JPWO2006041015A1 - Amino alcohol derivatives and their addition salts and immunosuppressants - Google Patents

Abstract

An aminoalcohol derivative having excellent immunosuppressive action and less side effects is provided. [MEANS FOR SOLVING PROBLEMS] An amino alcohol derivative represented by the general formula (1): (specific example: 2-amino-2- [4- [4- (benzyloxyphenoxy) -2-chlorophenyl] propyl-1, 3-propanediol). [Selection figure] None

Description

  The present invention relates to an aminoalcohol derivative useful as an immunosuppressant, an addition salt thereof, and a hydrate thereof.

  Immunosuppressants are widely used as therapeutic agents for rheumatoid arthritis, nephritis, osteoarthritis, systemic lupus erythematosus, chronic inflammatory diseases such as Crohn's disease, chronic inflammatory diseases such as inflammatory bowel disease, and allergic diseases such as asthma and dermatitis. Has been used. In particular, with the advancement of medical technology, many transplantation operations for tissues and organs have been carried out in recent medical practice, and how transplant rejection can be controlled well. Immunosuppressants play a very important role in this area as well.

  In organ transplantation, antimetabolites typified by azathioprine and mycophenolate mofetil, calcineurin inhibitors typified by cyclosporin A and tacrolimus, and corticosteroids typified by prednisolone are used. However, some of these drugs are insufficiently effective, and some drugs require blood concentration monitoring in order to avoid serious side effects such as kidney damage. It is not always satisfactory.

  Furthermore, in order to reduce the side effects of immunosuppressive drugs and obtain sufficient immunosuppressive action, multi-drug combination therapy using multiple drugs with different mechanism of action is common, and action different from the immunosuppressive drugs described above Development of new types of drugs with mechanisms is also desired.

  In order to solve such problems, the present inventors have focused on amino alcohol derivatives and searched for a new type of immunosuppressive agent.

Although 2-amino-1,3-propanediol derivatives are disclosed in Patent Document 1 and Patent Document 2 as immunosuppressive agents, amino alcohol derivatives having a diaryl sulfide group or a diaryl ether group, which are features of the present invention, are excellent. It was not known to show an immunosuppressive effect. In addition, Patent Document 3, Patent Document 4, Patent Document 5, Patent Document 6, and Patent Document 10 disclose that 2-amino-ethanol derivatives exhibit an immunosuppressive action, but have a different structure from the compound of the present application. It is to make. Further, amino alcohol derivatives having a diaryl sulfide group or a diaryl ether group that are very structurally similar to the compound of the present application are disclosed in Patent Document 7, Patent Document 8, and Patent Document 9, but the terminal end, which is a feature of the compound of the present application, is disclosed. Compounds having a substituent only at the para-position of the aryl group on the side are not included.
WO94 / 08943 pamphlet JP-A-9-2579602 WO02 / 06268 pamphlet Japanese Patent Laid-Open No. 2002-53575 JP-A-2002-167382 Japanese Patent Laid-Open No. 2002-316985 WO03 / 029205 pamphlet WO03 / 029184 pamphlet WO04 / 026817 Pamphlet WO04 / 024673 pamphlet

    The problem to be solved by the present invention is to provide an aminoalcohol derivative having an excellent immunosuppressive action and few side effects.

  As a result of intensive research on immunosuppressive agents that have different mechanisms of action from antimetabolites and calcineurin inhibitors, the present inventors have made a structure different from those of known immunosuppressive agents. Novel amino alcohol derivatives having a diaryl sulfide group or a diaryl ether group, particularly having a carbon chain containing an amino alcohol unit at the para position of one aryl group and a substituent at the para position of the other terminal aryl group The present invention was completed by finding that the compound has a strong immunosuppressive action.

That is, the present invention
1) General formula (1)

[Where
R ₁ may have a halogen atom, a trifluoromethyl group, a hydroxy group, a lower alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a phenyl group which may have a substituent, or a substituent. A good phenyloxy group, an aralkyl group which may have a substituent or an aralkyloxy group which may have a substituent; R ₂ represents a hydrogen atom, a halogen atom or a trifluoromethyl group;
R ₃ represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a lower alkenyl group having 2 to 4 carbon atoms, or a hydroxymethyl group,
X represents O, S, SO or SO ₂ , and n represents an integer of 1 to 4]
An amino alcohol derivative and a pharmacologically acceptable salt thereof and a hydrate thereof,

2) The compound represented by the general formula (1) is represented by the general formula (1a)

[Wherein R ₂ , X and n are the same as defined above]
1) the aminoalcohol derivative and the pharmacologically acceptable salt thereof and the hydrate thereof,

3) In the above general formula (1a), R ₂ is a chlorine atom, the amino alcohol derivative and pharmacologically acceptable salt and hydrate thereof according to 2),

4) The compound represented by the general formula (1) is
(1) 2-amino-2- [4- (4-benzyloxyphenoxy) -2-chlorophenyl] propyl-1,3-propanediol,
(2) 2-amino-2- [4- (4-benzyloxyphenylthio) -2-chlorophenyl] propyl-1,3-propanediol,
(3) 2-amino-2- [4- (4-benzyloxyphenylthio) -2-chlorophenyl] ethyl-1,3-propanediol,
(4) 2-amino-2- (4-biphenylthio-2-chlorophenyl) propyl-1,3-propanediol or (5) 2-amino-2- [4- (3 ′, 5′-dichlorobiphenylthio) ) -2-chlorophenyl] propyl-1,3-propanediol,
1) the amino alcohol derivative and pharmacologically acceptable salt thereof and hydrate thereof,

5) General formula (1)

[Where
R ₁ may have a halogen atom, a trifluoromethyl group, a hydroxy group, a lower alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a phenyl group which may have a substituent, or a substituent. A good phenyloxy group, an aralkyl group which may have a substituent or an aralkyloxy group which may have a substituent; R ₂ represents a hydrogen atom, a halogen atom or a trifluoromethyl group;
R ₃ represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a lower alkenyl group having 2 to 4 carbon atoms, or a hydroxymethyl group,
X represents O, S, SO or SO ₂ , and n represents an integer of 1 to 4]
An immunosuppressive agent characterized by comprising as an active ingredient at least one or more of an amino alcohol derivative represented by the formula, a pharmacologically acceptable salt and a hydrate thereof,

6) The compound represented by the general formula (1) is represented by the general formula (1a)

[Wherein R ₂ , X and n are the same as defined above]
An immunosuppressant comprising at least one or more of the amino alcohol derivatives and pharmacologically acceptable salts and hydrates thereof according to 5), which are compounds represented by:

7) The immunosuppressive agent according to 5) or 6), wherein the immunosuppressive agent is a prophylactic or therapeutic agent for rheumatoid arthritis,

8) The immunosuppressive agent according to 5) or 6), wherein the immunosuppressive agent is a preventive or therapeutic agent for psoriasis or atopic dermatitis,

9) The immunosuppressive agent according to 5) or 6), wherein the immunosuppressive agent is a preventive or therapeutic agent for bronchial asthma or hay fever,

10) The immunosuppressive agent according to 5) or 6), wherein the immunosuppressive agent is a preventive or therapeutic agent for rejection in organ transplantation and bone marrow transplantation,

11) The immunosuppressive agent according to 5) or 6), wherein the immunosuppressive agent is a prophylactic or therapeutic agent for autoimmune diseases such as inflammatory bowel disease, systemic lupus erythematosus (SLE), and Crohn's disease. ,
It is about.

  The present invention provides a novel amino alcohol derivative, particularly a diaryl sulfide or diaryl ether derivative having a carbon chain containing an amino alcohol unit at the para position of one aryl group and having a substituent at the para position of the other aryl group. It has been found that it has a strong immunosuppressive action. Such immunosuppressive compounds are used as preventive or therapeutic agents for rejection in organ transplantation and bone marrow transplantation, preventive or therapeutic agents for autoimmune diseases such as inflammatory bowel disease, systemic lupus erythematosus, Crohn's disease, rheumatoid arthritis It is useful as a prophylactic or therapeutic agent, a prophylactic or therapeutic agent for psoriasis or atopic dermatitis, and a prophylactic or therapeutic agent for bronchial asthma or hay fever.

  Hereinafter, the present invention will be described in detail.

  Examples of the pharmacologically acceptable salt of the compound represented by the general formula (1) in the present invention include hydrochloride, hydrobromide, acetate, trifluoroacetate, methanesulfonate, and citrate. And acid addition salts such as tartrate.

  In the general formula (1) of the present invention, the “halogen atom” represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and represents “a lower alkyl group having 1 to 4 carbon atoms” or “1 to 4 carbon atoms”. Examples of the “lower alkyl group” such as “lower alkoxy group” include linear or branched hydrocarbons having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl and t-butyl. “Lower alkenyl group having 2 to 4 carbon atoms” refers to vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 2-methylallyl, 3-butenyl and the like. C2-C4 hydrocarbon which has a saturated double bond is mentioned. “A phenyl group which may have a substituent” and “phenoxy group which may have a substituent” are halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom at an arbitrary position on the benzene ring. Examples thereof include those having an atom, a trifluoromethyl group, a lower alkyl group having 1 to 4 carbon atoms, and a lower alkoxy group having 1 to 4 carbon atoms. Examples of the “aralkyl group” in the “aralkyl group” and “aralkyloxy group” include a benzyl group, a diphenylmethyl group, a phenethyl group and a phenylpropyl group, and “an aralkyl group which may have a substituent”, “a substituent The aralkyloxy group optionally having a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a trifluoromethyl group, or a lower alkyl group having 1 to 4 carbon atoms at any position on the benzene ring. And those having a lower alkoxy group having 1 to 4 carbon atoms.

According to the present invention, among the compounds represented by the general formula (1), a compound in which R ₃ is a hydrogen atom or a hydroxymethyl group, that is, the general formula (1b)

[Wherein, D represents a hydrogen atom or a hydroxymethyl group, and R ₁ , R ₂ , X and n are as described above] can be produced, for example, by the route shown below.

<Synthesis route A>

  In the synthesis route A, the general formula (3)

[Wherein R ₄ represents a lower alkyl group having 1 to ₄ carbon atoms, Boc represents a t-butoxycarbonyl group, and R ₁ , R ₂ , X and n are as described above]
The compound represented by general formula (2)

[Wherein Y represents a chlorine atom, a bromine atom or an iodine atom, and R ₁ , R ₂ , X and n are as defined above] and a general formula (5)

[Wherein R ₄ and Boc are as described above]
In the presence of a base (Step A-1).

  The reaction is carried out using methanol, ethanol, 1,4-dioxane, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), tetrahydrofuran (THF) or the like as a reaction solvent, sodium hydride, potassium hydride, sodium alkoxide, In the presence of an inorganic base such as potassium alkoxide, the reaction can be performed at a reaction temperature of 0 ° C. to heating under reflux, preferably 80 ° C. to 100 ° C.

  In the synthesis route A, the general formula (4)

[Wherein R ₁ , R ₂ , D, X, Boc and n are as described above]
Can be produced by reducing the compound represented by formula (3) (step A-2).

Reactions include alkylborane derivatives such as borane (BH ₃ ) and 9-borabicyclo [3.3.1] nonane (9-BBN), diisopropylaluminum hydride (iBu ₂ AlH), sodium borohydride (NaBH ₄ ), hydrogenation A metal hydride complex compound such as aluminum lithium (LiAlH ₄ ), preferably lithium borohydride (LiBH ₄ ), THF, ethanol, methanol, etc. are used as a reaction solvent, the reaction temperature is −78 ° C. to heating under reflux, Preferably it can be carried out at room temperature.

  The compound represented by the general formula (1b) in the synthesis route A can be produced by acidolysis of the compound represented by the general formula (4) (step A-3).

  The reaction can be carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, or mixed with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane or ethyl acetate. The reaction can be carried out in a solution and the reaction temperature can be from 0 ° C. to room temperature.

Among the compounds represented by the general formula (1), a compound in which X is O and R ₃ is a hydroxymethyl group, that is, the general formula (1c)

[Wherein R ₁ , R ₂ and n are as described above]
And a compound represented by the general formula (1), wherein X is O and R ₃ is a hydrogen atom, that is, the general formula (1c ′)

[Wherein R ₁ , R ₂ and n are as described above]
The compound represented by can also be produced by the following synthetic route.

<Synthetic route B>

  In the synthesis route B, the general formula (7)

[Wherein R ₂ , R ₄ , Boc and n are as described above]
The compound represented by general formula (6)

[Wherein Y, R ₂ and n are as described above]
And a compound represented by the general formula (5) in the presence of a base (Step B-1).

  In the reaction, methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, etc. are used as a reaction solvent, and the reaction temperature is 0 in the presence of an inorganic base such as sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide. It can be carried out at a temperature of from 80 ° C to 100 ° C, preferably from 80 ° C to 100 ° C.

  In the synthesis route B, the general formula (8)

[Wherein R ₂ , D, Boc and n are as described above]
Can be produced by reducing the compound represented by the general formula (7) (step B-2).

For the reaction, alkylborane derivatives such as BH ₃ and 9-BBN, metal hydrogen complex compounds such as iBu ₂ AlH, NaBH ₄ and LiAlH ₄ , preferably LiBH ₄ are used, and THF, ethanol, methanol, etc. are used as a reaction solvent. The reaction temperature is −78 ° C. to heating under reflux, preferably at room temperature.

  In the synthesis route B, the general formula (9)

[Wherein M represents a carbon atom or a silicon atom, and R ₂ , R ₄ , Boc and n are as described above]
Among the compounds represented by the general formula (8), the compound represented by general formula (12) is a compound represented by the general formula (12).

[Wherein R ₄ is as described above]
Or general formula (13)

[Wherein R ₆ represents a lower alkyl group having 1 to 4 carbon atoms, and R ₄ is as described above]
Or general formula (14)

[Wherein R ₇ represents a chlorine atom or a trifluoromethanesulfonyloxy group, and R ₄ is as described above] can be produced by reacting the compound (Step B-3).

  The reaction with the compound represented by the general formula (12) or the general formula (13) is carried out in the presence of a Lewis acid such as zinc chloride or a catalyst such as camphorsulfonic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate. In the following, no solvent or DMF, THF, methylene chloride is used as a reaction solvent, and the reaction temperature can be from room temperature to 100 ° C.

  The reaction with the general formula (14) can be carried out using triethylamine, pyridine, 2,6-lutidine, imidazole, chloroform and acetonitrile at a reaction temperature of 0 ° C to 100 ° C.

  In the synthesis route B, the general formula (10)

[Wherein R ₂ , R ₄ , Boc and n are as described above] can be produced by hydrogenolysis of the compound represented by the general formula (9) (step B -4).

  The reaction is carried out in the presence of a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon, etc., in a solvent such as ethanol, methanol, THF, DMF, ethyl acetate, under normal to pressurized hydrogen pressure. Can be carried out at room temperature to 100 ° C.

  In the synthesis route B, the general formula (11)

[Wherein R ₁ , R ₂ , R ₄ , Boc and n are as described above] is a compound represented by the general formula (15) in the presence of the compound represented by the general formula (10) and copper acetate.

[Wherein R ₁ is as described above] can be produced by reacting the compound (Step B-5).

  In the reaction, it is preferable that methylene chloride or chloroform is used as a reaction solvent in the presence of a base such as triethylamine, and copper acetate is allowed to act at room temperature in the presence or absence of molecular sieves.

  In the synthesis route B, the compound represented by the general formula (1c) can be produced by acid-decomposing the compound represented by the general formula (11), or by acidolysis after desilylation ( Step B-6).

  The reaction can be carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, or trifluoroacetic acid, or mixed with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate. The reaction can be performed in a solution and the reaction temperature can be from 0 ° C. to room temperature.

  When M in the general formula (10) is a silicon atom, THF, DMF, 1,4-dioxane or the like is used as a solvent, and potassium fluoride, cesium fluoride, tetrabutylammonium fluoride is used at 0 ° C. to room temperature. After acting below, it can be synthesized by subjecting it to the acid decomposition reaction described above.

  In the synthesis route B, the general formula (9 ′)

[Wherein R ₅ represents a t-butyldimethylsilyl group or a methoxymethyl group, and R ₂ , Boc and n are as described above] are compounds represented by the general formula (8) , D can be produced by allowing t-butyldimethylsilyl chloride or methoxymethyl chloride to react with a compound in which D is a hydrogen atom in the presence of a base (step B-3 ′).

  The reaction can be carried out in the presence of an organic base such as triethylamine or diisopropylethylamine using DMF, THF, or methylene chloride as a reaction solvent at a reaction temperature of 0 ° C. to room temperature.

  In the synthesis route B, the general formula (10 ′)

[Wherein R ₂ , R ₅ , Boc and n are as described above]
Can be produced by hydrocracking the compound represented by the general formula (9 ′) (step B-4 ′).

  The reaction is carried out in the presence of a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon, etc., in a solvent such as ethanol, methanol, THF, DMF, ethyl acetate, under normal to pressurized hydrogen pressure. Can be carried out at room temperature to 100 ° C.

  In the synthesis route B, the general formula (11 ′)

[Wherein R ₁ , R ₂ , R ₅ , Boc and n are as described above] represents a compound represented by the general formula (15) in the presence of the compound represented by the general formula (10 ′) and copper acetate. ) Can be produced by the action of a compound represented by () (Step B-5 ′).

  In the reaction, it is preferable that methylene chloride or chloroform is used as a reaction solvent in the presence of a base such as triethylamine, and copper acetate is allowed to act at room temperature in the presence or absence of molecular sieves.

  In the synthesis route B, the compound represented by the general formula (1c ′) can be produced by acid-decomposing the compound represented by the general formula (11 ′) or by acid-decomposing after desilylation. (Step B-6 ′).

  The reaction can be carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, or mixed with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate. The reaction can be performed in a solution and the reaction temperature can be from 0 ° C. to room temperature.

  The compounds represented by the general formulas (1c) and (1c ′), that is, the general formula (1d)

[Wherein R ₁ , R ₂ , D and n are as described above] can also be produced by the following synthetic route.

<Synthetic route C>

  In the synthesis route C, the general formula (16)

[Wherein R ₂ , R ₄ , Boc and n are as described above] can be produced by hydrogenolysis of the compound represented by the general formula (7) (Step C -1).

  The reaction is carried out in the presence of a catalytic reduction catalyst such as palladium carbon, platinum carbon, platinum oxide, rhodium carbon, ruthenium carbon, etc., in a solvent such as ethanol, methanol, THF, DMF, ethyl acetate, under normal to pressurized hydrogen pressure. Can be carried out at room temperature to 100 ° C.

  In the synthesis route C, the general formula (17)

[Wherein R ₁ , R ₂ , R ₄ , Boc and n are as described above] are a compound represented by the general formula (16) and a compound represented by the general formula (15) Can be produced by the action (step C-2).

  In the reaction, it is preferable to use methylene chloride or chloroform as a reaction solvent in the presence of a base such as triethylamine and to allow copper acetate to act at room temperature in the presence or absence of molecular sieves.

  In the synthesis route C, the general formula (18)

[Wherein R ₁ , R ₂ , D, Boc and n are as described above]
Can be produced by reducing the compound represented by the general formula (17) (step C-3).

For the reaction, alkylborane derivatives such as BH ₃ and 9-BBN, metal hydrogen complex compounds such as iBu ₂ AlH, NaBH ₄ and LiAlH ₄ , preferably LiBH ₄ are used, and THF, ethanol, methanol, etc. are used as a reaction solvent. The reaction temperature is −78 ° C. to heating under reflux, preferably at room temperature.

  The compound represented by the general formula (1d) in the synthesis route C can be produced by acidolysis of the compound represented by the general formula (18) (step C-4).

  The reaction can be carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, trifluoroacetic acid, or mixed with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, or ethyl acetate. The reaction can be performed in a solution and the reaction temperature can be from 0 ° C. to room temperature.

Among the compounds represented by the general formula (1), a compound in which R ₃ is a lower alkyl group having 1 to 4 carbon atoms or an alkenyl group having 2 to 4 carbon atoms, that is, the general formula (1e)

[Wherein R ₈ represents a lower alkyl group having 1 to 4 carbon atoms or an alkenyl group having 2 to 4 carbon atoms, and R ₁ , R ₂ , X and n are as described above] It can be manufactured by a route.

  <Synthesis route D>

  In the synthesis route D, the general formula (19)

[Wherein R ₁ , R ₂ , R ₄ , R ₈ , X and n are as described above], the compound represented by the general formula (2) and the general formula (23)

[Wherein R ₄ and R ₈ are as described above] can be produced by acting in the presence of a base (step D-1).

  For the reaction, methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, etc. are used as reaction solvents, and the reaction temperature is 0 in the presence of an inorganic base such as sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, etc. It can be carried out at a temperature of from 80 ° C to 100 ° C, preferably from 80 ° C to 100 ° C.

  In the synthesis route D, the general formula (19 ′)

[Wherein R ₁ , R ₂ , R ₄ , X and n are as defined above], the compound represented by the general formula (2) and the general formula (24)

[Wherein, R ₄ is as described above] can be produced by reacting in the presence of a base (step D-2).

  In the reaction, methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, etc. are used as a reaction solvent, and the reaction temperature is 0 in the presence of an inorganic base such as sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide. It can be carried out at a temperature of from 80 ° C to 100 ° C, preferably from 80 ° C to 100 ° C.

  In the synthesis route D, the compound represented by the general formula (19) is obtained by converting the compound represented by the general formula (19 ′) into the general formula (25) in the presence of a base.

[Wherein R ₈ and Y are as described above] can be produced by reacting with each other.

  The reaction uses methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, etc. as the reaction solvent, and in the presence of an inorganic base such as sodium hydride, potassium hydride, sodium alkoxide, potassium alkoxide, the reaction temperature is The reaction can be performed at 0 ° C. to heating under reflux, preferably at 80 ° C. to 100 ° C.

  In the synthesis route D, the general formula (20)

[Wherein R ₁ , R ₂ , R ₄ , R ₈ , X and n are as described above] are produced by hydrolyzing the compound represented by the general formula (19). (Step D-4).

  The reaction is carried out in the presence of a base such as an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution or an aqueous lithium hydroxide solution, and the reaction solvent is methanol, ethanol, 1,4-dioxane, DMF, DMSO or the like, and the reaction temperature is 0 ° C to It can be carried out under heating to reflux. Moreover, it is preferable to use potassium hydroxide in an ethanol solvent at 50 ° C.

  In the synthesis route D, the general formula (21)

[Wherein R ₁ , R ₂ , R ₄ , R ₆ , R ₈ , X and n are as defined above], the compound represented by the above general formula (20) is converted by Curtius rearrangement. It can be manufactured (step D-5).

For the reaction, a general method for converting a carboxyl group into a carbamate can be used. For example, a method using ethyl chlorocarbonate and NaN ₃ , or preferably diphenyl phosphate azide (DPPA) in the presence of a base such as triethylamine, benzene Or stirring in a toluene solvent and then adding a lower alcohol such as methanol, ethanol, propanol, isopropanol, butanol, or t-butanol, and continuing the heating or stirring, or using only the lower alcohol as a reaction solvent, preferably under heating and stirring, It can be carried out under heating to reflux.

  In the synthesis route D, the general formula (22)

[Wherein R ₁ , R ₂ , R ₆ , R ₈ , X and n are as defined above] are produced by reducing the compound represented by the general formula (21). (Step D-6).

For the reaction, alkylborane derivatives such as BH ₃ and 9-BBN, metal hydrogen complex compounds such as iBu ₂ AlH, NaBH ₄ and LiAlH ₄ , preferably LiBH ₄ are used, and THF, ethanol, methanol, etc. are used as a reaction solvent. The reaction temperature is −78 ° C. to heating under reflux, preferably at room temperature.

  The compound represented by general formula (1e) in the synthetic pathway D can be manufactured by acid-decomposing or alkali-hydrolyzing the compound represented by the said general formula (22) (process D-7).

  The reaction can be carried out in an inorganic or organic acid such as acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid or trifluoroacetic acid, or mixed with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane or ethyl acetate. The reaction can be performed in a solution and the reaction temperature can be from 0 ° C. to room temperature. Alternatively, methanol, ethanol, 1,4-dioxane, DMSO, DMF, THF, or the like is used as a reaction solvent, and the reaction temperature is 0 ° C. in the presence of a base such as aqueous sodium hydroxide, aqueous potassium hydroxide, or aqueous lithium hydroxide. It can be carried out at 80 to 100 ° C., preferably under heating and reflux.

A compound in which X in each general formula is SO or SO ₂ can also be produced by oxidizing a compound in which the corresponding X is S.

  The reaction uses 1,4-dioxane, DMSO, DMF, THF, methylene chloride, chloroform, etc. as the reaction solvent, and potassium permanganate, metachloroperbenzoic acid, and hydrogen peroxide water are used as the oxidizing agent. Below, it can be carried out preferably at room temperature.

EXAMPLES Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.

<Reference Example 1>
4- (4-Benzyloxyphenylthio) -2-chlorobenzaldehyde

Parahydroxybenzenethiol (5.00 g) is dissolved in N, N-dimethylformamide (100 mL), 2-chloro-4-fluorobenzaldehyde (6.28 g) and potassium carbonate (5.56 g) are added, and the mixture is stirred at 50 ° C. for 5 hours. Stir. Under ice-cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and then saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off and silica gel column chromatography (hexane
: Ethyl acetate = 4: 1 followed by purification by 2: 1) to give 4- (4-hydroxyphenylthio) -2-chlorobenzaldehyde (10.1 g) as a pale yellow oil. The resulting aldehyde (10.0 g) was dissolved in methylene chloride (100 mL) under ice cooling, and ethyldiisopropylamine was dissolved.
(7.79 mL) and benzyl chloride (6.36 g) were added, and the mixture was stirred for 1 hour under ice cooling. Under ice-cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and then saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off and silica gel column chromatography (hexane
: Purified with ethyl acetate = 9: 1) to obtain the desired product (13.3 g) as a pale yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 5.12 (2H, s), 6.98-7.02 (2H, m),
7.05-7.08 (2H, m), 7.36-7.50 (7H, m), 7.74 (1H, d, J = 8.3Hz), 10.36 (1H, s).

<Reference Example 2>
4- (4-Benzyloxyphenoxy) -2-chlorobenzaldehyde

The target product was obtained as a brown powder by reacting with 2-chloro-4-fluorobenzaldehyde in the same manner as in Reference Example 1 using parabenzyloxyphenol.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 5.08 (2H, s), 6.88-6.92 (2H, m),
7.02 (4H, s), 7.33-7.43 (5H, m), 7.88 (1H, d, J = 8.3Hz), 10.34 (1H, s)

<Reference Example 3>
4 '-[4- (Benzyloxy) phenoxy] -2'-chlorocinnamic acid ethyl ester

60% sodium hydride (220 mg) was added to a solution of ethyl diethylphosphonoacetate (1.19 mL) in THF (30 mL) at 0 ° C. under an argon gas stream, and the mixture was stirred for 15 minutes, and then Reference Example 2 (1.43 g) was added. A THF (5 mL) solution was added. After stirring for 1 hour, 5% citric acid was added, extracted with ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15/1) to obtain the desired product (1.86 g) as a pale yellow powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.34 (3H, t, J = 7.3 Hz), 4.27 (2H,
q, J = 7.3Hz), 5.07 (2H, s), 6.34 (1H, d, J = 16.1Hz), 6.85 (1H, dd, J = 2.4, 8.8Hz), 6.94 (1H,
d, J = 2.4Hz), 7.33-7.46 (9H, m), 7.56 (1H, d, J = 8.8Hz), 8.03 (1H, d, J = 16.1Hz)

<Reference Example 4>
4 '-[4- (Benzyloxy) phenylthio] -2'-ethyl chlorocinnamate

The target product was obtained as a pale yellow powder by reacting in the same manner as in Reference Example 3 using the compound of Reference Example 1. ¹ H-NMR (400 MHz, CDCl ₃ )
δ 1.33 (3H, t, J = 7.3Hz), 4.26 (2H, q, J = 7.3Hz), 5.11 (2H, s), 6.35 (1H, d,
J = 15.9Hz), 6.96 (1H, dd, J = 1.2, 7.8Hz), 7.01-7.07 (3H, m), 7.34-7.49 (8H, m),
8.00 (1H, d, J = 15.9Hz)

<Reference Example 5>
4 '-(4-Bromophenylthio) -2'-chlorochlorocinnamate

After reacting in the same manner as in Reference Example 1 using parabromothiophenol, the resulting aldehyde was reacted in the same manner as in Reference Example 3 to obtain the desired product as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.34 (3H, t, J = 7.3 Hz), 4.27 (2H, q,
J = 7.3Hz), 6.39 (1H, d, J = 16.1Hz), 7.08 (1H, dd, J = 2.0, 8.3Hz), 7.23 (1H, d, J = 2.0Hz),
7.32 (2H, d, J = 8.3Hz), 7.50-7.53 (3H, m), 8.01 (1H, d, J = 16.1Hz)

<Reference Example 6>
4 '-(4-Biphenylthio) -2'-ethyl chlorocinnamate

Tetrakistriphenylphosphine palladium (179 mg), phenylboric acid (452 mg) in ethanol (5 mL) and 2 mol / L-Na ₂ CO ₃ aqueous solution (8.7 mL) were added to toluene (40 mL) of Reference Example 5 (1.23 g). Heated to reflux for 8 hours. Ethyl acetate was added, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 20/1) to obtain the desired product (1.07 g) as a pale yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.34 (3H, t, J = 7.3 Hz), 4.27 (2H,
q, J = 7.3Hz), 6.39 (1H, d, J = 16.1Hz), 7.12 (1H, dd, J = 2.0, 8.3Hz), 7.36-7.41 (1H,
m), 7.45-7.55 (5H, m), 7.60-7.64 (5H, m), 8.02 (1H, d, J = 16.1Hz).

<Reference Example 7>
Ethyl 4 '-[4- (3,5-dichlorophenyl) phenylthio] -2'-chlorocinnamate

The target product was obtained as a pale yellow oil by reacting the compound of Reference Example 5 and 3,5-dichlorophenylboric acid in the same manner as in Reference Example 6.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.34 (3H, t, J = 7.3 Hz), 4.27 (2H,
q, J = 7.3Hz), 6.40 (1H, d, J = 16.1Hz), 7.15 (1H, dd, J = 2.0, 8.3Hz), 7.29 (1H, d,
J = 2.0Hz), 7.37 (1H, t, J = 2.0Hz), 7.47 (2H, d, J = 1.5Hz), 7.50-7.56 (5H, m),
8.02 (1H, d, J = 16.1).

<Reference Example 8>
4 '-[4- (Benzyloxy) phenoxy] -2'-chlorodihydrocinnamyl alcohol

Reference Example 3 (1.86 g) was dissolved in ethanol (30 mL), and BiCl ₃ (719 mg) and NaBH ₄ (689 mg) were added with stirring at 0 ° C. After stirring at the same temperature for 30 minutes and at room temperature for 5 hours, water was added, insoluble matter was filtered off through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained residue was dissolved in THF (30 mL), LiAlH ₄ (173 mg) was added at 0 ° C., and the mixture was stirred for 1 hr. An aqueous sodium hydroxide solution was added, insolubles were filtered off through celite, the residue was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired product (1.50 g) as a colorless powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.31 (1H, br s), 1.84-1.91 (2H,
m), 2,78 (2H, t, J = 7.8Hz), 3.69 (2H, d, J = 6.4Hz), 5.06 (2H, s), 6.79 (1H, dd, J = 2.4,
8.3Hz), 6.92-6.96 (5H, m), 7.15 (1H, d, J = 8.3Hz), 7.30-7.45 (5H, m).

<Reference Example 9>
4 '-[4- (Benzyloxy) phenoxy] -2'-chlorodihydrocinnamyl iodide

While stirring a THF (30 mL) solution of Reference Example 8 (1.50 g) at 0 ° C., PPh ₃ (2.14 g), imidazole (554 mg) and I ₂ (2.07 g) were added and stirred for 30 minutes. A 5% aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was concentrated, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1) to obtain the desired product (1.79 g) as a colorless powder.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 2.08-2.15 (2H, m), 2.79 (2H, t,
J = 7.3Hz), 3.19 (2H, t, J = 6.8Hz), 5.06 (2H, s), 6.79 (1H, dd, J = 2.4, 8.3Hz),
6.93 (1H, d, J = 2.4Hz), 6.97 (4H, s), 7.16 (1H, d, J = 8.3Hz), 7.32-7.46 (5H, m).

<Reference Examples 10-12>
The compounds shown in Table 1 were synthesized by reacting the compounds of Reference Examples 4, 6, and 7 in the same manner as in Reference Examples 8 and 9.

<Reference Example 13>
4- [4- (Benzyloxy) phenylthio] -2-chlorophenethylaldehyde

(Methoxymethy) triphenylphosphonium chloride (8.28g) tetrahydrofuran under argon substitution and ice cooling
To the (280 mL) solution, t-butoxypotassium (6.76 g) was added and stirred for 1 hour, and a solution of Reference Example 1 (11.2 g) in tetrahydrofuran (20 mL) was added and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed in turn with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off and silica gel column chromatography (hexane
: Ethyl acetate = 6: 1 followed by purification by 2: 1) to obtain a vinyl ether (4.63 g) as a pale yellow oil. The obtained vinyl ether (4.63 g) was dissolved in tetrahydrofuran (66 mL), 6 mol / L hydrochloric acid aqueous solution (60 mL) was added, and the mixture was stirred at 60 ° C. for 3 hr. The mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Silica gel column chromatography (hexane
: Ethyl acetate = 6: 1, followed by purification by 4: 1) to obtain the desired product (3.70 g) as a colorless powder.
MS (EI +): 382 ([M] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.82 (2H, d, J = 1.8 Hz), 5.02 (2H,
s), 7.16 (2H, d, J = 1.8Hz), 7.25 (1H, d, J = 8.6Hz), 7.35 (1H, d, J = 1.2Hz), 7.50 (2H,
d, J = 8.6Hz), 7.54 (2H, d, J = 8.0Hz), 7.66 (1H, t, J = 8.0Hz), 8.20 (2H, dd, J = 1.2Hz,
8.6Hz), 9.75 (1H, t, 1.8Hz).

<Reference Example 14>
4- [4- (Benzyloxy) phenylthio] -2-chlorophenethyl iodide

Reference Example 13 was reduced with NaBH ₄ under ice cooling, and the alcohol was reacted in the same manner as Reference Example 9 to obtain the desired product as a pale yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.23-3.30 (2H, m), 3.31-3.40 (2H,
m), 5.03 (2H, s), 7.12-7.18 (2H, m), 7.23 (2H, d, J = 8.6Hz), 7.30 (1H, d, J = 1.2Hz),
7.47 (2H, d, J = 8.6Hz), 7.53 (2H, d, J = 8.0Hz), 7.66 (1H, t, J = 8.0Hz), 8.20 (2H, dd,
J = 1.2Hz, 8.6Hz).

<Reference Example 15>
4'-Benzyloxy-dihydrocinnamyl iodide

  Ethyl parabenzyloxydihydrocinnamate was reduced and iodinated in the same manner as in Reference Example 14 to obtain the desired product as a yellow powder.

<Example 1>
5-[(4-Benzyloxy) phenyl] -2-t-butoxycarbonylamino-2-ethoxycarbonylpentanoic acid ethyl ester

To a solution of diethyl 2-t-butoxycarbonylaminomalonate (11.7 g) in THF (180 mL) and DMF (30 mL), NaOtBu (4.09 g) was added and heated under reflux for 30 minutes, and then THF of Reference Example 15 (10.0 g) was added. (120 mL) solution was added and stirred at reflux for 8 hours. Ice water was added, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain the crude product as a pale yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.22 (6H, t, J = 7.1 Hz),
1.42 (9H, s), 1.44-1.47 (2H, m), 2.31 (2H, br s), 2.57 (2H, t, J = 7.6Hz),
4.11-4.27 (4H, m), 5.03 (2H, s), 5.92 (1H, br s), 7.06 (2H, d, J = 8.8Hz),
7.29-7.43 (5H, m), 8.88 (2H, d, J = 8.8Hz).

<Examples 2 to 6>
The compounds shown in Table 2 were synthesized by reacting in the same manner as in Example 1 using Reference Examples 9 to 12 and 14.

<Example 7>
Ethyl 5-[(4-trifluoromethylphenoxy) phenyl] -2-t-butoxycarbonylamino-2-ethoxycarbonylpentanoate

  The crude product obtained in Example 1 was dissolved in ethanol (300 mL), 10% Pd / C (2.00 g) was added, and the mixture was stirred at a hydrogen pressure of 294 kPa and 50 ° C. After 2 hours, the catalyst was removed by filtration through Celite, and the residue was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 then 2: 1) to give 5- (4-hydroxyphenyl) -2- Ethyl t-butoxycarbonylamino-2-ethoxycarbonylpentanoate (12.0 g) was obtained as a colorless oil.

Copper acetate (133 mg), triethylamine (0.205 mL), and MS4A (1.00 g) were added to a methylene chloride (5 mL) solution of the obtained phenol compound (300 mg) and paratrifluoromethylphenylboric acid (279 mg) at room temperature. And stirred for 1 day. Insoluble material was removed by filtration through Celite, and the residue was purified through silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the desired product (235 mg) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.24 (6H, t, J = 7.3 Hz), 1.42 (9H,
s), 1.46-1.52 (2H, m), 2.34 (2H, br s), 2.64 (2H, t, J = 7.8Hz), 4.18-4.25 (4H, m),
5.94 (1H, br s), 6.95 (2H, d, J = 8.3Hz), 7.01 (2H, d, J = 8.3Hz), 7.16 (2H, d,
J = 8.3Hz), 7.55 (2H, d, J = 8.3Hz).

<Examples 8 and 9>
2-t-butoxycarbonylamino-2- [4- (4-trifluoromethylphenoxy) phenyl] propyl-1,3-propanediol and 2-t-butoxycarbonylamino-5- [4- (4-trifluoro Methylphenoxy) phenyl] pentan-1-ol

LiBH ₄ (92.6 mg) and EtOH (0.5 mL) were added to a solution of Example 7 (235 mg) in THF (10 mL) at 0 ° C., and the mixture was stirred for 1 day while warming to room temperature. A saturated aqueous ammonium chloride solution was added, the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After concentrating the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 and then 3: 2) to obtain a diol form (147 mg) and a monool form (24.3 mg) as colorless oils.

Diol form; ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.44 (9H, s), 1.62-1.64 (4H,
m), 2.62 (2H, brs), 3.36 (2H, br s), 3.59 (2H, d, J = 11.2Hz), 3.83 (2H, d,
J = 11.2Hz), 4.91 (1H, br s), 6.97 (2H, d, J = 8.8Hz), 7.02 (2H, d, J = 8.8Hz), 7.18 (2H,
d, J = 8.8Hz), 7.55 (2H, d, J = 8.8Hz).
Monool form; ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.45 (9H, s),
1.53-1.77 (4H, m), 2.60-2.69 (2H, m), 3.54-3.57 (1H, m), 3.68 (2H, d, J = 8.3Hz),
4.62 (1H, br s), 6.97 (2H, d, J = 8.8Hz), 7.02 (2H, d, J = 8.8Hz), 7.18 (2H, d,
J = 8.8Hz), 7.55 (2H, d, J = 8.8Hz).

<Examples 10 to 17>
The compounds shown in Table 3 were synthesized by reacting the compounds of Examples 2 to 6 in the same manner as in Examples 8 and 9.

<Example 18>
2-Amino-2- [4- (4-trifluoromethylphenoxy) phenyl] propyl-1,3-propanediol hydrochloride

Example 8 (147 mg) was dissolved in methanol (3 mL), 10% HCl-AcOEt (3 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was concentrated to obtain the desired product (119 mg) as a colorless amorphous.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.58 (4H, br s), 2.56 (2H, t,
J = 6.8Hz), 3.40-3.48 (4H, m), 5.32 (2H, br s), 7.06 (2H, d, J = 8.8Hz), 7.08 (2H, d,
J = 8.8Hz), 7.28 (2H, d, J = 8.8Hz), 7.71 (2H, d, J = 8.8Hz), 7.76 (3H, br s).
FABMS [M + H] ⁺ 370

<Examples 19 to 27>
The compounds shown in Table 4 were synthesized by reacting the compounds of Examples 9 to 17 in the same manner as in Example 18.

Example 19: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.58 (4H, br s), 2.56 (2H,
t, J = 6.8Hz), 3.40-3.48 (4H, m), 5.32 (2H, br s), 7.06 (2H, d, J = 8.8Hz), 7.08 (2H,
d, J = 8.8Hz), 7.28 (2H, D, J = 8.8Hz), 7.71 (2H, d, J = 8.8Hz), 7.76 (3H, br s).

Example 20: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.57 (4H, br s), 2.60 (2H,
br s), 3.39-3.47 (4H, m), 5.08 (2H, s), 5.31 (2H, t, J = 4.9Hz), 6.85 (1H, dd, J = 2.4,
8.3Hz), 6.92 (1H, d, J = 2.4Hz), 7.00-7.07 (4H, m), 7.29-7.46 (6H, m), 7,75 (3H, br
s).

Example 21: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.50-1.64 (4H, m),
2.63 (2H, t, J = 7.3Hz), 3.07 (1H, br s), 3.40-3.45 (1H, m), 3.55-3.66 (1H, m),
5.08 (2H, s), 5.27 (1H, t, J = 4.9Hz), 6.85 (1H, dd, J = 2.4, 8.3Hz), 6.93 (1H, d,
J = 2.4Hz), 7.00-7.07 (4H, m), 7.29-7.46 (6H, m), 7.88 (3H, br s).

Example 22: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.70-1.75 (2H, m),
2.64-2.68 (2H, m), 3.49-3.54 (4H, m), 5.13 (2H, s), 5.36-5.39 (2H, m),
7.07-7.12 (4H, m), 7.26 (1H, d, J = 8.2Hz), 7.32-7.46 (7H, m), 7.79-7.87 (3H, br).
Elemental analysis (%): as C ₂₄ H ₂₆ ClNO ₄ S.HCl
C H N
Calculated value 60.00 5.66 2.92
Actual value 59.58 5.61 2.79

Example 23: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.50-1.56 (4H, m),
2.56-2.62 (2H, m), 3.38-3.42 (4H, m), 5.14 (2H, s), 5.26-5.29 (2H, m), 7.05 (1H, dd,
J = 1.8, 7.9Hz), 7.08-7.11 (3H, m), 7.25 (1H, d, J = 7.9Hz), 7.34-7.46 (7H, m),
7.60-7.68 (3H, br).
Elemental analysis (%): C ₂₅ H ₂₈ ClNO ₄ S.HCl
C H N
Calculated value 60.72 5.91 2.83
Actual value 60.61 5.85 2.66

Example 24: ¹ H-NMR (400 MHz, DMSO-d ₆ )
δ 1.58 (4H, br s), 2.65 (2H, br s), 3.39-3.47 (4H, m), 5.31 (2H, t, J = 4.9Hz),
7.27 (1H, dd, J = 2.0, 7.8Hz), 7.30-7.39 (3H, m), 7.42-7.49 (4H, m), 7.63-7.72 (7H,
m).

Example 25: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.50-1.68 (4H, m), 2.68 (2H,
t, J = 7.3Hz), 3.07 (1H, br s), 3.40-3.44 (1H, m), 3.55-3.59 (1H, m), 5.28 (1H, br
s), 7.27 (1H, dd, J = 2.0, 8.3Hz), 7.30-7.39 (3H, m), 7.42-7.49 (4H, m),
7.63-7.72 (4H, m), 7.88 (3H, br s).

Example 26: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.59 (4H, br s), 2.66 (2H,
br s), 3.39-3.47 (4H, m), 5.32 (2H, br s), 7.32 (1H, dd, J = 2.0, 7.8Hz),
7.38-7.42 (4H, m), 7.61 (1H, d, J = 2.0Hz), 7.74-7.78 (7H, m).

Example 27: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.50-1.68 (4H, m),
2.69 (2H, t, J = 7.3Hz), 3.07 (1H, br s), 3.40-3.47 (1H, m), 3.54-3.61 (1H, m),
5.28 (1H, br s), 7.31 (1H, dd, J = 2.0, 8.3Hz), 7.38-7.42 (4H, m), 7.60 (1H, t,
J = 2.0Hz), 7.72-7.77 (4H, m), 7.92 (3H, br s).

<Example 28>
2-allyl-4-[(4-benzyloxyphenylthio) -2-chlorophenyl] -2-ethoxycarbonylbutyrate ethyl

Under argon substitution, 60% sodium hydride (661 mg) was added to a mixed solution (80 mL) of diethyl malonate (2.61 mL) in tetrahydrofuran-N, N-dimethylformamide (7: 1) and stirred at 80 ° C. for 30 minutes. did. Tetrahydrofuran-N, N-dimethylformamide of Reference Example 14 (5.67 g) (7
1) The mixed solution (20 mL) was added and stirred at 80 ° C. for 30 minutes. The reaction vessel was ice-cooled, 60% sodium hydride (2.28 g) was added to the reaction mixture, and the mixture was stirred for 30 min. Thereafter, allyl iodide (5.21 mL) was added, and the mixture was stirred for 30 minutes. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off and silica gel column chromatography (hexane:
The product was purified by ethyl acetate = 20: 1) to obtain the desired product (3.56 g) as a pale yellow oil.
MS (EI +): 552 ([M] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.26 (6H, t, J = 7.3 Hz),
2.07-2.11 (2H, m), 2.56-2.63 (2H, m), 2.74 (2H, d, J = 7.3Hz), 4.19 (4H, q, J = 7.3Hz),
5.08 (2H, s), 5.12-5.18 (2H, m), 5.64-5.72 (1H, m), 6.96-6.99 (3H, m), 7.04 (1H, d,
J = 7.9Hz), 7.11 (1H, d, J = 1.8Hz), 7.32-7.45 (7H, m).

<Example 29>
2-Allyl-4-[(4-benzyloxyphenylthio) -2-chlorophenyl] -2-ethoxycarbonylbutyric acid

To a mixed solution (90 mL) of Example 28 (3.56 g) in ethanol-tetrahydrofuran (2: 1) was added 1 mol / L-potassium hydroxide aqueous solution (20 mL), and the mixture was heated to reflux for 2.5 hours. A 10% aqueous hydrochloric acid solution was added to the reaction solution to adjust the pH to 1, followed by extraction with ethyl acetate, washing with water and saturated brine in that order, and drying over anhydrous sodium sulfate. The solvent was distilled off and silica gel column chromatography (hexane
: Purified with ethyl acetate = 3: 1 and then 1: 1) to obtain the desired product (2.67 g) as a pale yellow oil.
MS (FAB +): 524 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.31 (3H, t, J = 7.3 Hz),
2.17-2.20 (2H, m), 2.58-2.67 (3H, m), 2.76-2.81 (1H, m), 4.22-4.28 (2H, m), 5.08 (2H,
s), 5.11-5.16 (2H, m), 5.61-5.71 (1H, m), 6.96-6.99 (3H, m), 7.03 (1H, d, J = 7.9Hz),
7.10 (1H, d, J = 1.8Hz), 7.32-7.45 (7H, m).

<Example 30>
2-allyl-4-[(4-benzyloxyphenylthio) -2-chlorophenyl] -2-methoxycarbonylaminobutyric acid ethyl ester

To a solution of Example 29 (1.22 g) in benzene (15.0 mL) were added triethylamine (0.42 mL) and diphenylphosphoric acid azide (550 μL), and the mixture was heated to reflux for 40 minutes. It returned to normal temperature, the methanol (15 mL) solution and sodium methoxide (251 mg) were added, and it heated and refluxed for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off and silica gel column chromatography (hexane
: Purified with ethyl acetate = 10: 1) to obtain the desired product (1.21 g) as a pale yellow oil.
MS (FAB +): 553 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.28 (3H, t, J = 7.3 Hz),
2.06-2.12 (1H, m), 2.44-2.51 (2H, m), 2.60-2.65 (2H, m), 3.05-3.15 (1H, m), 3.63 (3H,
s), 4.14-4.22 (2H, m), 5.05-5.07 (2H, m), 5.58-5.64 (1H, m), 5.80 (1H, br s),
6.93-6.99 (3H, m), 7.02 (1H, d, J = 7.9Hz), 7.10 (1H, d, J = 1.8Hz), 7.32-7.45 (7H, m).

<Example 31>
2-Allyl-4-[(4-benzyloxyphenylthio) -2-chlorophenyl] -2-methoxycarbonylaminobutanol

Under ice cooling, lithium borohydride (281 mg, 12.90 mmol) was added to a solution of Example 30 (1.43 g) in tetrahydrofuran (15 mL), ethanol (0.75 mL) was added dropwise, and the mixture was stirred for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off and silica gel column chromatography (hexane
: Purified with ethyl acetate = 3: 2) to obtain the desired product (1.10 g) as a colorless oil.
MS (FAB +): 512 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.82-1.94 (2H, m), 2.31-2.36 (1H,
m), 2.45-2.50 (1H, m), 2.64-2.71 (2H, m), 3.64 (3H, s), 3.71-3.81 (3H, m), 4.90 (1H,
br s), 5.08 (2H, s), 5.17-5.21 (2H, m), 5.80-5.89 (1H, m), 6.96-7.00 (3H, m),
7.08-7.12 (2H, m), 7.32-7.45 (7H, m).

<Example 32>
2-Allyl-2-amino-4-[(4-benzyloxyphenylthio) -2-chlorophenyl] -butanol

To a dimethyl sulfoxide (14 mL) solution of Example 31 (1.10 g), 5 mol / L-potassium hydroxide aqueous solution (14 mL) and 1 mol / L-lithium hydroxide aqueous solution (7 mL) were added, and the mixture was heated and stirred at 100 ° C. for 17 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off and silica gel column chromatography (aminated silica,
The product was purified with ethyl acetate alone and then with ethyl acetate: ethanol = 10: 1) to obtain the desired product (1.16 g) as colorless crystals.
MS (FAB +): 454 ([M + H] ⁺ )
¹ H-NMR (400 MHz, DMSO) δ 1.29 (2H, br s), 1.38-1.42 (2H, m), 2.08 (2H,
d, J = 7.9Hz), 2.57-2.70 (2H, m), 3.13-3.17 (2H, m), 4.56 (1H, t, J = 4.9Hz),
5.00-5.07 (2H, m), 5.13 (2H, s), 5.80-5.90 (1H, m), 7.03-7.10 (4H, m), 7.22 (1H, d,
J = 7.9Hz), 7.31-7.46 (7H, m).

<Example 33>
2-Allyl-2-amino-4-[(4-benzyloxyphenylthio) -2-chlorophenyl] -butanol hydrochloride

Example 32 (50 mg) was dissolved in a 10% hydrochloric acid methanol solution, and after 30 minutes, the solvent was distilled off to obtain the desired product (53.8 mg) as a colorless amorphous.
MS (FAB +): 454 ([M + H] ⁺ )
HRMS (FAB +): 454 ([M + H] ⁺ ) (mmu +2.0)
¹ H-NMR (400MHz, DMSO) δ 1.66-1.70 (2H, m), 2.40 (2H, m),
2.66-2.70 (2H, m), 3.48 (2H, m), 5.12 (2H, s), 5.13-5.26 (2H, m), 5.55 (1H, t,
J = 4.9Hz), 5.75-5.86 (1H, m), 7.06-7.13 (4H, m), 7.26 (1H, d, J = 8.6Hz),
7.32-7.46 (7H, m), 7.92-8.06 (3H, br).

  Next, the results of supporting the usefulness of the compounds of the present invention are shown by experimental examples.

<Experimental example> Inhibitory action of test compound on mouse host versus graft rejection reaction Transplantation, Vol. 55, No. 3, pages 578-591, 1993. . Spleens were collected from BALB / c male mice (Nippon Charles River). The spleen was taken out in RPMI-1640 medium (Gibco or Sigma) and crushed with two slide glasses and passed through a cell strainer (70 micron, Falcon) to make a spleen cell suspension. The splenocyte suspension was centrifuged to remove the supernatant, and then ammonium chloride-Tris isotonic buffer was added to lyse the red blood cells. After centrifugal washing with RPMI-1640 medium three times, it was suspended in RPMI-1640 medium. To this, mitomycin C (Kyowa Hakko) was added so that the final concentration was 25 μg / mL, and the cells were cultured at 37 ° C. under 5% CO ₂ for 30 minutes. After centrifugal washing with RPMI-1640 medium three times, the suspension was suspended in RPMI-1640 medium at 2.5 × 10 ⁸ cells / mL, and this was used as a stimulating cell suspension. Using a 27G needle and a microsyringe (Hamilton), 20 μL of the stimulated cell suspension (5 × 10 ⁶ cells / mouse) was subcutaneously injected into the right hind footpad of a C3H / HeN male mouse 6-10 weeks old (Claire Japan). Injected. The normal control group was injected with RPMI-1640 medium only. Four days later, the lymph node under the right knee was removed and weighed using a METTLER AT201 electronic balance (METTLER TOLEDO). The test compound was intraperitoneally administered once a day for a total of 4 times every day from the stimulating cell injection day to 3 days later. In the control group, a solvent having the same composition as that used for the preparation of the test compound was administered. Table 5 shows. In addition, the suppression rate was computed using the following formula.

  As described above, the effectiveness of the compound of the present invention represented by the general formula (1) was confirmed in an animal experiment model.

As described above, the present invention provides a novel amino alcohol derivative, particularly a diaryl sulfide having a carbon chain containing an amino alcohol unit at the para position of one aryl group and a substituent at the para position of the other aryl group. And diaryl ether derivatives have been found to have a strong immunosuppressive action. Such immunosuppressive compounds are used as preventive or therapeutic agents for rejection in organ transplantation and bone marrow transplantation, prophylactic or therapeutic agents for autoimmune diseases such as inflammatory bowel disease, systemic lupus erythematosus, Crohn's disease, rheumatoid arthritis It is useful as a prophylactic or therapeutic agent, a prophylactic or therapeutic agent for psoriasis or atopic dermatitis, and a prophylactic or therapeutic agent for bronchial asthma or hay fever.

Claims (11)

General formula (1)

[Where
R ₁ may have a halogen atom, a trifluoromethyl group, a hydroxy group, a lower alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a phenyl group which may have a substituent, or a substituent. A good phenyloxy group, an aralkyl group which may have a substituent or an aralkyloxy group which may have a substituent; R ₂ represents a hydrogen atom, a halogen atom or a trifluoromethyl group;
R ₃ represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a lower alkenyl group having 2 to 4 carbon atoms, or a hydroxymethyl group,
X represents O, S, SO or SO ₂ , and n represents an integer of 1 to 4]
An amino alcohol derivative, a pharmacologically acceptable salt and a hydrate thereof, which are represented by the formula: The compound represented by the general formula (1) is represented by the general formula (1a).

[Wherein R ₂ , X and n are the same as defined above]
The aminoalcohol derivative according to claim 1, a pharmacologically acceptable salt, and a hydrate thereof, wherein the compound is represented by the formula: The amino alcohol derivative, pharmacologically acceptable salt and hydrate thereof according to claim 2, wherein R ₂ in the general formula (1a) is a chlorine atom. The compound represented by the general formula (1) is
1) 2-amino-2- [4- (4-benzyloxyphenoxy) -2-chlorophenyl] propyl-1,3-propanediol,
2) 2-amino-2- [4- (4-benzyloxyphenylthio) -2-chlorophenyl] propyl-1,3-propanediol,
3) 2-amino-2- [4- (4-benzyloxyphenylthio) -2-chlorophenyl] ethyl-1,3-propanediol,
4) 2-amino-2- (4-biphenylthio-2-chlorophenyl) propyl-1,3-propanediol or 5) 2-amino-2- [4- (3 ′, 5′-dichlorobiphenylthio)- 2-chlorophenyl] propyl-1,3-propanediol,
The amino alcohol derivative and pharmacologically acceptable salt and hydrate thereof according to claim 1, wherein General formula (1)

[Where
R ₁ may have a halogen atom, a trifluoromethyl group, a hydroxy group, a lower alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a phenyl group which may have a substituent, or a substituent. A good phenyloxy group, an aralkyl group which may have a substituent or an aralkyloxy group which may have a substituent; R ₂ represents a hydrogen atom, a halogen atom or a trifluoromethyl group;
R ₃ represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a lower alkenyl group having 2 to 4 carbon atoms, or a hydroxymethyl group,
X represents O, S, SO or SO ₂ , and n represents an integer of 1 to 4]
An immunosuppressive agent comprising as an active ingredient at least one of an amino alcohol derivative represented by the formula (1), a pharmacologically acceptable salt, and a hydrate thereof. The compound represented by the general formula (1) is represented by the general formula (1a).

[Wherein R ₂ , X and n are the same as defined above]
An immunosuppressive agent comprising as an active ingredient at least one of the amino alcohol derivative according to claim 5, a pharmacologically acceptable salt, and a hydrate thereof. The immunosuppressive agent according to claim 5 or 6, wherein the immunosuppressive agent is a prophylactic or therapeutic agent for rheumatoid arthritis. The immunosuppressive agent according to claim 5 or 6, wherein the immunosuppressive agent is a preventive or therapeutic agent for psoriasis or atopic dermatitis. The immunosuppressive agent according to claim 5 or 6, wherein the immunosuppressive agent is a preventive or therapeutic agent for bronchial asthma or hay fever. The immunosuppressive agent according to claim 5 or 6, wherein the immunosuppressive agent is a preventive or therapeutic agent for rejection in organ transplantation and bone marrow transplantation. The immunosuppressive agent according to claim 5 or 6, wherein the immunosuppressive agent is a prophylactic or therapeutic agent for autoimmune diseases such as inflammatory bowel disease, systemic lupus erythematosus (SLE), and Crohn's disease. .