, J = 6.1Hz), 4.29-4.68 (3H, m),
6.97 (2H, d, J = 8.6Hz), 7.10-7.35 (11H, m), 7.45 (2
H, d, J = 8.7Hz), 8.66 (2H, d, J = 6.0Hz).

Example 14 N- (5- (4- (4-chlorophenyl) -4-hydroxypiperidino)
-2,2-bis (4-fluorophenyl) pentyl) acetamide hydrochloride

Embedded image 1-amino-5- [4- (4-chlorophenyl) -4 obtained in Reference Example 16
[Hydroxypiperidino] -2,2-bis (4-fluorophenyl) pentane (0.49 g) was dissolved in THF (5 ml), and triethylamine (0.14 ml) and acetyl chloride (0.07 ml) were added at room temperature. Stir for 1 hour. The reaction solution was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography and eluted with ethyl acetate-methanol (9: 1). After evaporating the solvent under reduced pressure, the title compound (0.36 g) was obtained as an amorphous powder as an amorphous powder. ¹ H-NMR (CDCl ₃ ) δ: 1.19-1.35 (2H, m), 1.63-1.78 (3
H, m), 1.87 (3H, s), 1.95-2.13 (4H, m), 2.24-2.38
(4H, m), 2.58-2.69 (2H, m) 3.95 (2H, d, J = 6.0Hz),
4.89-4.99 (1H, m), 7.01 (4H, t, J = 8.7Hz), 7.11-7.1
9 (4H, m), 7.24 (2H, d, J = 8.0Hz), 7.43 (2H, d, J = 9.
2Hz).

Example 15 N- (5- [4- (4-chlorophenyl) -4-hydroxypiperidino]
-2- (4-fluorophenyl) -2-phenylpentyl) acetamide hydrochloride

Embedded image 1-amino-5- [4- (4-chlorophenyl) -4 obtained in Reference Example 23
Using [-hydroxypiperidino] -2- (4-fluorophenyl) -2-phenylpentane (0.47 g), the title compound (0.38 g) was obtained as an amorphous powder in the same manner as in Example 14. Was. ¹ H-NMR (CDCl ₃ ) δ: 1.18-1.37 (2H, m), 1.60-1.73 (2
H, m), 1.84 (3H, s), 1.95-2.13 (4H, m), 2.22-2.40
(5H, m), 2.58-2.70 (2H, m) 3.95 (2H, d, J = 5.7Hz),
4.97-5.05 (1H, m), 6.99 (2H, t, J = 8.6Hz), 7.14-7.3
6 (9H, m), 7.42 (2H, d, J = 8.8Hz).

Formulation Example 1 (1) 10.0 g of the compound of Example 5-3 (2) Lactose 60.0 g (3) Corn starch 35.0 g (4) Gelatin 3.0 g (5) Magnesium stearate 2.0 g 10.0 g of the compound obtained in Example 5-3 and lactose
0 g and a mixture of 35.0 g of corn starch were mixed with 30 ml of a 10% by weight aqueous solution of gelatin (3.0 g as gelatin).
Using g), the mixture was granulated through a 1 mm mesh sieve, dried at 40 ° C. and sieved again. The obtained granules were mixed with 2.0 g of magnesium stearate and compressed. The resulting core tablets were coated with a sugar coating of an aqueous suspension of sucrose, titanium dioxide, talc and acacia.
Polish the coated tablets with beeswax to 100
0 coated tablets were obtained.

Formulation Example 2 (1) Compound of Example 5-3 10.0 g (2) Lactose 70.0 g (3) Corn starch 50.0 g (4) Soluble starch 7.0 g (5) Magnesium stearate 2.0 g An aqueous solution 70 of a soluble starch was prepared by adding 10.0 g of the compound obtained in Example 5-3 and 3.0 g of magnesium stearate.
after granulation in 7 ml (7.0 g as soluble starch), dried, 70.0 g lactose and 5 g corn starch.
0.0 g. The mixture was compressed to give 1000 tablets.

Experimental Example 1 ¹²⁵ I-RANTE using CHO cells expressing human MIP-1α / RANTES receptor (CHO (CCR) cells)
Measurement of S-binding inhibition activity 96-well microplate (CulturPlat)
e, Packard Instrument Com
pany, Meriden, CT, USA)
HO (CCR) cells 5 × 10 ⁴ / 100μl / wel
and cultured for 24 hours. After removing the medium, 35 μl
/ Well DMEM / 0.5% BSA, then DME
Test compound diluted with M / 0.5% BSA was added at 5 μl / w.
well, 10 μl / well of ¹²⁵ I-RANT
ES (final concentration: 200 pM) was added sequentially and incubated at room temperature for 40 minutes. Thereafter, the plate was washed twice with 200 μl / well of PBS, and 25 μl / well of ethanol was added thereto, followed by stirring. Further, a 200 μl / well scintillator (MicroScint-20, Pack)
ard Instrument Company), and after stirring, ¹²⁵ I-RANTE bound to cells was added.
The radioactivity of S was measured using TopCount (Packard I).
nstment Company). CHO cells (mock transfectant) transfected with the vector plasmid pAKKO-111H with a binding amount of 100% when no test compound is added.
Assuming that the amount of binding to s) was 0%, the concentration (IC ₅₀ value) that inhibited the binding of ¹²⁵ I-RANTES by 50% was determined. The results are shown in Table 1.

[0115]

[Table 1]

[0116] To examine the effect on rat cells in the measurement MIP-l [alpha] / RANTES receptor antagonist of the binding inhibition activity of ¹²⁵ I- human RANTES with Experimental Example 2 rat peritoneal macrophages, the ¹²⁵ I- human RANTES on rat peritoneal macrophages A binding assay was performed.
Rat peritoneal macrophages were obtained from female Wistar rats (7-1
Thioglycolate medium at 3 weeks)
A day later, the cells were leached into the peritoneal cavity, and the cells were washed with physiological saline and collected. Rat peritoneal macrophages are suspended in a binding buffer at about 5 × 10 ⁶ / ml, spread on a 96-well filter plate, and the test compound and ¹²⁵ I-RANTES (DuPont Company, Wilmington, DE, U.S.A.).
SA) was added and reacted at room temperature for 30 minutes. Thereafter, the cells were washed with a washing buffer, and the radioactivity of ¹²⁵ I-RANTES bound to the cells was measured with a γ counter. 100% binding without test compound added, large excess of unlabeled human RANTES
(PeproTech, Rocky Hill, NJ, USA), the amount of binding was defined as 0%, and the concentration (IC ₅₀ value) that inhibited the binding of ¹²⁵ I-RANTES by 50% was determined. The results are shown in Table 2.

[0117]

[Table 2] ^{1) 125} I for CHO cells expressing human MIP-1α / RANTES receptor
^{2) 125} I-human RANTES against rat peritoneal macrophages determined by a binding assay for -RANTES
Determined by a binding assay.

Experimental Example 3 Inhibitory effect on rat adjuvant arthritis [0118] Mycobacterium butyricum, Difco Laborat
ories, Detroit, MI, USA) is uniformly suspended in liquid paraffin (Nacalai Tesque, Kyoto), and its suspension is 250 μg / 50 μl / rat.
Was administered intradermally to the footpads of male Lewis rats (7 weeks old) to induce adjuvant arthritis. On day 14, the volume of the non-injected paw of the adjuvant was measured using a rat footpad edema volume measuring device (7150 P
Lethysmometer, Ugo Basile (Valese, Italy)), and the difference from the paw volume on day 0 before administration of an adjuvant intradermally was defined as paw edema volume. The volume of paw edema in the group administered with the test compound was (A), and the volume of paw edema in the group administered with vehicle (water) was
(B) In addition, the inhibition rate (%) was calculated as follows, with the difference in paw volume between day 14 and day 0 of the adjuvant-unadministered group, ie, normal rats, as (C). Inhibition rate (%) = {1-[(A)-(C)] ÷ [(B)-(C)]} x 100 The test compound is subcutaneously 10 mg / kg once daily from day 0, 14 times in total Was administered. Each group consisted of 6 mice. As a result, adjuvant non-injection foot edema was suppressed in the test compound administration group (Table 3).

[0119]

[Table 3]

[0120]

The present invention provides a preparation comprising an allergic disease, a diphenylmethane derivative and a pharmaceutically acceptable salt thereof. The derivative has excellent MIP-1α / RANTES as a prophylaxis and treatment for inflammatory diseases and the like.
Has receptor antagonism.

Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/445 ABX A61K 31/445 ABX ACD ACD ADA ADA ADU ADU AED AED AED C07D 211/62 C07D 211/62 211/70 211/70 401/06 213 401/06 213 401/12 211 401/12 211 401/14 211 401/14 211 413/06 211 413/06 211

Claims (8)

[Claims] (1) Formula (1) [Wherein X ¹ and Y ¹ are the same or different,
A phenyl group or a pyridyl group, each of which may be substituted with a halogen atom, wherein R ¹ is an optionally halogenated C _1-6 alkyl group or a group represented by the formula: (Wherein R ² represents a hydrogen atom, C _1-6 alkoxy-carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, a nicotinoyl group optionally substituted with a halogen atom, or Represents an isonicotinoyl group which may be substituted with a halogen atom). Or a salt thereof. 2. A compound of the formula Wherein X ² and Y ² are the same or different,
A phenyl group or a pyridyl group each of which may be substituted with a halogen atom, wherein R ³ is a C _1-6 alkyl group which may be substituted with a hydroxy group or a group represented by the formula: (Wherein, R ⁴ is (1) hydroxy, C _1-6 alkyl - carbonyloxy and a C _1-6 alkyl group optionally having a substituent selected from pyridyl, substituted with (2) a halogen atom or pyrrolidinyl A C _1-6 alkoxy group which may be substituted, (3) a pyridyl group which may have a substituent or (4) a phenyl group which may have a substituent.) Is shown. However, when R ³ is propyl or butyl substituted with a hydroxy group, it represents a phenyl group or a pyridyl group in which at least one of X ² and Y ² is substituted with a halogen atom. Or a salt thereof. 3. A compound of the formula Wherein X ³ and Y ³ are the same or different,
A phenyl group or a pyridyl group, each of which may be substituted with a halogen atom, Is - (CH ₂₎ n- (where n indicates an integer of 1 to 3) or _{- (CH 2) m-CH} = indicates (m represents an integer of 0 to 2), R ⁵ is a hydrogen atom or a C _1-6 alkoxy-
Indicates a carbonyl group. Or a salt thereof. 4. A compound of the formula Wherein X ⁴ and Y ⁴ are the same or different,
A phenyl group or a pyridyl group each of which may be substituted with a halogen atom, wherein R ⁶ is a C _1-6 alkyl group,
A piperidino group substituted with nicotinoyl or isonicotinoyl which may be substituted with a halogen atom,
It represents a pyridyl group which may have a substituent or a piperidino group substituted by a C _1-6 alkoxy-carbonyl. However, when R ⁶ is a methyl group, at least one of X ⁴ and Y ⁴ represents a phenyl group substituted with a halogen atom, or both represent a pyridyl group. Or a salt thereof. 5. A compound of the formula Wherein X ⁵ and Y ⁵ are the same or different,
A phenyl group or a pyridyl group, each of which may be substituted with a halogen atom, wherein ring A is a halogen atom, an oxo group, a C _1-6 alkyl group which may be halogenated, or a C ₁ group which may be halogenated; _It may be substituted with a _-6 alkoxy group. Or a salt thereof. 6. A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof. 7. MIP-1α / RANT comprising the compound according to claim 1 or a salt thereof.
ES receptor antagonist. 8. A compound of the formula Wherein each symbol is as defined in claim 2. And NH ₂ R ^{3 wherein} R ³ is as defined in claim 2. The method for producing a compound according to claim 2, wherein the reaction is carried out in the presence of a base.