JP2006503859A - Azabicyclic spiroether derivatives as receptor antagonists - Google Patents

Abstract

The present invention is a compound of formula (I): (wherein Z is —CR ⁹ R ¹⁰ CH ₂ — or —CH ₂ CR ⁹ R ¹⁰ —, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ And R ⁶ is as defined in the specification). This compound is of particular use in the treatment or prevention of depression, anxiety, pain, inflammation, migraine, vomiting or postherpetic neuralgia.
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Description

  The present invention relates to a class of azabicyclic compounds that are useful as tachykinin antagonists. More particularly, the compounds of the present invention are spiroether derivatives of 1-phenyl-8-azabicyclo [3.2.1] octane which are useful as neurokinin 1 (NK-1) receptor antagonists.

  The present invention relates to a compound of formula (I):

［式中、Ｚは、−ＣＲ^９Ｒ^１０ＣＨ_２−又は−ＣＨ_２ＣＲ^９Ｒ^１０−であり、
Ｒ^１は、水素、ヒドロキシ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_３−７シクロアルキル、Ｃ_３−７シクロアルキルＣ_１−４アルキル、Ｃ_１−６アルコキシ、フルオロＣ_１−６アルコキシ、ヒドロキシＣ_１−６アルキル、Ｃ_１−６アルコキシＣ_１−４アルキル、Ｃ_１−６アルコキシＣ_１−４アルコキシ、フルオロＣ_１−６アルコキシＣ_１−４アルキル、Ｃ_２−６アルケニルオキシ、Ｃ_３−７シクロアルコキシ、Ｃ_３−７シクロアルキルＣ_１−４アルコキシ、フェノキシ、ベンジルオキシ、シアノ、ハロゲン、ＮＲ^ａＲ^ｂ、ＳＲ^ａ、ＳＯＲ^ａ、ＳＯ_２Ｒ^ａ、ＯＳＯ_２Ｒ^ａ、ＮＲ^ａＣＯＲ^１２、ＣＯＲ^ａ、ＣＯ_２Ｒ^ａ若しくはＣＯＮＲ^ａＲ^ｂ（式中、Ｒ^ａ及びＲ^ｂは、それぞれ独立に、水素、Ｃ_１−４アルキル又はフルオロＣ_１−４アルキルを表す。）を表し、
Ｒ^２は、水素、ハロゲン、Ｃ_１−６アルキル若しくはＣ_１−６アルコキシを表し、
又はＲ^２がＲ^１に隣接するとき、これらは、一緒に結合して、窒素、酸素、硫黄、ＮＨ若しくはＮＲ^ｃから選択された１個若しくは２個の原子を含有する５員若しくは６員の飽和若しくは不飽和環（但し、この環は、ヒドロキシ、Ｃ_１−４アルキル、Ｃ_１−３アルコキシＣ_１−３アルキル、フルオロＣ_１−４アルキル、フェニル、＝Ｏ又は＝Ｓから選択された１個、２個又は３個の基によって場合により置換されており、Ｒ^ｃは、Ｃ_１−４アルキル、ヒドロキシＣ_１−４アルキル、Ｃ_１−４アルコキシＣ_１−４アルキル、フルオロＣ_１−４アルキル、フェニル又はベンジルである。）を形成することができ、
Ｒ^３は、水素、ハロゲン、Ｃ_１−６アルキル、フルオロＣ_１−６アルキル、Ｃ_１−６アルコキシ、フルオロＣ_１−６アルコキシ、Ｃ_３−７シクロアルキル、Ｃ_３−７シクロアルキルＣ_１−４アルキル、シアノ、ＳＲ^ａ、ＳＯＲ^ａ、ＳＯ_２Ｒ^ａ、ＮＲ^ａＲ^ｂ、ＮＲ^ａＣＯＲ^１２、ＣＯＲ^ａ、ＣＯ_２Ｒ^ａ、ＣＯＮＲ^ａＲ^ｂを表し、又はシアノ、ＣＯ_２Ｒ^ａ若しくはＣＯＮＲ^ａＲ^ｂによって置換されたＣ_１−４アルキル（式中、Ｒ^ａ及びＲ^ｂは、前記定義された通りである。）を表し、
又はＲ^３は、窒素、酸素及び硫黄から選択された１個、２個、３個若しくは４個のヘテロ原子を含有する５員若しくは６員の芳香族複素環式基（この基は、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、Ｃ_３−７シクロアルキル、Ｃ_３−７シクロアルキルＣ_１−４アルキル、トリフルオロメチル、ＯＣＦ_３、ＮＯ_２、ＣＮ、ＳＲ^ａ、ＳＯＲ^ａ、ＳＯ_２Ｒ^ａ、ＣＯＲ^ａ、ＣＯ_２Ｒ^ａ、フェニル、−（ＣＨ_２）_ｒＮＲ^ａＲ^ｂ、−（ＣＨ_２）_ｒＮＲ^ａＣＯＲ^ｂ、−（ＣＨ_２）_ｒＣＯＮＲ^ａＲ^ｂ又はＣＨ_２Ｃ（Ｏ）Ｒ^ａ（式中、Ｒ^ａ及びＲ^ｂは、前記定義された通りであり、ｒはゼロ、１又は２である。）から選択された１個又は２個の基によって場合により置換されている。）を表し、
Ｒ^４は、水素、ハロゲン、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、ＣＦ_３、ＯＣＦ_３、ＮＯ_２、ＣＮ、ＳＲ^ａ、ＳＯＲ^ａ、ＳＯ_２Ｒ^ａ、ＣＯ_２Ｒ^ａ、ＣＯＮＲ^ａＲ^ｂ、Ｃ_２−６アルケニル、Ｃ_２−６アルキニルを表し、又はＣ_１−４アルコキシによって置換されたＣ_１−４アルキル（式中、Ｒ^ａ及びＲ^ｂは、前記定義された通りである）を表し、
Ｒ^５は、水素、ハロゲン、Ｃ_１−６アルキル、ＣＦ_３を表し、又はＣ_１−４アルコキシによって置換されたＣ_１−６アルコキシを表し、
Ｒ^６は、水素、ヒドロキシ、ＣＯＲ^ａ、ＣＯ_２Ｒ^ａ、ＣＯＣＯＮＲ^ａＲ^ｂ、ＣＯＣＯ_２Ｒ^ａを表し、（ＣＯ_２Ｒ^ａ、ＣＯＮＲ^ａＲ^ｂ、ヒドロキシ、ＣＮ、ＣＯＲ^ａ、ＮＲ^ａＲ^ｂ、Ｃ（ＮＯＨ）ＮＲ^ａＲ^ｂ、ＣＯＮＨフェニル（Ｃ_１−４アルキル）、ＣＯＣＯ_２Ｒ^ａ、ＣＯＮＨＮＲ^ａＲ^ｂ、Ｃ（Ｓ）ＮＲ^ａＲ^ｂ、ＣＯＮＲ^ａＣ_１−６アルキルＲ^１４、ＣＯＮＲ^１１Ｃ_２−６アルケニル、ＣＯＮＲ^１１Ｃ_２−６アルキニル、ＣＯＣＯＮＲ^ａＲ^ｂ、ＣＯＮＲ^ａＣ（ＮＲ^ｂ）ＮＲ^ａＲ^ｂ、ＣＯＮＲ^ａヘテロアリール、並びに（Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、ハロゲン及びトリフルオロメチルから選択された１個、２個又は３個の置換基によって場合により置換された）フェニル）から選択された基によって場合により置換されたＣ_１−６アルキルを表し、
又はＲ^６は、式−ＣＨ_２Ｃ≡ＣＣＨ_２ＮＲ^７Ｒ^８（式中、Ｒ^７及びＲ^８は、下記に定義される通りである。）の基を表し、
又はＲ^６は、オキソによって場合により置換された、＝Ｏ若しくは＝Ｓによって場合により置換された１個、２個若しくは３個の窒素原子を含有する５員若しくは６員の複素環式環によって置換された、式−Ｙ−ＮＲ^７Ｒ^８の基によって場合により置換されたＣ_１−６アルキルを表し、
Ｙは、Ｃ_１−６アルキレン又はＣ_３−６シクロアルキルであり、
Ｒ^７は、水素又はＣ_１−４アルキル、Ｃ_３−７シクロアルキル、Ｃ_３−７シクロアルキルＣ_１−４アルキルを表し、又はＣ_１−４アルコキシ若しくはヒドロキシルによって置換されたＣ_２−４アルキルを表し、
Ｒ^８は、水素又はＣ_１−４アルキル、Ｃ_１−４アルコキシ、Ｃ_３−７シクロアルキル、Ｃ_３−７シクロアルキルＣ_１−４アルキルを表し、又はＣ_１−４アルコキシ、ヒドロキシル、ＣＯ_２Ｒ^ａ、ＮＲ^ａＲ^ｂ、アリール、アリールオキシ、ヘテロアリール若しくはＮ、Ｏ及びＳから選択された１個若しくは２個のヘテロ原子を含有する４員、５員若しくは６員のヘテロ脂肪族環から選択された基によって置換されたＣ_２−４アルキルを表し、
又はＲ^７、Ｒ^８及びそれらが結合している窒素原子は、ヒドロキシ、フェニル、ベンジル又はＣ_１−４アルコキシ若しくはヒドロキシル基によって場合により置換されたＣ_１−４アルコキシから選択された１個若しくは２個の基によって場合により置換され、二重結合を場合により含有する、４個から７個の環原子のヘテロ脂肪族環を形成し（この環は、酸素若しくは硫黄環原子、基Ｓ（Ｏ）若しくはＳ（Ｏ）_２又はＮＨ若しくはＮＲ^ｃ単位（式中、Ｒ^ｃは前記定義された通りである。）の一部である第二窒素原子を場合により含有してよい。）、
又はＲ^７、Ｒ^８及びそれらが結合している窒素原子は、６個から１２個の環原子の非芳香族アザ二環式環系を形成し、
又はＹ、Ｒ^７及びそれらが結合している窒素原子は、酸素環原子を場合により含有してよい４個から７個の環原子のヘテロ脂肪族環を形成し、
Ｒ^９は、水素、ヒドロキシ、オキソ、Ｃ_１−６アルキル、Ｃ_２−６アルケニル、Ｃ_２−６アルキニル、Ｃ_３−７シクロアルキル、Ｃ_３−７シクロアルキルＣ_１−４アルキル、フルオロＣ_１−６アルキル、Ｃ_１−６アルコキシ、フルオロＣ_１−６アルコキシ、ヒドロキシＣ_１−６アルキル、Ｃ_１−６アルコキシＣ_１−４アルキル、Ｃ_１−６アルコキシＣ_１−４アルコキシ、フルオロＣ_１−６アルコキシＣ_１−４アルキル、Ｃ_２−６アルケニルオキシ、Ｃ_２−６アルキニルオキシ、Ｃ_３−７シクロアルコキシ、Ｃ_３−７シクロアルキルＣ_１−４アルコキシ、アリール、アリール（ＣＨ_２）、アリールオキシ、アリール（ＣＨ_２）オキシ、シアノ、ハロゲン、ＮＲ^７Ｒ^８、ＣＨ_２ＮＲ^７Ｒ^８、ＳＲ^１２、ＳＯＲ^１２、ＳＯ_２Ｒ^１２、ＯＳＯ_２Ｒ^１２、ＮＲ^ａＣＯＲ^１２、ＣＨ（ＯＨ）Ｒ^１２、ＣＯＲ^１２、ＣＯ_２Ｒ^１２、ＣＯＮＲ^７Ｒ^８、ＣＨ_２ＯＲ^１３、ヘテロアリール又はヘテロアリールＣ_１−４アルキル（式中、Ｒ^ａは、前記定義された通りである。）を表し、
Ｒ^１０は、水素、ハロゲン又はヒドロキシを表し、
Ｒ^１１は、水素又はＣ_１−６アルキルを表し、
Ｒ^１２は、水素、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、フルオロＣ_１−６アルキルを表し、又はＣ_１−６アルキル、Ｃ_１−６アルコキシ、ハロゲン若しくはトリフルオロメチルから選択された１個、２個若しくは３個の置換基によって場合により置換されたフェニルを表し、
Ｒ^１３は、ヒドロキシ、ＣＯＲ^ａ、ＣＯ_２Ｒ^ａ、ＣＯＮＲ^ａＲ^ｂ及びヘテロアリール（式中、Ｒ^ａは、前記定義された通りである。）から選択された基によって置換されたＣ_１−４アルキルを表し、
Ｒ^１４は、ＯＲ^ａ、ＣＯＮＲ^ａＲ^ｂ又はヘテロアリールを表す。］
の化合物及びその医薬適合性の塩又はＮ−オキシドを提供する。

[Wherein Z is —CR ⁹ R ¹⁰ CH ₂ — or —CH ₂ CR ⁹ R ¹⁰ —,
R ¹ is hydrogen, hydroxy, C _1-6 alkyl, C _2-6 alkenyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, C _1-6 alkoxy, fluoro C _1-6 Alkoxy, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-4 alkyl, C _1-6 alkoxy C _1-4 alkoxy, fluoro C _1-6 alkoxy C _1-4 alkyl, C _2-6 alkenyloxy, C _3-7 cycloalkoxy, C _3-7 cycloalkyl C _1-4 alkoxy, phenoxy, benzyloxy, cyano, halogen, NR ^a R ^b , SR ^a , SOR ^a , SO ₂ R ^a , OSO ₂ R ^a , NR _{^{a COR 12, COR a, CO}} 2 R a or CONR ^a R ^b (wherein, ^{R a} and ^{R b} are each independently _{hydrogen, C 1-4} Represents an alkyl or fluoroalkyl _{C 1-4} alkyl.) Represent,
R ² represents hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy,
Or when R ² is adjacent to R ¹ , they are bonded together to form a 5 or 6 membered containing 1 or 2 atoms selected from nitrogen, oxygen, sulfur, NH or NR ^c A saturated or unsaturated ring wherein the ring is 1 selected from hydroxy, C _1-4 alkyl, C _1-3 alkoxyC _1-3 alkyl, fluoroC _1-4 alkyl, phenyl, ═O or ═S Optionally substituted by 2, 2 or 3 groups, R ^c is C _1-4 alkyl, hydroxy C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, fluoro C _1-4. Alkyl, phenyl or benzyl),
R ³ is hydrogen, halogen, C _1-6 alkyl, fluoro C _1-6 alkyl, C _1-6 alkoxy, fluoro C _1-6 alkoxy, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _{1- 4 represents} alkyl, cyano, SR ^a , SOR ^a , SO ₂ R ^a , NR ^a R ^b , NR ^a COR ¹² , COR ^a , CO ₂ R ^a , CONR ^a R ^b , or cyano, CO ₂ R ^a or CONR ^a R _{C 1-4} alkyl (wherein, ^{R a} and ^{R b} are as previously defined.), which is substituted by ^b represent,
Or R ³ is a 5- or 6-membered aromatic heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulfur (this group is C _{1 -6} alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, trifluoromethyl, OCF ₃ , NO ₂ , CN, SR ^a , SOR ^a , SO ₂ R ^a , COR ^a , CO ₂ R ^a , phenyl, — (CH ₂ ) _r NR ^a R ^b , — (CH ₂ ) _r NR ^a COR ^b , — (CH ₂ ) _r CONR ^a R ^b or CH ₂ C (O ) R ^a (wherein R ^a and R ^b are as defined above, r is zero, 1 or 2) optionally substituted by one or two groups selected from Represents)
R ⁴ is hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, CF ₃ , OCF ₃ , NO ₂ , CN, SR ^a , SOR ^a , SO ₂ R ^a , CO ₂ R ^a , CONR ^a R represents ^b, _{C 2-6 alkenyl, C 2-6} alkynyl, or _{C 1-4 C 1-4} alkyl substituted by alkoxy (wherein, ^{R a} and ^{R b} are as previously defined) Represents
R ⁵ represents hydrogen, halogen, C _1-6 alkyl, CF ₃ , or C _1-6 alkoxy substituted by C _1-4 alkoxy;
R ⁶ represents hydrogen, hydroxy, COR ^a , CO ₂ R ^a , COCONR ^a R ^b , COCO ₂ R ^a , (CO ₂ R ^a , CONR ^a R ^b , hydroxy, CN, COR ^a , NR ^a R ^b , C (NOH) NR ^a R ^b , CONH phenyl (C _1-4 alkyl), COCO ₂ R ^a , CONHNR ^a R ^b , C (S) NR ^a R ^b , CONR ^a C _1-6 alkyl R ¹⁴ , CONR ¹¹ C _2-6 alkenyl, CONR ¹¹ C _2-6 alkynyl, CONR ^a R ^b , CONR ^a C (NR ^b ) NR ^a R ^b , CONR ^a heteroaryl, and (C _1-6 alkyl, C _1-6 alkoxy ) Phenyl) optionally substituted by 1, 2 or 3 substituents selected from halogen and trifluoromethyl It represents C _1-6 alkyl optionally substituted by radicals,
Or R ⁶ represents a group of formula —CH ₂ C≡CCH ₂ NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are as defined below;
Or R ⁶ is substituted by a 5 or 6 membered heterocyclic ring optionally containing one, two or three nitrogen atoms, optionally substituted by oxo, optionally substituted by ═O or ═S Represents C _1-6 alkyl optionally substituted by a group of formula —Y—NR ⁷ R ⁸ ,
Y is C _1-6 alkylene or C _3-6 cycloalkyl,
R ⁷ represents hydrogen or C _1-4 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, or C _2-4 alkyl substituted by C _1-4 alkoxy or hydroxyl Represents
R ⁸ represents hydrogen or C _1-4 alkyl, C _1-4 alkoxy, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, or C _1-4 alkoxy, hydroxyl, CO ₂ From ^a 4-membered, 5-membered or 6-membered heteroaliphatic ring containing 1 or 2 heteroatoms selected from R ^a , NR ^a R ^b , aryl, aryloxy, heteroaryl or N, O and S _Represents C _2-4 alkyl substituted by a selected group,
Or R ^7, R ⁸ and the nitrogen atom to which they are attached, hydroxy, phenyl, one selected from C _1-4 alkoxy optionally substituted by benzyl or C _1-4 alkoxy or hydroxyl group or 2 Forming a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by 1 group and optionally containing a double bond, which is an oxygen or sulfur ring atom, the group S (O) Or optionally a second nitrogen atom that is part of a S (O) ₂ or NH or NR ^c unit, where R ^c is as defined above.
Or R ⁷ , R ⁸ and the nitrogen atom to which they are attached forms a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
Or Y, R ⁷ and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms optionally containing oxygen ring atoms;
R ⁹ is hydrogen, hydroxy, oxo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, fluoro C _{1 -6} alkyl, C _1-6 alkoxy, fluoro C _1-6 alkoxy, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-4 alkyl, C _1-6 alkoxy C _1-4 alkoxy, fluoro C _{1- 6} alkoxy C _1-4 alkyl, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-7 cycloalkoxy, C _3-7 cycloalkyl C _1-4 alkoxy, aryl, aryl (CH ₂ ), aryl Oxy, aryl (CH ₂ ) oxy, cyano, halogen, NR ⁷ R ⁸ , CH ₂ NR ⁷ R ⁸ , SR ¹² , SOR ¹² , S O ₂ R ¹² , OSO ₂ R ¹² , NR ^a COR ¹² , CH (OH) R ¹² , COR ¹² , CO ₂ R ¹² , CONR ⁷ R ⁸ , CH ₂ OR ¹³ , heteroaryl or heteroaryl C _1-4 alkyl Wherein R ^a is as defined above,
R ¹⁰ represents hydrogen, halogen or hydroxy,
R ¹¹ represents hydrogen or C _1-6 alkyl,
R ¹² represents hydrogen, C _1-6 alkyl, C _1-6 alkoxy, fluoro C _1-6 alkyl, or 1 selected from C _1-6 alkyl, C _1-6 alkoxy, halogen or trifluoromethyl. Represents phenyl optionally substituted by 2, 2 or 3 substituents;
R ¹³ is C ₁ -C ₁ substituted by a group selected from hydroxy, COR ^a , CO ₂ R ^a , CONR ^a R ^b and heteroaryl (wherein R ^a is as defined above). Represents ₄ alkyl,
R ¹⁴ represents OR ^a , CONR ^a R ^b or heteroaryl. ]
And pharmaceutically acceptable salts or N-oxides thereof.

A preferred class of compounds of the formula (I) is that R ¹ is a C _1-6 alkoxy, fluoro C _1-6 alkoxy or C _3-7 cycloalkoxy group, or R ¹ together with the group R ² is 1 A five-membered saturated ring containing oxygen atoms is formed, which ring is optionally substituted by a methyl group.

A particularly preferred class of compounds of formula (I) is where R ¹ is methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, 2-fluoroethoxy, cyclopropoxy, or R ¹ together with the group R ^{2 represents} —OCH (CH ₃ ) CH ₂ — or —N (CH ₃ ) C (O) C (CH ₃ ) ₂ —, completing a 5-membered saturated ring, or _{-CH (OH) CH 2 OC (} CH 3) (CF 3) -, - CH 2 CH 2 C (O) N (CH 3) - or _{-CH (OH) CH 2 C (} O) N (CH 3) -Represents a 6-membered saturated ring. Most particularly, R ¹ is methoxy or cyclopropoxy.

Another preferred class of compounds of formula (I) is that wherein R ² is a hydrogen, fluorine or chlorine atom, in particular a hydrogen atom.

Another preferred class of compounds of the formula (I) is that R ³ is a hydrogen or halogen atom or a fluoro C _1-6 alkoxy group, in particular fluorine, trifluoromethoxy or 2,2,2-trifluoroethoxy, or It is a 5-membered aromatic heterocyclic group as defined. Most preferably R ³ is trifluoromethoxy or 5- (trifluoromethyl) tetrazol-1-yl, especially trifluoromethoxy.

Particularly preferred types of formula (I) are those in which R ¹ is bonded to the 2-position of the phenyl ring and R ³ is bonded to the 5-position of the phenyl ring.

Another preferred class of compounds of formula (I) is that wherein R ⁴ is a hydrogen atom or a fluorine atom.

Another preferred class of compounds of formula (I) is that wherein R ⁵ is a hydrogen atom.

Another preferred class of compounds of formula (I) is that wherein R ⁶ is a hydrogen atom or a C _1-6 alkyl group. Most particularly, R ⁶ is hydrogen or methyl.

Also, R ⁶ is a C _1-6 alkyl group substituted by a 5-membered heterocyclic ring containing 2 or 3 nitrogen atoms as defined above, particularly CH ₂ , CH (CH ₃ ) And CH ₂ CH ₂ , especially CH ₂ , are also preferred types of compounds of formula (I).

In particular, the 5-membered ring is 1,3-imidazol-4-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-4-yl, 2-oxo-1,3-imidazole A heterocycle selected from -4-yl and 3-oxo-1,2,4-triazol-5-yl, both of which are optionally substituted by the group -Y-NR < ⁷ > R < ⁸ >. It is a cyclic ring.

  Particularly preferred heterocyclic rings are

から選択される。

Selected from.

Other preferred types of compounds of formula (I) are those in which R ⁹ is hydrogen, hydroxy, oxo, C _1-6 alkoxy, C _1-6 alkoxy C _1-4 alkyl, hydroxy C _1-4 alkyl, cyano, NR ⁷ R ⁸ , CH ₂ NR ⁷ R ⁸ , SO ₂ R ^d , CH (OH) R ¹² , COR ¹² , CO ₂ R ¹² , CONR ⁷ R ⁸ , phenyl, heteroaryl, heteroaryl C _1-4 alkyl or CH ₂ OR ¹³ , wherein the phenyl is optionally substituted with one or two substituents selected from C _1-4 alkyl, C _1-4 alkoxy, halogen or trifluoromethyl. It represents.

Another preferred class of compounds of formula (I) is that R ⁹ is hydrogen, SO ₂ R ^d (especially R ^d is phenyl) or CONR ⁷ R ⁸ (especially R ⁷ is C _1-4 Is alkyl, or C _2-4 alkyl substituted by hydroxyl or a C _1-2 alkoxy group, R ⁸ is hydrogen, C _1-4 alkyl, C _1-4 alkoxy, or hydroxyl or C ₁ a C _2-4 alkyl substituted by _-2 alkoxy group, or R ⁷ and R ^8, together with the nitrogen atom to which they are attached, azetidinyl, pyrrolidinyl, piperidinyl, morpholino, thiomorpholino, piperazino or nitrogen Depending on the atom, C _1-4 alkyl, hydroxy C _1-2 alkyl, C _1-4 alkoxy C _1-2 alkyl, phenyl or benzyl group. To form a substituted piperazino group).

Another preferred class of compounds of formula (I), R ¹⁰ is represents hydrogen, fluorine or hydroxy, and in particular R ¹⁰ is hydrogen.

For certain particularly suitable compounds of the invention, R ³ is pyrrole, furan, thiene, pyridine, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, pyrazine, pyrimidine, pyridazine, triazole, oxadiazole, Included are groups selected from thiadiazole, triazine and tetrazole, wherein each heteroaryl group is optionally substituted as defined above.

Preferred compounds of the invention are those wherein R ³ is furan, pyridine, pyrazole, imidazole, oxazole, isoxazole, pyrazine, pyrimidine, thiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,4 A group selected from oxadiazole, 1,3,4-oxadiazole and tetrazole, wherein each heteroaryl group is optionally substituted as defined above.

Particularly preferred compounds of the invention are those wherein R ³ is a group selected from furan, pyridine, pyrimidine, 1,2,3-triazole, 1,2,4-triazole and tetrazole, each heteroaryl group being Optionally substituted as defined above.

A particularly preferred type of compound of formula (I) is that R ³ is a group

［式中、Ｒ^１５は、水素、ハロゲン、Ｃ_１−６アルキル、Ｃ_１−６アルコキシ、ＣＦ_３、ＯＣＦ_３、ＮＯ_２、ＣＮ、ＳＲ^ａ、ＳＯＲ^ａ、ＳＯ_２Ｒ^ａ、ＣＯＲ^ａ、ＣＯ_２Ｒ^ａ、（ＣＨ_２）_ｒＣＯＮＲ^ａＲ^ｂ、（ＣＨ_２）_ｒＮＲ^ａＲ^ｂ又は（ＣＨ_２）_ｒＮＲ^ａＣＯＲ^ｂ（式中、Ｒ^ａ及びＲ^ｂは、水素又はＣ_１−４アルキルであり、ｒはゼロ、１又は２である。）である。］
であるものである。

[Wherein R ¹⁵ represents hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, CF ₃ , OCF ₃ , NO ₂ , CN, SR ^a , SOR ^a , SO ₂ R ^a , COR ^a , CO ₂ R ^a , (CH ₂ ) _r CONR ^a R ^b , (CH ₂ ) _r NR ^a R ^b or (CH ₂ ) _r NR ^a COR ^b (wherein R ^a and R ^b are hydrogen or C _1-4 Alkyl and r is zero, 1 or 2.). ]
It is what is.

  An optionally substituted tetrazolyl group is particularly preferred.

R ¹⁵ is preferably hydrogen, C _1-4 alkyl, especially methyl, CF ₃ , (CH ₂ ) _r CONR ^a R ^b , SOR ^a or SO ₂ R ^{a where} R ^a , R ^b and r are , As defined above). Most preferably R ¹⁵ is CF ₃ .

  One preferred group of compounds of the invention are those of formula (Ia) and pharmaceutically acceptable salts thereof.

（式中、Ｒ^１、Ｒ^２、Ｒ^３及びＲ^４は、式（Ｉ）に関して定義された通りであり、Ｚは−ＣＲ^９Ｒ^１０ＣＨ_２−である。）。

(Wherein R ¹ , R ² , R ³ and R ⁴ are as defined for formula (I) and Z is —CR ⁹ R ¹⁰ CH ₂ —).

With respect to compounds of formula (I), Y (if present) may be a straight chain, branched chain or cyclic group. Preferably Y contains 1 to 4 carbon atoms, most preferably 1 or 2 carbon atoms. Particularly preferred group Y is CH _2.

For compounds of formula (I), R ⁷ may suitably be a C _1-4 alkyl group or a C _2-4 alkyl group substituted by a hydroxyl or C _1-2 alkoxy group, R ⁸ may suitably be hydrogen or a C _1-4 alkyl group, or may be a C _2-4 alkyl group substituted by a hydroxyl or C _1-2 alkoxy group, or R ⁷ and R ^8. Together with the nitrogen atom to which they are attached, on the azetidinyl, pyrrolidinyl, piperidyl, morpholino, thiomorpholino, piperazino or nitrogen atom, by a C _1-4 alkyl group or by a hydroxyl or C _1-2 alkoxy group Can be linked to form a piperazino group substituted by a C _2-4 alkyl group substituted by

When the group NR ⁷ R ⁸ represents a heteroaliphatic ring of 4 to 7 ring atoms and the ring contains a double bond, a particularly preferred group is 3-pyrroline.

Where the group NR ⁷ R ⁸ represents a non-aromatic azabicyclic ring system, such a system may contain 6 to 12, preferably 7 to 10 ring atoms. Suitable rings include 5-azabicyclo [2.1.1] hexyl, 5-azabicyclo [2.2.1] heptyl, 6-azabicyclo [3.2.1] octyl, 2-azabicyclo [2.2. 2] Octyl, 6-azabicyclo [3.2.2] nonyl, 6-azabicyclo [3.3.1] nonyl, 6-azabicyclo [3.2.2] decyl, 7-azabicyclo [4.3.1] Decyl, 7-azabicyclo [4.4.1] undecyl and 8-azabicyclo [5.4.1] dodecyl, especially 5-azabicyclo [2.2.1] heptyl and 6-azabicyclo [3.2.1] Octyl is included.

R ⁸ represents C _2-4 alkyl substituted by 1 or 2 4 membered, 5 membered or 6 membered heteroaliphatic ring containing a heteroatom selected from N, O and S Suitable rings include azetidinyl, pyrrolidino, piperidino, piperazino, morpholino or thiomorpholino. Nitrogen-containing heteroaliphatic rings, particularly pyrrolidino and morpholino rings, are particularly preferred.

Particularly suitable units —Y—NR ⁷ R ⁸ include those where Y is CH ₂ or CH ₂ CH ₂ and NR ⁷ R ⁸ is amino, methylamino, dimethylamino, diethylamino, azetidinyl, pyrrolidino and morpholino. included.

In particular, Y is preferably CH ₂ and NR ⁷ R ⁸ is preferably dimethylamino, azetidinyl or pyrrolidino, especially dimethylamino.

  When every change occurs more than once in formula (I) or in every substituent, its definition at each occurrence is independent of its definition at every other occurrence.

When R ⁹ represents an oxo (═O) group, it is recognized that R ¹⁰ is absent and the group Z actually represents —C (O) CH ₂ — or —CH ₂ C (O) —. .

  As used herein, the term “alkyl” or “alkoxy” as a group or part of a group means that the group is straight or branched. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.

As used herein, the terms “fluoroC _1-6 alkyl” and “fluoroC _1-6 alkoxy” mean that one or more (especially 1 to 3) hydrogen atoms are fluorine atoms. Means a C _1-6 alkyl or C _1-6 alkoxy group substituted by Similarly, the term “fluoroC _1-4 alkyl” means a C _1-4 alkyl group in which one or more (especially 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Fluoro _{C 1-3} alkyl and fluoro _{C 1-3} alkoxy group, for _{example, CF 3, CH 2 CH 2} F, CH 2 CHF 2, CH 2 CF 3, OCF 3, OCH 2 CH 2 F, OCH 2 CHF 2 or OCH ₂ CF ₃ is particularly preferred, CF ₃ , OCF ₃ and OCH ₂ CF ₃ are most particularly preferred.

As used herein, the term "hydroxy C _1-6 alkyl", one or more (in particular, one to three) hydrogen atom, C _1-6 alkyl substituted by hydroxy group Means group. Preferred are hydroxy C _1-3 alkyl groups, especially those in which one hydrogen atom is replaced by a hydroxy group, for example, CH ₂ OH, CH ₂ CH ₂ OH and C (CH ₃ ) ₂ OH.

  A cycloalkyl group cited herein can represent, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. A suitable cycloalkylalkyl group may be, for example, cyclopropylmethyl.

  Similarly, a cycloalkoxy group cited herein may represent, for example, cyclopropoxy or cyclobutoxy.

  As used herein, the terms “alkenyl” and “alkynyl” as a group or part of a group means that the group is straight or branched. Examples of suitable alkenyl groups include vinyl and allyl. A suitable alkynyl group is propargyl.

As used herein, the term “aryl” as a group or part of a group refers to a monocyclic, fused bicyclic or linear bicyclic ring containing 6, 10 or 12 carbon atoms. Means an aromatic ring of formula, any of these rings being substituted by one, two or three substituents selected from halogen, C _1-6 alkyl, C _1-6 alkoxy or trifluoromethyl Has been replaced by Particular examples of such groups include phenyl, naphthyl and biphenyl. Phenyl is particularly preferred.

As used herein, the term “heteroaryl” as a group or part of a group refers to 5 to 10 ring members, one to four of which are selected from N, O and S Monocyclic or fused bicyclic heteroaromatic rings containing any of these rings, one or two, halogen, C _1-6 alkyl, C ₁ Optionally substituted by a substituent selected from _-6 alkoxy, trifluoromethyl or phenyl. Specific examples of such groups include pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl, tetrazolyl, indole, benzofuran , Benzthiophene, benzimidazole, benzoxazole and benzthiazole. Furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl and pyridyl are particularly preferred. When the ring is substituted, preferred substituents include methyl and phenyl groups.

  As used herein, the term “halogen” means fluorine, chlorine, bromine and iodine. The most suitable halogens are fluorine and chlorine, with fluorine being preferred unless otherwise stated.

  Specific compounds within the scope of the present invention include:

(1R ^* , 2R ^* , 4 ′S ^* , 5S ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan];
(1R ^* , 2R ^* , 4 ′S ^* , 5S ^* , 6R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -1 -Phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan];
(1R ^* , 2R ^* , 4 ′S ^* , 5S ^* )-4 ′-(2-cyclopropyloxy-5-trifluoromethoxyphenyl) -2 ′, 3 ′, 4 ′, 5′-tetrahydro-1- Phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan];
(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-isopropoxy-5-trifluoromethoxyphenyl) -1-phenyl Spiro [8-azabicyclo [3.2.1] octane-2,2'-furan];
(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2- (2 ′, 2′-difluoro) ethoxy-5-tri Fluoromethoxyphenyl) -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan];
(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-1-phenyl-4 ′-[2- (2,2,2-trifluoroethoxy ) -5-trifluoromethoxyphenyl) spiro [8-azabicyclo [3.2.1] octane-2,2'-furan];
(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-4 ′-[2- (2-fluoroethoxy) -5-trifluoromethoxyphenyl] -2 ′, 3 ′, 4 ′, 5′-tetrahydro -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan];
(1R ^* , 2R ^* , 4 ′S ^* , 5S ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-[(2RS) -2,3-dihydro-2-methoxy-5- Trifluoromethoxybenzofuran-7-yl] -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan];
(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -6- (morpholine -1-ylcarbonyl) -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan];
(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -6- (3 -Methoxypropylaminocarbonyl) -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan];
(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -6- (3 -Methoxypropylaminocarbonyl) -8-methyl-1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan];
And pharmaceutically acceptable salts thereof.

  In another aspect of the invention, the compounds of formula (I) can be prepared in the form of pharmaceutically acceptable salts, particularly acid addition salts.

  For use in medicine, the salts of the compounds of formula (I) are non-toxic pharmaceutically acceptable salts. However, other salts are useful in the preparation of compounds according to the present invention or non-toxic pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of the compounds according to the invention include, for example, solutions of the compounds according to the invention with hydrochloric acid, fumaric acid, p-toluenesulfonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid. Acid addition salts that can be formed by mixing with a solution of a pharmaceutically acceptable acid such as carbonic acid, phosphoric acid or sulfuric acid are included. Also, the amine group salts may include quaternary ammonium salts in which the amino nitrogen atom has a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl unit. In addition, when the compound of the present invention has acidic units, suitable pharmaceutically acceptable salts thereof include alkali metal salts such as sodium or potassium salts and alkaline earth metal salts such as metal salts such as calcium or magnesium salts. May be included.

  These salts form the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble or in a solvent such as water that is removed in vacuo or by lyophilization. It can be formed by conventional methods such as by reacting or by exchanging the anion of the salt present for other anions on a suitable ion exchange resin.

  The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs are functional derivatives of the compounds of formula (I) that can be readily converted in vivo to the required compounds of formula (I). General methods for the selection and preparation of suitable prodrug derivatives are described, for example, in H.C. Edited by Bundgaard, Elsevier, 1985, “Design of Prodrugs”.

  Prodrugs are biologically active substances (“parent drug” or “parent molecule”) that require transformation within the body to release the active drug and have improved conferring properties over the parent drug molecule. It may be a pharmacologically inactive derivative of In vivo conversion may be the result of several metabolic steps such as, for example, chemical or enzymatic hydrolysis of carboxylic esters, phosphate esters or sulfate esters or reduction or oxidation of sensitive functional groups.

  The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof such as hydrates.

  The compounds according to the invention have at least three asymmetric centers and therefore exist as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

  Preferred compounds of formula (I) and (Ia) are, for example, as possessed by the compound of example 11, ie the compound of formula (Ib)

に示されるように、１位、２位、４’位及び５位の立体化学を有する。

As shown in the figure, it has stereochemistry at the 1-position, 2-position, 4′-position and 5-position.

  Preferred definitions of the various substituents listed herein, alone or in combination, are represented by the general formulas and formulas (Ia) and (Ib) for the compounds of the invention, unless otherwise stated. It will be appreciated that this can be applied to a preferred class of compounds.

  The present invention further provides a pharmaceutical composition comprising one or more compounds of formula (I) together with a pharmaceutically acceptable carrier or excipient.

  Preferably, the composition according to the invention is for tablets, pills, capsules, powders, granules, solutions or suspensions for oral, parenteral or rectal administration or for administration by inhalation or insufflation. The unit dosage form is a suppository. Oral compositions such as tablets, pills, capsules or wafers are particularly preferred.

  A more detailed description of pharmaceutical compositions suitable for formulation of the compounds of the present invention is disclosed in US Pat. No. 6,071,927, the contents of which are hereby incorporated by reference. (See in particular, column 8, lines 50 to 10, column 4.)

  The present invention further provides a process for the manufacture of a pharmaceutical composition comprising a compound of formula (I), comprising combining a compound of formula (I) with a pharmaceutically acceptable carrier or excipient. To do.

  The compounds of formula (I) are valuable in the treatment of a wide variety of clinical conditions characterized by the presence of excess tachykinins, especially substance P activity. A comprehensive list of clinical conditions, uses and treatment methods in which the compounds of the present invention are useful is disclosed in US Pat. No. 6,071,927, the contents of which are hereby incorporated by reference. (See, in particular, column 10, lines 14 to 22, and line 18.)

  In particular, the compounds of the present invention are useful in the treatment of various central nervous system disorders. Such disorders include depression or more particularly depressive abnormalities such as single episode or recurrent major depressive disorder and dysthymic or bipolar abnormalities such as bipolar I abnormalities, Emotional abnormalities such as bipolar II abnormalities and circulatory temperament abnormalities; panic abnormalities with or without agoraphobia, agoraphobia with no history of panic abnormalities, specific phobias, eg, specific animals Anxiety such as phobia, social phobia, obsessive compulsive disorder, posttraumatic stress anomalies and acute stress anomalies and generalized anxiety are included.

  The compounds of the present invention are also particularly useful in the treatment of pain and pain. Diseases and conditions dominated by pain include acute trauma, osteoarthritis, rheumatoid arthritis, especially post-traumatic musculoskeletal pain, spinal pain, fascial pain syndrome, headache, migraine, perineostomy pain and burns Soft tissue and peripheral injuries such as

  The compounds of the invention are also associated with excessive mucus secretion such as respiratory diseases, in particular chronic obstructive airway disease, bronchial pneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome and bronchospasm In the treatment of inflammatory bowel diseases, psoriasis, connective tissue inflammation, osteoarthritis, rheumatoid arthritis, pruritus and sunburn, and allergic properties such as eczema and rhinitis Particularly useful in the treatment of abnormalities.

  The compounds of the present invention are also particularly useful in the treatment of gastrointestinal (GI) abnormalities, including GI inflammatory abnormalities and diseases such as ulcerative colitis, Crohn's disease and irritable bowel syndrome. .

  The compounds of the present invention may also be used for acute, delayed or provoking vomiting, such as chemotherapy, radiation, toxins, pregnancy, vestibular disorders, exercise, surgery, migraine and vomiting induced by fluctuations in intracranial pressure. It is particularly useful in the treatment of vomiting including. Most particularly, the compounds of formula (I) are induced by radiation, including radiation therapy as in cancer treatment, by anti-tumor (cytotoxic) drugs, including those routinely used in cancer chemotherapy. In the treatment of vomiting, it is used in the treatment of postoperative nausea and vomiting.

  The excellent pharmacological profile of the compounds of the present invention provides the opportunity to use them at low doses in therapy, thereby minimizing the risk of undesirable side effects.

  In the treatment of conditions associated with excess tachykinin, suitable dosage levels are about 0.001 to 50 mg / kg / day, particularly about 0.01 to about 25 mg / kg / day, such as about 0.05. To about 10 mg / kg / day.

  For example, in the treatment of conditions involving pain sensation neurotransmission, suitable dosage levels are about 0.001 to 25 mg / kg / day, preferably about 0.005 to 10 mg / kg / day, especially about 0. 005 to 5 mg / kg / day. The compound may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

  In the treatment of vomiting, a suitable dose level is about 0.001 to 10 mg / kg / day, preferably about 0.005 to 5 mg / kg / day, especially 0.01 to 3 mg / kg / day. The compound may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

  In the treatment of psychiatric disorders, suitable dosage levels are about 0.001 to 10 mg / kg / day, preferably about 0.005 to 5 mg / kg / day, especially 0.01 to 3 mg / kg / day. It is. The compound may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

  The amount of compound of formula (I) required for use in all treatments will vary depending on the particular compound or composition selected, as well as the route of administration, the nature of the condition being treated and the age and condition of the patient. And that it will ultimately be at the discretion of the attending physician.

  As used herein, the term “treatment” includes prophylactic use to prevent the occurrence or recurrence of any of the above conditions.

  According to general method (A), the compound of formula (I) is of formula (II)

の化合物と、式（ＩＩＩ）

A compound of formula (III)

（式中、Ｈａｌは、塩素、臭素又は好ましくはヨウ素である。）
の化合物との、例えば、トリ−ｏ−トリルホスフィン、ジメチルホルムアミド及びトリブチルアミン又はテトラブチルアンモニウムクロリド及びジメチルホルムアミド並びに還元剤、好ましくはギ酸又はギ酸カリウムのようなその塩と共に、酢酸パラジウムのようなパラジウム触媒を使用する還元的ヘック（Ｈｅｃｋ）反応による反応によって製造することができる。

(In the formula, Hal is chlorine, bromine or preferably iodine.)
Palladium such as palladium acetate with, for example, tri-o-tolylphosphine, dimethylformamide and tributylamine or tetrabutylammonium chloride and dimethylformamide and reducing agents, preferably formic acid or salts thereof such as potassium formate. It can be produced by a reaction by a reductive Heck reaction using a catalyst.

  According to another general method (B), the compound of formula (I) is of formula (IV)

（式中、それぞれのＲ^４５は、Ｃ_１−４アルキル基、好ましくはメチル又はｎ−ブチル基である。）
の化合物と、式（Ｖ）

(Wherein each R ⁴⁵ is a C _1-4 alkyl group, preferably a methyl or n-butyl group.)
And a compound of formula (V)

（式中、Ｒ^５０は、トリフラート（−ＯＳＯ_２ＣＦ_３）又はハロゲン原子、例えば、塩素、臭素若しくはヨウ素のような離脱基、特にトリフラート、臭素又はヨウ素である。）
の化合物との反応によって製造することができる。

(Wherein R ⁵⁰ is a triflate (—OSO ₂ CF ₃ ) or a leaving group such as a halogen atom, for example chlorine, bromine or iodine, in particular triflate, bromine or iodine.)
It can manufacture by reaction with the compound of this.

  This reaction is conveniently carried out in the presence of lithium chloride and a transition metal catalyst such as triphenylphosphine palladium (0). Suitable solvents for this reaction include aromatic hydrocarbons such as toluene, polar aprotic solvents such as dimethylformamide or ethers such as dioxane, and the reaction can be carried out from 80 ° C. to the reflux temperature of the solvent. Performed at temperature. The subsequent reduction of the double bond is carried out using the conditions of the following general method (G).

  In accordance with other general methods (C), the compound of formula (I) can be obtained by, for example A hydride such as formula (VI)

の化合物の還元によって製造することができる。

Can be prepared by reduction of the compound.

In accordance with other general methods (D), R ¹ is C _1-6 alkoxy, fluoro C _1-6 alkoxy, C _2-6 alkenoxy, C _3-7 cycloalkoxy, C _3-7 cycloalkyl C _1-4 Compounds of formula (I) which are alkoxy or benzyloxy are prepared in the presence of a base with a suitable alkyl-, fluoroalkyl-, alkenyl-, cycloalkyl-, cycloalkylalkyl- or aralkyl-halide, in particular iodide. Wherein R ¹ is hydroxy (hereinafter referred to as formula (VII))

として参照する。）の化合物の相互転換（ｉｎｔｅｒｃｏｎｖｅｒｓｉｏｎ）によって製造することができる。

Refer to as ) By the interconversion of compounds.

  Suitable bases include alkali metal hydrides such as sodium hydride in a suitable solvent such as dimethylformamide. This reaction is conveniently performed at about room temperature.

According to another general method (E), a compound of formula (I) is of formula (IX)
LG-R ^6a (IX)
[Wherein R ^6a is a group of formula R ⁶ or a precursor therefor as defined for formula (I) (other than H) and LG is an alkyl- or arylsulfonyloxy group (eg, mesylate Or a tosylate) or a leaving group such as a halogen atom (eg bromine, chlorine or iodine). ]
If R ^6a is a precursor group, by reaction with a compound of the above, it is converted to the group R ⁶ (in this method all reactive groups are protected and then optionally deprotected). Wherein R ⁶ is H (hereinafter referred to as formula (VIII)).

として参照する。）の対応する化合物の相互転換によって製造することができる。

Refer to as ) Of the corresponding compounds.

  This reaction can be carried out in a conventional manner, for example, in an organic solvent such as dimethylformamide, in the presence of an acid acceptor such as potassium carbonate.

A suitable alternative method for introducing the group R ⁶ is described, for example, in WO 95/18124.

  According to another general method (F), a compound of formula (I) is represented by formula (X)

の化合物から
（ａ）テトラヒドロフラン中でリチウムナフタレニドとの反応、この反応は、低温度、例えば約−７８℃の温度で実施される、又は
（ｂ）第一工程に於いて、酸化アルミニウムの存在下で、例えば、オキソンを使用するフェニルチオ単位の酸化、この反応は、ハロゲン化炭化水素、例えば、クロロホルムのような適切な溶媒中で、便利に室温で実施される、並びに第二工程に於いて、オルトリン酸水素二ナトリウムの存在下で、例えば、ナトリウムアマルガムを使用する、フェニルスルホニル単位の除去、この反応はアルコール、例えばメタノールのような適切な溶媒中で、低温度、例えば０℃から１０℃で実施される、
により製造することができる。

(A) reaction with lithium naphthalenide in tetrahydrofuran, this reaction being carried out at a low temperature, for example at a temperature of about -78 ° C, or (b) in the first step, In the presence, for example, oxidation of phenylthio units using oxone, the reaction is conveniently carried out in a suitable solvent such as a halogenated hydrocarbon, for example chloroform, at room temperature, as well as in the second step. Removing phenylsulfonyl units in the presence of disodium hydrogen orthophosphate, for example using sodium amalgam, the reaction in a suitable solvent such as an alcohol, for example methanol, at a low temperature, for example from 0 ° C. to 10 ° C. Carried out at ℃,
Can be manufactured.

  According to another general method (G), a compound of formula (I) is of formula (XI)

（式中、点線は、結合（ａ）又は結合（ｂ）での二重結合を表す。）
の化合物の還元によって製造することができる。

(In the formula, a dotted line represents a double bond at the bond (a) or the bond (b)).
Can be prepared by reduction of the compound.

  Suitable reducing conditions preferably include palladium or platinum or their hydroxides or in an appropriate solvent such as an alcohol such as methanol or ethanol or an ester such as ethyl acetate or an organic acid such as acetic acid or mixtures thereof. Catalytic hydrogenation using a metal catalyst such as an oxide or reduction using trifluoroacetic acid and triethylsilane.

  Further details of suitable procedures are described in the accompanying examples.

  The compound of formula (II) can be converted to the corresponding iodide by, for example, treating the stannane of formula (IV) with iodine in a suitable solvent such as dichloromethane at a low temperature, for example about −78 ° C. It can be produced by conversion. The iodine is then displaced by treatment with a suitable solvent, such as toluene, at an elevated temperature, such as about 100 ° C., for example with α, α′-azoisobutyronitrile and tributyltin hydride, to give the formula ( The compound of II) can be obtained.

  Also, the compound of formula (II) is a compound of formula (XII) using triphenylphosphine and diethyl azodicarboxylate in a suitable solvent such as tetrahydrofuran.

の化合物の環化によって製造することができる。

Can be prepared by cyclization of the compound

  The compound of formula (XII) is of formula (XIII)

のアセチレン化合物の部分還元によって製造することができる。

Can be produced by partial reduction of the acetylene compound.

  This reaction is conveniently carried out by catalytic hydrogenation using a metal catalyst such as palladium on calcium carbonate (Lindler catalyst) in the presence of lead poison. Other suitable methods will be readily apparent to those skilled in the art.

  The compound of formula (XIII) is of formula (XIV)

の化合物から、及び例えば、一般的な方法論を使用してＯ−トリメチルシリルプロパルギルアルコールから製造したグリニャール試薬から、引き続いてヒドロキシ保護基を除去することによって製造することができる。

And from, for example, Grignard reagents prepared from O-trimethylsilylpropargyl alcohol using general methodology, followed by removal of the hydroxy protecting group.

The compound of formula (IV) is obtained from the compound of formula (XIII) in the presence of a transition metal catalyst such as tetrakis (triphenylphosphine) palladium (0) in a suitable solvent such as ether, for example tetrahydrofuran. Reaction with a compound of formula (R ⁴⁵ ) ₃ SnH, for example tri (n-butyl) stannane, followed by use of, for example, triphenylphosphine and diethyl azodicarboxylate in a suitable solvent such as ether, for example tetrahydrofuran. It can be manufactured by a dehydration process.

  In addition, the compound of the formula (IV) has the formula (XV)

（式中、Ｒ^５０は、前記定義された通りである（好ましくはトリフラート基又は臭素若しくはヨウ素原子である。）。）
の化合物から、式（Ｒ^４５）_３Ｓｎ−Ｓｎ（Ｒ^４５）_３の化合物、例えばヘキサメチルジスタンナンとの反応によって製造することができる。この反応は、塩基、例えば炭酸リチウムと、トリフェニルホスフィンパラジウム（０）のような触媒との存在下で便利に実施される。この反応のための適切な溶媒には、テトラヒドロフランのようなエーテルが含まれ、反応は、室温と１００℃との間の温度、例えば約６０℃で実施される。

(Wherein R ⁵⁰ is as defined above (preferably a triflate group or a bromine or iodine atom).)
From the compound of formula (R ⁴⁵ ) ₃ Sn—Sn (R ⁴⁵ ) ₃ , for example, by reaction with hexamethyldistannan. This reaction is conveniently carried out in the presence of a base such as lithium carbonate and a catalyst such as triphenylphosphine palladium (0). Suitable solvents for this reaction include ethers such as tetrahydrofuran, and the reaction is carried out at a temperature between room temperature and 100 ° C., for example about 60 ° C.

A compound of formula (XV) can be introduced from a compound of formula (XX) in the presence of a base, for example sodium hexamethyldisilazide, followed by an enolization of a ketone followed by a suitable leaving group (for example When R ⁵⁰ is —OSO ₂ CF ₃ , use 2- [N, N-bis (trifluoromethylsulfonyl) amino] -5-chloropyridine or triflic anhydride. It can manufacture by reaction of these. This reaction is conveniently carried out at a low temperature, for example -80 ° C, in a suitable solvent such as an ether, for example tetrahydrofuran.

  The compound of formula (VI) is represented by formula (XVI)

の化合物の還元によって製造することができる。

Can be prepared by reduction of the compound.

  Suitable reducing conditions preferably include palladium or platinum or their hydroxides or in an appropriate solvent such as an alcohol such as methanol or ethanol or an ester such as ethyl acetate or an organic acid such as acetic acid or mixtures thereof. Catalytic hydrogenation using a metal catalyst such as an oxide or reduction using trifluoroacetic acid and triethylsilane.

  The compound of formula (XVI) is of formula (XVII)

の化合物から、３工程プロセスによって製造することができる。最初に、式（ＸＶＩＩ）の化合物を、芳香族炭化水素、例えばトルエン又はエーテル、例えばジエチルエーテル又はこれらの混合物のような適切な非プロトン性溶媒中で、例えば、レッド−Ａｌ（Ｒｅｄ−Ａｌ）（登録商標）を使用して還元する。次いで、得られた化合物を、ヨウ素を使用してヨウ素化する。最後に、トリス（ジベンジリジンアセトン）パラジウム（０）及び１，４−ビス（ジフェニルホスフィノ）ブタンのような遷移金属触媒並びにトリアルキルアミン、例えばイソプロピルジエチルアミンのような有機塩基の存在下で、一酸化炭素との反応により環化を起こさせる。この環化は、エーテル、例えばテトラヒドロフランのような非プロトン性溶媒中で便利に実施される。

Can be produced by a three-step process. First, the compound of formula (XVII) is converted into a suitable aprotic solvent such as an aromatic hydrocarbon such as toluene or ether such as diethyl ether or mixtures thereof, for example Red-Al (Red-Al). Reduce using (registered trademark). The resulting compound is then iodinated using iodine. Finally, in the presence of a transition metal catalyst such as tris (dibenzylidineacetone) palladium (0) and 1,4-bis (diphenylphosphino) butane and an organic base such as a trialkylamine, for example isopropyldiethylamine. Cyclization occurs by reaction with carbon monoxide. This cyclization is conveniently carried out in an aprotic solvent such as an ether, for example tetrahydrofuran.

  The compound of formula (XVII) is a compound of formula (XIV) and formula (XVIII)

の化合物との反応によって製造することができる。

It can manufacture by reaction with the compound of this.

  This reaction is conveniently carried out in the presence of ethylmagnesium bromide in a suitable aprotic solvent such as ether, for example tetrahydrofuran.

  Compounds of formula (X) can be prepared from compounds of formula (VII) by reaction with (1-iodo-cycloprop-1-yl) phenyl sulfide.

  A compound of formula (XI) uses an acid such as trifluoroacetic acid, formula (XIX)

の化合物の脱水によって製造することができる。この反応は、０℃と室温との間の温度で、ハロゲン化炭化水素、例えばジクロロメタンのような適切な有機溶媒を使用して、便利に実施される。

Can be produced by dehydration of the compound. This reaction is conveniently carried out using a suitable organic solvent such as a halogenated hydrocarbon, for example dichloromethane, at a temperature between 0 ° C. and room temperature.

  The compound of formula (XIX) has the formula (XX)

の化合物と、好ましくはマグネシウムと式（ＩＩＩ）の臭化物とを使用して、式（ＩＩＩ）の化合物から製造したグリニャール試薬との反応によって製造することができる。このカップリング反応は、低い温度、例えば約０℃で、エーテル、例えばジエチルエーテルのような適切な溶媒を使用して、便利に実施される。

And preferably using magnesium and a bromide of formula (III) by reaction with a Grignard reagent prepared from a compound of formula (III). This coupling reaction is conveniently carried out at a low temperature, eg about 0 ° C., using a suitable solvent such as an ether, eg diethyl ether.

  Compounds of formula (XX) can be prepared from compounds of formula (XIV) by various processes, for example by the following reaction sequence (Reaction Scheme A) or by analogous methods.

  The compound of formula (XIV) is of formula (XXI)

の化合物から、好ましくはアルコール、例えばメタノール若しくはエタノール又はエステル、例えば酢酸エチル又は有機酸、例えば酢酸又はこれらの混合物のような適切な溶媒中で、パラジウム若しくは白金又はこれらの水酸化物若しくは酸化物のような金属触媒を使用する接触水素化によって製造することができる。

Of palladium or platinum or a hydroxide or oxide thereof, preferably in a suitable solvent such as an alcohol, for example methanol or ethanol or an ester, for example ethyl acetate or an organic acid, for example acetic acid or mixtures thereof. It can be produced by catalytic hydrogenation using such a metal catalyst.

The compound of formula (XXI) (wherein R ⁶ is benzyl or allyl) has the formula (XXII)

の化合物（又は、式中、Ｏ⁻がＯＨである対応する化合物、この化合物は、臭化物又は塩化物イオンのような対イオンを伴う。）から、トリアルキルアミン、例えばトリエチルアミンのような有機塩基の存在下で、式Ｒ^９ＣＨ＝ＣＨ_２（特に、Ｒ^９がシアノである場合）、ＳＯ_２Ｒ^１３（特に、Ｒ^１３がフェニルである場合）又はＣＯ_２Ｒ^１３（特に、Ｒ^１３がｔｅｒｔ−ブチルである場合）のビニル化合物との反応によって製造することができる。この反応は、芳香族炭化水素、例えばトルエンのような非プロトン性溶媒中で便利に実施される。

Compound (or, wherein, O ^-. The corresponding compound is OH, the compound, with counter ions such as bromide or chloride ions) from a trialkylamine, for example, an organic base such as triethylamine In the presence, the formula R ⁹ CH═CH ₂ (especially when R ⁹ is cyano), SO ₂ R ¹³ (especially when R ¹³ is phenyl) or CO ₂ R ¹³ (especially R ¹³ is tert). In the case of -butyl) by reaction with a vinyl compound. This reaction is conveniently carried out in an aprotic solvent such as an aromatic hydrocarbon, for example toluene.

The reaction of formula (XXII) with acrylonitrile is particularly suitable for preparing compounds in which the R ⁹ substituent is located on any of the carbon atoms of the two-carbon bridge.

  The intermediates of the above formulas (II), (IV) and (XVIII) will be readily apparent to those skilled in the art, for example using the procedures described in the accompanying examples, if they are not commercially available By alternative procedures, for example, it can be prepared from the corresponding phenol derivative.

In a preferred embodiment of the above process, R ⁶ is a benzyl group. The various reduction reactions described above can conveniently replace the benzyl group with a hydrogen atom. It will be appreciated from the foregoing that compounds of formula (I) in which R ⁶ is a hydrogen atom are particularly preferred precursors to other compounds of formula (I).

  Compounds of formula (IX) and (XXII) are known compounds and can be prepared by methods similar to those described herein.

  It will be appreciated that the general methodology described above can be adapted to produce other compounds of the present invention using methods that will be readily apparent to those skilled in the art.

  During all of the above synthetic sequences it is necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is described in "Protective Groups in Organic Chemistry (Organic Chemistry)", J. Org. F. W. Edited by McOmie, Plenum Press, 1973, and T.W. W. Greene and P.M. G. M.M. Commonly described by Wuts, “Protective Groups in Organic Synthesis”, John Wiley & Sons, 1991 publication. This can be achieved by means of protecting groups. This protecting group can be removed at a convenient later stage using methods known in the art.

Exemplified compounds of the present invention were tested by the method described on pages 36 to 39 of WO 93/01165. This compound was found to be active in the test method with an IC ₅₀ at the human NK ₁ receptor of less than 100 nM.

  The following non-limiting examples serve to illustrate the preparation of the compounds of the present invention.

Explanation 1
O-vinyloxy-4-trifluoromethoxybenzene diethyl azodicarboxylate (19 mL, 121 mmol), 4-trifluoromethoxyphenol (20.5 g, 115 mmol), triphenylphosphine (31.5 g, 120 mmol) and 2 -To a stirred solution of bromoethanol (10 mL, 141 mmol) was added dropwise at + 5 ° C. The cold bath was removed and the reaction mixture was stirred at ambient temperature for 20 hours and concentrated in vacuo. The residue was treated with diethyl ether (50 mL) followed by hexane (200 mL). The solid was filtered off and the filtrate was concentrated. The residue was treated with dichloromethane (150 mL) followed by 50% aqueous NaOH (150 mL) and tetra-n-butylammonium hydrogen sulfate (40 g, 118 mmol). The mixture was stirred at room temperature for 3 hours, diluted with water (200 mL) and the layers were separated. The aqueous phase was extracted into diethyl ether. The combined organic extracts were washed with water, dried (Na ₂ SO ₄ ) and concentrated under atmospheric pressure using a Vigreux column (300 mm). The residue was distilled under reduced pressure to give the title compound (9.64 g, 41%, boiling point 64 ° C./20 mmHg) as a colorless liquid.

Explanation 2
O-cyclopropyloxy-4-trifluoromethoxybenzene Diethyl zinc (24 mL, raw, 235 mmol) was added to O-vinyloxy-4-trifluoromethoxybenzene (Description 1; 9.6 g) in dimethoxyethane (200 mL). 47 mmol), diiodomethane (37.7 mL, 470 mmol) was added dropwise over 30 minutes. The reaction mixture was heated under reflux for 13 hours, cooled to room temperature and quenched with saturated aqueous ammonium chloride. The layers were separated and the upper aqueous phase was extracted into hexane (2 × 50 mL). The combined organic extracts were washed with water and brine, dried (Na ₂ SO ₄ ), and concentrated under atmospheric pressure using a Bigelow column (300 mm). The residue was distilled under reduced pressure to give the title compound (6.7 g, 65%) as a colorless liquid.

Explanation 3
2-Cyclopropyloxy-5-trifluoromethoxybenzaldehyde A solution of tert-butyllithium in pentane (1.7 M, 30 mL, 51 mmol) was added to O-cyclopropyloxy-4-trifluoromethoxy in tetrahydrofuran (50 mL). To a stirred solution of benzene (Description 2; 5.2 g, 23.7 mmol) was added dropwise at −78 ° C. over 10 minutes. The mixture was stirred at −78 ° C. for 30 minutes and DMF (8 mL) was added dropwise. The reaction mixture was warmed to 0 ° C. over 90 minutes, quenched with saturated aqueous ammonium chloride and extracted into hexane (3 × 30 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by chromatography on silica gel (isohexane: diethyl ether 0-10%) to give the title compound (4.59 g, 84%) as a solid.

Explanation 4
2-Cyclopropyloxy-5-trifluoromethoxyphenylethyne Potassium carbonate (6.15 g, 44 mmol) was added to 2-cyclopropyloxy-5-trifluoromethoxybenzaldehyde (Description 3; 4) in dry methanol (50 mL). To a stirred solution of acetyldiazomethylphosphonate (6.15 g, 32 mmol) at + 5 ° C. The reaction mixture was stirred at + 5 ° C. for 30 minutes and at room temperature for 3.5 hours. The mixture was quenched with saturated aqueous ammonium chloride and extracted into hexane (3 × 30 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by chromatography on silica gel (isohexane: diethyl ether 0-45%) to give the title compound (4.2 g, 94%).

Explanation 5
N-benzyl-3-hydroxy-2-phenylpyridinium bromide A suspension of 3-hydroxy-2-phenylpyridine (20 g, 116 mmol) in toluene (250 mL) was heated at reflux for 30 minutes. Benzyl bromide (20 mL) was added and the reaction mixture was heated at reflux for 6 hours and then cooled using an ice bath. The solid residue was collected by filtration and washed twice with ether to give crude N-benzyl-3-hydroxy-2-phenylpyridinium bromide (36.5 g, 91%), which was used in the next step without further purification. Used in.

Explanation 6
(1R ^* , 5S ^* , 6R ^* )-8-benzyl-1-phenyl-6-phenylsulfonyl-8-azabicyclo [3.2.1] oct-3-en-2-one N-benzyl-3-hydroxy 2-Phenylpyridinium bromide (Description 5; 4.91 g, 14.3 mmol), phenyl vinyl sulfone (4.2 g, 25 mmol), triethylamine (2.8 mL, 20 mmol) and 1,4-dioxane (50 mL) The mixture was heated at reflux overnight. After cooling to room temperature, the reaction mixture was poured onto saturated aqueous NaHCO ₃ and extracted with ethyl acetate (3 × 100 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by chromatography on silica gel (isohexane: diethyl ether 10-70%) to give the title compound (4.84 g, 78%) as a yellow-orange foam. Crystallization from isohexane: diethyl ether gave the product as yellow orthorhombic crystals.

Explanation 7
(1R ^* , 5S ^* , 6R ^* )-8-Benzyl-1-phenyl-6-phenylsulfonyl-8-azabicyclo [3.2.1] octan-2-one 10% palladium on carbon (1 g) (1R ^* , 5S ^* , 6R ^* )-8-benzyl-1-phenyl-6-phenylsulfonyl-8-azabicyclo [3. as a slurry in (2 mL) in methanol (50 mL) and ethyl acetate (50 mL). 2.1] was added to a solution of octo-3-en-2-one (Description 6; 11 g, 25.6 mmol). The mixture was hydrogenated at 30 psi for 1 hour. The reaction mixture was filtered through a pad of Celite ™. The filter cake was washed with dichloromethane (1 L) and the combined filtrates were concentrated in vacuo to give the title compound (10.8 g, 98%).

Explanation 8
(1R ^* , 2S ^* , 5S ^* , 6R ^* )-8-benzyl-2- (2-cyclopropyloxy-5-trifluoromethoxyphenyl) ethynyl-1-phenyl-6-phenylsulfonyl-8-azabicyclo [3 2.1] Octan-2-ol A solution of n-butyllithium in hexane (1.6 M, 5 mL, 8 mmol) was added to 2-cyclopropyloxy-5-trifluoromethoxyphenylethyne in tetrahydrofuran (30 mL). (Description 4; 2.0 g, 8.2 mmol) was added dropwise at −78 ° C. to a stirred solution to form an orange solution that turned violet at the end of the addition. The mixture was stirred for 10 minutes and solid anhydrous cerium (III) chloride (2 g, 8.1 mmol) was added. The mixture was stirred at −78 ° C. for 30 minutes and (1R ^* , 5S ^* , 6R ^* )-8-benzyl-1-phenyl-6-phenylsulfonyl-8-azabicyclo [3.2. 1] A solution of octan-2-one (Description 7; 2.9 g, 6.7 mmol) was added dropwise. The reaction mixture was warmed to 0 ° C. over 30 minutes, stirred at 0 ° C. for 15 minutes, quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (3 × 100 mL). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by chromatography on silica gel (isohexane: ethyl acetate) to give the title compound (2.4 g, 53%), which was recrystallized from ethyl acetate: isohexane.

Explanation 9
(1R ^* , 2R ^* , 5S ^* , 6R ^* )-8-benzyl-2-[(Z) -2- (2-cyclopropyloxy-5-trifluoromethoxyphenyl) -2-iodoethenyl] -1-phenyl -6-Phenylsulfonyl-8-azabicyclo [3.2.1] octan-2-ol (1R ^* , 2S ^* , 5S ^* , 6R ^* )-8-benzyl-2- (2-cyclopropyloxy-5- Trifluoromethoxyphenyl) ethynyl-1-phenyl-6-phenylsulfonyl-8-azabicyclo [3.2.1] octan-2-ol (Description 8; 2.4 g, 3.6 mmol) was added to hot dry toluene ( 35 mL), cooled to room temperature, diethyl ether (15 mL) followed by Red-Al® (3.4 M in toluene, 1.8 mL, 6.12). It was treated with Rimoru). The mixture was stirred for 2 hours at room temperature and 30 minutes at + 40 ° C. The reaction mixture was cooled to −60 ° C. and a solution of iodine (2.5 g, 9.8 mmol) in toluene (35 mL) was added. The cold bath was removed and the mixture was stirred at ambient temperature for 30 minutes, treated with 10% aqueous Na ₂ SO ₃ and stirred for 1 hour. The phases were separated. The aqueous layer was extracted twice with ethyl acetate (2 × 50 mL). The combined organic extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by chromatography on silica gel (isohexane: ethyl acetate) to give the title compound (1.88 g, 66%).

Explanation 10
(1R ^* , 2R ^* , 5S ^* , 6R ^* )-8-benzyl-4 ′-(2-cyclopropyloxy-5-trifluoromethoxyphenyl) -1-phenyl-6-phenylsulfonylspiro [8-azabicyclo [ 3.2.1] Octane-2,2 ′ (5′H) -furan] -5′-one (1R ^* , 2R ^* , 5S ^* , 6R ^* )-8-benzyl-2-[(Z) — 2- (2-Cyclopropyloxy-5-trifluoromethoxyphenyl) -2-iodoethenyl] -1-phenyl-6-phenylsulfonyl-8-azabicyclo [3.2.1] octan-2-ol (Description 9; 690 mg, 0.86 mmol), 1,4-bis (diphenylphosphino) butane (45 mg, 0.1 mmol), Pd ₂ (dba) ₃ (140 mg, 1.5 mmol), ethyldi A mixture of isopropylamine (0.75 mL) and tetrahydrofuran (20 mL) was stirred at + 50 ° C. under an atmosphere of carbon monoxide (1 atm) for 24 hours. An additional portion of 1,4-bis (diphenylphosphino) butane (45 mg, 0.1 mmol) and Pd ₂ (dba) ₃ (140 mg, 1.5 mmol) was added and the mixture was stirred for an additional 24 hours. . After cooling to room temperature, the mixture was diluted with ethyl acetate and filtered through a pad of Celite ™. The filtrate was concentrated and the residue was purified by chromatography on silica gel (isohexane: ethyl acetate 0-35%) to give the title compound (350 mg, 58%).

Explanation 11
(1R ^* , 2R ^* , 4′R ^* , 5S ^* , 6R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -1 -Phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan] -5-one (1R ^* , 2R ^* , 5S ^* , 6R ^* )-8-benzyl- 2 ′-(2-Cyclopropyloxy-5-trifluoromethoxyphenyl) -1-phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2,2 ′ (5′H) — Furan] -5′-one (description 10; 349 mg, 0.5 mmol), a mixture of 5% palladium on charcoal (1 g, 1 mmol) and ethanol (20 mL) at 2.65 ° C. under hydrogen (1 atm). Stir for 5 hours. The reaction mixture was cooled to room temperature, flushed with nitrogen gas, and filtered through a pad of Celite ™. The filtrate was concentrated and purified by flash chromatography to give a mixture of phenol and n-propyl derivatives in a ratio of 3.4: 1. This mixture was treated with dry tetrahydrofuran (3 mL) followed by diethyl azodicarboxylate (0.15 mL, 0.95 mmol), triphenylphosphine (293 mg, 1.1 mmol) and methanol (0.2 mL) at room temperature. For 1 hour. The mixture was quenched with water (1 drop) and concentrated. The residue was purified by chromatography on silica gel (isohexane: ethyl acetate 0-100%) to give the title compound (180 mg, 61%).

Explanation 12
(1R ^* , 2R ^* , 4 ′S ^* , 5S ^* , 6R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -1 -Phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan] -5-one 1,8-diazabicyclo [5.4.0] -undec-7-ene (0.05 mL, 0.34 mmol) was added to (1R ^* , 2R ^* , 4′R ^* , 5S ^* , 6R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro in dichloromethane (2 mL). -4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -1-phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan] -5-one (Description 11; 150 mg, 0.26 mmol) It was added to the solution. A white precipitate formed. The mixture was stirred at room temperature overnight and then treated with hexane (2 mL) and cooled to -20 ° C. The solid was filtered off to give the title compound (100 mg, 66%) as white crystals.

Explanation 13
(1R ^* , 2R ^* , 5S ^* , 6R ^* )-8-benzyl-2- (3-hydroxypropynyl) -1-phenyl-6-phenylsulfonyl-8-azabicyclo [3.2.1] octane-2- A solution of n-butyllithium in hexane (1.6 M, 20 mL, 32 mmol) was added to a stirred −78 ° C. solution of O-trimethylsilylpropargyl alcohol (5 mL, 34.8 mmol) in tetrahydrofuran (50 mL). Added. After 30 minutes, (1R ^* , 5S ^* , 6R ^* )-8-benzyl-1-phenyl-6-phenylsulfonyl-8-azabicyclo [3.2.1] octan-2-one (20 mL) in tetrahydrofuran (20 mL) Description 7; 4.6 g, 10.7 mmol) of solution was added. The mixture was stirred for 30 minutes and then quenched by adding saturated ammonium chloride solution. The mixture was diluted with ethyl acetate and washed with water (2 × 100 mL). The organic layer was separated and treated with a solution of tetrabutylammonium fluoride (11.5 mL, 1.0 M solution in tetrahydrofuran) for 20 minutes at room temperature. The solution was washed with water (2 × 100 mL) then dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1: 1, 3: 2, and 2: 2 ethyl acetate / isohexane to give the title compound (4.12 g, 79%).

Explanation 14
(1R ^* , 2R ^* , 5S ^* , 6R ^* )-8-benzyl-2-[(Z) -3-hydroxypropenyl] -1-phenyl-6-phenylsulfonyl-8-azabicyclo [3.2.1] Octan-2-ol Lindlar catalyst (200 mg) was added to (1R ^* , 2R ^* , 5S ^* , 6R ^* )-8-benzyl-2- (3-hydroxypropynyl) -1-phenyl- in ethyl acetate (100 mL). To a solution of 6-phenylsulfonyl-8-azabicyclo [3.2.1] octan-2-ol (Description 13; 2.1 g, 4.3 mmol) was added. The mixture was stirred at room temperature for 8 hours, then filtered through Celite ™ and the filtrate was concentrated in vacuo to give the title compound (1.88 g, 90%).

Explanation 15
(1R ^* , 2R ^* , 5S ^* , 6R ^* )-8-benzyl-2 ′, 5′-dihydro-1-phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2, 2'-Fran]
Diethyl azodicarboxylate, 0.7 mL, 4.4 mmol was added to (1R ^* , 2R ^* , 5S ^* , 6R ^* )-8-benzyl-2-[(Z) -3-hydroxy in tetrahydrofuran (25 mL). Propenyl] -1-phenyl-6-phenylsulfonyl-8-azabicyclo [3.2.1] octan-2-ol (description 14; 1.8 g, 3.7 mmol) and triphenylphosphine (1.15 g, 4 .4 mmol) at + 5 ° C. was added dropwise. After 90 minutes, the mixture was diluted with ethyl acetate and washed (x2) with water (100 mL). The organic extract was separated, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 10, 20, 30 and 50% ethyl acetate / isohexane to give the title compound (1.48 g, 86%).

Explanation 16
(1R ^* , 2R ^* , 4 ′S ^* , 5S ^* , 6R ^* )-8-benzyl-4 ′-(2-benzyloxy-5-trifluoromethoxyphenyl) -2 ′, 3 ′, 4 ′, 5 '-Tetrahydro-1-phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan]
Palladium acetate (140 mg, 0.6 mmol) was added to (1R ^* , 2R ^* , 5S ^* , 6R ^* )-8-benzyl-2 ′, 5′-dihydro-1-phenyl-6-phenylsulfonylspiro [8- Azabicyclo [3.2.1] octane-2,2′-furan] (description 15; 2.9 g, 6.15 mmol), 2-benzyloxy-5-trifluoromethoxyiodobenzene (7.3 g, 18. 5 mmol), tetrabutylammonium chloride (1.7 g, 6.15 mmol), lithium chloride (2.6 g, 62 mmol), triethylamine (2.6 mL, 18 mmol), potassium formate (1.56 g, 18.5). Mmol), N, N-dimethylformamide (40 mL) and water (3 mL) were added to a degassed suspension. The mixture was stirred at 60 ° C. for 72 hours and then partitioned between brine and ethyl acetate. The organic layer was washed with water (× 3), then dried (MgSO _4), and filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5, 10, 15 and 30% ethyl acetate / isohexane to give the title compound (2.0 g, 44%).

Explanation 17
(1R ^* , 2R ^* , 4 ′S ^* , 5S ^* , 6R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-[2- (1-phenylthiocyclopropyloxy) -5 -Trifluoromethoxyphenyl] -1-phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan]
(1R ^* , 2R ^* , 4 ′S ^* , 5S ^* , 6R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-hydroxy-5-trifluoromethoxyphenyl) -1 -Phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan] (Example 10; 315 mg, 0.56 mmol), 1-iodo-1-phenylthiocyclo A mixture of propane (1.8 g, 6.5 mmol), silver carbonate (1.03 g, 3.7 mmol) and toluene (7 mL) was stirred at + 40 ° C. for 2 hours. The reaction mixture was cooled to room temperature and filtered through a pad of Celite ™. The filtrate was concentrated and purified by chromatography on silica gel (isohexane: ethyl acetate) to give the title compound (245 mg, 62%).

Explanation 18
(1R ^* , 2R ^* , 5S ^* , 6R ^* )-8-benzyl-2 ′, 5′-dihydro-1-phenyl-6-phenylsulfonyl-4′-tributylstannyl spiro [8-azabicyclo [3.2 .1] Octane-2,2′-furan]
Tetrakis (triphenylphosphine) palladium (0) (300 mg, 0.26 mmol) was added to (1R ^* , 2R ^* , 5S ^* , 6R ^* )-8-benzyl-2- (3-hydroxy) in tetrahydrofuran (50 mL). To a degassed solution of propynyl) -1-phenyl-6-phenylsulfonyl-8-azabicyclo [3.2.1] octan-2-ol (description 13; 1.8 g, 3.7 mmol). The mixture was cooled to + 5 ° C., after which tri-n-butyltin hydride (1.3 g, 4.4 mmol) was added. The mixture was warmed to room temperature and stirred for an additional 18 hours, after which triphenylphosphine (1 g, 3.7 mmol) and diethyl azodicarboxylate (0.65 g, 3.7 mmol) were added. After 3 hours, the mixture was concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5 and 10% ethyl acetate / isohexane to give the title compound (154 mg, 5.5%).

Explanation 19
(P-Toluenesulfonyloxy) propan-2-ol p-Toluenesulfonyl chloride (19.4 g, 102 mmol) was added to propane-1,2-diol (30 mL), triethylamine (15 mL, 106 mL) in dichloromethane (100 mL). Mmol), N, N-dimethylamine (108 mg, 0.87 mmol) was added at + 5 ° C. to a stirred solution. The mixture was stirred at + 5 ° C. for 2 hours and overnight at room temperature, then diluted with diethyl ether (300 mL) and washed with 2M aqueous hydrochloric acid, water (twice) and brine. The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated to give the title compound (22.8 g, 97%).

Explanation 20
2- (2-Iodo-4-trifluoromethoxyphenyloxy) -1- (p-toluenesulfonyloxy) propane diethyl azodicarboxylate (5 mL, 31.8 mmol) was added to (p-toluenesulfonyloxy) propane-2. To a stirred solution of o-ol (description 19; 7.6 g, 33 mmol), triphenylphosphine (9.0 g, 34 mmol) and 2-iodo-4-trifluoromethoxyphenol (10 mL, 33 mmol) dropwise at room temperature. Added by The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was purified by chromatography on silica gel (isohexane: ethyl acetate) to give the title compound (18.7 g).

Explanation 21
2,3-dihydro-2-methyl-5-trifluoromethoxybenzofuran (2-iodo-4-trifluoromethoxyphenyloxy) -1-p-toluenesulfonyloxypropane (Description 20; 16 g) in tetrahydrofuran (50 mL) 10 mL of a solution of 28 mmol) was added dropwise to a stirred mixture of magnesium shavings (5 g, 208 mmol) in tetrahydrofuran (20 mL). 1,2-Dibromoethane (0.1 mL) was added. An exothermic reaction started. The mixture was warmed to reflux and the remainder of the (2-iodo-4-trifluoromethoxyphenyloxy) -1-p-toluenesulfonyloxypropane solution was added dropwise. The reaction mixture was heated under reflux for 24 hours, then cooled to room temperature and quenched with 2M aqueous hydrochloric acid. This mixture was extracted with a 1: 1 mixture of isohexane: diethyl ether (3 × 100 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by chromatography on silica gel (isohexane: diethyl ether 0-15%) to give the title compound (2.8 g, 36%).

Explanation 22
2,3-Dihydro-7-iodo-2-methyl-5-trifluoromethoxybenzofuran iodine (2.8 g, 11 mmol) was added in 2,3-dihydro-2-methyl-5-chloroform (60 mL). To a stirred mixture of trifluoromethoxybenzofuran (Description 21; 2.8 g, 12.8 mmol), silver (I) trifluoroacetate (3.5 g, 15.8 mmol) was added in portions. The mixture was stirred at room temperature for 1 hour, filtered through a pad of Celite ™ and concentrated. The residue was treated with isohexane (150 mL) and washed with aqueous sodium sulfite. The organic layer was dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by chromatography on silica gel (isohexane: diethyl ether 0-4%) to give the title compound (3.76 g, 85%).

Explanation 23
(1R ^* , 5S ^* , 6RS) -8-Benzyl-6- (tert-butoxycarbonyl) -1-phenyl-8-azabicyclo [3.2.1] oct-3-en-2-one N-benzyl- A mixture of 3-hydroxy-2-phenylpyridinium bromide (255 g, 0.745 mol), tert-butyl acrylate (470 mL), triethylamine (150 mL) and 1,4-dioxane (1 L) was heated at reflux for 15 hours. And cooled to room temperature. The reaction mixture was poured onto saturated aqueous NaHCO ₃ (1 L) and extracted into a 1: 1 mixture of isohexane: diethyl ether (3 × 500 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by chromatography on silica gel (750 g, isohexane: diethyl ether 0-20%) to give (1R ^* , 5S ^* , 6R ^* )-8-benzyl-6- (tert-butoxycarbonyl)- 1-phenyl-8-azabicyclo [3.2.1] oct-3-en-2-one and (1R ^* , 5S ^* , 6S ^* )-8-benzyl-6- (tert-butoxycarbonyl) -1- A 2: 1 mixture of phenyl-8-azabicyclo [3.2.1] oct-3-en-2-one (205 g, 70%) was obtained as a yellow-orange foam. The isomers were separated on silica gel (isohexane: diethyl ether) and crystallized from isohexane: diethyl ether to give yellow orthorhombic crystals.

Description 23a: (1R ^* , 5S ^* , 6R ^* )-8-benzyl-6- (tert-butoxycarbonyl) -1-phenyl-8-azabicyclo [3.2.1] oct-3-en-2-one

Description 23b: (1R ^* , 5S ^* , 6S ^* )-8-benzyl-6- (tert-butoxycarbonyl) -1-phenyl-8-azabicyclo [3.2.1] oct-3-en-2-one

Explanation 24
(1R ^* , 5S ^* , 6RS) -8-Benzyl-6- (tert-butoxycarbonyl) -1-phenyl-8-azabicyclo [3.2.1] octan-2-one (1R ^* , 5S ^* , 6RS ) -8-Benzyl-6- (tert-butoxycarbonyl) -1-phenyl-8-azabicyclo [3.2.1] oct-3-en-2-one (description 23; 26 g, 66 mmol), on charcoal A mixture of 10% palladium (3.5 g, 3.3 mmol), ethyl acetate (50 mL) and methanol (100 mL) was stirred at room temperature under a hydrogen atmosphere (1 atm) for 1 hour. The reaction mixture was treated with dichloromethane (500 mL) and filtered through a pad of Celite ™. The filter cake was washed thoroughly with dichloromethane and the filtrate was concentrated to give the title compound as a solid (26 g, 100%). The isomers were separated on silica gel (isohexane: ethyl acetate) and crystallized from acetone: isohexane to give the pure ketone as colorless crystals.

6R ^* -epimer

6S ^* -epimer

Explanation 25
(1R ^* , 2S ^* , 5S ^* , 6RS) -8-Benzyl-6- (tert-butoxycarbonyl) -2- (3-hydroxypropynyl) -1-phenyl-8-azabicyclo [3.2.1] octane 2-ol A solution of n-butyllithium in hexane (1.6 M, 34 mL, 55.4 mmol) was added to a stirred solution of O-trimethylsilylpropargyl alcohol (8 mL, 52 mmol) in tetrahydrofuran (40 mL). Added dropwise at -78 ° C. This solution was passed through a syringe and (1R ^* , 5S ^* , 6RS) -8-benzyl-6- (tert-butoxycarbonyl) -1-phenyl-8-azabicyclo [3.2.1] in tetrahydrofuran (30 mL). ] To a stirred solution of octan-2-one (Description 24; 3: 1 mixture of C6 epimers, 5 g, 12.7 mmol) was added at -78 ° C over 30 minutes. The reaction mixture was stirred for 1 hour, quenched with acetic acid (3.1 mL), warmed to room temperature and concentrated in vacuo. The residue was treated with 1M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (50 mL) followed by tetrahydrofuran (75 mL). The mixture was stirred for 30 minutes and concentrated in vacuo. The residue was treated with ethyl acetate (200 mL), washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by chromatography on silica gel (isohexane: ethyl acetate) to give the title compound (4.05 g, 71%) as a 3: 1 mixture of C6 epimers.

6S ^* -epimer

6R ^* -epimer: (distinguishable signal)

Explanation 26
(1R ^* , 2S ^* , 5S ^* , 6RS) -8-Benzyl-6- (tert-butoxycarbonyl) -2-[(Z) -3-hydroxypropenyl] -1-phenyl-8-azabicyclo [3.2 .1] Octan-2-ol (1R ^* , 2S ^* , 5S ^* , 6RS) -8-benzyl-2- (3-hydroxypropynyl) -1-phenyl-6- (tert-butoxycarbonyl) -8-azabicyclo [3.2.1] Octan-2-ol (Description 25; 3: 1 mixture of C6 epimers, 4 g, 8.9 mmol), a mixture of Lindlar's catalyst (800 mg) and ethyl acetate (30 mL) in a hydrogen atmosphere ( And stirred at room temperature for 45 minutes. The reaction mixture was filtered through a pad of Celite ™. The filtrate was concentrated to give the title compound (4.0 g, 100%) as a 3: 1 mixture of C6 epimers.

6S ^* -epimer

6R ^* -epimer: (distinguishable signal)

Explanation 27
(1R ^* , 2R ^* , 5S ^* , 6RS) -8-benzyl-6- (tert-butoxycarbonyl) -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2 ′ (5 ′ H) -Fran]
(1R ^* , 2S ^* , 5S ^* , 6RS) -8-Benzyl-6- (tert-butoxycarbonyl) -2-[(Z) -3-hydroxypropenyl] -1-phenyl-8-azabicyclo [3.2 .1] Octan-2-ol (Description 26; 3: 1 mixture of C6 epimers, 4.0 g, 8.9 mmol), diethyl azodicarboxylate (1.8 mL, 11.4 mmol), triphenylphosphine (3 .6 g, 13.7 mmol), tetrahydrofuran (30 mL) was stirred at room temperature for 15 minutes. The mixture was treated with water (0.1 mL) and concentrated in vacuo. The residue was treated with diethyl ether followed by isohexane. The solid was filtered off and the filtrate was concentrated and purified by chromatography on silica gel (isohexane: diethyl ether 0-20%) to give the title compound (3.1 g, 81%) 3: 1 of the C6 epimer. Obtained as a mixture.

6R ^* -epimer

6S ^* -epimer

Explanation 28
(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-8-benzyl-4 ′-(2-benzyloxy-5-trifluoromethoxyphenyl) -6- (tert-butoxycarbonyl) -2 ′, 3 ', 4', 5'-Tetrahydro-1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan]
(1R ^* , 2R ^* , 5S ^* , 6RS) -8-benzyl-6- (tert-butoxycarbonyl) -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2 ′ (5 ′ H) -furan] (description 27; 3.1 g, 7.17 mmol), 2-benzyloxy-5-trifluoromethoxyphenyl iodide (8.7 g, 22.1 mmol), tetra-n-butylammonium chloride. (2.0 g, 6.2 mmol), lithium chloride (3.45 g, 77.5 mmol), potassium formate (2.8 g, 33 mmol), palladium (II) acetate (250 mg, 1.1 mmol), water A mixture of (0.5 mL) and N, N-dimethylformamide (30 mL) was stirred at + 70 ° C. for 20 hours. An additional batch of 2-benzyloxy-5-trifluoromethoxyphenyl iodide (3.6 g, 9.1 mmol) and palladium (II) acetate (130 mg, 0.56 mmol) was added and the reaction mixture was added +70 Stir at 24 ° C. for 24 hours. The mixture was cooled to room temperature, quenched with water and extracted into a 1: 1 mixture of isohexane: diethyl ether (3 × 100 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by chromatography on silica gel (isohexane: diethyl ether 0-45%) to give the title compound (3 g, 60%).

(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-8-benzyl-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-[2-hydroxy- (5-trifluoromethoxy) phenyl ] -1-Phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan]
Lithium naphthalenide (18 mL, 1.0 M solution in tetrahydrofuran) was added to (1R ^* , 2R ^* , 4 ′S ^* , 5S ^* , 6R ^* )-8-benzyl-4 ′-( 2-Benzyloxy-5-trifluoromethoxyphenyl) -2 ′, 3 ′, 4 ′, 5′-tetrahydro-1-phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2 , 2′-furan] (Description 16; 2 g, 2.7 mmol) was added dropwise to a stirred solution at −78 ° C. After 15 minutes, the mixture was quenched with saturated ammonium chloride solution and then allowed to warm to room temperature. The mixture was partitioned between ethyl acetate and brine. The organic layer was separated, dried (MgSO ₄ ), filtered and concentrated. The residue was chromatographed on silica gel eluting with 5, 10 and 20% ethyl acetate / isohexane to give the title compound (0.88 g, 64%).

(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-8-benzyl-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-isopropoxy-5-trifluoromethoxyphenyl) -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan]
(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-8-benzyl-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-[2-hydroxy- (5-trifluoromethoxy) phenyl ] -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan] (Example 1; 150 mg, 0.29 mmol), 2-bromopropane (55 mg, 0.44 mmol) ) And potassium carbonate (100 mg, 0.73 mmol) were stirred in 5 mL of N, N-dimethylformamide at 50 ° C. for 18 hours. After this time, the mixture was poured into 50 mL brine and extracted with ethyl acetate (50 mL). The organic layer was washed with water (× 3), then separated, dried (MgSO _4), and filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 10% ethyl acetate / isohexane to give the title compound (87 mg, 54%).

(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-8-benzyl-4 ′-[2- (2,2-difluoroethoxy) -5-trifluoromethoxyphenyl] -2 ′, 3 ′, 4 ', 5'-tetrahydro-1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan]
It was prepared in the same manner as in Example 2 using 2-bromo-1,1-difluoroethane as the alkylating agent.

(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-8-benzyl-2 ′, 3 ′, 4 ′, 5′-tetrahydro-1-phenyl-4 ′-[2- (2,2,2 -Trifluoroethoxy) -5-trifluoromethoxyphenyl] spiro [8-azabicyclo [3.2.1] octane-2,2'-furan]
Prepared in the same manner as in Example 2, using 2,2,2-trifluoroethyltrichloromethanesulfonate as the alkylating agent.

(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-8-benzyl-4 ′-[2- (2-fluoroethoxy) -5-trifluoromethoxyphenyl] -2 ′, 3 ′, 4 ′, 5′-Tetrahydro-1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan]
Prepared in the same manner as in Example 2, using 1-bromo-2-fluoroethane as alkylating agent.

(1R ^* , 2R ^* , 5S ^* , 6R ^* )-8-benzyl-2 ′, 5′-dihydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -1-phenyl-6-phenylsulfonyl Spiro [8-azabicyclo [3.2.1] octane-2,2'-furan]
Tetrakis (triphenylphosphine) palladium (0) (20 mg, 0.017 mmol) was added to (1R ^* , 2R ^* , 5S ^* , 6R ^* )-8-benzyl-2 ′, 5 ′ in toluene (10 mL). -Dihydro-1-phenyl-6-phenylsulfonyl-4'-tributylstannyl spiro [8-azabicyclo [3.2.1] octane-2,2'-furan] (description 18; 150 mg, 0.2 mmol) , Lithium chloride (50 mg, 1.2 mmol), 2-methoxy-5-trifluoromethoxyiodobenzene (100 mg, 0.3 mmol) and copper (I) iodide (10 mg, 0.05 mmol) were degassed. Added to the suspension. The mixture was heated to reflux for 18 hours. Upon cooling, the mixture was diluted with ethyl acetate (50 mL) and filtered through Celite ™. The filtrate was washed with water (25 mL), then dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 10, 20, and 30% ethyl acetate / isohexane to give the title compound (115 mg, 87%).

(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-8-benzyl-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-[(2RS) -2,3-dihydro-2- Methyl-5-trifluoromethoxybenzofuran-7-yl] -1-phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan]
(1R ^* , 2R ^* , 5S ^* , 6R ^* )-8-Benzyl-1-phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2,2 ′ (5′H) — Furan] (description 15; 500 mg, 1.05 mmol), 2,3-dihydro-7-iodo-2-methyl-5-trifluoromethoxybenzofuran (description 22; 1.11 g, 3.22 mmol), tetra- n-Butylammonium chloride (310 mg, 0.96 mmol), lithium chloride (640 mg, 1.48 mmol), potassium formate (420 mg, 5 mmol), palladium (II) acetate (47 mg, 0.21 mmol), water ( 0.2 mL) and N, N-dimethylformamide (5 mL) were stirred at + 65 ° C. for 24 hours. An additional batch of 2,3-dihydro-7-iodo-2-methyl-5-trifluoromethoxybenzofuran (0.7 g, 2.0 mmol) and palladium (II) acetate (22 mg, 0.1 mmol) was added The reaction mixture was stirred at + 65 ° C. for 48 hours. The mixture was cooled to room temperature, quenched with saturated aqueous NaHCO ₃ and extracted into diethyl ether. The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by chromatography on silica gel (isohexane: diethyl ether 0-45%) to give the title compound (320 mg, 44%) as a 1: 1 mixture of epimers.

(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-6- (tert-butoxycarbonyl) -2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-hydroxy-5-tri Fluoromethoxyphenyl) -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan]
(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-8-benzyl-4 ′-(2-benzyloxy-5-trifluoromethoxyphenyl) -6- (tert-butoxycarbonyl) -2 ′, 3 ', 4', 5'-tetrahydro-1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan] (description 28; 1.065 g, 1.52 mmol) on charcoal A mixture of 10% palladium (340 mg, 0.32 mmol) and ethanol (20 mL) was stirred at + 65 ° C. under a hydrogen atmosphere (1 atm) for 1.5 hours. The reaction mixture was cooled to room temperature, flushed with nitrogen gas, and filtered through a pad of Celite ™. The filtrate was concentrated to give the title compound (900 mg, 97%).

(1R ^* , 2R ^* , 4 ′S ^* , 5S ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -1-phenylspiro [8-Azabicyclo [3.2.1] octane-2,2′-furan]
A solution of lithium aluminum hydride in tetrahydrofuran (1 M, 2 mL) was added to (1R ^* , 2R ^* , 4 ′S ^* , 5S ^* , 6R ^* )-2 ′, 3 ′, 4 ′, tetrahydrofuran (4 mL). 5′-Tetrahydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -1-phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan] To a stirred suspension of -5-one (Description 12; 100 mg, 0.17 mmol) was added at + 5 ° C. The cold bath was removed and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was diluted with dichloromethane, treated with a small amount of saturated aqueous Na ₂ SO ₄ , stirred for 1 hour, and filtered through a pad of Celite ™. The filtrate was concentrated in vacuo. The residue was treated with tetrahydrofuran (3 mL) followed by triphenylphosphine (220 mg, 0.84 mmol) and diethyl azodicarboxylate (0.1 mL, 0.64 mmol) and stirred at room temperature overnight. The mixture was purified by chromatography on silica gel (dichloromethane: methanol) to give the title compound (35 mg, 48%).

  The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl and recrystallization from dichloromethane: isohexane.

  HCl salt:

(1R ^* , 2R ^* , 4 ′S ^* , 5S ^* , 6R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-hydroxy-5-trifluoromethoxyphenyl) -1 -Phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan]
(1R ^* , 2R ^* , 4 ′S ^* , 5S ^* , 6R ^* )-8-benzyl-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-benzyloxy-5-trifluoro Methoxyphenyl) -1-phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan] (description 16; 2.2 g, 2.97 mmol), 5 on charcoal A mixture of% palladium (3 g, 1.4 mmol) and ethanol (55 mL) was stirred at + 70 ° C. for 70 min under a hydrogen atmosphere (1 atm). The reaction mixture was cooled to room temperature, flushed with nitrogen gas, and filtered through a pad of Celite ™. The filtrate was concentrated to give the title compound (1.77 g, quantitative).

(1R ^* , 2R ^* , 4 ′S ^* , 5S ^* , 6R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -1 -Phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan]
(1R ^* , 2R ^* , 4 ′S ^* , 5S ^* , 6R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-hydroxy-5-trifluoromethoxyphenyl) -1 -Phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan] (Example 10; 60 mg, 0.11 mmol), diethyl azodicarboxylate (0.04 mL, 0.25 mmol), triphenylphosphine (68 mg, 0.26 mmol), methanol (0.2 mL) and tetrahydrofuran (2 mL) were stirred at room temperature overnight then concentrated in vacuo followed by methanol (2 mL). And treated with 4M aqueous NaOH (0.4 mL). The mixture was stirred at room temperature for 24 hours, diluted with brine and extracted into dichloromethane. The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by chromatography on silica gel (isohexane: ethyl acetate) to give the title compound (52 mg, 84%).

  The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl and recrystallization from ethyl acetate: diethyl ether.

  HCl salt:

(1R ^* , 2R ^* , 4 ′S ^* , 5S ^* )-4 ′-(2-cyclopropyloxy-5-trifluoromethoxyphenyl) -2 ′, 3 ′, 4 ′, 5′-tetrahydro-1- Phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan]
Oxone (400 mg, 0.65 mmol) was added to (1R ^* , 2R ^* , 4 ′S ^* , 5S ^* , 6R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-[2- (1-phenylthiocyclopropyloxy) -5-trifluoromethoxyphenyl] -1-phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan] (description 17 88 mg, 0.12 mmol), to a stirred mixture of wet aluminum oxide (5 g Al ₂ O ₃ in 1 mL water, 370 mg) and chloroform (5 mL) at room temperature. The reaction mixture was stirred for 5 hours, then filtered and concentrated to give crude disulfone (95 mg). Sodium amalgam (10%, 700 mg) was added in portions to a stirred mixture of disulfone (95 mg), disodium hydrogen orthophosphate (700 mg) and methanol (5 mL) at + 5 ° C. After the reaction was complete, the mixture was quenched with saturated aqueous NaHCO ₃ , decanted and extracted into dichloromethane. The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by chromatography on silica gel (dichloromethane: methanol) to give the title compound (34 mg, 60%).

  The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl and recrystallization from ethyl acetate: isohexane.

  HCl salt:

(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-isopropoxy-5-trifluoromethoxyphenyl) -1-phenyl Spiro [8-azabicyclo [3.2.1] octane-2,2′-furan] hydrochloride 20 mg of palladium hydroxide in ethanol (3 mL) (1R ^* , 2R ^* , 4 ′S ^* , 5R ^* ) -8-benzyl-2 ', 3', 4 ', 5'-tetrahydro-4'-(2-isopropoxy-5-trifluoromethoxyphenyl) -1-phenylspiro [8-azabicyclo [3.2.1] ] Octane-2,2'-furan] (Example 2; 84 mg, 0.15 mmol) was added. The mixture was hydrogenated at 45 psi using a Parr® apparatus for 4 hours. The mixture was filtered through Celite ™ and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel eluting with 150: 8: 1, dichloromethane: methanol: ammonia to give the title compound (42 mg, 60%).

  The hydrochloride salt was prepared by treatment with ethereal HCl.

(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2- (2 ′, 2′-difluoro) ethoxy-5-tri Fluoromethoxyphenyl) -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan] hydrochloride Prepared from Example 3 in the same manner as in Example 13.

(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-1-phenyl-4 ′-[2- (2,2,2-trifluoroethoxy ) -5-Trifluoromethoxyphenyl) spiro [8-azabicyclo [3.2.1] octane-2,2′-furan] hydrochloride Prepared from Example 4 in the same manner as in Example 13.

(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-4 ′-[2- (2-fluoroethoxy) -5-trifluoromethoxyphenyl] -2 ′, 3 ′, 4 ′, 5′-tetrahydro -1-Phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan] hydrochloride Prepared from Example 5 in the same manner as in Example 13.

(1R ^* , 2R ^* , 4′R ^* , 5S ^* , 6R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -1 -Phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan] hydrochloride 10% palladium on charcoal (100 mg) was added to (1R ^* , 2R ^* , 5S ^* , 6R ^* )-8-benzyl-2 ′, 5′-dihydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -1-phenyl-6-phenylsulfonylspiro [8- To a solution of azabicyclo [3.2.1] octane-2,2′-furan] (Example 6; 113 mg, 0.17 mmol) was added as a slurry in water (1 mL). This mixture was hydrogenated using a PAL® apparatus at 50 psi for 20 hours. The mixture was filtered through Celite ™ and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel eluting with 180: 8: 1, dichloromethane: methanol: ammonia to give the title compound (83 mg, 86%). The hydrochloride salt was prepared by treatment with ethereal HCl.

(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-[(2RS) -2,3-dihydro-2-methyl-5- Trifluoromethoxybenzofuran-7-yl] -1-phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan]
(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-8-benzyl-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-[(2RS) -2,3-dihydro-2- Methyl-5-trifluoromethoxybenzofuran-7-yl] -1-phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan] (Example 7; 200 mg, 0.29 mmol), 10% palladium on charcoal (375 mg, 0.35 mmol) and ethanol (25 mL) were stirred at + 70 ° C. for 30 min under hydrogen atmosphere (1 atm). The reaction mixture was cooled to room temperature, flushed with nitrogen gas, and filtered through a pad of Celite ™. The filtrate was concentrated to give the title compound (160 mg, 92%).

(1R ^* , 2R ^* , 4 ′S ^* , 5S ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-[(2RS) -2,3-dihydro-2-methyl-5- Trifluoromethoxybenzofuran-7-yl] -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan]
Sodium amalgam (10%, 2 g) was added to (1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-[(2RS) -2, 3-dihydro-2-methyl-5-trifluoromethoxybenzofuran-7-yl] -1-phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan] ( Example 18; 160 mg, 0.26 mmol), disodium hydrogen orthophosphate (500 mg), methanol (10 mL) was added in portions at + 5 ° C. After the reaction was complete, the mixture was quenched with saturated aqueous NaHCO ₃ , decanted and extracted into dichloromethane. The combined organic extracts were dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by chromatography on silica gel (dichloromethane: methanol) to give the title compound (83 mg, 67%).

  The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl and recrystallization from dichloromethane: tert-butyl methyl ether.

  HCl salt:

(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -6- (morpholine -1-ylcarbonyl) -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan]
Step (a)-(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-6- (tert-butoxycarbonyl) -2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2- Hydroxy-5-trifluoromethoxyphenyl) -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan] (Example 8; 900 mg, 1.73 mmol), azodicarboxylic acid A mixture of diethyl (0.37 mL, 1.72 mmol), triphenylphosphine (800 mg, 3.0 mmol), methanol (1 mL) and tetrahydrofuran (10 mL) was stirred at room temperature for 2 hours. A few drops of water were added and the mixture was concentrated. The residue was purified by chromatography on silica gel to give (1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-6- (tert-butoxycarbonyl) -2 ′, 3 ′, 4 ′, 5 ′. -Tetrahydro-4 '-(2-methoxy-5-trifluoromethoxyphenyl) -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan] and (1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-6- (tert-butoxycarbonyl) -2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -8 A 1: 1 mixture (500 mg) with -methyl-1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan] was obtained. The mixture was treated with dichloromethane (7 mL) and trifluoroacetic acid (3 mL), stirred at room temperature for 24 hours and concentrated. The residue was treated with dichloromethane (6 mL) to produce a solution of carboxylic acid.

Step (b)-A portion of this solution (2 mL) was added to morpholine (0.15 mL, 1.72 mmol), triethylamine (0.2 mL, 2.7 mmol), 1- (3-dimethylaminopropyl) -3 -Treated with ethylcarbodiimide hydrochloride (140 mg, 0.73 mmol) and 4-N, N-dimethylaminopyridine (10 mg, 0.08 mmol). The mixture was stirred for 4 days, diluted with dichloromethane, washed with 10% aqueous citric acid, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative TLC on silica gel (dichloromethane: methanol) to give the title compound (25 mg).

  The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl and recrystallization from dichloromethane: tert-butyl methyl ether.

  HCl salt:

(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -6- (3 -Methoxypropylaminocarbonyl) -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan];

(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -6- (3 -Methoxypropylaminocarbonyl) -8-methyl-1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan]
A portion (2 mL) of the solution from step (a) of Example 20 was added to 3-methoxypropylamine (0.15 mL, 1.94 mmol), triethylamine (0.2 mL, 2.7 mmol), 1- ( Treated with 3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (300 mg, 1.56 mmol) and 4-N, N-dimethylaminopyridine (20 mg, 0.16 mmol). The mixture was stirred for 4 days, diluted with dichloromethane, washed with 10% aqueous citric acid, dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by preparative TLC on silica gel (dichloromethane: methanol) to give (1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro- 6- (3-Methoxypropylaminocarbonyl) -4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan ] (21 mg) and (1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-6- (3-methoxypropylaminocarbonyl) -4 ′-( 2-Methoxy-5-trifluoromethoxyphenyl) -8-methyl-1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan] (21 mg) was obtained.

  Example 21:

  Example 22:

  The hydrochloride salts of Example 21 and Example 22 were prepared by treatment with ethereal HCl.

  HCl salt of Example 21:

  HCl salt of Example 22:

Claims (19)

Formula (I):

[Wherein Z is —CR ⁹ R ¹⁰ CH ₂ — or —CH ₂ CR ⁹ R ¹⁰ —,
R ¹ is hydrogen, hydroxy, C _1-6 alkyl, C _2-6 alkenyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, C _1-6 alkoxy, fluoro C _1-6 Alkoxy, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-4 alkyl, C _1-6 alkoxy C _1-4 alkoxy, fluoro C _1-6 alkoxy C _1-4 alkyl, C _2-6 alkenyloxy, C _3-7 cycloalkoxy, C _3-7 cycloalkyl C _1-4 alkoxy, phenoxy, benzyloxy, cyano, halogen, NR ^a R ^b , SR ^a , SOR ^a , SO ₂ R ^a , OSO ₂ R ^a , NR _{^{a COR 12, COR a, CO}} 2 R a or CONR ^a R ^b (wherein, ^{R a} and ^{R b} are each independently _{hydrogen, C 1-4} Represents an alkyl or fluoroalkyl _{C 1-4} alkyl.) Represent,
R ² represents hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy,
Or when R ² is adjacent to R ¹ , they are bonded together to form a 5 or 6 membered containing 1 or 2 atoms selected from nitrogen, oxygen, sulfur, NH or NR ^c A saturated or unsaturated ring wherein the ring is 1 selected from hydroxy, C _1-4 alkyl, C _1-3 alkoxyC _1-3 alkyl, fluoroC _1-4 alkyl, phenyl, ═O or ═S Optionally substituted by 2, 2 or 3 groups, R ^c is C _1-4 alkyl, hydroxy C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkyl, fluoro C _1-4. Alkyl, phenyl or benzyl),
R ³ is hydrogen, halogen, C _1-6 alkyl, fluoro C _1-6 alkyl, C _1-6 alkoxy, fluoro C _1-6 alkoxy, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _{1- 4 represents} alkyl, cyano, SR ^a , SOR ^a , SO ₂ R ^a , NR ^a R ^b , NR ^a COR ¹² , COR ^a , CO ₂ R ^a , CONR ^a R ^b , or cyano, CO ₂ R ^a or CONR ^a R _{C 1-4} alkyl (wherein, ^{R a} and ^{R b} are as previously defined.), which is substituted by ^b represent,
Or R ³ is a 5- or 6-membered aromatic heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and sulfur (this group is C _{1 -6} alkyl, C _1-6 alkoxy, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, trifluoromethyl, OCF ₃ , NO ₂ , CN, SR ^a , SOR ^a , SO ₂ R ^a , COR ^a , CO ₂ R ^a , phenyl, — (CH ₂ ) _r NR ^a R ^b , — (CH ₂ ) _r NR ^a COR ^b , — (CH ₂ ) _r CONR ^a R ^b or CH ₂ C (O ) R ^a (wherein R ^a and R ^b are as defined above, r is zero, 1 or 2) optionally substituted by one or two groups selected from Represents)
R ⁴ is hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, CF ₃ , OCF ₃ , NO ₂ , CN, SR ^a , SOR ^a , SO ₂ R ^a , CO ₂ R ^a , CONR ^a R It represents ^b, _{C 2-6 alkenyl, C 2-6} alkynyl, or _{C 1-4 C 1-4} alkyl (wherein substituted by alkoxy, ^{R a} and ^{R b} are as previously defined. )
R ⁵ represents hydrogen, halogen, C _1-6 alkyl, CF ₃ , or C _1-6 alkoxy substituted by C _1-4 alkoxy;
R ⁶ represents hydrogen, hydroxy, COR ^a , CO ₂ R ^a , COCONR ^a R ^b , COCO ₂ R ^a , (CO ₂ R ^a , CONR ^a R ^b , hydroxy, CN, COR ^a , NR ^a R ^b , C (NOH) NR ^a R ^b , CONH phenyl (C _1-4 alkyl), COCO ₂ R ^a , CONHNR ^a R ^b , C (S) NR ^a R ^b , CONR ^a C _1-6 alkyl R ¹⁴ , CONR ¹¹ C _2-6 alkenyl, CONR ¹¹ C _2-6 alkynyl, CONR ^a R ^b , CONR ^a C (NR ^b ) NR ^a R ^b , CONR ^a heteroaryl, and (C _1-6 alkyl, C _1-6 alkoxy ) Phenyl) optionally substituted by 1, 2 or 3 substituents selected from halogen and trifluoromethyl It represents C _1-6 alkyl optionally substituted by radicals,
Or R ⁶ represents a group of formula —CH ₂ C≡CCH ₂ NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are as defined below;
Or R ⁶ is substituted by a 5 or 6 membered heterocyclic ring optionally containing one, two or three nitrogen atoms, optionally substituted by oxo, optionally substituted by ═O or ═S Represents C _1-6 alkyl optionally substituted by a group of formula —Y—NR ⁷ R ⁸ ,
Y is C _1-6 alkylene or C _3-6 cycloalkyl,
R ⁷ represents hydrogen or C _1-4 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, or C _1-4 alkoxy, or C ₂ substituted by hydroxyl _-4 represents alkyl,
R ⁸ represents hydrogen or C _1-4 alkyl, C _1-4 alkoxy, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, or C _1-4 alkoxy, hydroxyl, CO ₂ From ^a 4-membered, 5-membered or 6-membered heteroaliphatic ring containing 1 or 2 heteroatoms selected from R ^a , NR ^a R ^b , aryl, aryloxy, heteroaryl or N, O and S _Represents C _2-4 alkyl substituted by a selected group,
Or R ^7, R ⁸ and the nitrogen atom to which they are attached, hydroxy, phenyl, one selected from C _1-4 alkoxy optionally substituted by benzyl or C _1-4 alkoxy or hydroxyl group or 2 Forming a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by 1 group and optionally containing a double bond, which is an oxygen or sulfur ring atom, the group S (O) Or optionally a second nitrogen atom that is part of a S (O) ₂ or NH or NR ^c unit, where R ^c is as defined above.
Or R ⁷ , R ⁸ and the nitrogen atom to which they are attached forms a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
Or Y, R ⁷ and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms optionally containing oxygen ring atoms;
R ⁹ is hydrogen, hydroxy, oxo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-4 alkyl, fluoro C _{1 -6} alkyl, C _1-6 alkoxy, fluoro C _1-6 alkoxy, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-4 alkyl, C _1-6 alkoxy C _1-4 alkoxy, fluoro C _{1- 6} alkoxy C _1-4 alkyl, C _2-6 alkenyloxy, C _2-6 alkynyloxy, C _3-7 cycloalkoxy, C _3-7 cycloalkyl C _1-4 alkoxy, aryl, aryl (CH ₂ ), aryl Oxy, aryl (CH ₂ ) oxy, cyano, halogen, NR ⁷ R ⁸ , CH ₂ NR ⁷ R ⁸ , SR ¹² , SOR ¹² , S O ₂ R ¹² , OSO ₂ R ¹² , NR ^a COR ¹² , CH (OH) R ¹² , COR ¹² , CO ₂ R ¹² , CONR ⁷ R ⁸ , CH ₂ OR ¹³ , heteroaryl or heteroaryl C _1-4 alkyl Wherein R ^a is as defined above,
R ¹⁰ represents hydrogen, halogen or hydroxy,
R ¹¹ represents hydrogen or C _1-6 alkyl,
R ¹² represents hydrogen, C _1-6 alkyl, C _1-6 alkoxy, fluoro C _1-6 alkyl, or 1 selected from C _1-6 alkyl, C _1-6 alkoxy, halogen or trifluoromethyl. Represents phenyl optionally substituted by 2, 2 or 3 substituents;
R ¹³ is C ₁ -C ₁ substituted by a group selected from hydroxy, COR ^a , CO ₂ R ^a , CONR ^a R ^b and heteroaryl (wherein R ^a is as defined above). Represents ₄ alkyl,
R ¹⁴ represents OR ^a , CONR ^a R ^b or heteroaryl. ]
And pharmaceutically acceptable salts or N-oxides thereof. A 5-membered saturated ring in which R ¹ is a C _1-6 alkoxy, fluoro C _1-6 alkoxy or C _3-7 cycloalkoxy group, or R ¹ together with the group R ² contains one oxygen atom The compound of claim 1, wherein the ring is optionally substituted with a methyl group. The compound of Claim 1 or Claim ² whose R < ² > is hydrogen, a fluorine, or a chlorine atom. 4. The method according to claim 1, wherein R ³ is a hydrogen or halogen atom, a fluoro C _1-6 alkoxy group or a 5-membered aromatic heterocyclic group as defined in claim 1. Compound. The compound according to any one of claims 1 to 4, wherein R ⁴ is hydrogen or fluorine. The compound according to any one of claims 1 to 5, wherein R ⁵ is a hydrogen atom. R ⁶ is hydrogen or C _1-6 alkyl or a C _1-6 alkyl group substituted by a 5-membered heterocyclic ring containing 2 or 3 nitrogen atoms as defined in claim 1. The compound according to any one of claims 1 to 6. Z is ^-CR 9 ^R 10 CH ₂ - A compound according to any one of claims 1 to 7. R ⁹ is hydrogen, hydroxy, oxo, C _1-6 alkoxy, C _1-6 alkoxy C _1-4 alkyl, hydroxy C _1-4 alkyl, cyano, NR ⁷ R ⁸ , CH ₂ NR ⁷ R ⁸ , SO ₂ R ^d , CH (OH) R ¹² , COR ¹² , CO ₂ R ¹² , CONR ⁷ R ⁸ , phenyl, heteroaryl, heteroaryl C _1-4 alkyl or CH ₂ OR ¹³ (wherein the phenyl is C ₁ Optionally substituted by one or two substituents selected from _-4 alkyl, _C1-4 alkoxy, halogen or trifluoromethyl). The described compound. The compound according to any one of claims 1 to 9, wherein R ¹⁰ is hydrogen, fluorine or hydroxy. Formula (Ia):

(Wherein R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1 and Z is —CR ⁹ R ¹⁰ CH ₂ —).
Or a pharmaceutically acceptable salt thereof. (1R ^* , 2R ^* , 4 ′S ^* , 5S ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan];
(1R ^* , 2R ^* , 4 ′S ^* , 5S ^* , 6R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -1 -Phenyl-6-phenylsulfonylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan];
(1R ^* , 2R ^* , 4 ′S ^* , 5S ^* )-4 ′-(2-cyclopropyloxy-5-trifluoromethoxyphenyl) -2 ′, 3 ′, 4 ′, 5′-tetrahydro-1- Phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan];
(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-isopropoxy-5-trifluoromethoxyphenyl) -1-phenyl Spiro [8-azabicyclo [3.2.1] octane-2,2'-furan];
(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2- (2 ′, 2′-difluoro) ethoxy-5-tri Fluoromethoxyphenyl) -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan];
(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-1-phenyl-4 ′-[2- (2,2,2-trifluoroethoxy ) -5-trifluoromethoxyphenyl) spiro [8-azabicyclo [3.2.1] octane-2,2'-furan];
(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-4 ′-[2- (2-fluoroethoxy) -5-trifluoromethoxyphenyl] -2 ′, 3 ′, 4 ′, 5′-tetrahydro -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan];
(1R ^* , 2R ^* , 4 ′S ^* , 5S ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-[(2RS) -2,3-dihydro-2-methoxy-5- Trifluoromethoxybenzofuran-7-yl] -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan];
(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -6- (morpholine -1-ylcarbonyl) -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2′-furan];
(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -6- (3 -Methoxypropylaminocarbonyl) -1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan];
(1R ^* , 2R ^* , 4 ′S ^* , 5R ^* )-2 ′, 3 ′, 4 ′, 5′-tetrahydro-4 ′-(2-methoxy-5-trifluoromethoxyphenyl) -6- (3 -Methoxypropylaminocarbonyl) -8-methyl-1-phenylspiro [8-azabicyclo [3.2.1] octane-2,2'-furan];
Or the compound of claim 1 selected from pharmaceutically acceptable salts thereof. The stereochemistry at the 1-position, 2-position, 4′-position and 5-position is of formula (Ib):

The compound according to any one of claims 1 to 10, which is as shown in the above.   14. A compound according to any one of claims 1 to 13 for use in therapy.   A pharmaceutical composition comprising a compound according to claim 1 together with at least one pharmaceutically acceptable carrier or excipient.   A method of treating or preventing a physiological disorder associated with excess tachykinin comprising administering to a patient in need thereof an amount of the compound of claim 1 that reduces tachykinin.   17. A method according to claim 16 for the treatment or prevention of pain or inflammation, migraine, vomiting, postherpetic neuralgia, depression or anxiety.   14. Use of a compound according to any one of claims 1 to 13 for the manufacture of a medicament for the treatment or prevention of physiological disorders associated with excess tachykinin.   14. Use of a compound according to any one of claims 1 to 13 for the manufacture of a medicament for the treatment or prevention of pain or inflammation, migraine, vomiting, postherpetic neuralgia, depression or anxiety.