JP2011195593A - Quinuclidine derivative as muscarinic m3 receptor antagonist - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide cycloalkyl-substituted alkyl esters of polycyclic amino alcohols, a method for their preparation, pharmaceutical compositions containing them, a method for their preparation, their use in therapy, and an intermediate used in preparation thereof.SOLUTION: The invention provides compounds of formula (I), wherein Ris an N-substituted quinuclidine. The compound are designated compounds not including (R)-3-(1-Phenyl-cycloheptanecarbonyloxy)-1-(pyridine-2-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane X.

Description

  The present invention relates to cycloalkyl-substituted alkyl esters of polycyclic aminoalcohols, processes for their preparation, pharmaceutical compositions containing them, processes for the preparation of pharmaceutical compositions, their use in therapy and intermediates used for their preparation. .

BACKGROUND OF THE INVENTION Muscarinic receptors are a family of G protein-coupled receptors (GPCRs) having _five family members M ₁ , M ₂ , M ₃ , M ₄ and M ₅ . Of the five muscarinic subtypes, three (M ₁ , M ₂ and M ₃ ) are known to exert physiological effects in human lung tissue.

  Parasympathetic nerves are the main pathway for mediating airway tone by releasing bronchoconstriction in the human airway by releasing acetylcholine to muscarinic receptors. Airway tone is increased in patients with respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD), and for this reason muscarinic receptor antagonists are being developed for treatment in airway diseases. Muscarinic receptor antagonists (antagonsists), often referred to as anticholinergics in practice, are widely accepted as first-line treatment for individuals with COPD, and their use has been thoroughly reviewed in the literature (e.g. Lee et al, Current Opinion in Pharmacology 2001, 1, 223-229).

  When used to treat respiratory disorders, muscarinic receptor antagonists are typically administered by inhalation. However, when administered by inhalation, a significant proportion of muscarinic receptor antagonists are often absorbed into the systemic circulation, leading to reported side effects such as dry mouth. In addition, most muscarinic antagonists have a relatively short duration of action and require administration several times a day. Such multiple daily dosing regimens are not only inconvenient to the patient, but also pose a significant risk of inappropriate treatment due to patient non-compliance with frequently repeated dosing schedules.

  Thus, there remains a need for new compounds that can block muscarinic receptors. In particular, there is a need for new muscarinic antagonists that are highly effective and have low systemic side effects when administered by inhalation. Furthermore, there is a need for new muscarinic antagonists that have a long duration of action when administered by inhalation and can be administered once or twice daily.

  WO 98/04517 describes arylcyclopropanes, arylcyclobutanes, arylcyclopentanes and arylcyclohexanecarboxylic esters having antimuscarinic activity on urinary bladder smooth muscle.

〔式中、
Ｒ^１およびＲ^２は、それらが両方とも結合している炭素原子と一体となって７員脂肪族炭素環式環を形成し、それは場合によりハロゲン、ヒドロキシル、Ｃ_１−６アルコキシ、ＮＨ_２、ＮＨ(Ｃ_１−６アルキル)、Ｎ(Ｃ_１−６アルキル)_２およびＣ_１−６アルキルから独立して選択される１個以上の置換基で置換されていてよく、該Ｃ_１−６アルキルは、場合によりハロゲンおよびヒドロキシルから独立して選択される１個以上の置換基で置換されていてよく；
Ｒ^３はフェニルまたは５〜６員ヘテロアリール環であり、この各々は、場合によりハロゲン、シアノ、ニトロ、ＳＨ、Ｓ(Ｏ)_０−２Ｒ^９、ＮＲ^１０Ｒ^１１、Ｓ(Ｏ)_２ＮＲ^１２Ｒ^１３、Ｃ(Ｏ)ＮＲ^１４Ｒ^１５、Ｃ(Ｏ)_２Ｒ^１６、ＮＲ^１７Ｓ(Ｏ)_２Ｒ^１８、ＮＲ^１９Ｃ(Ｏ)Ｒ^２０、ＮＲ^２１Ｃ(Ｏ)_２Ｒ^２２、ＮＲ^２３Ｃ(Ｏ)ＮＲ^２４Ｒ^２５、ＯＲ^２６およびＣ_１−６アルキルから独立して選択される１個以上の置換基で置換されていてよく、該Ｃ_１−６アルキルは場合によりハロゲン、ヒドロキシル、Ｃ_１−６アルコキシ、ＮＨ_２、ＮＨ(Ｃ_１−６アルキル)およびＮ(Ｃ_１−６アルキル)_２から独立して選択される１個以上の置換基で置換されていてよく； Our co-pending application PCT / GB2007 / 004350 has the formula (I):

[Where,
R ¹ and R ² together with the carbon atom to which they are bonded together form a 7-membered aliphatic carbocyclic ring, which is optionally halogen, hydroxyl, C _1-6 alkoxy, NH ₂ , Optionally substituted by one or more substituents independently selected from NH (C _1-6 alkyl), N (C _1-6 alkyl) ₂ and C _1-6 alkyl, said C _1-6 alkyl May be optionally substituted with one or more substituents independently selected from halogen and hydroxyl;
R ³ is phenyl or a 5-6 membered heteroaryl ring, each of which is optionally halogen, cyano, nitro, SH, S (O) _0-2 R ⁹ , NR ¹⁰ R ¹¹ , S (O) ₂ NR ¹² R ¹³ , C (O) NR ¹⁴ R ¹⁵ , C (O) ₂ R ¹⁶ , NR ¹⁷ S (O) ₂ R ¹⁸ , NR ¹⁹ C (O) R ²⁰ , NR ²¹ C (O) ₂ R ²² , Optionally substituted by one or more substituents independently selected from NR ²³ C (O) NR ²⁴ R ²⁵ , OR ²⁶ and C _1-6 alkyl, wherein the C _1-6 alkyl is optionally halogen, Optionally substituted with one or more substituents independently selected from hydroxyl, C _1-6 alkoxy, NH ₂ , NH (C _1-6 alkyl) and N (C _1-6 alkyl) ₂ ;

の基であり、ここで、
Ｙは−ＣＨ_２−、−ＣＨ_２ＣＨ_２−または−ＣＨ_２ＣＨ_２ＣＨ_２−およびであり、環基(II)の置換基は３位または４位に存在してよく；
ａは１または２であり；
ｂは１または２であり；
Ｚは−ＣＨ_２−であり；
Ｒ^５は式(IV)

の基であり、ここで、
ｗは０または１であり；
Ｒ^６は、場合によりハロゲン、ヒドロキシル、Ｃ_１−６アルコキシ、ＮＨ_２、ＮＨ(Ｃ_１−６アルキル)およびＮ(Ｃ_１−６アルキル)_２から独立して選択される１個以上の置換基で置換されていてよいＣ_１−４アルキレンであり；
ｗが０であるとき、ｙは０であり；ｗが１であるとき、ｙは０または１であり；
ＱはＯ、Ｓ(Ｏ)_０−２、ＮＲ^８、−ＣＯＮＲ^８−、−ＳＯ_２ＮＲ^８−、−ＮＲ^８ＣＯ−、−ＮＲ^８ＳＯ_２−、−ＯＣ(Ｏ)−、−Ｃ(Ｏ)Ｏ−、−ＨＣ＝ＣＨ−またはエチニレンであり；
Ｒ^７は環基Ｃｙｃ^１またはＣ_１−４アルキル基であり、該Ｃ_１−４アルキル基は、場合によりハロゲン、ヒドロキシル、Ｃ_１−４アルコキシ、ＮＨ_２、ＮＨ(Ｃ_１−４アルキル)、Ｎ(Ｃ_１−４アルキル)_２、環基Ｃｙｃ^２および−ＯＣｙｃ^２から独立して選択される１個以上の置換基で置換されていてよく；そしてＱがＯ、ＮＲ^８、−ＣＯＮＲ^８−、−ＳＯ_２ＮＲ^８−、−Ｃ(Ｏ)Ｏ−、−ＨＣ＝ＣＨ−またはエチニレンであるとき、Ｒ^７は、さらに水素であってよく； R ⁴ represents formula (II) or (IIIa) or (IIIb);

Where
Y _-CH 2 is -, - _{CH 2 CH} 2 - or _-CH 2 _CH 2 CH ₂ - is and the substituents ring group (II) may be present in the 3- or 4-position;
a is 1 or 2;
b is 1 or 2;
Z is —CH ₂ —;
R ⁵ represents formula (IV)

Where
w is 0 or 1;
R ⁶ is optionally one or more substituents independently selected from halogen, hydroxyl, C _1-6 alkoxy, NH ₂ , NH (C _1-6 alkyl) and N (C _1-6 alkyl) ₂ C _1-4 alkylene _optionally substituted with:
when w is 0, y is 0; when w is 1, y is 0 or 1;
Q is O, S (O) _0-2 , NR ⁸ , —CONR ⁸ —, —SO ₂ NR ⁸ —, —NR ⁸ CO—, —NR ⁸ SO ₂ —, —OC (O) —, —C ( O) O—, —HC═CH— or ethynylene;
R ⁷ is a cyclic group Cyc ¹ or a C _1-4 alkyl group, wherein the C _1-4 alkyl group is optionally halogen, hydroxyl, C _1-4 alkoxy, NH ₂ , NH (C _1-4 alkyl), Optionally substituted with one or more substituents independently selected from N (C _1-4 alkyl) ₂ , the cyclic groups Cyc ² and —OCyc ² ; and Q is O, NR ⁸ , —CONR ⁸ —. , —SO ₂ NR ⁸ —, —C (O) O—, —HC═CH— or ethynylene, R ⁷ may further be hydrogen;

Cyc ¹ and Cyc ² are each independently an aryl, heteroaryl, 3-8 membered aliphatic carbocyclic ring or 4-8 membered aliphatic heterocyclic ring, each of which is optionally halogen, cyano, nitro , SH, S (O) _0-2 R ⁹ , NR ¹⁰ R ¹¹ , S (O) ₂ NR ¹² R ¹³ , C (O) NR ¹⁴ R ¹⁵ , C (O) ₂ R ¹⁶ , NR ¹⁷ S (O ) Independently selected from ₂ R ¹⁸ , NR ¹⁹ C (O) R ²⁰ , NR ²¹ C (O) ₂ R ²² , NR ²³ C (O) NR ²⁴ R ²⁵ , OR ²⁶ , phenyl and C _1-6 alkyl Optionally substituted with one or more substituents, wherein the phenyl or C _1-6 alkyl is optionally halogen, hydroxyl, C _1-6 alkoxy, NH ₂ , NH (C _1-6 alkyl) and N (C _1-6 alkyl) independently of ₂ May be substituted with one or more selected substituents;
R ⁸ is hydrogen or C _1-6 alkyl;
R ⁹ and ^{R 18} are each independently _{C 1-6} alkyl, wherein _{C 1-6} alkyl is optionally halogen, _{hydroxyl, C 1-6} alkoxy, _NH 2, NH _{(C 1-6} alkyl) and May be substituted with one or more substituents independently selected from N (C _1-6 alkyl) ₂ ; and R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ^16. , R ¹⁷ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are each independently hydrogen or C _1-6 alkyl, wherein the C _1-6 alkyl is Substituted with one or more substituents independently selected from halogen, hydroxyl, C _1-6 alkoxy, NH ₂ , NH (C _1-6 alkyl) and N (C _1-6 alkyl) ₂ either good; or ^{R 1} And ^{R 11, R 12} and ^{R 13,} either ^{R 14} and ^{R 15} or ^{R 24} and ^{R 25} are, by their together with the nitrogen atom to have both attached, 4-8 membered aliphatic heterocyclic ring may form wherein ring, the heterocyclic ring is optionally halogen, it may be substituted with one or more substituents independently selected from hydroxyl and C _1-6 alkyl, wherein C _{1- 6} alkyl may be optionally substituted with one or more substituents independently selected from halogen and hydroxyl;
And X is a pharmaceutically acceptable anion of a monovalent or polyvalent acid]
Of the compound.

SUMMARY OF THE INVENTION The present invention provides compounds that fall within the scope of our co-pending application PCT / GB2007 / 004350, but are not specifically disclosed.

The present invention therefore provides a compound comprising a quaternary ammonium species selected from the group consisting of:
(R) -1-[(6-Methyl-pyridin-3-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -1-[(6-Methyl-pyrazin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1-[(6-trifluoromethyl-pyridazin-3-ylcarbamoyl) -methyl] -1-azonia-bicyclo [2.2.2] Octane X;
(R) -1- (benzo [d] isoxazol-3-ylcarbamoylmethyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1- (pyridazin-3-ylcarbamoylmethyl) -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(5-Methyl-isoxazol-3-ylcarbamoyl) -methyl] -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane X;
(R) -1-[(3-Methyl-isoxazol-5-ylcarbamoyl) -methyl] -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane X;
(R) -1-[(3-Fluoro-phenylcarbamoyl) -methyl] -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -1-[(5-Methyl-pyrazin-2-ylcarbamoyl) -methyl] -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane X;
(R) -1- (Benzo [d] isoxazol-3-ylcarbamoylmethyl) -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1- (pyrazin-2-ylcarbamoylmethyl) -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -3- [1- (3-Fluoro-phenyl) -cycloheptanecarbonyloxy] -1- (pyrazin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -3- [1- (3-Fluoro-phenyl) -cycloheptanecarbonyloxy] -1- (isoxazol-3-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyridin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyridin-4-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(5-Fluoro-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -1-[(5-Methyl-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;

(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyridin-3-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(2-Methyl-pyridin-4-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -1-phenylcarbamoylmethyl-3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyrimidin-4-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(2-fluoro-phenylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(2,3-difluoro-phenylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1- [2- (2,3-Dihydro-benzofuran-5-yl) -ethyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2 ] Octane X;
(R) -1- [2- (4-Fluoro-phenoxy) -ethyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyridazin-4-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(5-Fluoro-pyridin-3-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- [2- (pyridin-3-yloxy) -ethyl] -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(6-Methyl-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (o-tolylcarbamoyl-methyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (2-pyrazin-2-yl-ethyl) -1-azonia-bicyclo [2.2.2] octane X;
(S) -1- (3-phenoxy-propyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-{[2- (3-Fluoro-phenoxy) -ethylcarbamoyl] -methyl} -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] Octane X;
(R) -1-[(3,5-difluoro-phenylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1- [2- (4-Methoxy-benzyloxy) -ethyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1- (2-phenethyloxy-ethyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(2,6-difluoro-phenylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(methyl-phenyl-carbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;

(R) -1- [3- (4-Cyano-phenoxy) -propyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(2,5-difluoro-phenylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1- [2- (4-cyano-benzyloxy) -ethyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1-[(6-trifluoromethyl-pyridin-2-ylcarbamoyl) -methyl] -1-azonia-bicyclo [2.2.2] Octane X;
(R) -1-[(4-Methyl-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -1-[(5-Chloro-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (p-tolylcarbamoyl-methyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (m-tolylcarbamoyl-methyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1- (oxazol-2-ylcarbamoylmethyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(6-Methyl-pyridazin-3-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyrimidin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(5-Cyano-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyrimidin-5-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(3-Fluoro-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -1-[(3-Fluoro-pyridin-4-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- {2-[(pyrazine-2-carbonyl) -amino] -ethyl} -1-azonia-bicyclo [2.2.2] octane X;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-([1,2,4] thiadiazol-5-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- {3-[(pyridine-2-carbonyl) -amino] -propyl} -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(2-Methyl-pyrimidin-4-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -1-[(6-Methyl-pyrimidin-4-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- {2-[(pyridine-2-carbonyl) -amino] -ethyl} -1-azonia-bicyclo [2.2.2] octane X; and
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (3-pyridin-4-yl-propyl) -1-azonia-bicyclo [2.2.2] octane X;
(Wherein X is a pharmaceutically acceptable anion of a monovalent or polyvalent acid).

  The compounds of formula (I) above and the compounds of the present invention contain an anion X that binds to the positive charge of the quaternary nitrogen atom. Anion X can be a pharmaceutically acceptable anion of any monovalent or polyvalent (eg, divalent) acid. In one embodiment of the invention, X is an anion of a mineral acid such as chloride, bromide, iodide, sulfate, nitrate or phosphate; or an anion of a suitable organic acid such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate Methanesulfonate, p-toluenesulfonate, benzenesulfonate, napadisylate (naphthalene-1,5-disulfonate) (eg heminapadisylate), 2,5-dichlorobenzenesulfonate, 1-hydroxynaphthalene-2-sulfonate or xinafoate ( 1-hydroxy-2-naphthoate).

(式中、Ｘは一価または多価酸の薬学的に許容されるアニオンである)。 The present invention also provides a compound selected from the group consisting of:

(Wherein X is a pharmaceutically acceptable anion of a monovalent or polyvalent acid).

  It will be appreciated that certain compounds of the present invention may exist in solvated, eg hydrated, as well as unsolvated forms. The present invention should be understood to include all such solvated forms. Certain compounds of the present invention may exist as tautomers. Tautomers and mixtures thereof also constitute an aspect of the present invention.

The compounds of the present invention exhibit valuable pharmaceutical properties. For example, the compounds of the invention the muscarinic receptor, in particular show activity as antagonists of the muscarinic M ₃ receptors. In addition, the compounds also exhibit the desired plasma protein binding properties. Plasma protein binding can be a beneficial property for compounds administered by inhalation because they can reduce the effects of any systemic side effects that the compounds may have.

The compounds of the present invention have activity as pharmaceuticals, particularly as anticholinergics, including muscarinic receptor (M1, M2, and M3) antagonists, particularly M3 antagonists. Diseases and conditions that can be treated with the present compounds include the following:
1. Respiratory: Airway obstructive disease including: both intermittent and persistent, and all severity bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (aspirin Bronchitis, including dust-induced asthma, and other causes of airway hyperresponsiveness; chronic obstructive pulmonary disease (COPD); infectious and eosinophilic bronchitis Emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonia; unexplained fibrotic alveolitis; idiopathic fibrotic alveolitis; idiopathic interstitial pneumonia; Fibrosis as a complication of tumor treatment and pulmonary fibrosis, including chronic infections, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the pulmonary vasculature , Line Pulmonary hypertension; chronic cough associated with inflammatory and secretory abnormalities of the respiratory tract, and antitussive activity including treatment of iatrogenic cough; acute and chronic rhinitis including drug-induced rhinitis, and vasomotor rhinitis; Perennial and seasonal allergic rhinitis including neural rhinitis (hay fever); nasal polyposis; acute viral infections including the common cold, and respiratory syncytial virus, influenza virus, coronavirus (including SARS) or adeno Infectious diseases caused by viruses;

2. Bones and joints: primary and, for example, arthritis associated with or including osteoarthritis / osteoarthritis, both secondary to congenital hip dysplasia; cervical and lumbar spondylitis Rheumatoid arthritis and Still's disease; ankylosing spondylitis, psoriatic arthritis, reactive arthritis and spondarthropathy, including seronegative spondyloarthropathy; septic arthritis and others Tuberculosis including arthopathies and bone disorders such as Pott disease and Ponce disease; acute and chronic crystals including urate gout, calcium pyrophosphate deposition, and calcium apatite-related tendons, bursa and synovial inflammation Induced synovitis; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and localized scleroderma; systemic lupus erythematosus Mixed connective tissue disease and undifferentiated connective tissue disease; inflammatory myopathy including dermatomyositis and polymyositis; polymyalgia rheumatica; juvenile arthritis including idiopathic inflammatory arthritis of any joint distribution And related syndromes, and rheumatic fever and systemic complications; giant cell arteritis, Takayasu arteritis, Churg-Strauss syndrome, nodular polyarteritis, microscopic polyarteritis, and viral infections, hypersensitivity reactions, cryo Vasculitis, including vasculitis associated with globulins and paraproteins; lower back pain; familial Mediterranean fever, Maccle Wells syndrome, and Familial Hibernian Fever, Kikuchi disease; drug-induced joints Pain (arthalgias), tendonitis (tendonititides), and myopathy;

3. Pain and connective tissue remodeling of musculoskeletal disorders due to injury [eg motor injury] or disease: arthritiss (eg rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy), other joint diseases (eg Disc degeneration or temporal mandibular joint degeneration), bone remodeling diseases (e.g. osteoporosis, Paget's disease or osteonecrosis), polychondritis, scleroderma, mixed connective tissue disorders, spondyloarthropathy or periodontal diseases (e.g. Periodontitis);

4. Skin: psoriasis, atopic dermatitis, contact dermatitis or other eczema dermatitis, and delayed type hypersensitivity reaction; vegetative and photodermatitis; seborrheic dermatitis, herpetic dermatitis, lichen planus Psoriasis, sclerotrophic lichen, gangrenous pyoderma, cutaneous sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, hives, angioedema, vasculitis, toxic erythema, cutaneous eosinophil Cytomegaly, alopecia areata, androgenetic baldness, Sweet syndrome, Weber-Christian syndrome, erythema multiforme; both infectious and non-infectious cellulitis; panniculitis; cutaneous lymphoma, nonmelanoma skin cancer and Other dysplastic lesions; drug-induced disorders including fixed drug eruption;

5. Eyes: blepharitis; including perennial and spring allergic conjunctivitis; conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmunity; degenerative or inflammatory disorders affecting the retina; Ophthalmitis including ophthalmitis; sarcoidosis; infections including viral, fungal, and bacterial;

6. Gastrointestinal tract: glossitis, gingivitis, periodontitis; esophagitis including reflux; eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, proctitis, anal pruritus; celiac disease Colitis, including irritable bowel syndrome, and food-related allergies that can act away from the intestine (eg migraine, rhinitis or eczema);

7. Abdomen: hepatitis including autoimmunity, alcoholic and viral; liver fibrosis and cirrhosis; cholecystitis; both acute and chronic pancreatitis;

8. Urogenital: Nephritis including interstitial and glomerulonephritis; Nephrotic syndrome; Cystitis including acute and chronic (interstitial) cystitis and Hanner ulcer; Acute and chronic urethritis, prostatitis, epididymis Ovarian and fallopianitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both men and women);

9. Allograft rejection: for example, acute and chronic transplant rejection after transplantation or post-transfusion of kidney, heart, liver, lung, bone marrow, skin or retina; or chronic graft-versus-host disease;

10. CNS: Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; Myasthenia gravis; neuropathies including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain caused by cancer and tumor invasion, diabetic, postherpetic, and HIV-related neuropathy Acute and chronic pain, including pain syndrome (acute, intermittent or permanent of either central or peripheral origin); neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes;

11. Other autoimmune and allergic disorders, including Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome ;

12. Other disorders with inflammatory or immunological components; including acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome, and neoplastic paradoxes;

13. Cardiovascular: atherosclerosis affecting coronary vessels and peripheral circulation; pericarditis; myocarditis, including myocardial sarcoid, inflammatory and autoimmune cardiomyopathy; ischemia reperfusion injury; infectious (eg syphilis) Prosthetic), endocarditis, valvitis, and aortitis; vasculitis; disorders of proximal and peripheral veins, including phlebitis and thrombosis, including complications of deep vein thrombosis and varicose veins;

14. Oncology: prostate, breast, lung, ovary, pancreas, intestine and colon, stomach, skin and brain tumors and malignant tumors affecting the bone marrow (including leukemia) and lymphoproliferative system, including Hodgkin and non-Hodgkin lymphoma, General cancer treatment; including prevention and treatment of metastasis and tumor recurrence, and paraneoplastic syndromes; and

15. Gastrointestinal tract: Celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminate colitis, irritable bowel disorder, irritable bowel syndrome, Non-inflammatory diarrhea, food-related allergies that develop at sites away from the intestine, such as migraine, rhinitis and eczema.

  The invention therefore further provides a compound of the invention as defined above for use in therapy.

  In another aspect, the present invention provides the use of a compound of the invention as defined above in the manufacture of a medicament for use in therapy.

  In the context of the present specification, the term “treatment” also includes “prophylaxis” unless there are different specific indications. The terms “therapeutic” and “therapeutically” should be construed accordingly.

  A further aspect of the present invention is a method of treating or preventing a disease state in a mammal having or at risk of a disease, wherein the compound of the invention as defined above is in a therapeutically effective amount in a mammal in need of such treatment. A method is provided comprising administering.

  The invention also provides a compound of the invention as defined above for the treatment of chronic obstructive pulmonary disease (COPD) (eg irreversible COPD).

  The invention also provides a compound of the invention as defined above for the treatment of asthma.

  The invention also provides the use of a compound of the invention as defined above for chronic obstructive pulmonary disease (COPD) (eg irreversible COPD).

  The invention also provides the use of a compound of the invention as defined above for the treatment of asthma.

  The invention also provides the use of a compound of the invention as defined above in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease (COPD) (eg irreversible COPD).

  The invention also provides the use of a compound of the invention as defined above in the manufacture of a medicament for the treatment of asthma.

  The present invention further provides a method of treating chronic obstructive pulmonary disease (COPD) (eg, irreversible COPD) in a warm-blooded animal, eg, a human, wherein the effective amount of the book is as defined above for a mammal in need of such treatment. A method is provided comprising administering a compound of the invention.

  The invention further provides a method of treating asthma in a warm-blooded animal, eg, a human, comprising administering to a mammal in need of such treatment an effective amount of a compound of the invention as defined above. To do.

  In order to use the compounds of this invention for therapeutic treatment of warm-blooded animals such as humans, the components are usually formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice.

  Thus, in another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention as defined above and a pharmaceutically acceptable adjuvant, diluent or carrier. In a further aspect, the present invention provides a method for making the composition comprising mixing the active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the dosage form, the pharmaceutical composition may be, for example, 0.05 to 99% w (weight percent), such as 0.05 to 80% w, such as 0.10 to 70% w, such as 0.10 to 50% w. All weight percentages are based on total composition.

  The pharmaceutical compositions of the invention may be administered in a standard manner for the disease state desired to be treated, for example by topical (eg lung and / or respiratory tract or skin), oral, rectal or parenteral administration. For these purposes, the compounds of the invention can be obtained by means known in the art, e.g. aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions (lipids ) Emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions may be formulated.

  Suitable pharmaceutical compositions of the invention are those suitable for oral administration in unit dosage form, eg tablets or capsules, containing 0.1 mg to 1 g of active ingredient.

In other aspects, the pharmaceutical composition of the invention is suitable for intravenous, subcutaneous or intramuscular injection. Each patient may receive an intravenous, subcutaneous or intramuscular dose of, for example, 0.01 mgkg ^{−1 to} 100 mgkg ⁻¹ , for example 0.1 mgkg ^{−1 to} 20 mgkg ⁻¹ of a compound of the invention, Administer 1 to 4 times daily. Intravenous, subcutaneous and intramuscular doses may be given by means of bolus injection. Alternatively, intravenous doses may be given by continuous infusion over a period of time. Alternatively, each patient receives a daily oral dose approximately equivalent to the parenteral dose, and the composition is administered 1 to 4 times daily.

  Other suitable pharmaceutical compositions of the invention are those suitable for inhalation administration, which is particularly useful for treating compounds of the invention when treating respiratory diseases such as chronic obstructive pulmonary disease (COPD) or asthma. This is a useful method of administration. When administered by inhalation, the compounds of the present invention are in the μg range, eg 0.1-500 μg, 0.1-50 μg, 0.1-40 μg, 0.1-30 μg, 0.1-20 μg, 0.1-10 μg. Effective at doses of 5-10 μg, 5-50 μg, 5-40 μg, 5-30 μg, 5-20 μg, 5-10 μg, 10-50 μg, 10-40 μg, 10-30 μg, or 10-20 μg active ingredient Can be used.

  In one embodiment of the invention there is provided a pharmaceutical composition comprising a compound of the invention as defined above formulated for administration by inhalation together with a pharmaceutically acceptable adjuvant, diluent or carrier.

  When administered by inhalation, the active ingredient is dispersed in a suitable propellant with or without further excipients such as ethanol, surfactants, smoothing agents or stabilizers May be used for administration of Suitable propellants are hydrocarbon, chlorofluorocarbon and hydrofluoroalkane (eg heptafluoroalkane) propellants, or a mixture of such propellants. Preferred propellants are P134a and P227, each of which may be used alone or in combination with other propellants and / or surfactants and / or other excipients. Nebulizable aqueous suspensions or, preferably, solutions may also be used as unit dose or multi-dose formulations with or without appropriate pH and / or adjustment.

  A dry powder inhaler may be used for administration of the active ingredient alone or in combination with a pharmaceutically acceptable carrier, in the latter case as a pulverized powder or as an ordered mixture . A dry powder inhaler may be a single dose or multiple doses and may utilize a dry powder or a powder-containing capsule.

  Metered dose inhalers, nebulizers and dry powder inhalers are known and a variety of such devices are available.

  The invention further provides for the treatment of one or more of the described conditions with a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention simultaneously with one or more other therapeutic agents or It relates to combination therapy, including administering sequentially or as a combination formulation.

  Especially for the treatment of inflammatory diseases such as (but not limited to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis, and inflammatory bowel disease The compounds of the invention can be combined with the following agents:

  Non-selective cyclooxygenase COX-1 / COX-2 inhibitors (eg piroxicam, diclofenac, propionic acid such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, phenamates such as mefenam, whether topical or systemic Non-steroidal anti-inflammatory drugs (hereinafter NSAIDs) including acids, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin; selective COX-2 inhibitors such as meloxicam, celecoxib, rofecoxib, valdecoxib, Lumarocoxib, parecoxib and etoroxib); cyclooxygenase-inhibiting nitric oxide donor (CINOD); glucocorticosteroid (local, oral, intramuscular, Methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofin or other parenteral or oral gold preparations; analgesics; diacerein; Eg, hyaluronic acid derivatives; and nutritional supplements such as glucosamine.

  The present invention still further includes compounds of the present invention with alpha-, beta-, and gamma-interferon; insulin-like growth factor type I (IGF-1); IL including interleukin (IL) 1-17, and inter Inhibitors such as leukin antagonists or anakinra; tumor necrosis factor alpha (TNF-α) inhibitors such as anti-TNF monoclonal antibodies (eg, infliximab; adalimumab, and CDP-870) and TNF receptors including immunoglobulin molecules (eg, etanercept) In combination with body antagonists and low molecular weight agents such as pentoxifylline, including cytokines or agonists or antagonists of cytokine function (acting on cytokine signaling pathways such as modulators of SOCS systems) To.

  In addition, the present invention relates to a combination of a compound of the present invention and a monoclonal antibody that targets B lymphocytes (eg CD20 (rituximab), MRA-aILl6R and T lymphocytes, CTLA4-Ig, HuMax Il-15).

The present invention still further relates to compounds of the present invention and modulators of chemokine receptor function such as CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (C-C Family for); CXCR1, CXCR2, CXCR3, the CXCR4 and CXCR5 (CX-C family) and a combination of antagonists of _CX 3 CR1 for the _CX 3 -C family.

  The present invention further includes matrix metalloprotease (MMP) inhibitors, ie stromelysin, collagenase, and gelatinase, and aggrecanase; in particular collagenase-1 (MMP-), comprising a compound of the invention and an agent such as doxycycline. 1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 ( MMP-11) and a combination of MMP-9 and MMP-12.

  The present invention still further relates to a compound of the present invention and a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist, eg; zileuton; ABT-761; Tepoxaline; Abbott-79175; Abbott-85761; N- (5-substituted) -thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenol hydrazone; methoxytetrahydropyran such as Zeneca ZD-2138; -210661; pyridinyl-substituted 2-cyanonaphthalene compounds such as L-739,010; 2-cyanoquinoline compounds such as L-746,530; or indole or quinoline compounds such as MK-591, MK-886, and BAY x 1005.

  The present invention further includes a compound of the present invention and a phenothiazine-3-1s, such as L-651,392; an amidino compound, such as CGS-25019c; a benzoxalamine, such as ontazolast; a benzenecarboximidamide, such as BIIL 284/260; Selected from the group consisting of compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195 A combination of leukotriene (LT) B4, LTC4, LTD4, and LTE4 receptor antagonists.

  The present invention still further comprises a selective PDE comprising a compound of the invention and a phosphodiesterase (PDE) inhibitor, for example, methylxanthanine including theophylline and aminophylline; a PDE4 inhibitor or a PDE5 inhibitor including an isoform PDE4D inhibitor. It relates to a combination of isozyme inhibitors.

  The present invention further applies to the compounds of the present invention orally, topically or parenterally; histamine type 1 receptor antagonists such as cetirizine, loratadine, desloratadine, fexofenadine, acribastine, terfenadine, It relates to combinations of astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclidine, or mizolastine.

  The present invention still further relates to the combination of a compound of the invention and a proton pump inhibitor (eg omeprazole) or a gastroprotective histamine type 2 receptor antagonist.

  The invention further relates to the combination of a compound of the invention and an antagonist of the histamine type 4 receptor.

  The present invention still further relates to compounds of the present invention and alpha-1 / alpha-2 adrenergic receptor agonist vasoconstrictor sympathomimetics such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydro It relates to a combination of chloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethyl norepinephrine hydrochloride.

  The present invention still further includes a compound of the present invention and a beta-adrenergic receptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, vitorterol mesi It relates to a combination of rate, pyrbuterol, or indacaterol or its chiral enantiomer.

  The invention further relates to the combination of a compound of the invention and a chromone, such as sodium cromoglycate or nedocromil sodium.

  The present invention still further relates to the combination of a compound of the invention and a glucocorticoid, for example flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.

  The invention further relates to the combination of a compound of the invention and an agent that modulates a nuclear hormone receptor, such as PPAR.

  The present invention still further relates to the combination of a compound of the invention and an immunoglobulin (Ig) or Ig preparation or antagonist or an antibody that modulates Ig function, such as anti-IgE (eg omalizumab).

  The invention further relates to the combination of a compound of the invention and other systemically or topically applied anti-inflammatory agents such as thalidomide or derivatives thereof, retinoids, dithranol or calcipotriol.

The present invention still further includes a combination of a compound of the invention and an aminosalicylate and sulfapyridine, such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and an immunomodulator, such as thiopurine, and a corticosteroid, such as budesonide. Related to the combination.

  The present invention further includes compounds of the present invention and antibacterial agents such as penicillin derivatives, tetracyclines, macrolides, beta-lactams, fluoroquinolones, metronidazoles, inhaled aminoglycosides; acyclovir, famciclovir, valacyclovir, ganciclovir, cidofovir, amantadine Antiviral agents including rimantadine, ribavirin, zanamavir and oseltamavir; protease inhibitors such as indinavir, nelfinavir, ritonavir and saquinavir; nucleoside reverse transcriptase inhibitors such as didanosine, lamivudine, stavudine, sarcitabine or Or a combination of non-nucleoside reverse transcriptase inhibitors such as nevirapine or efavirenz.

  The present invention still further relates to compounds of the invention and cardiovascular agents such as calcium channel blockers, beta-adrenergic receptor blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin-2 receptor antagonists; lipid lowering agents such as Statins or fibrates; modulators of blood cell morphology such as pentoxifylline; thrombolysis, or anticoagulants such as platelet aggregation inhibitors.

  The present invention further includes compounds of the present invention and CNS agents such as antidepressants (e.g., sertraline), antiparkinson agents (e.g., deprenyl, L-dopa, ropinirole, pramipexole, MAOB inhibitors such as selegiline and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine agonists, dopamine agonists or inhibitors of neuronal nitric oxide synthase), or anti-Alzheimer agents such as donepezil, rivastigmine, It relates to a combination of tacrine, a COX-2 inhibitor, propentophilin or metrifonate.

  The present invention still further relates to compounds of the present invention and acute or chronic pain treatment agents, such as centrally or peripherally acting analgesics (e.g. opioids or derivatives thereof), carbamazepine, phenytoin, sodium valloproate, amitriptyline ( amitryptiline) or other antidepressant, paracetamol, or a combination of non-steroidal anti-inflammatory agents.

  The invention further relates to the combination of a compound of the invention and a local anesthetic (including inhalation) applied parenterally or topically, for example lignocaine or a derivative thereof.

  The compounds of the present invention can also be used in combination with anti-osteoporotic agents, including hormonal agents such as raloxifene, or biphosphonates such as alendronate.

  The present invention still further includes a compound of the present invention: (i) a tryptase inhibitor; (ii) a platelet activating factor (PAF) antagonist; (iii) an interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibition Agents (v) adhesion molecule inhibitors including VLA-4 antagonists; (vi) cathepsins; (vii) kinase inhibitors such as tyrosine kinases (eg Btk, Itk, Jak3 or MAP such as gefitinib or imatinib mesylate), serine / Threonine kinases (eg MAP kinase inhibitors such as p38, JNK, protein kinase A, B or C, or IKK) or inhibitors of kinases involved in the cell cycle (eg cyclin dependent kinases); (viii) glucose- 6-phosphate dehydrogenase inhibitors; (ix) kinin-B1.- or B2 .. receptor antagonists; x) anti-gout agents such as colchicine; (xi) xanthine oxidase inhibitors such as allopurinol; (xii) uric acid excretion promoters such as probenecid, sulfinpyrazone or benzbromarone; (xiii) growth hormone secretagogues; (Xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor such as basic fibroblast growth factor (bFGF); (xvii) granulocyte-macrophage colony-stimulating factor (GM-CSF); (xviii) capsaicin cream; (xix) tachykinin NK1 or NK3 receptor antagonists such as NKP-608C, SB-233412 (talnetant) or D-4418; (xx) elastase inhibitors such as UT-77. Or ZD-0892; (xxi) TNF-alpha converting enzyme inhibitor (TACE); (xxii) inducible monoacid A nitrogen synthase (iNOS) inhibitor; (xxiii) a chemoattractant receptor homologous molecule expressed on TH2 cells (eg, a CRTH2 antagonist); (xxiv) a P38 inhibitor; (xxv) a toll-like receptor (TLR) Agents that modulate function, (xxvi) agents that modulate purinergic receptor function, such as P2X7; or (xxvii) transcription factor activation inhibitors such as NFkB, API, or STATS.

The compounds of the invention can also be used in combination with existing therapeutic agents for the treatment of cancer, for example suitable agents include:
(i) anti-proliferative / anti-neoplastic agents or combinations thereof used in medical oncology, such as alkylating agents (eg cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan or Nitrosourea); antimetabolites (eg antifolates, eg fluoropyrimidines such as 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); antitumor antibiotics (eg anthracyclines) Eg, adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mitramycin); Ca alkaloids, such as vincristine, vinblastine, vindesine or vinorelbine, or a taxoid, e.g. taxol or taxotere); or topoisomerase inhibitors (for example epipodophyllotoxins, e.g., etoposide, teniposide, amsacrine, topotecan or a camptothecin);
(ii) cytostatics such as antiestrogens (e.g. tamoxifen, toremifene, raloxifene, droloxifene or iodoxifene), estrogen receptor downregulators (e.g. fulvestrant), antiandrogens (e.g. bicalutamide, flutamide, nilutamide) Or cyproterone acetate), LHRH antagonists or LHRH agonists (e.g. goserelin, leuprorelin or buserelin), progestogens (e.g. megestrol acetate), aromatase inhibitors (e.g. like anastrozole, letrozole, borazole or exemestane) Or a 5α-reductase inhibitor, such as finasteride;
(iii) agents that inhibit cancer cell invasion (eg, metalloproteinase inhibitors, such as inhibitors of marimastat or urokinase plasminogen activator receptor function);
(iv) Growth factor function inhibitors, eg: growth factor antibodies (eg anti-erbb2 antibody trastuzumab or anti-erbb1 antibody cetuximab [C225]), farnesyltransferase inhibitors, tyrosine kinase inhibitors or serine / threonine kinase inhibitors, epithelial cells Growth factor family inhibitors (eg EGFR family tyrosine kinase inhibitors such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, AZD1839) N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamide- N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) quinazolin-4-amine (CI 1033)) A platelet-derived growth factor family inhibitor, or a hepatocyte growth factor family inhibitor;

(v) anti-angiogenic agents such as those that block the action of vascular endothelial growth factor (eg anti-vascular endothelial growth factor antibody bevacizumab, compounds disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354) ), Or compounds that act by other mechanisms (eg, inhibitors of linomide, integrin αvβ3 function or angiostatin);
(vi) a vascular injury agent such as combretastatin A4 or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;
(vii) agents used for antisense therapy, such as those directed to one of the above targets, such as ISIS 2503, anti-ras antisense;
(viii) Gene therapy approaches such as approaches to replace abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene directed enzyme prodrug therapy) approaches such as cytosine deaminase, thymidine kinase or bacterial nitroreductase enzymes And approaches to increase patient tolerance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy; or
(ix) immunotherapeutic approaches such as ex vivo and in vivo approaches that enhance the immunogenicity of patient tumor cells such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor, T cell anergy Approaches to reduce, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines and approaches using anti-idiotype antibodies.

In a further aspect, the present invention provides a first active ingredient which is a compound of the invention as described above, and:
A phosphodiesterase inhibitor, a β2 adrenergic receptor agonist, a chemokine receptor function modulator, a kinase function inhibitor, a protease inhibitor, a steroidal glucocorticoid receptor agonist, and a nonsteroidal glucocorticoid receptor agonist, Provided is a medicament comprising a combination of at least one further active ingredient.

The medicament of this embodiment can be, for example, a pharmaceutical composition comprising a mixture of the first and further active ingredients. Alternatively, the medicament may comprise, for example, the first and further active ingredients in separate pharmaceutical formulations suitable for simultaneous, sequential or separate administration to a patient in need thereof.
The medicament of this aspect is particularly useful for the treatment of respiratory diseases such as asthma, COPD or rhinitis.

Phosphodiesterase inhibitors that can be used in this aspect of the medicament include PDE4 inhibitors, such as inhibitors of isoform PDE4D, PDE3 inhibitors and PDE5 inhibitors. Examples are compounds
(Z) -3- (3,5-dichloro-4-pyridyl) -2- [4- (2-indanyloxy-5-methoxy-2-pyridyl] propenenitrile,
N- [9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo [3,2,1-jk] [1,4] benzodiazepin-3 (R) -yl] pyridine- 3-carboxamide (CI-1044)
3- (benzyloxy) -1- (4-fluorobenzyl) -N- [3- (methylsulfonyl) phenyl] -1H-indole-2-carboxamide,
(1S-exo) -5- [3- (bicyclo [2.2.1] hept-2-yloxy) -4-methoxyphenyl] tetrahydro-2 (1H) -pyrimidinone (achizolam),
N- (3,5, dichloro-4-pyridinyl) -2- [1- (4-fluorobenzyl) -5-hydroxy-1H-indol-3-yl] -2-oxoacetamide (AWD-12-281) ,
β- [3- (cyclopentyloxy) -4-methoxyphenyl] -1,3-dihydro-1,3-dioxo-2H-isoindole-2-propanamide (CDC-801),
N- [9-Methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo [3,2,1-jk] [1,4] benzodiazepin-3 (R) -yl] pyridine- 4-carboxamide (CI-1018),
cis- [4-Cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid (silomilast)
8-amino-1,3-bis (cyclopropylmethyl) xanthine (cipamfylline)
N- (2,5-dichloro-3-pyridinyl) -8-methoxy-5-quinolinecarboxamide (D-4418),
5- (3,5-di-tert-butyl-4-hydroxybenzylidene) -2-iminothiazolidin-4-one (Darbufelone),
2-methyl-1- [2- (1-methylethyl) pyrazolo [1,5-a] pyridin-3-yl] -1-propanone (ibudilast),
Methanesulfonic acid 2- (2,4-dichlorophenylcarbonyl) -3-ureidobenzofuran-6-yl (Lirimilast),
(−)-(R) -5- (4-methoxy-3-propoxyphenyl) -5-methyloxazolidine-2-one (mesopram),
(−)-Cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a, 10b-hexahydro-6- (4-diisopropylaminocarbonylphenyl) -benzo [c] [1, 6] Naphthyridine (Pumafentrine),
3- (cyclopropylmethoxy) -N- (3,5-dichloro-4-pyridyl) -4- (difluoromethoxy) benzamide (roflumilast),
N-oxide of roflumilast,
5,6-diethoxybenzo [b] thiophene-2-carboxylic acid (Tibenelast)
2,3,6,7-tetrahydro-2- (mesitylimino) -9,10-dimethoxy-3-methyl-4H-pyrimido [6,1-a] isoquinolin-4-one (trequinsin) and 3-[[3 -(Cyclopentyloxy) -4-methoxyphenyl] -methyl] -N-ethyl-8- (1-methylethyl) -3H-purin-6-amine (V-11294A)
including.

Β ₂ -adrenergic receptor agonists that can be used in this aspect of the medicament are metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol (eg as sulfate), formoterol (eg as fumarate), salmeterol (eg as (As xinafoate), terbutaline, orciprenaline, vitorterol (eg as mesylate), pyrbuterol or indacaterol. Β ₂ -adrenergic receptor agonists of this embodiment are long acting β ₂ -agonists such as salmeterol (eg as xinafoate), formoterol (eg as fumarate), bambuterol (eg as hydrochloride), carmoterol (TA 2005, chemically 2 (1H) -quinolone, 8-hydroxy-5- [1-hydroxy-2-[[2- (4-methoxy-phenyl) -1-methylethyl] -amino] ethyl]- Monohydrochloride, identified as [R- (R ^* , R ^* )], also identified by Chemical Abstract Service Registry Number 137888-11-0 and also described in US Pat. No. 4,579,854), indacaterol (CAS no 312753-06-3; QAB-149), formanilide derivatives such as 3- (4-{[6-({(2R) -2- [3- (formylamino)-] described in WO2002 / 76933 4-hydroxy Enyl] -2-hydroxyethyl} amino) hexyl] oxy} -butyl) -benzenesulfonamide, benzenesulfonamide derivatives such as 3- (4-{[6-({(2R) -2] described in WO2002 / 88167 -Hydroxy-2- [4-hydroxy-3- (hydroxy-methyl) phenyl] ethyl} amino) -hexyl] oxy} butyl) benzenesulfonamide, an arylaniline receptor agonist described in WO2003 / 042164 and WO2005 / 025555, Indole derivatives as described in WO 2004/032921 and US 2005/222144 and the compounds GSK 159797, GSK 159802, GSK 597901, GSK 642444 and GSK 678007.

Modulators of chemokine receptor function that can be used in the medicament of this aspect include CCR1 receptor antagonists.
Inhibitors of kinase function that can be used in the medicament of this aspect include p38 kinase inhibitors and IKK inhibitors.
Protease inhibitors that can be used in the medicament of this embodiment include inhibitors of neutrophil elastase or inhibitors of MMP12.

  Steroidal glucocorticoid receptor agonists that can be used in the pharmaceutical of this embodiment include budesonide, fluticasone (eg as propionate), mometasone (eg as furoate), beclomethasone (eg 17-propionic acid or 17,21-diionic). (As propionate), ciclesonide, loteprednol (e.g. as etabonate), etipredonol (e.g. as dicloacetate), triamcinolone (e.g. as acetonide), flunisolide, zoticasone, flumoxonide, rofreponide, e.g. As), prednisolone, prednisone, tipredane, steroid esters such as 6α, 9α-difluoro-17α-[(2-furanylcarbonyl) Oxy] -11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid-fluoromethyl ester, 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo -17α-propionyloxy-androst-1,4-diene-17β-carbothioic acid- (2-oxo-tetrahydro-furan-3S-yl) ester and 6α, 9α-difluoro-11β-hydroxy-16α-methyl-17α -[(4-Methyl-1,3-thiazole-5-carbonyl) oxy] -3-oxo-androst-1,4-diene-17β-carbothioic acid-fluoromethyl ester, steroid esters according to DE 4129535, WO2002 / 00679, steroids according to WO 2005/041980, or sterol Id GSK 870086, GSK 685698 and GSK 799943.

  Modulators of non-steroidal glucocorticoid receptor agonists that can be used in the medicament of this embodiment can include those described in WO2006 / 046916.

  The invention is illustrated by the following non-limiting examples. In the examples, the following figures are shown:

The X-ray powder diffraction pattern of Form A of Example 14. The X-ray powder diffraction pattern of Form A of Example 15.

  In the examples, NMR spectra were obtained at a proton frequency of either 300 or 400 or 500 MHz on a Varian Unity Inova spectrometer, or at a proton frequency of either 400 or 500 MHz on a Bruker DRX spectrometer, or 600 MHz on a Bruker Avance spectrometer. Measured at a frequency or proton frequency of 300 MHz with a Bruker Avance DPX 300 spectrometer. MS spectra were measured on either an Agilent 1100 MSD G1946D spectrometer or a Hewlett Packard HP1100 MSD G1946A spectrometer or a Waters Micromass ZQ2000 spectrometer. The nomenclature was created using Autonom 2000 (version 4.01.305) software supplied by MDL.

  XRPD data was collected using either a PANalytical CubiX PRO machine or a PANalytical X-Pert machine.

X-ray powder diffraction-XRPD-PANalytical CubiX PRO
Data were collected on a PANalytical CubiX PRO machine in a θ-θ configuration, ranging from 2 ° to 40 ° 2θ, with a 100 second exposure per 0.02 ° increment. X-rays were generated with a copper long-precision focus tube operating at 45 kV and 40 mA. The wavelength of the copper X-ray was 1.5418 mm. Data was collected on a zero background holder with ˜2 mg of the compound. The holder was made of a single crystal of silicon, which was cut along a non-diffractive plane and then polished to an optical planar finish. X X-ray projection on this surface was canceled by Bragg quenching.

X-ray powder diffraction -PANalytical X-Pert
Data was collected on an ANalytical X-Pert machine, in a 2θ-θ configuration, ranging from 2 ° to 40 ° 2θ, with a 100 second exposure per 0.02 ° increment. X-rays were generated with a copper long-precision focus tube operating at 45 kV and 40 mA. The wavelength of the copper X-ray was 1.5418 mm. Data was collected on a zero background holder with ˜2 mg of the compound. The holder was made of a single crystal of silicon, which was cut along a non-diffractive plane and then polished to an optical planar finish. X X-ray projection on this surface was canceled by Bragg quenching.

  The DSC thermogram was measured using a TA Q1000 differential scanning calorimeter with an aluminum pan and a perforated lid. The sample weight varied between 0.5 and 5 mg. This step was performed at a test temperature of 25-300 ° C. under a nitrogen gas flow (50 ml / min), increasing the temperature at a constant rate of 10 ° C./min.

  TGA thermograms were measured with a TA Q500 Thermogravimetric Analyzer using a platinum pan. The sample weight varied from 1 to 5 mg. This step was carried out at a test temperature of 25-300 ° C. under a nitrogen gas flow (60 ml / min), increasing the temperature at a constant rate of 10 ° C./min.

  GVS profiles were measured using a Dynamic Vapor Sorption DVS-1 instrument. Approximately 4-10 mg of a solid sample was placed in a glass container and the sample weight was recorded during the dual cycle process (40-90-0-90-0% relative humidity (RH) at 10% RH stage).

Abbreviations used in the experimental chapter:
Aq = aqueous DCE = 1,2-dichloroethane DCM = dichloromethane DMF = dimethylformamide DMSO = dimethyl sulfoxide EtOAc = ethyl acetate EtOH = ethanol GVS = gravity vapor adsorption HATU = O- (7-azabenzotriazol-1-yl) -N , N, N ′, N′-tetramethyluronium hexafluorophosphate MeCN-acetonitrile MeOH = methanol RT = RT
Rt = retention time THF = tetrahydrofuran Satd = saturated DSC = differential scanning calorimetry TGA = T thermogravimetric analysis XRPD = X-ray powder diffraction

マグネシウム(１.２ｇ)の無水テトラヒドロフラン(６０mL)溶液に、窒素環境下に、１結晶のヨウ素、続いてブロモベンゼン(７.８５ｇ)を、反応が一定した還流を維持するような速度で添加した。反応混合物を２０分間撹拌し、次いでシクロヘプタノン(４.４８ｇ)を注意しながら添加した。１０分間撹拌後飽和水性塩化アンモニウム(１０mL)を添加し、反応を水(１００mL)およびイソヘキサン(１００mL)に分配した。有機層を乾燥させ(ＭｇＳＯ_４)、蒸発させて、副題化合物(７.６ｇ)を油状物として得た。
¹H NMR (300 MHz, CDCl₃) δ 7.53 - 7.47 (m, 2H), 7.36 - 7.29 (m, 2H), 7.26 - 7.19 (m, 1H), 2.07 (ddd, 2H), 1.97 - 1.50 (m, 11H)。 Example 1: (R) -1-[(6-Methyl-pyridin-3-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride a) 1-phenyl-cycloheptanol

To a solution of magnesium (1.2 g) in anhydrous tetrahydrofuran (60 mL), under a nitrogen environment, one crystal of iodine followed by bromobenzene (7.85 g) was added at such a rate that the reaction maintained a constant reflux. . The reaction mixture was stirred for 20 minutes and then cycloheptanone (4.48 g) was carefully added. After stirring for 10 minutes, saturated aqueous ammonium chloride (10 mL) was added and the reaction was partitioned between water (100 mL) and isohexane (100 mL). The organic layer was dried (MgSO ₄ ) and evaporated to give the subtitle compound (7.6 g) as an oil.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.53-7.47 (m, 2H), 7.36-7.29 (m, 2H), 7.26-7.19 (m, 1H), 2.07 (ddd, 2H), 1.97-1.50 (m , 11H).

１−フェニル−シクロヘプタノール(実施例１ａ)(７.６ｇ)をテトラヒドロフラン(１００mL)に溶解し、水素化ナトリウム(油中６０％、２.０ｇ)を添加した。反応を６０℃で５分間撹拌し、ヨードメタン(７.１ｇ)を添加した。混合物を６０℃で一夜維持し、次いでさらに水素化ナトリウム(油中６０％、２.０ｇ)およびヨードメタン(７.１ｇ)を添加し、反応を７０時間還流した。反応混合物を水(１００mL)およびイソヘキサン(１００mL)に分配し、有機層を分離し、乾燥させ(ＭｇＳＯ_４)、蒸発させて、副題化合物(１１.３１ｇ)を得た。
¹H NMR (300 MHz, CDCl₃) δ 7.43 - 7.37 (m, 2H), 7.37 - 7.30 (m, 2H), 7.24 - 7.19 (m, 1H), 2.98 (s, 3H), 2.12 - 1.88 (m, 4H), 1.88 - 1.45 (m, 8H)。 b) 1-methoxy-1-phenyl-cycloheptane

1-Phenyl-cycloheptanol (Example 1a) (7.6 g) was dissolved in tetrahydrofuran (100 mL) and sodium hydride (60% in oil, 2.0 g) was added. The reaction was stirred at 60 ° C. for 5 minutes and iodomethane (7.1 g) was added. The mixture was maintained at 60 ° C. overnight, then more sodium hydride (60% in oil, 2.0 g) and iodomethane (7.1 g) were added and the reaction was refluxed for 70 hours. The reaction mixture was partitioned between water (100 mL) and isohexane (100 mL) and the organic layer was separated, dried (MgSO ₄ ) and evaporated to give the subtitle compound (11.31 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.43-7.37 (m, 2H), 7.37-7.30 (m, 2H), 7.24-7.19 (m, 1H), 2.98 (s, 3H), 2.12-1.88 (m , 4H), 1.88-1.45 (m, 8H).

カリウム(２.６２ｇ)およびナトリウム(０.５２ｇ)を、一緒に、１２０℃で鉱油中、窒素環境下に３０分間加熱し、次いで室温に冷却した。油状物を取り、エーテル(１００mL)に変え、１−メトキシ−１−フェニル−シクロヘプタン(実施例１ｂ)(４.９ｇ)を添加し、反応を窒素下、一夜室温で撹拌した。反応を−７８℃に冷却し、固体二酸化炭素(〜２０ｇ)を撹拌しながら添加した。反応を室温に温め、水(１５０mL)を、窒素環境下に、注意深く添加した。水性層を分離し、濃塩酸で中和し、ジエチルエーテル(１５０mL)で抽出した。有機層を乾燥させ(ＭｇＳＯ_４)、蒸発させて、副題化合物(４.１５ｇ)を油状物として得た。
¹H NMR (300 MHz, CDCl₃) δ 7.40 - 7.20 (m, 5H), 2.49 - 2.35 (m, 2H), 2.16 - 2.03 (m, 2H), 1.76 - 1.47 (m, 8H)。 c) 1-phenyl-cycloheptanecarboxylic acid

Potassium (2.62 g) and sodium (0.52 g) were heated together at 120 ° C. in mineral oil under a nitrogen environment for 30 minutes and then cooled to room temperature. The oil was taken and changed to ether (100 mL), 1-methoxy-1-phenyl-cycloheptane (Example 1b) (4.9 g) was added and the reaction was stirred at room temperature overnight under nitrogen. The reaction was cooled to −78 ° C. and solid carbon dioxide (˜20 g) was added with stirring. The reaction was warmed to room temperature and water (150 mL) was carefully added under a nitrogen environment. The aqueous layer was separated, neutralized with concentrated hydrochloric acid and extracted with diethyl ether (150 mL). The organic layer was dried (MgSO ₄ ) and evaporated to give the subtitle compound (4.15 g) as an oil.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.40-7.20 (m, 5H), 2.49-2.35 (m, 2H), 2.16-2.03 (m, 2H), 1.76-1.47 (m, 8H).

１−フェニル−シクロヘプタンカルボン酸(実施例１ｃ)(４.１５ｇ)をメタノール(１５０mL)および濃塩酸(５mL)中、２４時間還流した。溶媒を蒸発させ、残留物をエーテル(１００mL)に溶解し、それを水(１００mL)、飽和重炭酸ナトリウム(５０mL)および水(１００mL)で洗浄し、乾燥させ(ＭｇＳＯ_４)、蒸発させて、副題化合物(３.５ｇ)を油状物として得た。
¹H NMR (300 MHz, CDCl₃) δ 7.37 - 7.18 (m, 5H), 3.63 (s, 3H), 2.47 - 2.35 (m, 2H), 2.08 - 1.97 (m, 2H), 1.70 - 1.48 (m, 8H)。 d) 1-phenyl-cycloheptanecarboxylic acid methyl ester

1-Phenyl-cycloheptanecarboxylic acid (Example 1c) (4.15 g) was refluxed in methanol (150 mL) and concentrated hydrochloric acid (5 mL) for 24 hours. The solvent was evaporated and the residue was dissolved in ether (100 mL) which was washed with water (100 mL), saturated sodium bicarbonate (50 mL) and water (100 mL), dried (MgSO ₄ ) and evaporated. The subtitle compound (3.5 g) was obtained as an oil.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.37-7.18 (m, 5H), 3.63 (s, 3H), 2.47-2.35 (m, 2H), 2.08-1.97 (m, 2H), 1.70-1.48 (m , 8H).

１−フェニル−シクロヘプタンカルボン酸メチルエステル(実施例１ｄ)(１.０ｇ)および(Ｒ)−キヌクリジン−３−オール(０.３９ｇ)を、ナトリウム(〜５mg)含有ヘプタン(５０mL)中、ディーン・スターク装置で２４時間還流した。ヘプタン(２０mL)をトルエン(２０mL)に変え、還流を３日間続けた。反応を水(５０mL)およびエーテル(５０mL)に分配し、エーテル層を分離し、乾燥させ(ＭｇＳＯ_４)、蒸発させた。粗生成物を酢酸エチル／トリエチルアミン(９９／１)で溶出するシリカカラムクロマトグラフィーで精製して、表題化合物を油状物として得た(０.８３ｇ)。
ｍ／ｅ ３２８ [Ｍ＋Ｈ]^＋
1H NMR (300 MHz, CDCl₃) δ 7.35 - 7.27 (m, 4H), 7.23 - 7.16 (m, 1H), 4.78 - 4.71 (m, 1H), 3.12 (ddd, 1H), 2.79 - 2.32 (m, 7H), 2.16 - 1.98 (m, 2H), 1.91 - 1.80 (m, 1H), 1.70 - 1.34 (m, 12H)。 e) 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester

1-Phenyl-cycloheptanecarboxylic acid methyl ester (Example 1d) (1.0 g) and (R) -quinuclidin-3-ol (0.39 g) were mixed with Dean in sodium (˜5 mg) heptane (50 mL). -Refluxed in a Stark apparatus for 24 hours. Heptane (20 mL) was changed to toluene (20 mL) and reflux was continued for 3 days. The reaction was partitioned between water (50 mL) and ether (50 mL), the ether layer was separated, dried (MgSO ₄ ) and evaporated. The crude product was purified by silica column chromatography eluting with ethyl acetate / triethylamine (99/1) to give the title compound as an oil (0.83 g).
m / e 328 [M + H] ^+
1 H NMR (300 MHz, CDCl ₃ ) δ 7.35-7.27 (m, 4H), 7.23-7.16 (m, 1H), 4.78-4.71 (m, 1H), 3.12 (ddd, 1H), 2.79-2.32 (m , 7H), 2.16-1.98 (m, 2H), 1.91-1.80 (m, 1H), 1.70-1.34 (m, 12H).

６−メチルピリジン−３−アミン(１ｇ)およびトリエチルアミン(２.２mL)の乾燥ＴＨＦ(２０mL)の混合物を撹拌し、−６０℃に冷却した。２−クロロアセチルクロライド(１.５６７ｇ)を、撹拌している混合物にシリンジにより添加して、黄色懸濁液が形成された。混合物を−６０℃で分析により出発物質の完全な消失が示されるまで撹拌した。反応スラリーを水に注ぎ、生成物を酢酸エチル(２×１５０mL)で抽出した。合わせた有機抽出物を硫酸マグネシウムで乾燥させ、濃縮乾固した。粗褐色固体をエーテルから再結晶して、副題化合物(７００mg)を得た。
¹H NMR (400 MHz, DMSO-D₆) δ 10.40 (1H, s), 8.60 (1H, d), 7.91 (1H, dd), 7.22 (1H, d), 4.27 (2H, s), 2.42 (3H, s)。 f) 2-Chloro-N- (6-methyl-pyridin-3-yl) -acetamide

A mixture of 6-methylpyridin-3-amine (1 g) and triethylamine (2.2 mL) in dry THF (20 mL) was stirred and cooled to −60 ° C. 2-Chloroacetyl chloride (1.567 g) was added to the stirring mixture via syringe to form a yellow suspension. The mixture was stirred at −60 ° C. until analysis showed complete disappearance of starting material. The reaction slurry was poured into water and the product was extracted with ethyl acetate (2 × 150 mL). The combined organic extracts were dried over magnesium sulfate and concentrated to dryness. The crude brown solid was recrystallized from ether to give the subtitle compound (700 mg).
¹ H NMR (400 MHz, DMSO-D ₆ ) δ 10.40 (1H, s), 8.60 (1H, d), 7.91 (1H, dd), 7.22 (1H, d), 4.27 (2H, s), 2.42 ( 3H, s).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１ｅ)(５２mg)をアセトニトリル(２mL)に溶解し、２−クロロ−Ｎ−(６−メチルピリジン−３−イル)アセトアミド(実施例１ｆ)(２９mg)を添加した。反応混合物を１０日間撹拌し、酢酸エチル(４mL)およびイソヘキサン(１４mL)で希釈した。混合物を５日間静置し、そうして得られた結晶を分離し、ジエチルエーテル(０.５mL)で洗浄して、表題化合物を固体として得た(３６mg)。
m/e 476 [M]^+
1H NMR (400 MHz, DMSO-D₆) δ 11.33 (s, 1H), 8.70 (d, 1H), 7.91 (dd, 1H), 7.38 - 7.30 (m, 4H), 7.27 (d, 1H), 7.28 - 7.20 (m, 1H), 5.16 - 5.07 (m, 1H), 4.36 (d, 1H), 4.31 (d, 1H), 4.16 - 4.07 (m, 1H), 3.72 - 3.54 (m, 4H), 3.44 - 3.34 (m, 2H), 2.44 (s, 3H), 2.42 - 2.28 (m, 2H), 2.22 - 2.10 (m, 2H), 2.01 - 1.86 (m, 3H), 1.83 - 1.71 (m, 1H), 1.69 - 1.41 (m, 8H)。 Example 1: (R) -1-[(6-Methyl-pyridin-3-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride

1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 1e) (52 mg) was dissolved in acetonitrile (2 mL) and 2 -Chloro-N- (6-methylpyridin-3-yl) acetamide (Example 1f) (29 mg) was added. The reaction mixture was stirred for 10 days and diluted with ethyl acetate (4 mL) and isohexane (14 mL). The mixture was left to stand for 5 days and the crystals so obtained were separated and washed with diethyl ether (0.5 mL) to give the title compound as a solid (36 mg).
m / e 476 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ) δ 11.33 (s, 1H), 8.70 (d, 1H), 7.91 (dd, 1H), 7.38-7.30 (m, 4H), 7.27 (d, 1H), 7.28-7.20 (m, 1H), 5.16-5.07 (m, 1H), 4.36 (d, 1H), 4.31 (d, 1H), 4.16-4.07 (m, 1H), 3.72-3.54 (m, 4H), 3.44-3.34 (m, 2H), 2.44 (s, 3H), 2.42-2.28 (m, 2H), 2.22-2.10 (m, 2H), 2.01-1.86 (m, 3H), 1.83-1.71 (m, 1H ), 1.69-1.41 (m, 8H).

６−メチル−ピラジン−２−イルアミン(１５０mg)および炭酸カリウム(５７１mg)をジクロロメタン(２５mL)に添加した。２−ブロモアセチルブロマイド(０.１２０mL)を撹拌しながら懸濁液に添加した。反応を一夜撹拌し、次いで水(０.１mL)をさらに撹拌しながら添加した。さらに炭酸カリウム(５７１mg)、２−ブロモアセチルブロマイド(０.１２０mL)および水(０.１mL)を、２時間にわたり、反応の進行が完了するまで添加した。反応を水(１００mL)で希釈し、注意深く塩酸で酸性化し、ジクロロメタン(２×５０mL)で抽出し、それを乾燥させ、蒸発させて、副題化合物を得て、それを粗製のまま使用した(３６５mg)。
¹H NMR (400 MHz, CDCl₃) δ 9.45 (s, 1H), 9.37 (s, 1H), 8.33 (s, 1H), 4.05 (s, 2H), 2.51 (s, 3H)。 Example 2: (R) -1-[(6-Methyl-pyrazin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane bromide a) 2-Bromo-N- (6-methyl-pyrazin-2-yl) -acetamide

6-Methyl-pyrazin-2-ylamine (150 mg) and potassium carbonate (571 mg) were added to dichloromethane (25 mL). 2-Bromoacetyl bromide (0.120 mL) was added to the suspension with stirring. The reaction was stirred overnight and then water (0.1 mL) was added with further stirring. Further potassium carbonate (571 mg), 2-bromoacetyl bromide (0.120 mL) and water (0.1 mL) were added over 2 hours until the reaction progress was complete. The reaction was diluted with water (100 mL), carefully acidified with hydrochloric acid and extracted with dichloromethane (2 × 50 mL), which was dried and evaporated to give the subtitle compound that was used crude (365 mg ).
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.45 (s, 1H), 9.37 (s, 1H), 8.33 (s, 1H), 4.05 (s, 2H), 2.51 (s, 3H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１ｅ)(７０mg)および２−ブロモ−Ｎ−(６−メチルピラジン−２−イル)アセトアミド(実施例２ａ)(４９.２mg)をアセトニトリル(１mL)に溶解し、一夜静置した。結晶が静置により分離し、濾過し、アセトニトリル(２×１mL)、酢酸エチル(２×３mL)およびジエチルエーテル(２×３mL)で洗浄し、乾燥させて、表題化合物(２４mg)を得た。
m/e 477 [M]^+
1H NMR (400 MHz, DMSO-D₆) δ 11.33 (s, 1H), 9.09 (s, 1H), 8.37 (s, 1H), 7.38 - 7.31 (m, 4H), 7.27 - 7.22 (m, 1H), 5.15 - 5.09 (m, 1H), 4.36 - 4.25 (m, 2H), 4.16 - 4.07 (m, 1H), 3.68 - 3.56 (m, 4H), 3.46 - 3.33 (m, 1H), 2.47 (s, 3H), 2.42 - 2.29 (m, 2H), 2.24 - 2.11 (m, 2H), 2.04 - 1.87 (m, 3H), 1.83 - 1.73 (m, 1H), 1.68 - 1.45 (m, 9H)。 Example 2: (R) -1-[(6-Methyl-pyrazin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane bromide

1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 1e) (70 mg) and 2-bromo-N- (6- Methylpyrazin-2-yl) acetamide (Example 2a) (49.2 mg) was dissolved in acetonitrile (1 mL) and allowed to stand overnight. The crystals separated by standing, filtered, washed with acetonitrile (2 × 1 mL), ethyl acetate (2 × 3 mL) and diethyl ether (2 × 3 mL) and dried to give the title compound (24 mg).
m / e 477 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ) δ 11.33 (s, 1H), 9.09 (s, 1H), 8.37 (s, 1H), 7.38-7.31 (m, 4H), 7.27-7.22 (m, 1H ), 5.15-5.09 (m, 1H), 4.36-4.25 (m, 2H), 4.16-4.07 (m, 1H), 3.68-3.56 (m, 4H), 3.46-3.33 (m, 1H), 2.47 (s , 3H), 2.42-2.29 (m, 2H), 2.24-2.11 (m, 2H), 2.04-1.87 (m, 3H), 1.83-1.73 (m, 1H), 1.68-1.45 (m, 9H).

６−トリフルオロメチル−ピリダジン−３−イルアミン(０.０４２ｇ)(ＷＯ２００７０４８７７９に記載された方法に準じた方法で製造)をジクロロメタン(４０mL)に溶解し、炭酸カリウム(０.２１４ｇ)と撹拌した。２−ブロモアセチルブロマイド(０.１２mL)を添加し、１.５時間撹拌を続けた。水(０.２４mL)を添加し、反応混合物を１.５時間撹拌し、その後水(４０mL)を添加し、反応混合物をさらに１.５時間撹拌した。ジクロロメタンを分離し、乾燥させ(ＭｇＳＯ_４)、蒸発させて、副題化合物を白色固体として得た(０.０５３ｇ)。
m/e 284/286 [M+H]^+
1H NMR (400 MHz, DMSO-D₆) δ 11.04 (s, 1H), 8.79 (d, 1H), 7.91 (d, 1H), 4.31 (s, 2H)。 Example 3: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1-[(6-trifluoromethyl-pyridazin-3-ylcarbamoyl) -methyl] -1-azonia-bicyclo [2. 2.2] Octane bromide a) 2-Bromo-N- (6-trifluoromethyl-pyridazin-3-yl) -acetamide

6-Trifluoromethyl-pyridazin-3-ylamine (0.042 g) (prepared according to the method described in WO2007048779) was dissolved in dichloromethane (40 mL) and stirred with potassium carbonate (0.214 g). 2-Bromoacetyl bromide (0.12 mL) was added and stirring was continued for 1.5 hours. Water (0.24 mL) was added and the reaction mixture was stirred for 1.5 hours, after which water (40 mL) was added and the reaction mixture was stirred for an additional 1.5 hours. The dichloromethane was separated, dried (MgSO ₄ ) and evaporated to give the subtitle compound as a white solid (0.053g).
m / e 284/286 [M + H] ^+
1 H NMR (400 MHz, DMSO-D ₆ ) δ 11.04 (s, 1H), 8.79 (d, 1H), 7.91 (d, 1H), 4.31 (s, 2H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１ｅ)(６１.１mg)および２−ブロモ−Ｎ−(６−トリフルオロメチル−ピリダジン−３−イル)−アセトアミド(実施例３ａ)(５３.０mg)をアセトニトリル(２mL)に溶解し、一夜静置した。溶媒を蒸発させ、生成物を１０％メタノールのジクロロメタン溶液で溶出するシリカカラムクロマトグラフィーで精製して、表題化合物(１０７mg)を得た。
m/e 531 [M]^+
1H NMR (400 MHz, DMSO-D₆) δ 12.17 (s, 1H), 8.50 (d, 1H), 8.36 (d, 1H), 7.40 - 7.32 (m, 4H), 7.28 - 7.23 (m, 1H), 5.17 - 5.10 (m, 1H), 4.57 - 4.42 (m, 2H), 4.22 - 4.14 (m, 1H), 3.76 - 3.61 (m, 4H), 3.47 (dd, 1H), 2.43 - 2.30 (m, 2H), 2.25 - 2.12 (m, 2H), 2.07 - 1.88 (m, 3H), 1.86 - 1.73 (m, 1H), 1.72 - 1.44 (m, 9H)。 Example 3: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1-[(6-trifluoromethyl-pyridazin-3-ylcarbamoyl) -methyl] -1-azonia-bicyclo [2. 2.2] Octane bromide

1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 1e) (61.1 mg) and 2-bromo-N- ( 6-Trifluoromethyl-pyridazin-3-yl) -acetamide (Example 3a) (53.0 mg) was dissolved in acetonitrile (2 mL) and allowed to stand overnight. The solvent was evaporated and the product was purified by silica column chromatography eluting with 10% methanol in dichloromethane to give the title compound (107 mg).
m / e 531 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ) δ 12.17 (s, 1H), 8.50 (d, 1H), 8.36 (d, 1H), 7.40-7.32 (m, 4H), 7.28-7.23 (m, 1H ), 5.17-5.10 (m, 1H), 4.57-4.42 (m, 2H), 4.22-4.14 (m, 1H), 3.76-3.61 (m, 4H), 3.47 (dd, 1H), 2.43-2.30 (m , 2H), 2.25-2.12 (m, 2H), 2.07-1.88 (m, 3H), 1.86-1.73 (m, 1H), 1.72-1.44 (m, 9H).

ベンゾ[ｄ]イソキサゾール−３−イルアミン(１ｇ)および炭酸セシウム(２.４２ｇ)の乾燥ＤＭＦ(２０mL)の混合物に、ｒｔで撹拌しながら、ブロモアセチルクロライド(０.６２mL)を滴下した。混合物を８時間撹拌後、反応を水に注ぎ(１００mL)、生成物をエーテル(２×２００mL)で抽出した。合わせた抽出物を硫酸マグネシウムで乾燥させ、濃縮乾固した。粗生成物をエーテル／イソヘキサン(４／６)を使用してシリカゲルで精製して、副題化合物を無色固体として得た(０.５ｇ)。
ｍ／ｅ ２１０ [Ｍ＋Ｈ]^＋ Example 4: (R) -1- (Benzo [d] isoxazol-3-ylcarbamoylmethyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane Bromide a) N-benzo [d] isoxazol-3-yl-2-chloro-acetamide

Bromoacetyl chloride (0.62 mL) was added dropwise to a mixture of benzo [d] isoxazol-3-ylamine (1 g) and cesium carbonate (2.42 g) in dry DMF (20 mL) with stirring at rt. After stirring the mixture for 8 hours, the reaction was poured into water (100 mL) and the product was extracted with ether (2 × 200 mL). The combined extracts were dried over magnesium sulfate and concentrated to dryness. The crude product was purified on silica gel using ether / isohexane (4/6) to give the subtitle compound as a colorless solid (0.5 g).
m / e 210 [M + H] ⁺

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１ｅ)(１１４mg)およびＮ−ベンゾ[ｄ]イソキサゾール−３−イル−２−クロロ−アセトアミド(実施例４ａ)(８９mg)をアセトニトリル(１０mL)に溶解し、１週間静置した。得られた結晶を濾取し、ジエチルエーテル(３×１０mL)で洗浄して、表題化合物を固体として得た(１２０mg)。
m/e 502 [M]^+
1H NMR (400 MHz, DMSO-D₆) δ 12.15 (s, 1H), 8.16 (d, 1H), 7.74 (d, 1H), 7.72 - 7.67 (m, 1H), 7.44 - 7.39 (m, 1H), 7.38 - 7.30 (m, 4H), 7.27 - 7.19 (m, 1H), 5.18 - 5.11 (m, 1H), 4.63 - 4.46 (m, 2H), 4.17 (ddd, 1H), 3.76 - 3.61 (m, 4H), 3.49 (dd, 1H), 2.43 - 2.29 (m, 2H), 2.24 - 2.12 (m, 2H), 2.03 - 1.89 (m, 3H), 1.86 - 1.74 (m, 1H), 1.70 - 1.44 (m, 9H)。 Example 4: (R) -1- (Benzo [d] isoxazol-3-ylcarbamoylmethyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane Chloride

1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 1e) (114 mg) and N-benzo [d] isoxazole-3 -Il-2-chloro-acetamide (Example 4a) (89 mg) was dissolved in acetonitrile (10 mL) and allowed to stand for 1 week. The resulting crystals were collected by filtration and washed with diethyl ether (3 × 10 mL) to give the title compound as a solid (120 mg).
m / e 502 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ) δ 12.15 (s, 1H), 8.16 (d, 1H), 7.74 (d, 1H), 7.72-7.67 (m, 1H), 7.44-7.39 (m, 1H ), 7.38-7.30 (m, 4H), 7.27-7.19 (m, 1H), 5.18-5.11 (m, 1H), 4.63-4.46 (m, 2H), 4.17 (ddd, 1H), 3.76-3.61 (m , 4H), 3.49 (dd, 1H), 2.43-2.29 (m, 2H), 2.24-2.12 (m, 2H), 2.03-1.89 (m, 3H), 1.86-1.74 (m, 1H), 1.70-1.44 (m, 9H).

エチル２−(チオフェン−２−イル)アセテート(２.３５ｇ)をテトラヒドロフラン(３０mL)に溶解し、−７８℃に冷却した。リチウムビス(トリメチルシリル)アミド(２.３１ｇ)のＴＨＦ(１Ｍ溶液、１３.８mL)を添加し、溶液を３０分間撹拌した。４−ブロモ−ブト−１−エン(１.４mL)を添加し、反応混合物を室温に温め、１時間撹拌した。反応混合物を−７８℃に再冷却し、リチウムビス(トリメチルシリル)アミド(２.３１ｇ)のＴＨＦ(１Ｍ溶液、１３.８mL)を添加し、溶液を３０分間撹拌した。４−ブロモ−ブト−１−エン(１.４mL)を添加し、反応混合物を室温に温め、一夜静置した。ＨＰＬＣ−ＭＳ分析は反応が不完全であることを示し、従って反応を再び−７８℃に冷却し、さらにリチウムビス(トリメチルシリル)アミド(１Ｍ溶液、１０mL)および４−ブロモ−ブト−１−エン(１.０mL)を、上記に略記した方法に従い添加した。さらに２時間撹拌後、水(３０mL)を添加し、反応をジエチルエーテル(２×６０mL)で抽出した。合わせた有機抽出物を乾燥させ(ＭｇＳＯ_４)、蒸発させた。得られた油状物を酢酸エチル／イソヘキサン(１／９９)で溶出するシリカカラムクロマトグラフィーで精製して、副題化合物(３.１８ｇ)を得た。
¹H NMR (400 MHz, DMSO-D₆) δ 7.21 (dd, 1H), 6.97 - 6.94 (m, 2H), 5.79 (ddt, 2H), 5.01 (dq, 2H), 4.95 (dq, 2H), 4.17 (q, 2H), 2.22 - 2.08 (m, 4H), 2.00 - 1.85 (m, 4H), 1.24 (t, 3H)。 Example 5: (R) -1- (pyridazin-3-ylcarbamoylmethyl) -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane Bromide a) 2-but-3-enyl-2-thiophen-2-yl-hex-5-enoic acid ethyl ester

Ethyl 2- (thiophen-2-yl) acetate (2.35 g) was dissolved in tetrahydrofuran (30 mL) and cooled to -78 ° C. Lithium bis (trimethylsilyl) amide (2.31 g) in THF (1M solution, 13.8 mL) was added and the solution was stirred for 30 minutes. 4-Bromo-but-1-ene (1.4 mL) was added and the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was re-cooled to −78 ° C., lithium bis (trimethylsilyl) amide (2.31 g) in THF (1M solution, 13.8 mL) was added and the solution was stirred for 30 minutes. 4-Bromo-but-1-ene (1.4 mL) was added and the reaction mixture was warmed to room temperature and allowed to stand overnight. HPLC-MS analysis showed that the reaction was incomplete, so the reaction was again cooled to -78 [deg.] C and further lithium bis (trimethylsilyl) amide (1M solution, 10 mL) and 4-bromo-but-1-ene ( 1.0 mL) was added according to the method outlined above. After stirring for a further 2 hours, water (30 mL) was added and the reaction was extracted with diethyl ether (2 × 60 mL). The combined organic extracts were dried (MgSO ₄ ) and evaporated. The resulting oil was purified by silica column chromatography eluting with ethyl acetate / isohexane (1/99) to give the subtitle compound (3.18 g).
¹ H NMR (400 MHz, DMSO-D ₆ ) δ 7.21 (dd, 1H), 6.97-6.94 (m, 2H), 5.79 (ddt, 2H), 5.01 (dq, 2H), 4.95 (dq, 2H), 4.17 (q, 2H), 2.22-2.08 (m, 4H), 2.00-1.85 (m, 4H), 1.24 (t, 3H).

２−ブト−３−エニル−２−チオフェン−２−イル−ヘキシ−５−エン酸エチルエステル(実施例５ａ)(３.１８ｇ)のジクロロメタン(１００mL)溶液に、Grubbs触媒(第二世代、Sigma-Aldrich Company Ltd)(０.１００ｇ)を添加した。混合物を窒素下還流まで温めた。２０時間後、混合物を室温に冷却し、油状物となるまで蒸発させた。酢酸エチル／イソヘキサン(１０：９０)で溶出するシリカカラムクロマトグラフィーでの精製により、副題化合物(２.６０ｇ)を無色油状物として得た。
¹H NMR (400 MHz, DMSO-D₆) δ 7.19 (dd, 1H), 6.98 - 6.92 (m, 2H), 5.72 (t, 2H), 4.15 (q, 2H), 2.66 - 2.59 (m, 2H), 2.25 - 2.14 (m, 6H), 1.21 (t, 3H)。 b) 1-thiophen-2-yl-cyclohept-4-enecarboxylic acid ethyl ester

To a solution of 2-but-3-enyl-2-thiophen-2-yl-hex-5-enoic acid ethyl ester (Example 5a) (3.18 g) in dichloromethane (100 mL) was added Grubbs catalyst (2nd generation, Sigma -Aldrich Company Ltd) (0.100 g) was added. The mixture was warmed to reflux under nitrogen. After 20 hours, the mixture was cooled to room temperature and evaporated to an oil. Purification by silica column chromatography eluting with ethyl acetate / isohexane (10:90) gave the subtitle compound (2.60 g) as a colorless oil.
¹ H NMR (400 MHz, DMSO-D ₆ ) δ 7.19 (dd, 1H), 6.98-6.92 (m, 2H), 5.72 (t, 2H), 4.15 (q, 2H), 2.66-2.59 (m, 2H ), 2.25-2.14 (m, 6H), 1.21 (t, 3H).

１−チオフェン−２−イル−シクロヘプト−４−エンカルボン酸エチルエステル(実施例５ｂ)(２.８６ｇ)をエタノール(３０mL)に溶解し、トリス(トリフェニルホスフィン)ロジウム(Ｉ)クロライド(０.１００ｇ)を添加した。反応混合物を急速に５気圧の水素下一夜撹拌した。さらにトリス(トリフェニルホスフィン)ロジウム(Ｉ)クロライド(０.０５０ｇ)を添加し、反応混合物を５気圧の水素下３日間撹拌した。３回目のトリス(トリフェニルホスフィン)ロジウム(Ｉ)クロライド(０.０５０ｇ)を添加し、反応混合物を３気圧の水素下に一夜撹拌した。内容物を蒸発乾固し、酢酸エチル／イソヘキサン(５／９５)で溶出するシリカで精製して、副題化合物(２.５００ｇ)を透明でほぼ無色の油状物として得た。
m/e 253 [M+H⁺]
¹H NMR (400 MHz, DMSO-D₆) δ 7.17 (dd, 1H), 6.95 - 6.91 (m, 2H), 4.13 (q, 2H), 2.53 (dd, 2H), 2.14 - 2.03 (m, 2H), 1.70 - 1.50 (m, 8H), 1.20 (t, 3H)。 c) 1-thiophen-2-yl-cycloheptanecarboxylic acid ethyl ester

1-thiophen-2-yl-cyclohept-4-enecarboxylic acid ethyl ester (Example 5b) (2.86 g) was dissolved in ethanol (30 mL) and tris (triphenylphosphine) rhodium (I) chloride (0. 100 g) was added. The reaction mixture was rapidly stirred overnight at 5 atm hydrogen. Further tris (triphenylphosphine) rhodium (I) chloride (0.050 g) was added and the reaction mixture was stirred under 5 atmospheres of hydrogen for 3 days. A third portion of tris (triphenylphosphine) rhodium (I) chloride (0.050 g) was added and the reaction mixture was stirred overnight under 3 atmospheres of hydrogen. The contents were evaporated to dryness and purified on silica eluting with ethyl acetate / isohexane (5/95) to give the subtitle compound (2.500 g) as a clear, almost colorless oil.
m / e 253 [M + H ⁺ ]
¹ H NMR (400 MHz, DMSO-D ₆ ) δ 7.17 (dd, 1H), 6.95-6.91 (m, 2H), 4.13 (q, 2H), 2.53 (dd, 2H), 2.14-2.03 (m, 2H ), 1.70-1.50 (m, 8H), 1.20 (t, 3H).

１−チオフェン−２−イル−シクロヘプタンカルボン酸エチルエステル(実施例５ｃ)(２.５ｇ)および(Ｒ)−キヌクリジン−３−オール(２.０８ｇ)をトルエン(３５０mL)に溶解し、水素化ナトリウム(０.１ｇ)を窒素下添加した。混合物を２０時間加熱還流し、その後トルエンを注意深く留去して〜１００mL残し、それを冷却し、水(１００mL)で洗浄し、乾燥させ(ＭｇＳＯ_４)、蒸発させた。粗生成物を酢酸エチル／トリエチルアミン(９９／１)で溶出するシリカカラムクロマトグラフィーで精製して、副題化合物(２.８４ｇ)を得た。
m/e 334 [M+H⁺]
¹H NMR (400 MHz, CDCl₃) δ 7.18 (t, 1H), 6.95 - 6.92 (m, 2H), 4.77 - 4.72 (m, 1H), 3.14 (ddd, 1H), 2.83 - 2.64 (m, 4H), 2.59 - 2.50 (m, 3H), 2.18 - 2.08 (m, 2H), 1.95 - 1.90 (m, 1H), 1.71 - 1.44 (m, 11H), 1.34 - 1.23 (m, 1H)。 d) 1-thiophen-2-yl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester

1-thiophen-2-yl-cycloheptanecarboxylic acid ethyl ester (Example 5c) (2.5 g) and (R) -quinuclidin-3-ol (2.08 g) were dissolved in toluene (350 mL) and hydrogenated. Sodium (0.1 g) was added under nitrogen. The mixture was heated to reflux for 20 hours, after which the toluene was carefully distilled off to leave ˜100 mL which was cooled, washed with water (100 mL), dried (MgSO ₄ ) and evaporated. The crude product was purified by silica column chromatography eluting with ethyl acetate / triethylamine (99/1) to give the subtitle compound (2.84 g).
m / e 334 [M + H ⁺ ]
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.18 (t, 1H), 6.95-6.92 (m, 2H), 4.77-4.72 (m, 1H), 3.14 (ddd, 1H), 2.83-2.64 (m, 4H ), 2.59-2.50 (m, 3H), 2.18-2.08 (m, 2H), 1.95-1.90 (m, 1H), 1.71-1.44 (m, 11H), 1.34-1.23 (m, 1H).

ピリダジン−３−イルアミン(２.７ｇ)およびジイソプロピルエチルアミン(６.３mL)のジクロロメタン(１００mL)懸濁液に、０℃で、ブロモ酢酸無水物(９.０ｇ)のジクロロメタン(１０mL)を滴下した。混合物を０℃で０.５時間撹拌し、次いでｒｔに温めた。得られた懸濁液を濾過し、ジクロロメタンで洗浄し、乾燥させて、副題化合物を固体として得た(２.０ｇ)。
¹H NMR (400 MHz, DMSO-D₆) δ 11.51 (s, 1H), 9.00 (dd, 1H), 8.28 (dd, 1H), 7.74 - 7.68 (m, 1H), 4.15 (s, 2H)。 e) 2-Bromo-N-pyridazin-3-yl-acetamide

To a suspension of pyridazin-3-ylamine (2.7 g) and diisopropylethylamine (6.3 mL) in dichloromethane (100 mL) was added dropwise bromoacetic anhydride (9.0 g) in dichloromethane (10 mL) at 0 ° C. The mixture was stirred at 0 ° C. for 0.5 h and then warmed to rt. The resulting suspension was filtered, washed with dichloromethane and dried to give the subtitle compound as a solid (2.0 g).
¹ H NMR (400 MHz, DMSO-D ₆ ) δ 11.51 (s, 1H), 9.00 (dd, 1H), 8.28 (dd, 1H), 7.74-7.68 (m, 1H), 4.15 (s, 2H).

１−チオフェン−２−イル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例５ｄ)(８０mg)および２−ブロモ−Ｎ−ピリダジン−３−イル−アセトアミド(実施例５ｅ)(５２mg)をアセトニトリル(３mL)に溶解し、一夜撹拌した。酢酸エチル(９mL)およびイソヘキサン(４mL)を添加し、一夜撹拌した。得られた結晶を濾取し、次いで酢酸エチルで摩砕して、表題化合物(１４mg)を得た。
m/e 469 [M⁺]
¹H NMR (400 MHz, DMSO-D₆) δ 11.68 (s, 1H), 9.05 (dd, 1H), 8.25 (d, 1H), 7.79 (dd, 1H), 7.44 (dd, 1H), 7.03 (dd, 1H), 6.99 (dd, 1H), 5.14 - 5.09 (m, 1H), 4.37 (s, 2H), 4.17 - 4.08 (m, 1H), 3.76 - 3.57 (m, 4H), 3.57 - 3.46 (m, 1H), 2.48 - 2.42 (m, 1H), 2.29 - 2.22 (m, 1H), 2.21 - 2.11 (m, 1H), 2.07 - 1.90 (m, 4H), 1.90 - 1.80 (m, 1H), 1.78 - 1.68 (m, 1H), 1.66 - 1.46 (m, 8H)。 Example 5: (R) -1- (pyridazin-3-ylcarbamoylmethyl) -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

1-thiophen-2-yl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 5d) (80 mg) and 2-bromo-N -Pyridazin-3-yl-acetamide (Example 5e) (52 mg) was dissolved in acetonitrile (3 mL) and stirred overnight. Ethyl acetate (9 mL) and isohexane (4 mL) were added and stirred overnight. The resulting crystals were collected by filtration and then triturated with ethyl acetate to give the title compound (14 mg).
m / e 469 [M ⁺ ]
¹ H NMR (400 MHz, DMSO-D ₆ ) δ 11.68 (s, 1H), 9.05 (dd, 1H), 8.25 (d, 1H), 7.79 (dd, 1H), 7.44 (dd, 1H), 7.03 ( dd, 1H), 6.99 (dd, 1H), 5.14-5.09 (m, 1H), 4.37 (s, 2H), 4.17-4.08 (m, 1H), 3.76-3.57 (m, 4H), 3.57-3.46 ( m, 1H), 2.48-2.42 (m, 1H), 2.29-2.22 (m, 1H), 2.21-2.11 (m, 1H), 2.07-1.90 (m, 4H), 1.90-1.80 (m, 1H), 1.78-1.68 (m, 1H), 1.66-1.46 (m, 8H).

撹拌している重炭酸ナトリウム(１.２４２ｇ)および５−メチル−イソキサゾール−３−イルアミン(１.４５ｇ)のジクロロメタン(５０mL)懸濁液に、２−ブロモアセチルブロマイド(１.２８mL)を滴下した。反応混合物を一夜撹拌し、次いで水(２×５０mL)で洗浄した。有機フラクションを分離し、硫酸マグネシウムで乾燥させ、蒸発させて、副題化合物(２７９mg)を得た。
¹H NMR (400 MHz, DMSO-D₆) δ 11.32 (s, 1H), 6.62 (s, 1H), 4.06 (s, 2H), 2.38 (s, 3H)。 Example 6: (R) -1-[(5-Methyl-isoxazol-3-ylcarbamoyl) -methyl] -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [ 2.2.2] Octane bromide a) 2-Bromo-N- (5-methyl-isoxazol-3-yl) -acetamide

2-Bromoacetyl bromide (1.28 mL) was added dropwise to a stirring suspension of sodium bicarbonate (1.242 g) and 5-methyl-isoxazol-3-ylamine (1.45 g) in dichloromethane (50 mL). . The reaction mixture was stirred overnight and then washed with water (2 × 50 mL). The organic fraction was separated, dried over magnesium sulfate and evaporated to give the subtitle compound (279 mg).
¹ H NMR (400 MHz, DMSO-D ₆ ) δ 11.32 (s, 1H), 6.62 (s, 1H), 4.06 (s, 2H), 2.38 (s, 3H).

１−チオフェン−２−イル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例５ｄ)(６８mg)および２−ブロモ−Ｎ−(５−メチル−イソキサゾール−３−イル)−アセトアミド(実施例６ａ)(４５mg)をアセトニトリル(２mL)に溶解し、一夜撹拌した。酢酸エチル(１０mL)およびイソヘキサン(９mL)を添加し、一夜撹拌した。得られた結晶を濾取し、酢酸エチルで洗浄して、表題化合物(８２mg)を得た。
m/e 472 [M⁺]
¹H NMR (400 MHz, DMSO-D₆) δ 11.55 (s, 1H), 7.44 (dd, 1H), 7.03 (dd, 1H), 6.99 (dd, 1H), 6.61 (s, 1H), 5.13 - 5.08 (m, 1H), 4.31 (d, 1H), 4.26 (d, 1H), 4.14 - 4.05 (m, 1H), 3.72 - 3.55 (m, 4H), 3.53 - 3.43 (m, 1H), 2.54 - 2.42 (m, 1H), 2.41 (d, 3H), 2.27 - 2.22 (m, 1H), 2.19 - 2.13 (m, 1H), 2.07 - 1.90 (m, 4H), 1.89 - 1.77 (m, 1H), 1.77 - 1.65 (m, 1H), 1.63 - 1.48 (m, 8H)。 Example 6: (R) -1-[(5-Methyl-isoxazol-3-ylcarbamoyl) -methyl] -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [ 2.2.2] Octane bromide

1-thiophen-2-yl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 5d) (68 mg) and 2-bromo-N -(5-Methyl-isoxazol-3-yl) -acetamide (Example 6a) (45 mg) was dissolved in acetonitrile (2 mL) and stirred overnight. Ethyl acetate (10 mL) and isohexane (9 mL) were added and stirred overnight. The obtained crystals were collected by filtration and washed with ethyl acetate to give the title compound (82 mg).
m / e 472 [M ⁺ ]
¹ H NMR (400 MHz, DMSO-D ₆ ) δ 11.55 (s, 1H), 7.44 (dd, 1H), 7.03 (dd, 1H), 6.99 (dd, 1H), 6.61 (s, 1H), 5.13- 5.08 (m, 1H), 4.31 (d, 1H), 4.26 (d, 1H), 4.14-4.05 (m, 1H), 3.72-3.55 (m, 4H), 3.53-3.43 (m, 1H), 2.54- 2.42 (m, 1H), 2.41 (d, 3H), 2.27-2.22 (m, 1H), 2.19-2.13 (m, 1H), 2.07-1.90 (m, 4H), 1.89-1.77 (m, 1H), 1.77-1.65 (m, 1H), 1.63-1.48 (m, 8H).

３−メチル−イソキサゾール−５−イルアミン(２.９ｇ)および炭酸カリウム(９.８ｇ)をジクロロメタン(１００mL)に室温で懸濁させ、２−ブロモアセチルブロマイド(６ｇ)を滴下した。混合物を一夜撹拌した。水(０.３mL)をさらなる炭酸カリウム(３ｇ)と共に添加し、反応混合物をさらに３０分間撹拌した。反応混合物を水に注ぎ(１００mL)、ジクロロメタン(２×５０mL)で抽出した。合わせた有機抽出物を硫酸マグネシウムで乾燥させ、次いで真空で蒸発させた。粗生成物を酢酸エチル／イソヘキサン(５０：５０)で溶出するシリカカラムクロマトグラフィーで精製して、副題化合物(４.８ｇ)を得た。
¹H NMR (300 MHz, CDCl₃) δ 11.97 (s, 1H), 6.16 (s, 1H), 4.09 (s, 2H), 2.19 (s, 3H)。 Example 7: (R) -1-[(3-Methyl-isoxazol-5-ylcarbamoyl) -methyl] -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [ 2.2.2] Octane bromide a) 2-Bromo-N- (3-methyl-isoxazol-5-yl) -acetamide

3-Methyl-isoxazol-5-ylamine (2.9 g) and potassium carbonate (9.8 g) were suspended in dichloromethane (100 mL) at room temperature, and 2-bromoacetyl bromide (6 g) was added dropwise. The mixture was stirred overnight. Water (0.3 mL) was added along with additional potassium carbonate (3 g) and the reaction mixture was stirred for an additional 30 minutes. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (2 × 50 mL). The combined organic extracts were dried over magnesium sulfate and then evaporated in vacuo. The crude product was purified by silica column chromatography eluting with ethyl acetate / isohexane (50:50) to give the subtitle compound (4.8 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 11.97 (s, 1H), 6.16 (s, 1H), 4.09 (s, 2H), 2.19 (s, 3H).

１−チオフェン−２−イル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例５ｄ)(５０mg)および２−ブロモ−Ｎ−(３−メチルイソキサゾール−５−イル)アセトアミド(実施例７ａ)(３２mg)をアセトニトリル(２mL)に溶解し、一夜静置した。酢酸エチル(１０mL)およびイソヘキサン(１０mL)を添加し、結晶を濾取し、酢酸エチルで洗浄し、乾燥させて、表題化合物(３７mg)を得た。
m/e 472 [M⁺]
¹H NMR (400 MHz, DMSO-D₆) δ 12.21 (s, 1H), 7.44 (dd, 1H), 7.03 (dd, 1H), 6.99 (dd, 1H), 6.18 (s, 1H), 5.15 - 5.07 (m, 1H), 4.35 (d, 1H), 4.30 (d, 1H), 4.14 - 4.05 (m, 1H), 3.73 - 3.54 (m, 4H), 3.54 - 3.43 (m, 1H), 3.17 (d, 1H), 2.47 - 2.42 (m, 1H), 2.27 - 2.20 (m, 1H), 2.21 (s, 3H), 2.19 - 2.12 (m, 1H), 2.08 - 1.77 (m, 4H), 1.77 - 1.65 (m, 1H), 1.65 - 1.46 (m, 8H)。 Example 7: (R) -1-[(3-Methyl-isoxazol-5-ylcarbamoyl) -methyl] -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [ 2.2.2] Octane bromide

1-thiophen-2-yl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 5d) (50 mg) and 2-bromo-N -(3-Methylisoxazol-5-yl) acetamide (Example 7a) (32 mg) was dissolved in acetonitrile (2 mL) and allowed to stand overnight. Ethyl acetate (10 mL) and isohexane (10 mL) were added and the crystals were collected by filtration, washed with ethyl acetate and dried to give the title compound (37 mg).
m / e 472 [M ⁺ ]
¹ H NMR (400 MHz, DMSO-D ₆ ) δ 12.21 (s, 1H), 7.44 (dd, 1H), 7.03 (dd, 1H), 6.99 (dd, 1H), 6.18 (s, 1H), 5.15- 5.07 (m, 1H), 4.35 (d, 1H), 4.30 (d, 1H), 4.14-4.05 (m, 1H), 3.73-3.54 (m, 4H), 3.54-3.43 (m, 1H), 3.17 ( d, 1H), 2.47-2.42 (m, 1H), 2.27-2.20 (m, 1H), 2.21 (s, 3H), 2.19-2.12 (m, 1H), 2.08-1.77 (m, 4H), 1.77- 1.65 (m, 1H), 1.65-1.46 (m, 8H).

重炭酸ナトリウム(１ｇ)および３−フルオロアニリン(０.４６ｇ)のジクロロメタン(１００mL)懸濁液に、２−ブロモアセチルブロマイド(０.３６mL)を滴下した。一夜撹拌後、反応混合物を水で洗浄し、硫酸マグネシウムで乾燥させ、蒸発させて、副題化合物(１.０７ｇ)を得た。
m/e 232 [M+H⁺]
¹H NMR (300 MHz, CDCl₃) δ 8.14 (s, 1H), 7.50 (dt, 1H), 7.31 (td, 1H), 7.18 (ddd, 1H), 6.87 (tdd, 1H), 4.03 (s, 2H)。 Example 8: (R) -1-[(3-Fluoro-phenylcarbamoyl) -methyl] -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane bromide a) 2-Bromo-N- (3-fluoro-phenyl) -acetamide

2-Bromoacetyl bromide (0.36 mL) was added dropwise to a suspension of sodium bicarbonate (1 g) and 3-fluoroaniline (0.46 g) in dichloromethane (100 mL). After stirring overnight, the reaction mixture was washed with water, dried over magnesium sulfate and evaporated to give the subtitle compound (1.07 g).
m / e 232 [M + H ⁺ ]
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.14 (s, 1H), 7.50 (dt, 1H), 7.31 (td, 1H), 7.18 (ddd, 1H), 6.87 (tdd, 1H), 4.03 (s, 2H).

１−チオフェン−２−イル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例５ｄ)(９６mg)および２−ブロモ−Ｎ−(３−フルオロ−フェニル)−アセトアミド(実施例８ａ)(６７mg)をアセトニトリル(２mL)に溶解し、一夜静置した。ジエチルエーテル(１０mL)およびイソヘキサン(８mL)を添加し、混合物を一夜静置した。得られた結晶を濾取し、ジエチルエーテルで洗浄して、表題化合物(９０mg)を得た。
m/e 485 [M⁺]
¹H NMR (400 MHz, DMSO-D₆) δ 10.84 (s, 1H), 7.58 (dt, 1H), 7.46 - 7.39 (m, 2H), 7.33 - 7.29 (m, 1H), 7.04 (dd, 1H), 7.02 - 6.96 (m, 2H), 5.15 - 5.10 (m, 1H), 4.33 - 4.24 (m, 2H), 4.17 - 4.07 (m, 1H), 3.77 - 3.58 (m, 4H), 3.51 (dd, 1H), 2.56 - 2.44 (m, 1H), 2.28 - 2.22 (m, 1H), 2.21 - 2.12 (m, 1H), 2.08 - 1.70 (m, 6H), 1.66 - 1.47 (m, 8H)。 Example 8: (R) -1-[(3-Fluoro-phenylcarbamoyl) -methyl] -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane bromide

1-thiophen-2-yl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 5d) (96 mg) and 2-bromo-N -(3-Fluoro-phenyl) -acetamide (Example 8a) (67 mg) was dissolved in acetonitrile (2 mL) and allowed to stand overnight. Diethyl ether (10 mL) and isohexane (8 mL) were added and the mixture was left overnight. The obtained crystals were collected by filtration and washed with diethyl ether to give the title compound (90 mg).
m / e 485 [M ⁺ ]
¹ H NMR (400 MHz, DMSO-D ₆ ) δ 10.84 (s, 1H), 7.58 (dt, 1H), 7.46-7.39 (m, 2H), 7.33-7.29 (m, 1H), 7.04 (dd, 1H ), 7.02-6.96 (m, 2H), 5.15-5.10 (m, 1H), 4.33-4.24 (m, 2H), 4.17-4.07 (m, 1H), 3.77-3.58 (m, 4H), 3.51 (dd , 1H), 2.56-2.44 (m, 1H), 2.28-2.22 (m, 1H), 2.21-2.12 (m, 1H), 2.08-1.70 (m, 6H), 1.66-1.47 (m, 8H).

乾燥ＤＭＦ(３０mL)に溶解した５−メチル−ピラジン−２−イルアミンおよび炭酸セシウム(１１.２ｇ)にブロモアセチルブロマイド(２.８９ｇ)を添加し、混合物をｒｔで２時間撹拌した。水(２００mL)を添加し、混合物を酢酸エチル(２×１００mL)で抽出し、硫酸マグネシウムで乾燥させた。抽出物を〜５０mLまで濃縮し、イソヘキサン(１００mL)を添加して、副題化合物を固体として得た(１.６４ｇ)。
¹H NMR (400 MHz, DMSO-D₆) δ 11.06 (1H, s), 9.17 (1H, s), 8.31 (1H, d), 4.16 (2H, s), 2.46 (3H, s)。 Example 9: (R) -1-[(5-Methyl-pyrazin-2-ylcarbamoyl) -methyl] -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [ 2.2.2] Octane bromide a) 2-Bromo-N- (5-methyl-pyrazin-2-yl) -acetamide

Bromoacetyl bromide (2.89 g) was added to 5-methyl-pyrazin-2-ylamine and cesium carbonate (11.2 g) dissolved in dry DMF (30 mL) and the mixture was stirred at rt for 2 h. Water (200 mL) was added and the mixture was extracted with ethyl acetate (2 × 100 mL) and dried over magnesium sulfate. The extract was concentrated to ˜50 mL and isohexane (100 mL) was added to give the subtitle compound as a solid (1.64 g).
¹ H NMR (400 MHz, DMSO-D ₆ ) δ 11.06 (1H, s), 9.17 (1H, s), 8.31 (1H, d), 4.16 (2H, s), 2.46 (3H, s).

１−チオフェン−２−イル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例５ｄ)(４８mg)をアセトニトリル(２mL)に溶解し、２−ブロモ−Ｎ−(５−メチル−ピラジン−２−イル)−アセトアミド(実施例９ａ)(３３mg)を添加した。１週間撹拌後、ジエチルエーテル(８mL)およびイソヘキサン(５mL)を添加した。結晶を濾過により回収し、酢酸エチル(２×４mL)で洗浄し、乾燥させて、表題化合物(２６mg)を得た。
m/e 483 [M⁺]
¹H NMR (400 MHz, DMSO-D₆) δ 11.26 (s, 1H), 9.15 (s, 1H), 8.36 (s, 1H), 7.44 (dd, 1H), 7.04 (dd, 1H), 6.99 (dd, 1H), 5.15 - 5.08 (m, 1H), 4.33 (s, 2H), 4.13 (ddd, 1H), 3.75 - 3.57 (m, 4H), 3.56 - 3.46 (m, 1H), 2.48 (s, 3H), 2.50 - 2.44 (m, 1H), 2.28 - 2.22 (m, 1H), 2.20 - 2.11 (m, 1H), 2.08 - 1.90 (m, 4H), 1.90 - 1.80 (m, 1H), 1.79 - 1.69 (m, 1H), 1.64 - 1.48 (m, 8H)。 Example 9: (R) -1-[(5-Methyl-pyrazin-2-ylcarbamoyl) -methyl] -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [ 2.2.2] Octane bromide

1-thiophen-2-yl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 5d) (48 mg) in acetonitrile (2 mL) Upon dissolution, 2-bromo-N- (5-methyl-pyrazin-2-yl) -acetamide (Example 9a) (33 mg) was added. After stirring for 1 week, diethyl ether (8 mL) and isohexane (5 mL) were added. The crystals were collected by filtration, washed with ethyl acetate (2 × 4 mL) and dried to give the title compound (26 mg).
m / e 483 [M ⁺ ]
¹ H NMR (400 MHz, DMSO-D ₆ ) δ 11.26 (s, 1H), 9.15 (s, 1H), 8.36 (s, 1H), 7.44 (dd, 1H), 7.04 (dd, 1H), 6.99 ( dd, 1H), 5.15-5.08 (m, 1H), 4.33 (s, 2H), 4.13 (ddd, 1H), 3.75-3.57 (m, 4H), 3.56-3.46 (m, 1H), 2.48 (s, 3H), 2.50-2.44 (m, 1H), 2.28-2.22 (m, 1H), 2.20-2.11 (m, 1H), 2.08-1.90 (m, 4H), 1.90-1.80 (m, 1H), 1.79- 1.69 (m, 1H), 1.64-1.48 (m, 8H).

１−チオフェン−２−イル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例５ｄ)(７１mg)およびＮ−ベンゾ[ｄ]イソキサゾール−３−イル−２−クロロ−アセトアミド(実施例４ａ)(５４mg)をアセトニトリル(１０mL)に溶解し、６日間静置した。得られた結晶を濾取し、ジエチルエーテル(３×１０mL)で洗浄して、表題化合物(８２mg)を得た。
m/e 509 [M⁺]
¹H NMR (400 MHz, DMSO-D₆) δ 12.16 (s, 1H), 8.17 (d, 1H), 7.74 (d, 1H), 7.72 - 7.67 (m, 1H), 7.44 - 7.39 (m, 2H), 7.04 (dd, 1H), 6.98 (dd, 1H), 5.16 - 5.11 (m, 1H), 4.64 - 4.50 (m, 2H), 4.21 - 4.13 (m, 1H), 3.82 - 3.64 (m, 4H), 3.59 (dd, 1H), 2.56 - 2.44 (m, 2H), 2.29 - 2.22 (m, 1H), 2.22 - 2.13 (m, 1H), 2.08 - 1.89 (m, 3H), 1.89 - 1.81 (m, 1H), 1.80 - 1.69 (m, 1H), 1.64 - 1.47 (m, 8H)。 Example 10: (R) -1- (Benzo [d] isoxazol-3-ylcarbamoylmethyl) -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2 .2] Octane chloride

1-thiophen-2-yl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 5d) (71 mg) and N-benzo [d Isoxazol-3-yl-2-chloro-acetamide (Example 4a) (54 mg) was dissolved in acetonitrile (10 mL) and allowed to stand for 6 days. The obtained crystals were collected by filtration and washed with diethyl ether (3 × 10 mL) to give the title compound (82 mg).
m / e 509 [M ⁺ ]
¹ H NMR (400 MHz, DMSO-D ₆ ) δ 12.16 (s, 1H), 8.17 (d, 1H), 7.74 (d, 1H), 7.72-7.67 (m, 1H), 7.44-7.39 (m, 2H ), 7.04 (dd, 1H), 6.98 (dd, 1H), 5.16-5.11 (m, 1H), 4.64-4.50 (m, 2H), 4.21-4.13 (m, 1H), 3.82-3.64 (m, 4H ), 3.59 (dd, 1H), 2.56-2.44 (m, 2H), 2.29-2.22 (m, 1H), 2.22-2.13 (m, 1H), 2.08-1.89 (m, 3H), 1.89-1.81 (m , 1H), 1.80-1.69 (m, 1H), 1.64-1.47 (m, 8H).

撹拌しているピラジン−２−イルアミン(１.８７ｇ)および炭酸カリウム(８.１９ｇ)のジクロロメタン(２５mL)懸濁液に、２−ブロモアセチルブロマイド(１.７２mL)を滴下した。反応混合物を一夜撹拌し、次いで水(２×５０mL)で洗浄した。有機相を分離し、硫酸マグネシウムで乾燥させ、蒸発させて、副題化合物(０.７０ｇ)を得た。
¹H NMR (400 MHz, CDCl₃) δ 9.51 (d, 1H), 8.63 (s, 1H), 8.42 (d, 1H), 8.30 (dd, 1H), 4.06 (s, 2H)。 Example 11: (R) -1- (pyrazin-2-ylcarbamoylmethyl) -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane Bromide a) 2-bromo-N-pyrazin-2-yl-acetamide

2-Bromoacetyl bromide (1.72 mL) was added dropwise to a stirring suspension of pyrazin-2-ylamine (1.87 g) and potassium carbonate (8.19 g) in dichloromethane (25 mL). The reaction mixture was stirred overnight and then washed with water (2 × 50 mL). The organic phase was separated, dried over magnesium sulfate and evaporated to give the subtitle compound (0.70 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.51 (d, 1H), 8.63 (s, 1H), 8.42 (d, 1H), 8.30 (dd, 1H), 4.06 (s, 2H).

１−チオフェン−２−イル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例５ｄ)(１１６mg)および２−ブロモ−Ｎ−ピラジン−２−イル−アセトアミド(実施例１１ａ)(７５mg)をアセトニトリル(２mL)に溶解し、一夜静置した。ジエチルエーテル(１０mL)およびイソヘキサン(８mL)を添加し、混合物を一夜静置した。得られた結晶を濾取し、ジエチルエーテルで洗浄して、表題化合物(１１７mg)を得た。
m/e 469 [M⁺]
¹H NMR (400 MHz, DMSO-D₆) δ 11.38 (s, 1H), 9.28 (s, 1H), 8.50 - 8.45 (m, 2H), 7.44 (dd, 1H), 7.04 (dd, 1H), 6.99 (dd, 1H), 5.15 - 5.09 (m, 1H), 4.36 (s, 2H), 4.18 - 4.08 (m, 1H), 3.76 - 3.58 (m, 4H), 3.58 - 3.46 (m, 1H), 3.33 - 3.29 (m, 1H), 2.55 - 2.43 (m, 1H), 2.29 - 2.22 (m, 1H), 2.21 - 2.12 (m, 1H), 2.08 - 1.88 (m, 3H), 1.88 - 1.79 (m, 1H), 1.79 - 1.72 (m, 1H), 1.64 - 1.48 (m, 8H)。 Example 11: (R) -1- (pyrazin-2-ylcarbamoylmethyl) -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

1-thiophen-2-yl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 5d) (116 mg) and 2-bromo-N -Pyrazin-2-yl-acetamide (Example 11a) (75 mg) was dissolved in acetonitrile (2 mL) and allowed to stand overnight. Diethyl ether (10 mL) and isohexane (8 mL) were added and the mixture was left overnight. The obtained crystals were collected by filtration and washed with diethyl ether to give the title compound (117 mg).
m / e 469 [M ⁺ ]
¹ H NMR (400 MHz, DMSO-D ₆ ) δ 11.38 (s, 1H), 9.28 (s, 1H), 8.50-8.45 (m, 2H), 7.44 (dd, 1H), 7.04 (dd, 1H), 6.99 (dd, 1H), 5.15-5.09 (m, 1H), 4.36 (s, 2H), 4.18-4.08 (m, 1H), 3.76-3.58 (m, 4H), 3.58-3.46 (m, 1H), 3.33-3.29 (m, 1H), 2.55-2.43 (m, 1H), 2.29-2.22 (m, 1H), 2.21-2.12 (m, 1H), 2.08-1.88 (m, 3H), 1.88-1.79 (m , 1H), 1.79-1.72 (m, 1H), 1.64-1.48 (m, 8H).

(３−フルオロ−フェニル)−酢酸メチルエステル(４.３０ｇ)をテトラヒドロフラン(２０mL)に溶解し、−７８℃に冷却した。リチウムビス(トリメチルシリル)アミド(２５.６mL、１Ｍ ＴＨＦ溶液)を添加し、溶液を３０分間撹拌した。４−ブロモ−ブト−１−エン(２.６０mL)を添加し、反応内容物を室温に温め、１時間撹拌した。反応混合物を再び−７８℃に冷却した。リチウムビス(トリメチルシリル)アミド(２５.６mL、１Ｍ ＴＨＦ溶液)を添加し、溶液を３０分間撹拌した。４−ブロモ−１−ブテン(２.６０mL)を添加し、反応混合物を室温に温め、１時間撹拌した。内容物を再び−７８℃に冷却し、さらにリチウムビス(トリメチルシリル)アミド(２５.６mL、１Ｍ ＴＨＦ溶液)および４−ブロモ−１−ブテン(２.６０mL)を、上記に略記した方法に従い添加した。一夜撹拌後、水(２０mL)を添加し、反応混合物ジエチルエーテル(２×６０mL)で抽出した。合わせた有機抽出物を硫酸マグネシウムで乾燥させ、蒸発させた。得られた液体を酢酸エチル／イソヘキサン(１／９９)で溶出するシリカカラムクロマトグラフィーで精製して、副題化合物(５.０ｇ)を得た。
m/e 277 [M+H]⁺ Example 12: (R) -3- [1- (3-Fluoro-phenyl) -cycloheptanecarbonyloxy] -1- (pyrazin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2 ] Octane bromide a) 2-but-3-enyl-2- (3-fluoro-phenyl) -hex-5-enoic acid methyl ester

(3-Fluoro-phenyl) -acetic acid methyl ester (4.30 g) was dissolved in tetrahydrofuran (20 mL) and cooled to -78 ° C. Lithium bis (trimethylsilyl) amide (25.6 mL, 1M THF solution) was added and the solution was stirred for 30 minutes. 4-Bromo-but-1-ene (2.60 mL) was added and the reaction contents were warmed to room temperature and stirred for 1 hour. The reaction mixture was cooled again to -78 ° C. Lithium bis (trimethylsilyl) amide (25.6 mL, 1M THF solution) was added and the solution was stirred for 30 minutes. 4-Bromo-1-butene (2.60 mL) was added and the reaction mixture was warmed to room temperature and stirred for 1 hour. The contents were again cooled to −78 ° C. and further lithium bis (trimethylsilyl) amide (25.6 mL, 1M in THF) and 4-bromo-1-butene (2.60 mL) were added according to the method outlined above. . After stirring overnight, water (20 mL) was added and the reaction mixture was extracted with diethyl ether (2 × 60 mL). The combined organic extracts were dried with magnesium sulfate and evaporated. The resulting liquid was purified by silica column chromatography eluting with ethyl acetate / isohexane (1/99) to give the subtitle compound (5.0 g).
m / e 277 [M + H] ⁺

２−ブト−３−エニル−２−(３−フルオロ−フェニル)−ヘキシ−５−エン酸メチルエステル(実施例１２ａ)(５.０ｇ)のジクロロメタン(１００mL)溶液に、Grubbs触媒(第二世代、Sigma-Aldrich Company Ltd)(０.０５ｇ)を添加した。混合物を窒素下還流まで温めた。２０時間後、反応を室温に冷却し、油状物となるまで蒸発させたおよび酢酸エチル／イソヘキサン(５／９５)で溶出するシリカカラムクロマトグラフィーで精製して、油状物を得た。生成物の分析により相当量の出発物質が存在することが示されたため、混合物を上記の反応条件および精製に再び付して、副題化合物を無色油状物として得た(３.６０ｇ)。
m/e 249 [M+H]⁺ b) 1- (3-Fluoro-phenyl) -cyclohept-4-enecarboxylic acid methyl ester

To a solution of 2-but-3-enyl-2- (3-fluoro-phenyl) -hex-5-enoic acid methyl ester (Example 12a) (5.0 g) in dichloromethane (100 mL) was added Grubbs catalyst (second generation). Sigma-Aldrich Company Ltd) (0.05 g). The mixture was warmed to reflux under nitrogen. After 20 hours, the reaction was cooled to room temperature, evaporated to an oil and purified by silica column chromatography eluting with ethyl acetate / isohexane (5/95) to give an oil. Since analysis of the product showed that a significant amount of starting material was present, the mixture was resubmitted to the reaction conditions and purification described above to give the subtitle compound as a colorless oil (3.60 g).
m / e 249 [M + H] ⁺

１−(３−フルオロ−フェニル)−シクロヘプト−４−エンカルボン酸メチルエステル(実施例１２ｂ)(１.０９ｇ)をメタノール(２０mL)に溶解し、パラジウム炭素(５０mg)を添加し、混合物を４気圧の水素下で一夜撹拌した。溶液を濾過し、蒸発させて、副題化合物(１.０９ｇ)を得た。
m/e 251 [M+H]⁺ c) 1- (3-Fluoro-phenyl) -cycloheptanecarboxylic acid methyl ester

1- (3-Fluoro-phenyl) -cyclohept-4-enecarboxylic acid methyl ester (Example 12b) (1.09 g) was dissolved in methanol (20 mL), palladium on carbon (50 mg) was added, and the mixture was converted to 4 Stir overnight under atmospheric hydrogen. The solution was filtered and evaporated to give the subtitle compound (1.09 g).
m / e 251 [M + H] ⁺

１−(３−フルオロ−フェニル)−シクロヘプタンカルボン酸メチルエステル(実施例１２ｃ)(０.２８０ｇ)をトルエン(１００mL)に溶解し、(Ｒ)−キヌクリジン−３−オール(０.３２０ｇ)を添加した。トルエン(１０mL)をディーン・スターク装置で留去し、冷却後水素化ナトリウム(１０mg)を添加した。反応をディーン・スターク装置で４時間還流し、その後さらなる量の水素化ナトリウム(１０mg)を添加し、反応をさらに４時間加熱還流した。室温に冷却後、トルエンを水で洗浄し、乾燥させ(ＭｇＳＯ_４)、蒸発させた。残留物を酢酸エチル／イソヘキサン／トリエチルアミン(５０／５０／１)、次いで酢酸エチル／トリエチルアミン(９９／１)で溶出するカラムクロマトグラフィーで精製して、副題化合物(０.２００ｇ)を得た。
m/e 346 [M+H]^+
1H NMR (399.824 MHz, CDCl₃) δ 7.26 (td, 1H), 7.10 - 7.07 (m, 1H), 7.04 (dd, 1H), 6.90 (ddd, 1H), 4.78 - 4.73 (m, 1H), 3.14 (ddd, 1H), 2.79 - 2.66 (m, 3H), 2.66 - 2.56 (m, 1H), 2.53 - 2.46 (m, 1H), 2.46 - 2.36 (m, 2H), 2.13 - 1.99 (m, 2H), 1.90 - 1.85 (m, 1H), 1.73 - 1.40 (m, 11H), 1.29 - 1.18 (m, 1H)。 d) 1- (3-Fluoro-phenyl) -cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester

1- (3-Fluoro-phenyl) -cycloheptanecarboxylic acid methyl ester (Example 12c) (0.280 g) was dissolved in toluene (100 mL) and (R) -quinuclidin-3-ol (0.320 g) was dissolved. Added. Toluene (10 mL) was distilled off with a Dean-Stark apparatus, and after cooling, sodium hydride (10 mg) was added. The reaction was refluxed for 4 hours on a Dean-Stark apparatus, after which an additional amount of sodium hydride (10 mg) was added and the reaction was heated to reflux for an additional 4 hours. After cooling to room temperature, toluene was washed with water, dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography eluting with ethyl acetate / isohexane / triethylamine (50/50/1) and then ethyl acetate / triethylamine (99/1) to give the subtitle compound (0.200 g).
m / e 346 [M + H] ^+
1 H NMR (399.824 MHz, CDCl ₃ ) δ 7.26 (td, 1H), 7.10-7.07 (m, 1H), 7.04 (dd, 1H), 6.90 (ddd, 1H), 4.78-4.73 (m, 1H), 3.14 (ddd, 1H), 2.79-2.66 (m, 3H), 2.66-2.56 (m, 1H), 2.53-2.46 (m, 1H), 2.46-2.36 (m, 2H), 2.13-1.99 (m, 2H ), 1.90-1.85 (m, 1H), 1.73-1.40 (m, 11H), 1.29-1.18 (m, 1H).

１−(３−フルオロ−フェニル)−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１２ｄ)(０.１００ｇ)をアセトニトリル(８mL)に溶解し、２−ブロモ−Ｎ−ピラジン−２−イル−アセトアミド(実施例１１ａ)(０.０５ｇ)を添加した。反応混合物を３日間撹拌し、ジエチルエーテル(８mL)で希釈し、さらに１０分間撹拌し、得られた固体を濾過し、ジエチルエーテル(３×８mL)で洗浄して、固体を得て、それを熱ブタノン(８mL)から再結晶して、表題化合物を固体として得た(０.０８１ｇ)。
m/e 481 [M⁺]
¹H NMR (399.826 MHz, DMSO-D₆) δ 11.42 (s, 1H), 9.28 (s, 1H), 8.49 - 8.45 (m, 2H), 7.40 (td, 1H), 7.19 - 7.12 (m, 2H), 7.09 (td, 1H), 5.17 - 5.10 (m, 1H), 4.40 - 4.30 (m, 2H), 4.16 - 4.07 (m, 1H), 3.71 - 3.57 (m, 4H), 3.52 - 3.41 (m, 1H), 2.43 - 2.27 (m, 2H), 2.26 - 2.19 (m, 1H), 2.19 - 2.09 (m, 1H), 2.05 - 1.87 (m, 3H), 1.86 - 1.76 (m, 1H), 1.71 - 1.46 (m, 9H)。 Example 12: (R) -3- [1- (3-Fluoro-phenyl) -cycloheptanecarbonyloxy] -1- (pyrazin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2 ] Octane bromide

1- (3-Fluoro-phenyl) -cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 12d) (0.100 g) was dissolved in acetonitrile. (8 mL) and 2-bromo-N-pyrazin-2-yl-acetamide (Example 11a) (0.05 g) was added. The reaction mixture was stirred for 3 days, diluted with diethyl ether (8 mL) and stirred for an additional 10 minutes, the resulting solid was filtered and washed with diethyl ether (3 × 8 mL) to give a solid that was Recrystallization from hot butanone (8 mL) gave the title compound as a solid (0.081 g).
m / e 481 [M ⁺ ]
¹ H NMR (399.826 MHz, DMSO-D ₆ ) δ 11.42 (s, 1H), 9.28 (s, 1H), 8.49-8.45 (m, 2H), 7.40 (td, 1H), 7.19-7.12 (m, 2H ), 7.09 (td, 1H), 5.17-5.10 (m, 1H), 4.40-4.30 (m, 2H), 4.16-4.07 (m, 1H), 3.71-3.57 (m, 4H), 3.52-3.41 (m , 1H), 2.43-2.27 (m, 2H), 2.26-2.19 (m, 1H), 2.19-2.09 (m, 1H), 2.05-1.87 (m, 3H), 1.86-1.76 (m, 1H), 1.71 -1.46 (m, 9H).

イソキサゾール−３−イルアミン(１.１４ｇ)をジクロロメタン(５０mL)に溶解し、炭酸カリウム(３.７４ｇ)を添加した。ブロモアセチルクロライド(１.１２mL)を撹拌しながらゆっくり添加し、懸濁液を一夜撹拌した。反応混合物を水(２×５０mL)で洗浄し、乾燥させ、蒸発させた。生成物をジクロロメタン／イソヘキサンから再結晶して、副題化合物(２.３ｇ)を得た。
¹H NMR (299.946 MHz, CDCl₃) δ 8.94 (s, 1H), 8.34 (s, 1H), 7.06 (s, 1H), 4.03 (s, 2H)。 Example 13: (R) -3- [1- (3-Fluoro-phenyl) -cycloheptanecarbonyloxy] -1- (isoxazol-3-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2 ] Octane bromide a) 2-Bromo-N-isoxazol-3-yl-acetamide

Isoxazol-3-ylamine (1.14 g) was dissolved in dichloromethane (50 mL) and potassium carbonate (3.74 g) was added. Bromoacetyl chloride (1.12 mL) was added slowly with stirring and the suspension was stirred overnight. The reaction mixture was washed with water (2 × 50 mL), dried and evaporated. The product was recrystallized from dichloromethane / isohexane to give the subtitle compound (2.3 g).
¹ H NMR (299.946 MHz, CDCl ₃ ) δ 8.94 (s, 1H), 8.34 (s, 1H), 7.06 (s, 1H), 4.03 (s, 2H).

１−(３−フルオロ−フェニル)−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１２ｄ)(５０mg)および２−ブロモ−Ｎ−イソキサゾール−３−イル−アセトアミド(実施例１３ａ)(３０mg)をアセトニトリル(４mL)に溶解し、一夜撹拌した。溶液をジエチルエーテル(１２mL)で希釈し、一夜撹拌した。得られた結晶を濾取し、エーテル(３×１０mL)で洗浄し、乾燥させて、表題化合物を固体として得た(４８mg)。
m/e 470 [M⁺]
¹H NMR (399.826 MHz, DMSO-D₆) δ 11.69 (s, 1H), 8.90 (d, 1H), 7.40 (td, 1H), 7.18 - 7.07 (m, 3H), 6.91 (d, 1H), 5.16 - 5.10 (m, 1H), 4.31 (d, 1H), 4.25 (d, 1H), 4.09 (ddd, 1H), 3.68 - 3.53 (m, 4H), 3.43 (dd, 1H), 2.42 - 2.27 (m, 2H), 2.25 - 2.19 (m, 1H), 2.18 - 2.09 (m, 1H), 2.04 - 1.88 (m, 3H), 1.85 - 1.75 (m, 1H), 1.69 - 1.51 (m, 9H)。 Example 13: (R) -3- [1- (3-Fluoro-phenyl) -cycloheptanecarbonyloxy] -1- (isoxazol-3-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2 ] Octane bromide

1- (3-Fluoro-phenyl) -cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 12d) (50 mg) and 2-bromo -N-isoxazol-3-yl-acetamide (Example 13a) (30 mg) was dissolved in acetonitrile (4 mL) and stirred overnight. The solution was diluted with diethyl ether (12 mL) and stirred overnight. The resulting crystals were collected by filtration, washed with ether (3 × 10 mL) and dried to give the title compound as a solid (48 mg).
m / e 470 [M ⁺ ]
¹ H NMR (399.826 MHz, DMSO-D ₆ ) δ 11.69 (s, 1H), 8.90 (d, 1H), 7.40 (td, 1H), 7.18-7.07 (m, 3H), 6.91 (d, 1H), 5.16-5.10 (m, 1H), 4.31 (d, 1H), 4.25 (d, 1H), 4.09 (ddd, 1H), 3.68-3.53 (m, 4H), 3.43 (dd, 1H), 2.42-2.27 ( m, 2H), 2.25-2.19 (m, 1H), 2.18-2.09 (m, 1H), 2.04-1.88 (m, 3H), 1.85-1.75 (m, 1H), 1.69-1.51 (m, 9H).

フェニルマグネシウムブロマイド(ジエチルエーテル中３.０Ｍ溶液)(２７１mL)を、撹拌している(オーバーヘッドスターラー)シクロヘプタンカルボニトリル(５０ｇ)の２２９mL ジエチルエーテル溶液に、窒素下、穏やかな還流が維持されるような速度で添加した。反応混合物を、次いで３時間加熱還流した。ＴＬＣは反応混合物中に出発物質が存在しないことを示した。反応混合物を室温に冷却し、窒素下に一夜置いた。反応混合物を０℃に冷却し、１０２mL ４Ｎ ＨＣｌ(水性)の滴下により、温度を２０℃以下に維持しながら処理した。４Ｎ 硫酸(２０３mL)を最初に急速に、次いで終わりに向かってより速く滴下した。氷浴を除き、ジエチルエーテルを留去した。反応混合物を８０−９０℃で３.５時間加熱し、次いで室温に冷却し、一夜静置した。混合物をエーテル(約４５０mL)および水(１００mL)で希釈した。層を分離し、水性層をエーテル(２×４００mL)で抽出した。有機層を合わせ、飽和水性炭酸水素ナトリウム(６００mL)および塩水(６００mL)で洗浄し、硫酸マグネシウムで乾燥させ、濾取し、蒸発させて、副題化合物をオレンジ色液体として得た(８６.５ｇ)。
¹H NMR (300 MHz, CDCl₃) δ 7.96-7.91 (d, 2H), 7.54-7.49 (m, 1H), 7.48-7.40 (t, 2H), 3.48-3.37 (m, 1H), 1.98-1.88 (m, 2H), 1.85-1.44 (m, 10H)。 Example 14: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- (pyridin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride a) Cyclo Heptyl-phenyl-methanone

Phenylmagnesium bromide (3.0 M solution in diethyl ether) (271 mL) was added to a stirred (overhead stirrer) cycloheptanecarbonitrile (50 g) in 229 mL diethyl ether solution to maintain a gentle reflux under nitrogen. Was added at a moderate rate. The reaction mixture was then heated to reflux for 3 hours. TLC showed no starting material present in the reaction mixture. The reaction mixture was cooled to room temperature and placed under nitrogen overnight. The reaction mixture was cooled to 0 ° C. and treated with dropwise addition of 102 mL 4N HCl (aq) keeping the temperature below 20 ° C. 4N sulfuric acid (203 mL) was added dropwise rapidly first and then faster towards the end. The ice bath was removed and diethyl ether was distilled off. The reaction mixture was heated at 80-90 ° C. for 3.5 hours, then cooled to room temperature and allowed to stand overnight. The mixture was diluted with ether (ca. 450 mL) and water (100 mL). The layers were separated and the aqueous layer was extracted with ether (2 × 400 mL). The organic layers were combined and washed with saturated aqueous sodium bicarbonate (600 mL) and brine (600 mL), dried over magnesium sulfate, filtered and evaporated to give the subtitle compound as an orange liquid (86.5 g). .
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96-7.91 (d, 2H), 7.54-7.49 (m, 1H), 7.48-7.40 (t, 2H), 3.48-3.37 (m, 1H), 1.98-1.88 (m, 2H), 1.85-1.44 (m, 10H).

スルフリルクロライド(２１０mL)を非希釈(neat)シクロヘプチル−フェニル−メタノン(実施例１４ａ)(８６.５ｇ)に、０℃で、約１時間かけて滴下した。ガス発生と発熱が観察された。内部温度を添加中１５℃以下に維持し、発生したガスをＮａＯＨの１０.２Ｍ水性溶液を通して洗浄した。反応混合物を一夜加熱還流した。反応混合物を０℃に冷却し、撹拌しながら氷(１Ｌ)に粗押しだ。層を分離し、水性層をエーテル(２×４００mL)で抽出した。合わせた有機層を水(６００mL)、飽和水性炭酸水素ナトリウム(６００mL)、および塩水(６００mL)で洗浄し、硫酸マグネシウムで乾燥させ、濾取し、蒸発させて、副題化合物を褐色油状物として得た(１００ｇ)。
¹H NMR (400 MHz, CDCl₃) δ 8.10-8.06 (d, 2H), 7.52-7.46 (t, 1H), 7.44-7.36 (t, 2H), 2.50 (ddd, 2H), 2.29 (ddd, 2H), 1.84-1.73 (m, 2H), 1.68-1.58 (m, 2H), 1.58-1.43 (m, 4H)。 b) (1-chloro-cycloheptyl) -phenyl-methanone

Sulfuryl chloride (210 mL) was added dropwise to neat cycloheptyl-phenyl-methanone (Example 14a) (86.5 g) at 0 ° C. over about 1 hour. Gas evolution and exotherm were observed. The internal temperature was maintained below 15 ° C. during the addition and the evolved gas was washed through a 10.2 M aqueous solution of NaOH. The reaction mixture was heated to reflux overnight. The reaction mixture was cooled to 0 ° C. and roughly pushed into ice (1 L) with stirring. The layers were separated and the aqueous layer was extracted with ether (2 × 400 mL). The combined organic layers are washed with water (600 mL), saturated aqueous sodium bicarbonate (600 mL), and brine (600 mL), dried over magnesium sulfate, filtered and evaporated to give the subtitle compound as a brown oil. (100 g).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10-8.06 (d, 2H), 7.52-7.46 (t, 1H), 7.44-7.36 (t, 2H), 2.50 (ddd, 2H), 2.29 (ddd, 2H ), 1.84-1.73 (m, 2H), 1.68-1.58 (m, 2H), 1.58-1.43 (m, 4H).

(１−クロロ−シクロヘプチル)−フェニル−メタノン(実施例１４ｂ)(１００ｇ)の７５０mL ジオキサン溶液を硝酸銀(１３７ｇ)の濁った水(８５mL)溶液の滴下により急速に処理し、沈殿を形成させた。反応混合物を７５℃で４.５時間加熱した。反応混合物を室温に冷却し、次いで濾取し、約２００mLまで濃縮した。水(２００mL)およびエーテル(３００mL)を添加し、層を分離した。水性層をエーテル(２×２５０mL)で抽出した。合わせた有機層を１０％水性炭酸ナトリウム(３×２５０mL)で抽出した。合わせた塩基性抽出物を９０℃で４０分間以上加熱し、次いで室温に冷却し、濃ＨＣｌ(水性)で酸性化した。得られた褐色固体を濾取し、水(×２)で洗浄し、真空下で５０℃で乾燥させた。熱エタノール(４０mL)からの結晶化により、副題化合物を薄褐色結晶として得た(９.８３ｇ)。
¹H NMR (400 MHz, CD₃OD) δ 7.36-7.26 (m, 4H), 7.21-7.15 (m, 1H), 2.43-2.35 (m, 2H), 2.07-1.98 (m, 2H), 1.70-1.53 (m, 8H)。 c) 1-phenyl-cycloheptanecarboxylic acid

A 750 mL dioxane solution of (1-chloro-cycloheptyl) -phenyl-methanone (Example 14b) (100 g) was rapidly treated by dropwise addition of a cloudy water (85 mL) solution of silver nitrate (137 g) to form a precipitate. . The reaction mixture was heated at 75 ° C. for 4.5 hours. The reaction mixture was cooled to room temperature, then filtered and concentrated to about 200 mL. Water (200 mL) and ether (300 mL) were added and the layers were separated. The aqueous layer was extracted with ether (2 × 250 mL). The combined organic layers were extracted with 10% aqueous sodium carbonate (3 × 250 mL). The combined basic extracts were heated at 90 ° C. over 40 minutes, then cooled to room temperature and acidified with concentrated HCl (aq). The resulting brown solid was collected by filtration, washed with water (x2) and dried at 50 ° C under vacuum. Crystallization from hot ethanol (40 mL) gave the subtitle compound as pale brown crystals (9.83 g).
¹ H NMR (400 MHz, CD ₃ OD) δ 7.36-7.26 (m, 4H), 7.21-7.15 (m, 1H), 2.43-2.35 (m, 2H), 2.07-1.98 (m, 2H), 1.70- 1.53 (m, 8H).

トリメチルシリルジアゾメタンの２.０Ｍ溶液(２９.２mL)を、１−フェニル−シクロヘプタンカルボン酸(実施例１４ｃ)(９.８ｇ)のメタノール(８５mL)およびトルエン(３００mL)中の溶液に、窒素雰囲気下滴下した。４５分後、反応混合物を真空下濃縮し、粗生成物を０−１０％酢酸エチル／シクロヘキサンで溶出するカラムクロマトグラフィーで精製して、生成物を薄黄色油状物として得た(９.２５ｇ)。
¹H NMR (300 MHz, CD₃OD) δ 7.32-7.24 (m, 4H), 7.21-7.12 (m, 1H), 3.60 (s, 3H), 2.43-2.32 (m, 2H), 2.07-1.96 (m, 2H), 1.65-1.58 (m, 8H)。 d) 1-phenyl-cycloheptanecarboxylic acid methyl ester

A 2.0 M solution of trimethylsilyldiazomethane (29.2 mL) was added to a solution of 1-phenyl-cycloheptanecarboxylic acid (Example 14c) (9.8 g) in methanol (85 mL) and toluene (300 mL) under a nitrogen atmosphere. It was dripped. After 45 minutes, the reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography eluting with 0-10% ethyl acetate / cyclohexane to give the product as a pale yellow oil (9.25 g). .
¹ H NMR (300 MHz, CD ₃ OD) δ 7.32-7.24 (m, 4H), 7.21-7.12 (m, 1H), 3.60 (s, 3H), 2.43-2.32 (m, 2H), 2.07-1.96 ( m, 2H), 1.65-1.58 (m, 8H).

(Ｒ)−(３)−キヌクリジノール(１０.１３ｇ)および１−フェニル−シクロヘプタンカルボン酸メチルエステル(実施例１４ｄ)(９.２５ｇ)のトルエン(９０mL)溶液を、ディーン・スターク・トラップを用い３０分間加熱還流した。反応混合物を室温に冷却し、トラップを外した。水素化ナトリウム(鉱油中６０％分散)(３.１９ｇ)を窒素下少しずつ添加し、反応混合物を窒素下、一夜加熱還流した。反応混合物を氷浴で冷却し、酢酸エチル(２００mL)および水(２００mL)で希釈した。混合物を濾過し、層を分離した。水性層を酢酸エチル(２×２５０mL)で抽出し、合わせた有機層を塩水で洗浄し、硫酸マグネシウムで乾燥させ、蒸発させて、粗生成物を得て、それを１％トリエチルアミン含有ＥｔＯＡｃで溶出するシリカゲルクロマトグラフィーで精製して、副題化合物を無色油状物として得た(７.６３ｇ)。
¹H NMR (400 MHz, CD₃OD) δ 7.34-7.28 (m, 4H), 7.23-7.17 (m, 1H), 4.80-4.75 (m, 1H), 3.12 (ddd, 1H), 2.75-2.65 (m, 3H), 2.53-2.37 (m, 4H), 2.14-2.06 (m, 2H), 1.88-1.85 (m, 1H), 1.69-1.54 (m, 10H), 1.54-1.42 (m, 1H), 1.35-1.24 (m, 1H)。 e) 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester

A solution of (R)-(3) -quinuclidinol (10.13 g) and 1-phenyl-cycloheptanecarboxylic acid methyl ester (Example 14d) (9.25 g) in toluene (90 mL) was used in a Dean-Stark trap. Heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature and the trap was removed. Sodium hydride (60% dispersion in mineral oil) (3.19 g) was added in portions under nitrogen and the reaction mixture was heated to reflux overnight under nitrogen. The reaction mixture was cooled in an ice bath and diluted with ethyl acetate (200 mL) and water (200 mL). The mixture was filtered and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 × 250 mL) and the combined organic layers were washed with brine, dried over magnesium sulfate and evaporated to give the crude product which was eluted with 1% triethylamine in EtOAc. Purification by silica gel chromatography gave the subtitle compound as a colorless oil (7.63 g).
¹ H NMR (400 MHz, CD ₃ OD) δ 7.34-7.28 (m, 4H), 7.23-7.17 (m, 1H), 4.80-4.75 (m, 1H), 3.12 (ddd, 1H), 2.75-2.65 ( m, 3H), 2.53-2.37 (m, 4H), 2.14-2.06 (m, 2H), 1.88-1.85 (m, 1H), 1.69-1.54 (m, 10H), 1.54-1.42 (m, 1H), 1.35-1.24 (m, 1H).

２−アミノ−ピリジン(１.０ｇ)の乾燥ジクロロメタン(１０.６mL)溶液を、窒素下、０℃で、トリエチルアミン(１.６３mL)で処理し、続いてクロロアセチルクロライド(０.９３mL)をゆっくり添加した。反応混合物を室温に温めた。２時間後、混合物をジクロロメタンおよび水に分配した。相を分離し、水性層をジクロロメタン(×２)で抽出した。合わせた有機層を塩水で洗浄し、硫酸マグネシウムで乾燥させ、濾取し、濃縮して、粗生成物を得て、それを０−３０％酢酸エチル／シクロヘキサンで溶出するシリカゲルクロマトグラフィーで精製して、表題化合物(１.４３ｇ)をピンク色固体として得た。さらなる精製を、４０−６０石油エーテルでの摩砕により達成して、１.１５ｇの所望の生成物を得た。本物質の０.９４ｇ分の還流アセトニトリル(２.４mL)からの結晶化により、副題化合物をピンク色固体として得た(０.７３ｇ)。
¹H NMR (400 MHz, CDCl₃):δ 8.96 (s, 1H), 8.32 (ddd, 1H), 8.21 (d, 1H), 7.76 (ddd, 1H), 7.12 (ddd, 1H), 4.20 (s, 2H)。 f) 2-Chloro-N-pyridin-2-yl-acetamide

A solution of 2-amino-pyridine (1.0 g) in dry dichloromethane (10.6 mL) is treated with triethylamine (1.63 mL) at 0 ° C. under nitrogen, followed by slow addition of chloroacetyl chloride (0.93 mL). Added. The reaction mixture was warmed to room temperature. After 2 hours, the mixture was partitioned between dichloromethane and water. The phases were separated and the aqueous layer was extracted with dichloromethane (x2). The combined organic layers are washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude product which is purified by silica gel chromatography eluting with 0-30% ethyl acetate / cyclohexane. To give the title compound (1.43 g) as a pink solid. Further purification was achieved by trituration with 40-60 petroleum ether to give 1.15 g of the desired product. Crystallization of this material from 0.94 g of refluxing acetonitrile (2.4 mL) gave the subtitle compound as a pink solid (0.73 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.96 (s, 1H), 8.32 (ddd, 1H), 8.21 (d, 1H), 7.76 (ddd, 1H), 7.12 (ddd, 1H), 4.20 (s , 2H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(２５４mg)のアセトニトリル(５mL)溶液を２−クロロ−Ｎ−ピリジン−２−イル−アセトアミド(実施例１４ｆ)(１４６mg)で処理し、得られた黄色溶液を室温で一夜撹拌し、その間に固体が沈殿した。反応混合物を〜２mLのエーテルで処理し、固体を濾取し、エーテルで洗浄し、真空下で乾燥させて、表題化合物を灰白色固体として得た(２１７mg)。還流アセトニトリル(２０mL)からの結晶化により、９８mgの表題化合物を白色結晶性固体として得た。
m/e 462 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 11.09 (s, 1H), 8.34-8.32 (d, 1H), 7.97 (d, 1H), 7.85-7.79 (t, 1H), 7.33-7.25 (m, 4H), 7.21-7.13 (m, 2H), 5.07 (m, 1H), 4.29 (s, 2H), 4.07 (ddd, 1H), 3.65-3.51 (m, 4H), 3.41-3.29 (m, 1H), 2.36-2.23 (m, 2H), 2.17-2.04 (m, 2H), 1.99-1.81 (m, 3H), 1.78-1.66 (m, 1H), 1.77-1.19 (m, 9H)。 Example 14: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- (pyridin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride

1-Phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e) (254 mg) in acetonitrile (5 mL) was added to 2-chloro Treatment with -N-pyridin-2-yl-acetamide (Example 14f) (146 mg) and the resulting yellow solution was stirred overnight at room temperature, during which time a solid precipitated. The reaction mixture was treated with ˜2 mL of ether and the solid was collected by filtration, washed with ether and dried under vacuum to give the title compound as an off-white solid (217 mg). Crystallization from refluxing acetonitrile (20 mL) gave 98 mg of the title compound as a white crystalline solid.
m / e 462 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 11.09 (s, 1H), 8.34-8.32 (d, 1H), 7.97 (d, 1H), 7.85-7.79 (t, 1H), 7.33-7.25 ( m, 4H), 7.21-7.13 (m, 2H), 5.07 (m, 1H), 4.29 (s, 2H), 4.07 (ddd, 1H), 3.65-3.51 (m, 4H), 3.41-3.29 (m, 1H), 2.36-2.23 (m, 2H), 2.17-2.04 (m, 2H), 1.99-1.81 (m, 3H), 1.78-1.66 (m, 1H), 1.77-1.19 (m, 9H).

Preparation of Example 14: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- (pyridin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride crystals Form A
A solution of 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e) (254 mg, 0.78 mmol) in acetonitrile (5 mL). Was treated with 2-chloro-N-pyridin-2-yl-acetamide (Example 14f) (146 mg) and the resulting yellow solution was stirred overnight at room temperature during which time a solid precipitated. The reaction mixture was treated with 2 mL of ether, the solid collected by filtration, washed with ether and dried under vacuum to give the title compound (217 mg) as an off-white solid. Crystallization from refluxing acetonitrile (20 mL) gave 98 mg of the title compound as a white crystalline solid.
m / e 462 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 11.09 (s, 1H), 8.34-8.32 (d, 1H), 7.97 (d, 1H), 7.85-7.79 (t, 1H), 7.33-7.25 ( m, 4H), 7.21-7.13 (m, 2H), 5.07 (m, 1H), 4.29 (s, 2H), 4.07 (ddd, 1H), 3.65-3.51 (m, 4H), 3.41-3.29 (m, 1H), 2.36-2.23 (m, 2H), 2.17-2.04 (m, 2H), 1.99-1.81 (m, 3H), 1.78-1.66 (m, 1H), 1.77-1.19 (m, 9H).

Analysis of Example 14: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- (pyridin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride crystals Form A
The crystal sample of crystal form A of Example 14 obtained by the above method was analyzed by XRPD (PANalytical X'Pert system), DSC and TGA.
The melting point of Example 14 chloride Form A as determined by DSC was found to be 239 ° C. (onset) (± 2 ° C.). The weight loss observed prior to melting by TGA was negligible. GVS determination resulted in a negligible weight gain (% w / w) at 80% RH (± 0.2%).
The XRPD spectrum of chloride form A of Example 14 is shown in FIG.

２−アミノピリジン(４８.８mmol)の無水ＴＨＦ(９８mL)溶液に、室温でＥｔ_３Ｎ(５８.６mmol)およびブロモアセチルブロマイド(５８.６mmol)を滴下した混合物を一夜撹拌し、飽和ＮａＨＣＯ_３(水性)でクエンチした。ＥｔＯＡｃを混合物に添加し、層を分離した。水性相をＥｔＯＡｃで抽出し、合わせた有機物を乾燥させ(ＭｇＳＯ_４)、真空で褐色固体になるまで濃縮した。１−２％ＭｅＯＨ／ジクロロメタンで溶出するフラッシュシリカゲルクロマトグラフィーでの精製により、副題化合物を黄色固体として得た(１.１４ｇ)。
¹H NMR (400 MHz, CDCl₃):δ 8.75 (s, 1H), 8.26 (ddd, 1H), 8.10 (d, 1H), 7.67 (ddd, 1H), 7.03 (ddd, 1H), 3.94 (s, 2H)。 Example 15: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- (pyridin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane bromide a) 2 -Bromo-N-pyridin-2-yl-acetamide

To a solution of 2-aminopyridine (48.8 mmol) in anhydrous THF (98 mL), Et ₃ N (58.6 mmol) and bromoacetyl bromide (58.6 mmol) were added dropwise at room temperature, and the mixture was stirred overnight, and saturated NaHCO _{3 (} Quenched with _aqueous . EtOAc was added to the mixture and the layers were separated. The aqueous phase was extracted with EtOAc and the combined organics were dried (MgSO ₄ ) and concentrated in vacuo to a brown solid. Purification by flash silica gel chromatography eluting with 1-2% MeOH / dichloromethane gave the subtitle compound as a yellow solid (1.14 g).
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.75 (s, 1H), 8.26 (ddd, 1H), 8.10 (d, 1H), 7.67 (ddd, 1H), 7.03 (ddd, 1H), 3.94 (s , 2H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(０.７９mmol)および２−ブロモ−Ｎ−ピリジン−２−イル−アセトアミド(実施例１５ａ)(０.８７mmol)を、一緒に無水ＭｅＣＮ中、室温で２.５日間撹拌した。反応混合物を真空で濃縮し、黄色固体を２−８％ＭｅＯＨ／ジクロロメタンで溶出するフラッシュシリカゲルカラムクロマトグラフィーで精製して、黄褐色固体を得て、それを沸騰ＭｅＣＮから結晶化して、表題化合物を白色固体として得た(２１１mg)。
m/e 462 [M]^+
1H NMR (400 MHz, DMSO-D₆) δ 11.02 (s, 1H), 8.33 (ddd, 1H), 7.97 (d, 1H), 7.86-7.80 (m, 1H), 7.32-7.25 (m, 4H), 7.23-7.12 (m, 2H), 5.09-5.04 (m, 1H), 4.23 (s, 2H), 4.06 (ddd, 1H), 3.63-3.49 (m, 4H), 3.41-3.29 (m, 1H), 2.37-2.22 (m, 2H), 2.17-2.04 (m, 2H), 1.98-1.83 (m, 3H), 1.78-1.66 (m, 1H), 1.65-1.39 (m, 9H)。 Example 15: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- (pyridin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane bromide

1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e) (0.79 mmol) and 2-bromo-N-pyridine 2-yl-acetamide (Example 15a) (0.87 mmol) was stirred together in anhydrous MeCN at room temperature for 2.5 days. The reaction mixture is concentrated in vacuo and the yellow solid is purified by flash silica gel column chromatography eluting with 2-8% MeOH / dichloromethane to give a tan solid that crystallizes from boiling MeCN to give the title compound. Obtained as a white solid (211 mg).
m / e 462 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ) δ 11.02 (s, 1H), 8.33 (ddd, 1H), 7.97 (d, 1H), 7.86-7.80 (m, 1H), 7.32-7.25 (m, 4H ), 7.23-7.12 (m, 2H), 5.09-5.04 (m, 1H), 4.23 (s, 2H), 4.06 (ddd, 1H), 3.63-3.49 (m, 4H), 3.41-3.29 (m, 1H ), 2.37-2.22 (m, 2H), 2.17-2.04 (m, 2H), 1.98-1.83 (m, 3H), 1.78-1.66 (m, 1H), 1.65-1.39 (m, 9H).

Preparation of Example 15: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- (pyridin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane bromide crystals Form A
1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e) (0.79 mmol) and 2-bromo-N-pyridine 2-yl-acetamide (Example 15a) (0.87 mmol) was stirred together in anhydrous MeCN at room temperature for 2.5 days. The reaction mixture was concentrated in vacuo and the yellow solid was purified by flash silica gel column chromatography eluting with 2-8% MeOH / dichloromethane to give a tan solid. The solid was dissolved in refluxing MeCN and the solution was cooled to room temperature. The resulting crystals were collected by filtration and washed with a small amount of cold MeCN to give the title compound (211 mg) as a white crystalline solid.
m / e 462 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 11.02 (s, 1H), 8.33 (ddd, 1H), 7.97 (d, 1H), 7.86-7.80 (m, 1H), 7.32-7.25 (m, 4H), 7.23-7.12 (m, 2H), 5.09-5.04 (m, 1H), 4.23 (s, 2H), 4.06 (ddd, 1H), 3.63-3.49 (m, 4H), 3.41-3.29 (m, 1H), 2.37-2.22 (m, 2H), 2.17-2.04 (m, 2H), 1.98-1.83 (m, 3H), 1.78-1.66 (m, 1H), 1.65-1.39 (m, 9H).

Analysis of Example 15: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- (pyridin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane bromide crystals Form A
The crystal sample of crystal form A of Example 15 obtained by the above method was analyzed by XRPD (PANalytical X'Pert system), DSC and TGA.
The melting point of Example 15 bromide Form A determined by DSC was found to be 230 ° C. (onset) (± 2 ° C.). The weight loss observed prior to melting by TGA was negligible. GVS determination resulted in a negligible weight gain (% w / w) at 80% RH (± 0.2%).
The XRPD spectrum of bromide form A of Example 15 is shown in FIG.

４−アミノピリジン(０.９６ｇ)の乾燥ジクロロメタン(１０mL)懸濁液を、窒素下、氷浴で０℃に冷却した。トリエチルアミン(１.５６mL)を添加し、続いてクロロアセチルクロライド(０.８９mL)をゆっくり添加した。氷浴を除き、反応混合物を室温にした。反応混合物を水(２０mL)およびジクロロメタン(２５mL)で希釈した。固体を濾取し、ペンタンで洗浄し、乾燥させて、表題化合物を褐色固体として得た(０.８７ｇ)。濾液の層を分離し、有機層を水で洗浄し、乾燥させ、溶媒を蒸発させて、暗色褐色ガラスを得た。ペンタンでの摩砕により、別のバッチの表題化合物(０.９１ｇ)を得た。
¹H NMR (400 MHz, DMSO-D₆) δ 10.79 (s, 1H), 8.47 (d, 2H), 7.59 (d, 2H), 4.33 (s, 2H)。 Example 16: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- (pyridin-4-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride a) 2 -Chloro-N-pyridin-4-yl-acetamide

A suspension of 4-aminopyridine (0.96 g) in dry dichloromethane (10 mL) was cooled to 0 ° C. with an ice bath under nitrogen. Triethylamine (1.56 mL) was added followed by the slow addition of chloroacetyl chloride (0.89 mL). The ice bath was removed and the reaction mixture was allowed to come to room temperature. The reaction mixture was diluted with water (20 mL) and dichloromethane (25 mL). The solid was collected by filtration, washed with pentane and dried to give the title compound as a brown solid (0.87 g). The filtrate layers were separated and the organic layer was washed with water, dried and the solvent was evaporated to give a dark brown glass. Trituration with pentane gave another batch of the title compound (0.91 g).
¹ H NMR (400 MHz, DMSO-D ₆ ) δ 10.79 (s, 1H), 8.47 (d, 2H), 7.59 (d, 2H), 4.33 (s, 2H).

２−クロロ−Ｎ−ピリジン−４−イル−アセトアミド(実施例１６ａ)(３０mg)を１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(５３mg)のアセトニトリル(１mL)溶液に添加した。反応混合物を室温で２４時間撹拌した。ジエチルエーテル(２mL)を添加し、反応混合物を濾過して、明褐色固体を得た。固体を数回ジエチルエーテルで洗浄し、真空下、４０℃で乾燥させた。０−１０％ＭｅＯＨ／ジクロロメタンで溶出するカラムクロマトグラフィーでの精製により、表題化合物を白色固体として得た(２０mg)。
m/e 462 [M]^+
1H NMR (400 MHz, DMSO-D₆) δ 11.34 (s, 1H), 8.46 (d, 2H), 7.55 (d, 2H), 7.34-7.26 (m, 4H), 7.22-7.17 (m, 1H), 5.08 (m, 1H), 4.30 (s, 2H), 4.11-4.02 (m, 1H), 3.65-3.51 (m, 4H), 3.42-3.30 (m, 1H), 2.38-2.24 (m, 2H), 2.17-2.06 (m, 2H), 1.99-1.84 (m, 3H), 1.79-1.67 (m, 1H), 1.69-1.26 (m, 9H)。 Example 16: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- (pyridin-4-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride

2-Chloro-N-pyridin-4-yl-acetamide (Example 16a) (30 mg) was converted to 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3. -Yl) ester (Example 14e) (53 mg) was added to a solution of acetonitrile (1 mL). The reaction mixture was stirred at room temperature for 24 hours. Diethyl ether (2 mL) was added and the reaction mixture was filtered to give a light brown solid. The solid was washed several times with diethyl ether and dried at 40 ° C. under vacuum. Purification by column chromatography eluting with 0-10% MeOH / dichloromethane gave the title compound as a white solid (20 mg).
m / e 462 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ) δ 11.34 (s, 1H), 8.46 (d, 2H), 7.55 (d, 2H), 7.34-7.26 (m, 4H), 7.22-7.17 (m, 1H ), 5.08 (m, 1H), 4.30 (s, 2H), 4.11-4.02 (m, 1H), 3.65-3.51 (m, 4H), 3.42-3.30 (m, 1H), 2.38-2.24 (m, 2H ), 2.17-2.06 (m, 2H), 1.99-1.84 (m, 3H), 1.79-1.67 (m, 1H), 1.69-1.26 (m, 9H).

表題化合物(０.９９ｇ、７３％、白色固体)を、２−アミノ−５−フルオロ−ピリジンを使用する以外実施例１４ｆで使用した方法に従い製造した。
¹H NMR (400 MHz, DMSO-D₆) δ 10.91 (s, 1H), 8.35 (d, 1H), 8.10 (dd, 1H), 7.80-7.74 (m, 1H), 4.34 (s, 2H)。 Example 17: (R) -1-[(5-Fluoro-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride a) 2-Chloro-N- (5-fluoro-pyridin-2-yl) -acetamide

The title compound (0.99 g, 73%, white solid) was prepared according to the method used in Example 14f except using 2-amino-5-fluoro-pyridine.
¹ H NMR (400 MHz, DMSO-D ₆ ) δ 10.91 (s, 1H), 8.35 (d, 1H), 8.10 (dd, 1H), 7.80-7.74 (m, 1H), 4.34 (s, 2H).

２−クロロ−Ｎ−(５−フルオロ−ピリジン−２−イル)−アセトアミド(実施例１７ａ)(３１mg)を、１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(４９mg)のアセトニトリル(１mL)溶液に添加した。反応混合物を室温で一夜撹拌した。ジエチルエーテル(２mL)を反応混合物に添加し、白色固体を濾取し、数回ジエチルエーテルで洗浄し、真空下、４０℃で乾燥させて、表題化合物(４９mg)を得た。
m/e 480 [M]^+
1H NMR (400 MHz, DMSO-D₆) δ 11.19 (s, 1H), 8.36 (d, 1H), 8.02 (m, 1H), 7.81 (ddd, 1H), 7.33-7.26 (m, 4H), 7.22-7.17 (m, 1H), 5.07 (m, 1H), 4.26 (s, 2H), 4.11-4.03 (m, 1H), 3.64-3.50 (m, 4H), 3.41-3.29 (m, 1H), 2.36-2.23 (m, 2H), 2.17-2.05 (m, 2H), 1.99-1.82 (m, 3H), 1.78-1.65 (m, 1H), 1.70-1.41 (m, 9H)。 Example 17: (R) -1-[(5-Fluoro-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride

2-Chloro-N- (5-fluoro-pyridin-2-yl) -acetamide (Example 17a) (31 mg) was added to 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2. 2.2] Oct-3-yl) ester (Example 14e) (49 mg) was added to a solution of acetonitrile (1 mL). The reaction mixture was stirred overnight at room temperature. Diethyl ether (2 mL) was added to the reaction mixture and the white solid was collected by filtration, washed several times with diethyl ether and dried under vacuum at 40 ° C. to give the title compound (49 mg).
m / e 480 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ) δ 11.19 (s, 1H), 8.36 (d, 1H), 8.02 (m, 1H), 7.81 (ddd, 1H), 7.33-7.26 (m, 4H), 7.22-7.17 (m, 1H), 5.07 (m, 1H), 4.26 (s, 2H), 4.11-4.03 (m, 1H), 3.64-3.50 (m, 4H), 3.41-3.29 (m, 1H), 2.36-2.23 (m, 2H), 2.17-2.05 (m, 2H), 1.99-1.82 (m, 3H), 1.78-1.65 (m, 1H), 1.70-1.41 (m, 9H).

表題化合物(０.５０ｇ)を、２−アミノ−５−ピコリンを使用する以外実施例１４ｆで使用した方法に従い製造した。
¹H NMR (400 MHz, DMSO-D₆) δ 10.69 (s, 1H), 8.17 (dt, 1H), 7.95 (d, 1H), 7.63 (dd, 1H), 4.32 (s, 2H), 2.25 (s, 3H)。 Example 18: (R) -1-[(5-Methyl-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride a) 2-chloro-N- (5-methyl-pyridin-2-yl) -acetamide

The title compound (0.50 g) was prepared according to the method used in Example 14f except using 2-amino-5-picoline.
¹ H NMR (400 MHz, DMSO-D ₆ ) δ 10.69 (s, 1H), 8.17 (dt, 1H), 7.95 (d, 1H), 7.63 (dd, 1H), 4.32 (s, 2H), 2.25 ( s, 3H).

表題化合物(３６mg)を、実施例１７の製造に使用した方法に従い、２−クロロ−Ｎ−(５−メチル−ピリジン−２−イル)−アセトアミド(実施例１８ａ)を２−クロロ−Ｎ−(５−フルオロ−ピリジン−２−イル)−アセトアミドの代わりに使用して製造した。
m/e 476 [M]^+
1H NMR (400 MHz, DMSO-D₆) δ 10.98 (s, 1H), 8.17 (d, 1H), 7.88 (d, 1H), 7.65 (dd, 1H), 7.33-7.25 (m, 4H), 7.23-7.17 (m, 1H), 5.07 (m, 1H), 4.24 (s, 2H), 4.10-4.02 (m, 1H), 3.64-3.50 (m, 4H), 3.40-3.27 (m, 1H), 2.37-2.22 (m, 2H), 2.23 (s, 3H), 2.17-2.04 (m, 2H), 1.97-1.84 (m, 3H), 1.78-1.66 (m, 1H), 1.66-1.35 (m, 9H)。 Example 18: (R) -1-[(5-Methyl-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride

The title compound (36 mg) was prepared according to the method used for the preparation of Example 17 and 2-chloro-N- (5-methyl-pyridin-2-yl) -acetamide (Example 18a) was converted to 2-chloro-N- ( Prepared using instead of 5-fluoro-pyridin-2-yl) -acetamide.
m / e 476 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ) δ 10.98 (s, 1H), 8.17 (d, 1H), 7.88 (d, 1H), 7.65 (dd, 1H), 7.33-7.25 (m, 4H), 7.23-7.17 (m, 1H), 5.07 (m, 1H), 4.24 (s, 2H), 4.10-4.02 (m, 1H), 3.64-3.50 (m, 4H), 3.40-3.27 (m, 1H), 2.37-2.22 (m, 2H), 2.23 (s, 3H), 2.17-2.04 (m, 2H), 1.97-1.84 (m, 3H), 1.78-1.66 (m, 1H), 1.66-1.35 (m, 9H ).

３−アミノピリジン(３５０mg)および水酸化ナトリウム(０.６ｇ)の混合物を水(８mL)に溶解し、反応混合物を氷浴で冷却した。クロロアセチルクロライド(１.１９mL)を滴下し、反応混合物を室温で一夜撹拌した。反応混合物をジクロロメタンで抽出し、有機層を濃縮し、０−６０％酢酸エチル／シクロヘキサンで溶出するカラムクロマトグラフィーで精製して、表題化合物(０.１０ｇ)を白色固体として得た。
¹H NMR (400 MHz, DMSO-D₆) δ 10.51 (s, 1H), 8.73 (d, 1H), 8.30 (dd, 1H), 8.03 (ddd, 1H), 7.40-7.35 (m, 1H), 4.30 (s, 2H)。 Example 19: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- (pyridin-3-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride a) 2 -Chloro-N-pyridin-3-yl-acetamide

A mixture of 3-aminopyridine (350 mg) and sodium hydroxide (0.6 g) was dissolved in water (8 mL) and the reaction mixture was cooled in an ice bath. Chloroacetyl chloride (1.19 mL) was added dropwise and the reaction mixture was stirred overnight at room temperature. The reaction mixture was extracted with dichloromethane and the organic layer was concentrated and purified by column chromatography eluting with 0-60% ethyl acetate / cyclohexane to give the title compound (0.10 g) as a white solid.
¹ H NMR (400 MHz, DMSO-D ₆ ) δ 10.51 (s, 1H), 8.73 (d, 1H), 8.30 (dd, 1H), 8.03 (ddd, 1H), 7.40-7.35 (m, 1H), 4.30 (s, 2H).

表題化合物(７８mg)を、実施例１５にし使用した方法に準じる方法で、２−クロロ−Ｎ−ピリジン−３−イル−アセトアミドを２−ブロモ−Ｎ−ピリジン−２−イル−アセトアミドの代わりに使用して、製造した。
m/e 462 [M]^+
1H NMR (400 MHz, DMSO-D₆) δ 11.27 (s, 1H), 8.76 (d, 1H), 8.30 (dd, 1H), 7.98 (ddd, 1H), 7.37 (ddd, 1H), 7.33-7.25 (m, 4H), 7.22-7.15 (m, 1H), 5.07 (d, 1H), 4.28 (dd, 2H), 4.11-4.03 (m, 1H), 3.65-3.50 (m, 4H), 3.41-3.29 (m, 1H), 2.37-2.21 (m, 2H), 2.19-2.05 (m, 2H), 1.97-1.83 (m, 3H), 1.78-1.66 (m, 1H), 1.71-1.27 (m, 9H)。 Example 19: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- (pyridin-3-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride

Use the title compound (78 mg) in a manner analogous to that used in Example 15 but using 2-chloro-N-pyridin-3-yl-acetamide instead of 2-bromo-N-pyridin-2-yl-acetamide. And manufactured.
m / e 462 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ) δ 11.27 (s, 1H), 8.76 (d, 1H), 8.30 (dd, 1H), 7.98 (ddd, 1H), 7.37 (ddd, 1H), 7.33- 7.25 (m, 4H), 7.22-7.15 (m, 1H), 5.07 (d, 1H), 4.28 (dd, 2H), 4.11-4.03 (m, 1H), 3.65-3.50 (m, 4H), 3.41- 3.29 (m, 1H), 2.37-2.21 (m, 2H), 2.19-2.05 (m, 2H), 1.97-1.83 (m, 3H), 1.78-1.66 (m, 1H), 1.71-1.27 (m, 9H ).

表題化合物(１.０ｇ)を、４−アミノ−２−メチルピリジンを使用する以外実施例１４ｆで使用した方法に従い製造した。
¹H NMR (400 MHz, DMSO-D₆) δ 10.64 (s, 1H), 8.32 (d, 1H), 7.44 (d, 1H), 7.38-7.35 (m, 1H), 4.30 (s, 2H), 2.42 (s, 3H)。 Example 20: (R) -1-[(2-Methyl-pyridin-4-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride a) 2-chloro-N- (2-methyl-pyridin-4-yl) -acetamide

The title compound (1.0 g) was prepared according to the method used in Example 14f except using 4-amino-2-methylpyridine.
¹ H NMR (400 MHz, DMSO-D ₆ ) δ 10.64 (s, 1H), 8.32 (d, 1H), 7.44 (d, 1H), 7.38-7.35 (m, 1H), 4.30 (s, 2H), 2.42 (s, 3H).

表題化合物を実施例１７の製造に使用した方法に準じる方法を使用して製造した。０−２０％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーによりさらに精製して、表題化合物を白色固体として得た(５７mg)。
m/e 476 [M]^+
1H NMR (400 MHz, DMSO-D₆) δ 11.32 (s, 1H), 8.31 (d, 1H), 7.43 (d, 1H), 7.35-7.26 (m, 5H), 7.22-7.16 (m, 1H), 5.09-5.04 (m, 1H), 4.30 (dd, 2H), 4.09-4.01 (m, 1H), 3.64-3.49 (m, 4H), 3.41-3.29 (m, 1H), 2.38 (s, 3H), 2.39-2.23 (m, 2H), 2.17-2.05 (m, 2H), 1.97-1.82 (m, 3H), 1.78-1.65 (m, 1H), 1.65-1.41 (m, 9H)。 Example 20: (R) -1-[(2-Methyl-pyridin-4-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride

The title compound was prepared using a method analogous to the method used for preparing Example 17. Further purification by silica gel chromatography eluting with 0-20% MeOH / dichloromethane gave the title compound as a white solid (57 mg).
m / e 476 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ) δ 11.32 (s, 1H), 8.31 (d, 1H), 7.43 (d, 1H), 7.35-7.26 (m, 5H), 7.22-7.16 (m, 1H ), 5.09-5.04 (m, 1H), 4.30 (dd, 2H), 4.09-4.01 (m, 1H), 3.64-3.49 (m, 4H), 3.41-3.29 (m, 1H), 2.38 (s, 3H ), 2.39-2.23 (m, 2H), 2.17-2.05 (m, 2H), 1.97-1.82 (m, 3H), 1.78-1.65 (m, 1H), 1.65-1.41 (m, 9H).

ブロモアセチルブロマイド(９.６mL)および炭酸カリウム(１１.４ｇ)のジクロロメタン(１００mL)溶液に、アニリン(５mL)を、１５−２０間にわたり、反応混合物が温かくなり、白色沈殿が形成するのに注意しながら滴下した。４.５時間後反応混合物を水に注ぎ、数分間振盪し、次いで相を分離した。有機層を水で洗浄し、小容量まで濃縮して固体の沈殿を得て、それを濾取して、副題化合物(９７０mg)を白色固体として得た。
¹H NMR (400 MHz, CDCl₃):δ 8.10 (s, 1H), 7.53 (d, 2H), 7.40-7.33 (m, 2H), 7.17 (t, 1H), 4.03 (s, 2H)。 Example 21: (R) -1-Phenylcarbamoylmethyl-3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide a) 2-Bromo-N-phenyl -Acetamide

Add aniline (5 mL) to a solution of bromoacetyl bromide (9.6 mL) and potassium carbonate (11.4 g) in dichloromethane (100 mL) over 15-20, taking care that the reaction mixture becomes warm and a white precipitate forms. While dripping. After 4.5 hours, the reaction mixture was poured into water and shaken for several minutes, then the phases were separated. The organic layer was washed with water and concentrated to a small volume to give a solid precipitate that was collected by filtration to give the subtitle compound (970 mg) as a white solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.10 (s, 1H), 7.53 (d, 2H), 7.40-7.33 (m, 2H), 7.17 (t, 1H), 4.03 (s, 2H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(５０mg)のアセトニトリル(１mL)溶液に２−ブロモ−Ｎ−フェニルアセトアミド(実施例２１ａ)(３６mg)を添加した。反応混合物を室温で３日間撹拌した。エーテルを反応混合物に添加し、得られた固体を濾過により回収し、乾燥させて、表題化合物を無色固体として得た(３９mg)。
m/e 461 [M]^+
1H NMR (DMSO-D₆):δ 10.49 (s, 1H), 7.53-7.50 (m, 2H), 7.35-7.24 (m, 6H), 7.21-7.16 (m, 1H), 7.12-7.07 (m, 1H), 5.08 (m, 1H), 4.21-4.11 (m, 2H), 4.06 (dd, 1H), 3.64-3.49 (m, 4H), 3.27 (s, 1H), 2.37-2.21 (m, 2H), 2.18-2.04 (m, 2H), 1.98-1.88 (m, 3H), 1.77-1.66 (m, 1H), 1.70-1.30 (m, 9H)。 Example 21: (R) -1-phenylcarbamoylmethyl-3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

1-Phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e) (50 mg) in acetonitrile (1 mL) in 2-bromo -N-phenylacetamide (Example 21a) (36 mg) was added. The reaction mixture was stirred at room temperature for 3 days. Ether was added to the reaction mixture and the resulting solid was collected by filtration and dried to give the title compound as a colorless solid (39 mg).
m / e 461 [M] ^+
1 H NMR (DMSO-D ₆ ): δ 10.49 (s, 1H), 7.53-7.50 (m, 2H), 7.35-7.24 (m, 6H), 7.21-7.16 (m, 1H), 7.12-7.07 (m , 1H), 5.08 (m, 1H), 4.21-4.11 (m, 2H), 4.06 (dd, 1H), 3.64-3.49 (m, 4H), 3.27 (s, 1H), 2.37-2.21 (m, 2H ), 2.18-2.04 (m, 2H), 1.98-1.88 (m, 3H), 1.77-1.66 (m, 1H), 1.70-1.30 (m, 9H).

クロロアセチルクロライド(１.２２mmol)の無水ＣＨＣｌ_３(２.４mL)溶液を、４−アミノピリミジン(１.１１mmol)およびＥｔ_３Ｎ(１.６６mmol)の無水ＣＨＣｌ_３(２２mL)中の混合物に室温でゆっくり滴下した。明黄色混合物が徐々にオレンジ色に変わり、４時間後反応をＨ_２Ｏ(１mL)でクエンチした。１５分間撹拌後混合物を減圧下濃縮乾固し、残留物をフラッシュシリカゲルクロマトグラフィー(１−２％ＭｅＯＨ／ジクロロメタン)で精製して、黄色固体(１２２mg)を得た。
¹H NMR (400 MHz, DMSO-D₆):δ 11.21 (s, 1H), 8.93-8.90 (m, 1H), 8.70 (d, 1H), 8.03 (dd, 1H), 4.40 (s, 2H)。 Example 22: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- (pyrimidin-4-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride a) 2 -Chloro-N-pyrimidin-4-yl-acetamide

A solution of chloroacetyl chloride (1.22 mmol) in anhydrous CHCl ₃ (2.4 mL) was added to a mixture of 4-aminopyrimidine (1.11 mmol) and Et ₃ N (1.66 mmol) in anhydrous CHCl ₃ (22 mL) at room temperature. Was slowly added dropwise. The light yellow mixture gradually turned orange and after 4 h the reaction was quenched with H ₂ O (1 mL). After stirring for 15 minutes, the mixture was concentrated to dryness under reduced pressure and the residue was purified by flash silica gel chromatography (1-2% MeOH / dichloromethane) to give a yellow solid (122 mg).
¹ H NMR (400 MHz, DMSO-D ₆ ): δ 11.21 (s, 1H), 8.93-8.90 (m, 1H), 8.70 (d, 1H), 8.03 (dd, 1H), 4.40 (s, 2H) .

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(０.４４mmol)および２−クロロ−Ｎ−ピリミジン−４−イル−アセトアミド(実施例２２ａ)(０.４８mmol)の無水ＭｅＣＮ(２mL)を、一緒に室温で２.５日間撹拌した。反応混合物を真空で濃縮し、残留物をフラッシュシリカゲルクロマトグラフィー(２−１０％ＭｅＯＨ／ジクロロメタン)で精製して、表題化合物を明黄色固体として得た(１３４mg)。
m/e 463 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 11.44 (s, 1H), 8.91 (s, 1H), 8.72 (d, 1H), 7.94 (d, 1H), 7.32-7.25 (m, 4H), 7.22-7.17 (m, 1H), 5.10-5.04 (m, 1H), 4.30 (s, 2H), 4.10-4.02 (m, 1H), 3.61-3.49 (m, 4H), 3.40-3.28 (m, 1H), 2.36-2.21 (m, 2H), 2.18-2.04 (m, 2H), 2.00-1.84 (m, 3H), 1.75-1.66 (m, 1H), 1.66-1.39 (m, 9H)。 Example 22: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- (pyrimidin-4-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride

1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e) (0.44 mmol) and 2-chloro-N-pyrimidine -4-yl-acetamide (Example 22a) (0.48 mmol) of anhydrous MeCN (2 mL) was stirred together at room temperature for 2.5 days. The reaction mixture was concentrated in vacuo and the residue was purified by flash silica gel chromatography (2-10% MeOH / dichloromethane) to give the title compound as a light yellow solid (134 mg).
m / e 463 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 11.44 (s, 1H), 8.91 (s, 1H), 8.72 (d, 1H), 7.94 (d, 1H), 7.32-7.25 (m, 4H) , 7.22-7.17 (m, 1H), 5.10-5.04 (m, 1H), 4.30 (s, 2H), 4.10-4.02 (m, 1H), 3.61-3.49 (m, 4H), 3.40-3.28 (m, 1H), 2.36-2.21 (m, 2H), 2.18-2.04 (m, 2H), 2.00-1.84 (m, 3H), 1.75-1.66 (m, 1H), 1.66-1.39 (m, 9H).

２−フルオロアニリン(２mL)および炭酸カリウム(４.３ｇ)のジクロロメタン(５０mL)中の混合物に、ブロモアセチルブロマイド(３.６mL)を添加した。反応混合物を４時間撹拌し、次いで水を添加し、相を分離した。有機層を濃縮し、残留物をエーテルで処理し、再び蒸発させて、副題化合物(４.９８ｇ)をクリーム色固体として得て、それをさらに精製せずに使用した。
¹H NMR (400 MHz, CDCl₃):δ 8.38 (s, 1H), 8.26 (t, 1H), 7.18-7.09 (m, 3H), 4.05 (s, 2H)。 Example 23: (R) -1-[(2-Fluoro-phenylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide a) 2-Bromo-N- (2-fluoro-phenyl) -acetamide

Bromoacetyl bromide (3.6 mL) was added to a mixture of 2-fluoroaniline (2 mL) and potassium carbonate (4.3 g) in dichloromethane (50 mL). The reaction mixture was stirred for 4 hours, then water was added and the phases were separated. The organic layer was concentrated and the residue was treated with ether and evaporated again to give the subtitle compound (4.98 g) as a cream solid that was used without further purification.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.38 (s, 1H), 8.26 (t, 1H), 7.18-7.09 (m, 3H), 4.05 (s, 2H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(５６mg)および２−ブロモ−Ｎ−(２−フルオロ−フェニル)−アセトアミド(実施例２３ａ)(４４mg)のアセトニトリル(１mL)中の混合物を室温で３０時間撹拌した。得られた沈殿を濾過により回収し、エーテルで洗浄し、５０℃で真空下乾燥させて、表題化合物(５２mg)を無色固体として得た。
m/e 479 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 10.34 (s, 1H), 7.83-7.77 (m, 1H), 7.32-7.16 (m, 8H), 5.12-5.03 (m, 1H), 4.25 (s, 2H), 4.10-4.02 (m, 1H), 3.63-3.51 (m, 4H), 3.41-3.29 (m, 1H), 2.37-2.23 (m, 2H), 2.17-2.06 (m, 2H), 1.98-1.88 (m, 3H), 1.79-1.67 (m, 1H), 1.66-1.39 (s, 9H)。 Example 23: (R) -1-[(2-Fluoro-phenylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e) (56 mg) and 2-bromo-N- (2- A mixture of fluoro-phenyl) -acetamide (Example 23a) (44 mg) in acetonitrile (1 mL) was stirred at room temperature for 30 hours. The resulting precipitate was collected by filtration, washed with ether and dried under vacuum at 50 ° C. to give the title compound (52 mg) as a colorless solid.
m / e 479 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 10.34 (s, 1H), 7.83-7.77 (m, 1H), 7.32-7.16 (m, 8H), 5.12-5.03 (m, 1H), 4.25 ( s, 2H), 4.10-4.02 (m, 1H), 3.63-3.51 (m, 4H), 3.41-3.29 (m, 1H), 2.37-2.23 (m, 2H), 2.17-2.06 (m, 2H), 1.98-1.88 (m, 3H), 1.79-1.67 (m, 1H), 1.66-1.39 (s, 9H).

２,３−ジフルオロアニリン(６３０mg)および炭酸カリウム(１.０１ｇ)のジクロロメタン(３０mL)中の混合物に、ブロモアセチルブロマイド(０.８６mL)を添加した。反応混合物を５時間撹拌し、次いで水を添加し、相を分離した。有機層を濃縮して、副題化合物とブロモアセチルブロマイドの２：１混合物を得た。残留物をジクロロメタンに溶解し、水で洗浄した。揮発物を蒸発させて、副題化合物(１.１５ｇ)を灰白色固体として得て、それをさらに精製せずに使用した。
¹H NMR (400 MHz, CDCl₃):δ 8.38 (s, 1H), 8.03 (t, 1H), 7.12-7.05 (m, 1H), 7.00-6.92 (m, 1H), 4.05 (d, 2H). Example 24: (R) -1-[(2,3-difluoro-phenylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] Octane bromide a) 2-Bromo-N- (2,3-difluoro-phenyl) -acetamide

To a mixture of 2,3-difluoroaniline (630 mg) and potassium carbonate (1.01 g) in dichloromethane (30 mL) was added bromoacetyl bromide (0.86 mL). The reaction mixture was stirred for 5 hours, then water was added and the phases were separated. The organic layer was concentrated to give a 2: 1 mixture of the subtitle compound and bromoacetyl bromide. The residue was dissolved in dichloromethane and washed with water. The volatiles were evaporated to give the subtitle compound (1.15 g) as an off-white solid that was used without further purification.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.38 (s, 1H), 8.03 (t, 1H), 7.12-7.05 (m, 1H), 7.00-6.92 (m, 1H), 4.05 (d, 2H) .

表題化合物(無色固体、２８mg、３１％)を、実施例２３で使用した方法に準じる方法により、２−ブロモ−Ｎ−(２,３−ジフルオロ−フェニル)−アセトアミド(実施例２４ａ)を２−ブロモ−Ｎ−(２−フルオロ−フェニル)−アセトアミドの代わりに使用して製造した。
m/e 497 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 10.54 (s, 1H), 7.58 (t, 1H), 7.32-7.16 (m, 7H), 5.13-5.04 (m, 1H), 4.26 (s, 2H), 4.10-4.02 (m, 1H), 3.62-3.49 (m, 4H), 3.42-3.29 (m, 1H), 2.37-2.23 (m, 2H), 2.17-2.06 (m, 2H), 1.98-1.85 (m, 3H), 1.79-1.67 (m, 1H), 1.66-1.40 (m, 9H)。 Example 24: (R) -1-[(2,3-difluoro-phenylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] Octane bromide

The title compound (colorless solid, 28 mg, 31%) was prepared according to the method used in Example 23, and 2-bromo-N- (2,3-difluoro-phenyl) -acetamide (Example 24a) was converted to 2- Prepared using instead of bromo-N- (2-fluoro-phenyl) -acetamide.
m / e 497 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 10.54 (s, 1H), 7.58 (t, 1H), 7.32-7.16 (m, 7H), 5.13-5.04 (m, 1H), 4.26 (s, 2H), 4.10-4.02 (m, 1H), 3.62-3.49 (m, 4H), 3.42-3.29 (m, 1H), 2.37-2.23 (m, 2H), 2.17-2.06 (m, 2H), 1.98- 1.85 (m, 3H), 1.79-1.67 (m, 1H), 1.66-1.40 (m, 9H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(１２６mg)および５−(２−ブロモ−エチル)−２,３−ジヒドロ−ベンゾフラン(１０５mg、０.４６mmol)のアセトニトリル(１.５mL)中の混合物を室温で２２時間撹拌した。揮発物を蒸発させ、残留物をジクロロメタン、次いで５％、次いで１０％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製した。関連フラクションを合わせ、蒸発させ、残留物をジクロロメタンで摩砕して、灰白色泡状物を得た。逆相ＨＰＬＣ(０.１％ギ酸含有５−９８％ＭｅＣＮ／Ｈ_２Ｏ)でさらに精製して、表題化合物(７０mg)を白色ガム状固体として得た。
m/e 474 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 8.35 (s, 1H), 7.35-7.26 (m, 4H), 7.24-7.18 (m, 1H), 7.12 (s, 1H), 6.95 (d, 1H), 6.68 (d, 1H), 5.08-5.01 (m, 1H), 4.46 (t, 2H), 3.87-3.78 (m, 1H), 3.47-3.25 (m, 5H), 3.20-3.06 (m, 3H), 3.04-2.97 (m, 1H), 2.86-2.75 (m, 2H), 2.39-2.23 (m, 2H), 2.18-2.10 (m, 2H), 2.01-1.78 (m, 3H), 1.69-1.44 (m, 10H)。 Example 25: (R) -1- [2- (2,3-dihydro-benzofuran-5-yl) -ethyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2 .2.2] Octane formate

1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e) (126 mg) and 5- (2-bromo-ethyl) A mixture of -2,3-dihydro-benzofuran (105 mg, 0.46 mmol) in acetonitrile (1.5 mL) was stirred at room temperature for 22 hours. Volatiles were evaporated and the residue was purified by silica gel chromatography eluting with dichloromethane then 5% then 10% MeOH / dichloromethane. The relevant fractions were combined and evaporated and the residue was triturated with dichloromethane to give an off-white foam. Further purification by reverse phase HPLC (5-98% MeCN / H ₂ O with 0.1% formic acid) afforded the title compound (70 mg) as a white gummy solid.
m / e 474 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 8.35 (s, 1H), 7.35-7.26 (m, 4H), 7.24-7.18 (m, 1H), 7.12 (s, 1H), 6.95 (d, 1H), 6.68 (d, 1H), 5.08-5.01 (m, 1H), 4.46 (t, 2H), 3.87-3.78 (m, 1H), 3.47-3.25 (m, 5H), 3.20-3.06 (m, 3H), 3.04-2.97 (m, 1H), 2.86-2.75 (m, 2H), 2.39-2.23 (m, 2H), 2.18-2.10 (m, 2H), 2.01-1.78 (m, 3H), 1.69- 1.44 (m, 10H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(５０mg)および１−(２−ブロモエトキシ)−４−フルオロベンゼン(５０mg)のアセトニトリル(１mL)中の混合物を室温で２２時間撹拌した。０.１％ギ酸含有５−９８％ＭｅＣＮ／Ｈ_２Ｏを用いる分取ＨＰＬＣでの精製により、表題化合物(１９mg)を無色油状物として得た。
m/e 466 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 8.39 (s, 1H), 7.28-7.23 (m, 4H), 7.20-7.11 (m, 3H), 6.97-6.92 (m, 2H), 5.06-4.99 (m, 1H), 4.39-4.28 (m, 2H), 3.93 (ddd, 1H), 3.70-3.56 (m, 2H), 3.56-3.46 (m, 4H), 3.15-3.03 (m, 1H), 2.35-2.20 (m, 2H), 2.15-2.03 (m, 2H), 1.97-1.78 (m, 3H), 1.73-1.61 (m, 1H), 1.61-1.39 (m, 9H)。 Example 26: (R) -1- [2- (4-Fluoro-phenoxy) -ethyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane Formate

1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e) (50 mg) and 1- (2-bromoethoxy)- A mixture of 4-fluorobenzene (50 mg) in acetonitrile (1 mL) was stirred at room temperature for 22 hours. Purification by preparative HPLC using 0.1% formic acid containing 5-98% MeCN / _{H 2} O, to give the title compound (19 mg) as a colorless oil.
m / e 466 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 8.39 (s, 1H), 7.28-7.23 (m, 4H), 7.20-7.11 (m, 3H), 6.97-6.92 (m, 2H), 5.06- 4.99 (m, 1H), 4.39-4.28 (m, 2H), 3.93 (ddd, 1H), 3.70-3.56 (m, 2H), 3.56-3.46 (m, 4H), 3.15-3.03 (m, 1H), 2.35-2.20 (m, 2H), 2.15-2.03 (m, 2H), 1.97-1.78 (m, 3H), 1.73-1.61 (m, 1H), 1.61-1.39 (m, 9H).

ピリダジン−４−イルアミン(１.０ｇ)の乾燥ジクロロメタン(１０mL)溶液を、窒素下、氷浴で０℃に冷却した。トリエチルアミン(１.６mL)を添加し、続いてクロロアセチルクロライド(０.９２mL)をゆっくり添加した。添加完了後氷浴を除き、反応混合物を室温にし、２時間撹拌した。反応混合物を水(２５mL)およびジクロロメタン(３０mL)で希釈した。固体を濾取し、ペンタン、水およびさらにペンタンで洗浄して、副題化合物(０.８７ｇ、４８％)を褐色固体として得た。
¹H NMR (400 MHz, DMSO-D₆):δ 11.17 (s, 1H), 9.33 (dd, 1H), 9.07 (dd, 1H), 7.94 (dd, 1H), 4.39 (s, 2H)。 Example 27: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyridazin-4-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octaneformate a) 2-Chloro-N-pyridazin-4-yl-acetamide

A solution of pyridazin-4-ylamine (1.0 g) in dry dichloromethane (10 mL) was cooled to 0 ° C. with an ice bath under nitrogen. Triethylamine (1.6 mL) was added followed by the slow addition of chloroacetyl chloride (0.92 mL). After the addition was complete, the ice bath was removed and the reaction mixture was allowed to reach room temperature and stirred for 2 hours. The reaction mixture was diluted with water (25 mL) and dichloromethane (30 mL). The solid was collected by filtration and washed with pentane, water and further pentane to give the subtitle compound (0.87 g, 48%) as a brown solid.
¹ H NMR (400 MHz, DMSO-D ₆ ): δ 11.17 (s, 1H), 9.33 (dd, 1H), 9.07 (dd, 1H), 7.94 (dd, 1H), 4.39 (s, 2H).

２−クロロ−Ｎ−ピリダジン−４−イル−アセトアミド(実施例２７ａ)(５８mg)を、１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(１００mg)のアセトニトリル(２mL)溶液に添加した。反応混合物を室温で２４時間撹拌した。ジエチルエーテル(２mL)を反応混合物に添加し、１５分間撹拌した。固体を濾取し、ジエチルエーテルで洗浄し、真空下、４０℃で一夜乾燥させた。濾液を蒸発させ、固体と合わせ、０−１５％ＭｅＯＨ／ジクロロメタンで溶出するカラムクロマトグラフィーで精製した。逆相分取ＨＰＬＣで０.１％ギ酸含有１５％ＭｅＣＮ／Ｈ_２Ｏで１％／分上昇させる勾配でさらに精製して、表題化合物(１９mg)を無色ガム状物として得た。
m/e 463 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 9.17 (s, 1H), 8.89 (d, 1H), 8.41 (s, 1H), 7.80 (dd, 1H), 7.32-7.25 (m, 4H), 7.21-7.15 (m, 1H), 5.08-5.02 (m, 1H), 4.28-4.14 (m, 2H), 4.04 (dd, 1H), 3.66 (d, 2H), 3.62-3.48 (m, 2H), 3.45-3.33 (m, 1H), 2.37-2.23 (m, 2H), 2.14-2.05 (m, 2H), 1.96-1.83 (m, 3H), 1.75-1.62 (m, 1H), 1.56-1.42 (m, 9H)。 Example 27: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- (pyridazin-4-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octaneformate

2-Chloro-N-pyridazin-4-yl-acetamide (Example 27a) (58 mg) was converted to 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] octo- 3-yl) ester (Example 14e) (100 mg) was added to a solution of acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 24 hours. Diethyl ether (2 mL) was added to the reaction mixture and stirred for 15 minutes. The solid was collected by filtration, washed with diethyl ether and dried overnight at 40 ° C. under vacuum. The filtrate was evaporated, combined with the solid and purified by column chromatography eluting with 0-15% MeOH / dichloromethane. Further purification on reverse phase preparative HPLC with a gradient of 1% / min with 15% MeCN / H ₂ O containing 0.1% formic acid gave the title compound (19 mg) as a colorless gum.
m / e 463 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 9.17 (s, 1H), 8.89 (d, 1H), 8.41 (s, 1H), 7.80 (dd, 1H), 7.32-7.25 (m, 4H) , 7.21-7.15 (m, 1H), 5.08-5.02 (m, 1H), 4.28-4.14 (m, 2H), 4.04 (dd, 1H), 3.66 (d, 2H), 3.62-3.48 (m, 2H) , 3.45-3.33 (m, 1H), 2.37-2.23 (m, 2H), 2.14-2.05 (m, 2H), 1.96-1.83 (m, 3H), 1.75-1.62 (m, 1H), 1.56-1.42 ( m, 9H).

３−アミノ−５−フルオロピリジン(１ｇ)の乾燥ジクロロメタン(１０mL)溶液を、窒素下、氷浴で０℃に冷却した。トリエチルアミン(１.３６mL)を添加し、続いてクロロアセチルクロライド(０.７８mL)をゆっくり添加した。添加完了後、氷浴を除き、反応混合物を室温にし、２時間撹拌した。反応混合物を水(２５mL)およびジクロロメタン(３０mL)で希釈した。有機層を水(２×２０mL)で洗浄し、乾燥させ(ＭｇＳＯ_４)、蒸発させて、粗生成物を得た。０−３０％酢酸エチル／シクロヘキサンで溶出するシリカゲルクロマトグラフィーで精製して、副題化合物(１.０ｇ)を黄褐色固体として得た。
¹H NMR (400 MHz, DMSO-D₆):δ 10.77 (s, 1H), 8.56 (t, 1H), 8.33 (d, 1H), 8.04 (dt, 1H), 4.33 (s, 2H)。 Example 28: (R) -1-[(5-Fluoro-pyridin-3-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride a) 2-chloro-N- (5-fluoro-pyridin-3-yl) -acetamide

A solution of 3-amino-5-fluoropyridine (1 g) in dry dichloromethane (10 mL) was cooled to 0 ° C. with an ice bath under nitrogen. Triethylamine (1.36 mL) was added followed by the slow addition of chloroacetyl chloride (0.78 mL). After the addition was complete, the ice bath was removed and the reaction mixture was allowed to reach room temperature and stirred for 2 hours. The reaction mixture was diluted with water (25 mL) and dichloromethane (30 mL). The organic layer was washed with water (2 × 20 mL), dried (MgSO ₄ ) and evaporated to give the crude product. Purification by silica gel chromatography eluting with 0-30% ethyl acetate / cyclohexane gave the subtitle compound (1.0 g) as a tan solid.
¹ H NMR (400 MHz, DMSO-D ₆ ): δ 10.77 (s, 1H), 8.56 (t, 1H), 8.33 (d, 1H), 8.04 (dt, 1H), 4.33 (s, 2H).

２−クロロ−Ｎ−(５−フルオロ−ピリジン−３−イル)−アセトアミド(実施例２８ａ)(５３mg)を１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(８４mg)のアセトニトリル(２mL)溶液に添加した。反応混合物を室温で２４時間撹拌した。固体を濾取し、真空下、４０℃で乾燥させて、表題化合物(４７mg、３５％)を白色固体として得た。
m/e 480 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 11.53 (s, 1H), 8.58 (s, 1H), 8.34 (d, 1H), 7.99 (dt, 1H), 7.32-7.25 (m, 4H), 7.21-7.15 (m, 1H), 5.09-5.04 (m, 1H), 4.29 (s, 2H), 4.10-4.02 (m, 1H), 3.63-3.51 (m, 4H), 3.41-3.29 (m, 1H), 2.37-2.23 (m, 2H), 2.16-2.05 (m, 2H), 1.96-1.83 (m, 3H), 1.78-1.65 (m, 1H), 1.65-1.39 (m, 9H)。 Example 28: (R) -1-[(5-Fluoro-pyridin-3-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride

2-Chloro-N- (5-fluoro-pyridin-3-yl) -acetamide (Example 28a) (53 mg) was converted to 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2 .2] Oct-3-yl) ester (Example 14e) (84 mg) was added to a solution of acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 24 hours. The solid was collected by filtration and dried under vacuum at 40 ° C. to give the title compound (47 mg, 35%) as a white solid.
m / e 480 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 11.53 (s, 1H), 8.58 (s, 1H), 8.34 (d, 1H), 7.99 (dt, 1H), 7.32-7.25 (m, 4H) , 7.21-7.15 (m, 1H), 5.09-5.04 (m, 1H), 4.29 (s, 2H), 4.10-4.02 (m, 1H), 3.63-3.51 (m, 4H), 3.41-3.29 (m, 1H), 2.37-2.23 (m, 2H), 2.16-2.05 (m, 2H), 1.96-1.83 (m, 3H), 1.78-1.65 (m, 1H), 1.65-1.39 (m, 9H).

副題化合物(０.９９ｇ、６３％)をＷＯ２００４／０００８２９に記載の方法に従って製造した。 Example 29: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- [2- (pyridin-3-yloxy) -ethyl] -1-azonia-bicyclo [2.2.2] octane Formate a) 2- (pyridin-3-yloxy) -ethanol

The subtitle compound (0.99 g, 63%) was prepared according to the method described in WO2004 / 000829.

２−(ピリジン−３−イルオキシ)−エタノール(２００mg)の５mL ジクロロメタン溶液を０℃に冷却し、四臭化炭素(５２４mg)、続いてトリフェニルホスフィン(４１５mg)で少しずつ添加した。反応混合物を０℃で３０分間、次いで室温で４５分間撹拌した。揮発物を蒸発させ、残留物を０−１００％ＥｔＯＡｃ／ペンタンで溶出するシリカゲルクロマトグラフィーで精製して、表題化合物(２０４mg)を無色液体として得て、それをさらに精製せずに使用した。
¹H NMR (400 MHz, CDCl₃):δ 8.34 (dd, 1H), 8.28-8.22 (m, 1H), 7.25-7.20 (m, 2H), 4.35 (t, 2H), 3.66 (t, 2H)。 b) 3- (2-Bromo-ethoxy) -pyridine

A solution of 2- (pyridin-3-yloxy) -ethanol (200 mg) in 5 mL dichloromethane was cooled to 0 ° C. and added in portions with carbon tetrabromide (524 mg) followed by triphenylphosphine (415 mg). The reaction mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 45 minutes. The volatiles were evaporated and the residue was purified by silica gel chromatography eluting with 0-100% EtOAc / pentane to give the title compound (204 mg) as a colorless liquid that was used without further purification.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.34 (dd, 1H), 8.28-8.22 (m, 1H), 7.25-7.20 (m, 2H), 4.35 (t, 2H), 3.66 (t, 2H) .

表題化合物(１０mg、１３％、無色ガム状物)を、実施例２５の製造に使用した方法に準じる方法を使用して、３−(２−ブロモ−エトキシ)−ピリジン(実施例２９ｂ)を５−(２−ブロモ−エチル)−２,３−ジヒドロ−ベンゾフランの代わりに使用して製造した。
m/e 449 [M]^+
1H NMR (400 MHz, DMSO-D6):δ 8.51 (s, 1H), 8.29 (d, 1H), 8.21 (dd, 1H), 7.38-7.33 (m, 2H), 7.28-7.24 (m, 4H), 7.19-7.14 (m, 1H), 5.06-4.99 (m, 1H), 4.51-4.39 (m, 2H), 3.99-3.90 (m, 1H), 3.74-3.59 (m, 2H), 3.57-3.37 (m, 3H), 3.14-3.05 (m, 1H), 2.36-2.22 (m, 2H), 2.14-2.05 (m, 2H), 1.98-1.82 (m, 3H), 1.74-1.62 (m, 1H), 1.62-1.38 (m, 9H)。 Example 29: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- [2- (pyridin-3-yloxy) -ethyl] -1-azonia-bicyclo [2.2.2] octane Formate

The title compound (10 mg, 13%, colorless gum) was prepared using a method analogous to the method used for the preparation of Example 25 to give 3- (2-bromo-ethoxy) -pyridine (Example 29b). Prepared using instead of-(2-bromo-ethyl) -2,3-dihydro-benzofuran.
m / e 449 [M] ^+
1 H NMR (400 MHz, DMSO-D6): δ 8.51 (s, 1H), 8.29 (d, 1H), 8.21 (dd, 1H), 7.38-7.33 (m, 2H), 7.28-7.24 (m, 4H ), 7.19-7.14 (m, 1H), 5.06-4.99 (m, 1H), 4.51-4.39 (m, 2H), 3.99-3.90 (m, 1H), 3.74-3.59 (m, 2H), 3.57-3.37 (m, 3H), 3.14-3.05 (m, 1H), 2.36-2.22 (m, 2H), 2.14-2.05 (m, 2H), 1.98-1.82 (m, 3H), 1.74-1.62 (m, 1H) 1.62-1.38 (m, 9H).

副題化合物(０.９５ｇ、５８％、白色固体)を、実施例２８ａの製造に使用した方法に準じる方法を使用して、２−アミノ−６−ピコリンを３−アミノ−５−フルオロピリジンの代わりに使用して、製造した。
¹H NMR (400 MHz, DMSO-D₆):δ 10.73 (s, 1H), 7.86 (d, 1H), 7.69 (t, 1H), 7.03-6.96 (m, 1H), 4.32 (s, 2H), 2.41 (s, 3H)。 Example 30: (R) -1-[(6-Methyl-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride a) 2-Chloro-N- (6-methyl-pyridin-2-yl) -acetamide

The subtitle compound (0.95 g, 58%, white solid) was used in place of 3-amino-5-fluoropyridine using a method analogous to that used in the preparation of Example 28a. Used to manufacture.
¹ H NMR (400 MHz, DMSO-D ₆ ): δ 10.73 (s, 1H), 7.86 (d, 1H), 7.69 (t, 1H), 7.03-6.96 (m, 1H), 4.32 (s, 2H) , 2.41 (s, 3H).

表題化合物(３４mg、４３％、白色固体)を、実施例１７の製造に使用した方法に準じる方法を使用して、２−クロロ−Ｎ−(６−メチル−ピリジン−２−イル)−アセトアミド(実施例３０ａ)を２−クロロ−Ｎ−(５−フルオロ−ピリジン−２−イル)−アセトアミドの代わりに使用して、製造した。
m/e 476 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 11.01 (s, 1H), 7.79 (d, 1H), 7.71 (t, 1H), 7.32-7.25 (m, 4H), 7.23-7.16 (m, 1H), 7.02 (d, 1H), 5.09-5.04 (m, 1H), 4.24 (s, 2H), 4.06 (ddd, 1H), 3.63-3.50 (m, 4H), 3.38-3.29 (m, 1H), 2.38 (s, 3H), 2.38-2.23 (m, 2H), 2.17-2.04 (m, 2H), 2.00-1.82 (m, 3H), 1.78-1.66 (m, 1H), 1.65-1.40 (m, 9H)。 Example 30: (R) -1-[(6-Methyl-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride

The title compound (34 mg, 43%, white solid) was prepared from 2-chloro-N- (6-methyl-pyridin-2-yl) -acetamide (using a method analogous to that used for the preparation of Example 17. Example 30a) was prepared using 2-chloro-N- (5-fluoro-pyridin-2-yl) -acetamide instead.
m / e 476 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 11.01 (s, 1H), 7.79 (d, 1H), 7.71 (t, 1H), 7.32-7.25 (m, 4H), 7.23-7.16 (m, 1H), 7.02 (d, 1H), 5.09-5.04 (m, 1H), 4.24 (s, 2H), 4.06 (ddd, 1H), 3.63-3.50 (m, 4H), 3.38-3.29 (m, 1H) , 2.38 (s, 3H), 2.38-2.23 (m, 2H), 2.17-2.04 (m, 2H), 2.00-1.82 (m, 3H), 1.78-1.66 (m, 1H), 1.65-1.40 (m, 9H).

副題化合物(０.８３ｇ、４９％、灰白色固体)を、実施例２８ａの製造に使用した方法に準じる方法を使用して、ｏ−トルイジンを３−アミノ−５−フルオロピリジンの代わりに使用して、製造した。
¹H NMR (400 MHz, DMSO-D₆):δ 9.62 (s, 1H), 7.39 (d, 1H), 7.23-7.08 (m, 3H), 4.29 (s, 2H), 2.23 (s, 3H)。 Example 31: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (o-tolylcarbamoyl-methyl) -1-azonia-bicyclo [2.2.2] octane bromide a) 2- Chloro-N-o-tolyl-acetamide

The subtitle compound (0.83 g, 49%, off-white solid) was used in place of 3-amino-5-fluoropyridine using a method analogous to that used for the preparation of Example 28a. Manufactured.
¹ H NMR (400 MHz, DMSO-D ₆ ): δ 9.62 (s, 1H), 7.39 (d, 1H), 7.23-7.08 (m, 3H), 4.29 (s, 2H), 2.23 (s, 3H) .

表題化合物(２５mg、３５％、白色固体)を、実施例１７の製造に使用した方法に準じる方法を使用して、２−クロロ−Ｎ−ｏ−トリル−アセトアミド(実施例３１ａ)を２−クロロ−Ｎ−(５−フルオロ−ピリジン−２−イル)−アセトアミドの代わりに使用して、製造した。
m/e 475 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 10.26 (s, 1H), 7.34 (dd, 1H), 7.31-7.25 (m, 4H), 7.23-7.09 (m, 4H), 5.11-5.05 (m, 1H), 4.31 (dd, 2H), 4.07 (ddd, 1H), 3.68-3.52 (m, 4H), 3.40-3.31 (m, 1H), 2.38-2.22 (m, 2H), 2.19 (s, 3H), 2.17-2.06 (m, 2H), 1.97-1.84 (m, 3H), 1.79-1.67 (m, 1H) 1.65-1.39 (m, 9H)。 Example 31: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- (o-tolylcarbamoyl-methyl) -1-azonia-bicyclo [2.2.2] octane bromide

The title compound (25 mg, 35%, white solid) was prepared from 2-chloro-N-o-tolyl-acetamide (Example 31a) with 2-chloro using a method analogous to that used for the preparation of Example 17. Prepared using instead of -N- (5-fluoro-pyridin-2-yl) -acetamide.
m / e 475 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 10.26 (s, 1H), 7.34 (dd, 1H), 7.31-7.25 (m, 4H), 7.23-7.09 (m, 4H), 5.11-5.05 ( m, 1H), 4.31 (dd, 2H), 4.07 (ddd, 1H), 3.68-3.52 (m, 4H), 3.40-3.31 (m, 1H), 2.38-2.22 (m, 2H), 2.19 (s, 3H), 2.17-2.06 (m, 2H), 1.97-1.84 (m, 3H), 1.79-1.67 (m, 1H) 1.65-1.39 (m, 9H).

２−(２'−ヒドロキシエチル)ピラジン(０.９１ｇ)の３０mL ジクロロメタン溶液に、０℃で、四臭化炭素(２.６５ｇ)、続いてトリフェニルホスフィン(２.１ｇ)を少しずつ添加した。溶液は極めて暗い色になった。１時間撹拌後反応混合物をＨＭＮ珪藻土に吸着させ、０−５％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製して、クリーム色固体(３.０７ｇ)を得て、それを０−５０％ＥｔＯＡｃ／ペンタンで溶出するシリカゲルクロマトグラフィーでさらに精製して、副題化合物(０.４７ｇ、３４％)を黄色油状物として得た。
¹H NMR (400 MHz, CDCl₃):δ 8.56-8.48 (m, 3H), 3.78 (t, 2H), 3.37 (t, 2H)。 Example 32: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- (2-pyrazin-2-yl-ethyl) -1-azonia-bicyclo [2.2.2] octane bromide a 2- (2-Bromo-ethyl) -pyrazine

To a 30 mL dichloromethane solution of 2- (2′-hydroxyethyl) pyrazine (0.91 g) at 0 ° C. was added carbon tetrabromide (2.65 g) followed by triphenylphosphine (2.1 g) in small portions. . The solution became very dark. After stirring for 1 hour, the reaction mixture was adsorbed onto HMN diatomaceous earth and purified by silica gel chromatography eluting with 0-5% MeOH / dichloromethane to give a cream solid (3.07 g) which was treated with 0-50% EtOAc. Further purification by silica gel chromatography eluting with / pentane gave the subtitle compound (0.47 g, 34%) as a yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.56-8.48 (m, 3H), 3.78 (t, 2H), 3.37 (t, 2H).

２−(２−ブロモ−エチル)−ピラジン(実施例３２ａ)(４３mg)を、１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(５０mg)のアセトニトリル(１mL)溶液に添加した。反応混合物を室温で６８時間撹拌した。揮発物を蒸発させ、生成物を０−２０％ＭｅＯＨ／ジクロロメタン０−２０％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製した。関連フラクションを合わせ、濃縮し、ジクロロメタンに溶解し、濾取し、蒸発させて、表題化合物(３０mg)を黄色ガム状ガラスとして得た。
m/e 434 [M]^+
1H NMR (400 MHz, CD₃OD):δ 8.60 (d, 1H), 8.54 (dd, 1H), 8.51 (d, 1H), 7.31-7.24 (m, 4H), 7.21-7.15 (m, 1H), 5.05-4.98 (m, 1H), 3.86 (ddd, 1H), 3.57 (t, 2H), 3.49-3.30 (m, 3H), 3.24-3.12 (m, 3H), 3.08-2.97 (m, 1H), 2.36-2.19 (m, 2H), 2.15-2.06 (m, 2H), 1.97-1.78 (m, 3H), 1.71-1.59 (m, 1H), 1.57-1.37 (m, 9H)。 Example 32: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (2-pyrazin-2-yl-ethyl) -1-azonia-bicyclo [2.2.2] octane bromide

2- (2-Bromo-ethyl) -pyrazine (Example 32a) (43 mg) was converted to 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3- Yl) ester (Example 14e) (50 mg) was added to a solution of acetonitrile (1 mL). The reaction mixture was stirred at room temperature for 68 hours. Volatiles were evaporated and the product was purified by silica gel chromatography eluting with 0-20% MeOH / dichloromethane 0-20% MeOH / dichloromethane. The relevant fractions were combined, concentrated, dissolved in dichloromethane, filtered and evaporated to give the title compound (30 mg) as a yellow gum.
m / e 434 [M] ^+
1 H NMR (400 MHz, CD ₃ OD): δ 8.60 (d, 1H), 8.54 (dd, 1H), 8.51 (d, 1H), 7.31-7.24 (m, 4H), 7.21-7.15 (m, 1H ), 5.05-4.98 (m, 1H), 3.86 (ddd, 1H), 3.57 (t, 2H), 3.49-3.30 (m, 3H), 3.24-3.12 (m, 3H), 3.08-2.97 (m, 1H ), 2.36-2.19 (m, 2H), 2.15-2.06 (m, 2H), 1.97-1.78 (m, 3H), 1.71-1.59 (m, 1H), 1.57-1.37 (m, 9H).

(Ｓ)−(＋)−３−キヌクリジノール(２９９mg)および１−フェニル−シクロヘプタンカルボン酸メチルエステル(実施例１４ｄ)(４５５mg)の６.５mL 乾燥トルエン溶液を、窒素下、水素化ナトリウムの６０％分散(９４mg)で処理し、混合物を２４時間加熱還流し、次いで室温に冷却し、終末の間静置した。ＥｔＯＡｃおよび飽和ＮａＨＣＯ_３(水性)を添加し、相を分離した。水性相をＥｔＯＡｃ(×３)で抽出し、合わせた有機層を塩水で洗浄し、乾燥させ(ＭｇＳＯ_４)、蒸発させて、粗生成物を得た。０−１０％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製して、副題化合物(３８４mg)を黄色油状物として得た。
¹H NMR (300 MHz, CD₃OD):δ 7.39-7.27 (m, 4H), 7.25-7.14 (m, 1H), 4.80 (dt, 1H), 3.16 (ddd, 1H), 2.83-2.64 (m, 3H), 2.56-2.34 (m, 4H), 2.15-2.04 (m, 2H), 1.91-1.86 (m, 1H), 1.72-1.44 (m, 11H), 1.38-1.25 (m, 1H)。 Example 33: (S) -1- (3-phenoxy-propyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octaneformate a) 1- Phenyl-cycloheptanecarboxylic acid (S)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester

A 6.5 mL dry toluene solution of (S)-(+)-3-quinuclidinol (299 mg) and 1-phenyl-cycloheptanecarboxylic acid methyl ester (Example 14d) (455 mg) was diluted with 60% sodium hydride under nitrogen. Treated with% dispersion (94 mg), the mixture was heated to reflux for 24 hours, then cooled to room temperature and allowed to stand for the end. EtOAc and saturated NaHCO _{3 (aq)} were added and the phases were separated. The aqueous phase was extracted with EtOAc (× 3), the combined organic layers were washed with brine, dried (MgSO _4), and evaporated to give the crude product. Purification by silica gel chromatography eluting with 0-10% MeOH / dichloromethane gave the subtitle compound (384 mg) as a yellow oil.
¹ H NMR (300 MHz, CD ₃ OD): δ 7.39-7.27 (m, 4H), 7.25-7.14 (m, 1H), 4.80 (dt, 1H), 3.16 (ddd, 1H), 2.83-2.64 (m , 3H), 2.56-2.34 (m, 4H), 2.15-2.04 (m, 2H), 1.91-1.86 (m, 1H), 1.72-1.44 (m, 11H), 1.38-1.25 (m, 1H).

３−フェノキシプロピルブロマイド(０.０２６mL)の混合物を１−フェニル−シクロヘプタンカルボン酸(Ｓ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例３３ａ)(５０mg)のアセトニトリル(１mL)溶液に添加した。反応混合物を室温で７２時間撹拌し、次いで５０℃で３日間加熱した。揮発物を蒸発させ、残留物を、０−１０％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製して、５７mgの吸湿性泡状物を得た。０.１％ギ酸含有５−９５％ＭｅＣＮ／Ｈ_２Ｏで溶出するＣ１８カラムを使用する逆相ＨＰＬＣで３０分間精製して、表題化合物(４３mg)を油状物として得た。
m/e 462 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 8.38 (s, 1H), 7.34-7.24 (m, 6H), 7.23-7.17 (m, 1H), 6.94-6.87 (m, 3H), 5.07-4.97 (m, 1H), 3.98 (t, 2H), 3.87-3.77 (m, 1H), 3.44-3.26 (m, 5H), 3.16-3.09 (m, 1H), 3.01-2.90 (m, 1H), 2.38-2.23 (m, 2H), 2.16-1.77 (m, 7H), 1.69-1.43 (m, 10H)。 Example 33: (S) -1- (3-phenoxy-propyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octaneformate

A mixture of 3-phenoxypropyl bromide (0.026 mL) was converted to 1-phenyl-cycloheptanecarboxylic acid (S)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 33a). (50 mg) in acetonitrile (1 mL) was added. The reaction mixture was stirred at room temperature for 72 hours and then heated at 50 ° C. for 3 days. Volatiles were evaporated and the residue was purified by silica gel chromatography eluting with 0-10% MeOH / dichloromethane to give 57 mg of hygroscopic foam. Purification by reverse phase HPLC using a C18 column eluting with 5-95% MeCN / H ₂ O containing 0.1% formic acid gave the title compound (43 mg) as an oil.
m / e 462 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 8.38 (s, 1H), 7.34-7.24 (m, 6H), 7.23-7.17 (m, 1H), 6.94-6.87 (m, 3H), 5.07- 4.97 (m, 1H), 3.98 (t, 2H), 3.87-3.77 (m, 1H), 3.44-3.26 (m, 5H), 3.16-3.09 (m, 1H), 3.01-2.90 (m, 1H), 2.38-2.23 (m, 2H), 2.16-1.77 (m, 7H), 1.69-1.43 (m, 10H).

２−(３−フルオロフェノキシ)エチルアミン(０.９３ｇ)および炭酸カリウム(１.２４ｇ)のジクロロメタン(２０mL)の混合物を、０℃で、ブロモアセチルブロマイド(１.０４mL)で処理した。反応混合物を０℃で３０分間、次いで室温で６時間撹拌した。水を添加し、混合物を発泡が止むまで撹拌した。有機層を分離し、有機層を蒸発させて、粗生成物を得て、それを０−５０％ＥｔＯＡｃ／ペンタンで溶出するシリカゲルクロマトグラフィーで精製して、副題化合物(１.１７ｇ)を褐色油状物として得た。
¹H NMR (400 MHz, CDCl₃):δ 7.24 (dt, 1H), 6.90 (s, 1H), 6.71-6.66 (m, 2H), 6.63 (dt, 1H), 4.06 (t, 2H), 3.90 (s, 2H), 3.71 (q, 2H)。 Example 34: (R) -1-{[2- (3-Fluoro-phenoxy) -ethylcarbamoyl] -methyl} -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2. 2.2] Octane bromide a) 2-Bromo-N- [2- (3-fluoro-phenoxy) -ethyl] -acetamide

A mixture of 2- (3-fluorophenoxy) ethylamine (0.93 g) and potassium carbonate (1.24 g) in dichloromethane (20 mL) was treated with bromoacetyl bromide (1.04 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C. for 30 minutes and then at room temperature for 6 hours. Water was added and the mixture was stirred until effervescence ceased. The organic layer was separated and the organic layer was evaporated to give the crude product, which was purified by silica gel chromatography eluting with 0-50% EtOAc / pentane to give the subtitle compound (1.17 g) as a brown oil. Obtained as a thing.
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.24 (dt, 1H), 6.90 (s, 1H), 6.71-6.66 (m, 2H), 6.63 (dt, 1H), 4.06 (t, 2H), 3.90 (s, 2H), 3.71 (q, 2H).

表題化合物(７０mg、７６％、黄色泡状物)を実施例３２の製造に使用した方法に準じる方法により２−ブロモ−Ｎ−[２−(３−フルオロ−フェノキシ)−エチル]−アセトアミド(実施例３４ａ)を２−(２−ブロモ−エチル)−ピラジンの代わりに使用して、製造した。
m/e 523 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 8.74 (t, 1H), 7.33-7.23 (m, 5H), 7.23-7.16 (m, 1H), 6.79-6.71 (m, 3H), 5.09-5.02 (m, 1H), 4.03-3.94 (m, 5H), 3.57-3.40 (m, 6H), 3.33-3.22 (m, 1H), 2.35-2.20 (m, 2H), 2.10 (d, 2H), 1.96-1.82 (m, 3H), 1.74-1.62 (m, 1H), 1.62-1.40 (m, 9H)。 Example 34: (R) -1-{[2- (3-Fluoro-phenoxy) -ethylcarbamoyl] -methyl} -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2. 2.2] Octane bromide

2-Bromo-N- [2- (3-fluoro-phenoxy) -ethyl] -acetamide (implemented by a method analogous to that used for the preparation of Example 32 for the title compound (70 mg, 76%, yellow foam). Prepared using example 34a) instead of 2- (2-bromo-ethyl) -pyrazine.
m / e 523 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 8.74 (t, 1H), 7.33-7.23 (m, 5H), 7.23-7.16 (m, 1H), 6.79-6.71 (m, 3H), 5.09- 5.02 (m, 1H), 4.03-3.94 (m, 5H), 3.57-3.40 (m, 6H), 3.33-3.22 (m, 1H), 2.35-2.20 (m, 2H), 2.10 (d, 2H), 1.96-1.82 (m, 3H), 1.74-1.62 (m, 1H), 1.62-1.40 (m, 9H).

副題化合物(２.０２ｇ、無色蝋状固体)を、３,５−ジフルオロアニリンを２,６−ジフルオロアニリンの代わりに使用する以外、実施例３８ａの製造に使用した方法に準じる方法を使用して製造した。
¹H NMR (400 MHz, CDCl₃):δ 8.17 (s, 1H), 7.16 (d, 2H), 6.63 (td, 1H), 4.02 (s, 2H)。 Example 35: (R) -1-[(3,5-difluoro-phenylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] Octane bromide a) 2-Bromo-N- (3,5-difluoro-phenyl) -acetamide

The subtitle compound (2.02 g, colorless waxy solid) was used in a manner analogous to that used for the preparation of Example 38a, except that 3,5-difluoroaniline was used instead of 2,6-difluoroaniline. Manufactured.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.17 (s, 1H), 7.16 (d, 2H), 6.63 (td, 1H), 4.02 (s, 2H).

２−ブロモ−Ｎ−(３,５−ジフルオロ−フェニル)−アセトアミド(４２mg)(実施例３５ａ)および１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(５０mg)のＭｅＣＮ(１mL)中の混合物を室温で７２時間撹拌した。固体沈殿を濾取し、エーテルで洗浄し、５０℃で、真空下に一夜乾燥させた。母液を蒸発させ、エーテルで処理し、得られた固体を濾取した。固体を合わせ、熱イソプロピルアルコールから結晶化させて、表題化合物(１５mg)を無色固体として得た。
m/e 497 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 10.89 (s, 1H), 7.33-7.17 (m, 7H), 7.01 (tt, 1H), 5.13-5.06 (m, 1H), 4.26-4.14 (m, 2H), 4.10-4.01 (m, 1H), 3.63-3.49 (m, 4H), 3.43-3.32 (m, 1H), 2.38-2.23 (m, 2H), 2.18-2.06 (m, 2H), 1.98-1.86 (m, 3H), 1.79-1.67 (m, 1H), 1.65-1.41 (m, 9H)。 Example 35: (R) -1-[(3,5-difluoro-phenylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] Octane bromide

2-Bromo-N- (3,5-difluoro-phenyl) -acetamide (42 mg) (Example 35a) and 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] A mixture of oct-3-yl) ester (Example 14e) (50 mg) in MeCN (1 mL) was stirred at room temperature for 72 hours. The solid precipitate was collected by filtration, washed with ether and dried at 50 ° C. under vacuum overnight. The mother liquor was evaporated and treated with ether and the resulting solid was collected by filtration. The solids were combined and crystallized from hot isopropyl alcohol to give the title compound (15 mg) as a colorless solid.
m / e 497 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 10.89 (s, 1H), 7.33-7.17 (m, 7H), 7.01 (tt, 1H), 5.13-5.06 (m, 1H), 4.26-4.14 ( m, 2H), 4.10-4.01 (m, 1H), 3.63-3.49 (m, 4H), 3.43-3.32 (m, 1H), 2.38-2.23 (m, 2H), 2.18-2.06 (m, 2H), 1.98-1.86 (m, 3H), 1.79-1.67 (m, 1H), 1.65-1.41 (m, 9H).

１−(２−ブロモ−エトキシメチル)−４−メトキシ−ベンゼン(４２mg)および１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(５０mg)のＭｅＣＮ(１mL)中の混合物を室温で１６時間撹拌し、次いで８０℃で、窒素下、一夜加熱した。さらに１.１当量の１−(２−ブロモ−エトキシメチル)−４−メトキシ−ベンゼンを添加し、混合物を８０℃でさらに４８時間加熱した。揮発物を蒸発させ、粗生成物を０−１０％の１０％濃ＮＨ_３／ＭｅＯＨ溶液のジクロロメタン溶液で溶出するシリカゲルクロマトグラフィーで精製して、６１mgの油状物を得て、それを２２０nmでＵＶ検出しながら０.１％ギ酸含有５−９５％ＭｅＯＨ／Ｈ_２Ｏで溶出する逆相ＨＰＬＣ(Gemini ５μM Ｃ６フェニルカラム)で３０分間にわたりさらに精製した。関連フラクションを合わせ、蒸発させて、表題化合物(３４mg)を油状物として得た。
m/e 492 [M]^+
1H NMR (400 MHz, CD₃OD):δ 8.48 (s, 1H), 7.31-7.16 (m, 7H), 6.91-6.86 (m, 2H), 5.09-5.03 (m, 1H), 4.44-4.39 (m, 2H), 3.92-3.63 (m, 6H), 3.46-3.29 (m, 5H), 2.99-2.88 (m, 1H), 2.43-2.28 (m, 2H), 2.24-2.20 (m, 1H), 2.15-1.86 (m, 4H), 1.75-1.51 (m, 10H)。 Example 36: (R) -1- [2- (4-Methoxy-benzyloxy) -ethyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] Octane formate

1- (2-Bromo-ethoxymethyl) -4-methoxy-benzene (42 mg) and 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl ) A mixture of ester (Example 14e) (50 mg) in MeCN (1 mL) was stirred at room temperature for 16 hours and then heated at 80 ° C. under nitrogen overnight. An additional 1.1 equivalents of 1- (2-bromo-ethoxymethyl) -4-methoxy-benzene was added and the mixture was heated at 80 ° C. for an additional 48 hours. The volatiles were evaporated and the crude product was purified by silica gel chromatography eluting with 0-10% 10% concentrated NH ₃ / MeOH solution in dichloromethane to give 61 mg of an oil which was UV irradiated at 220 nm. Further purification on reverse phase HPLC (Gemini 5 μM C6 phenyl column) eluting with 5-95% MeOH / H ₂ O containing 0.1% formic acid with detection for 30 min. The relevant fractions were combined and evaporated to give the title compound (34 mg) as an oil.
m / e 492 [M] ^+
1 H NMR (400 MHz, CD ₃ OD): δ 8.48 (s, 1H), 7.31-7.16 (m, 7H), 6.91-6.86 (m, 2H), 5.09-5.03 (m, 1H), 4.44-4.39 (m, 2H), 3.92-3.63 (m, 6H), 3.46-3.29 (m, 5H), 2.99-2.88 (m, 1H), 2.43-2.28 (m, 2H), 2.24-2.20 (m, 1H) , 2.15-1.86 (m, 4H), 1.75-1.51 (m, 10H).

表題化合物(６８mg、７７％、ガム状固体)を、実施例３６に使用した方法に準じる方法に従い、[２−(２−ブロモ−エトキシ)−エチル]−ベンゼンを１−(２−ブロモ−エトキシメチル)−４−メトキシ−ベンゼンの代わりに使用して、製造した。
m/e 476 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 7.32-7.11 (m, 10H), 5.00-4.92 (m, 1H), 3.80-3.65 (m, 3H), 3.60 (t, 2H), 3.41-3.11 (m, 6H), 2.99-2.88 (m, 1H), 2.77 (t, 2H), 2.38-2.21 (m, 2H), 2.17-2.04 (m, 2H), 1.99-1.89 (m, 1H), 1.84-1.67 (m, 2H), 1.67-1.32 (m, 10H)。 Example 37: (R) -1- (2-phenethyloxy-ethyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

The title compound (68 mg, 77%, gummy solid) was treated according to the method used in Example 36 with [2- (2-bromo-ethoxy) -ethyl] -benzene as 1- (2-bromo-ethoxy). Prepared using instead of methyl) -4-methoxy-benzene.
m / e 476 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 7.32-7.11 (m, 10H), 5.00-4.92 (m, 1H), 3.80-3.65 (m, 3H), 3.60 (t, 2H), 3.41- 3.11 (m, 6H), 2.99-2.88 (m, 1H), 2.77 (t, 2H), 2.38-2.21 (m, 2H), 2.17-2.04 (m, 2H), 1.99-1.89 (m, 1H), 1.84-1.67 (m, 2H), 1.67-1.32 (m, 10H).

２,６−ジフルオロアニリン(１.１２ｇ)および炭酸カリウム(１.８ｇ)の５０mL ジクロロメタン中の混合物に、ブロモアセチルブロマイド(１.５mL)を添加し、混合物を室温で１７時間撹拌した。水を添加し、混合物を数時間撹拌し、次いで相を疎水性フリットで分離し、有機層を蒸発させた。粗生成物を０−１００％ＥｔＯＡｃ／シクロヘキサンで溶出するシリカゲルクロマトグラフィーで精製して、副題化合物(０.９２ｇ)を白色固体として得た。
¹H NMR (400 MHz, CDCl₃):δ 7.74 (s, 1H), 7.31-7.21 (m, 1H), 6.98 (t, 2H), 4.08 (s, 2H)。 Example 38: (R) -1-[(2,6-difluoro-phenylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] Octane bromide a) 2-Bromo-N- (2,6-difluoro-phenyl) -acetamide

To a mixture of 2,6-difluoroaniline (1.12 g) and potassium carbonate (1.8 g) in 50 mL dichloromethane was added bromoacetyl bromide (1.5 mL) and the mixture was stirred at room temperature for 17 hours. Water was added and the mixture was stirred for several hours, then the phases were separated with a hydrophobic frit and the organic layer was evaporated. The crude product was purified by silica gel chromatography eluting with 0-100% EtOAc / cyclohexane to give the subtitle compound (0.92 g) as a white solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.74 (s, 1H), 7.31-7.21 (m, 1H), 6.98 (t, 2H), 4.08 (s, 2H).

２−ブロモ−Ｎ−(２,６−ジフルオロ−フェニル)−アセトアミド(実施例３８ａ)(４２mg)および１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(５０mg)のＭｅＣＮ(１mL)中の混合物を室温で１９時間撹拌した。さらに２０mg ２−ブロモ−Ｎ−(２,６−ジフルオロ−フェニル)−アセトアミドを添加し、撹拌をさらに２２時間続けた。揮発物を蒸発させ、残留物を０−１０％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製して、表題化合物(４１mg)を無色泡状物として得た。
m/e 497 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 10.40 (s, 1H), 7.42-7.35 (m, 1H), 7.31-7.25 (m, 4H), 7.22-7.16 (m, 3H), 5.12-5.05 (m, 1H), 4.32-4.27 (m, 2H), 4.10-4.02 (m, 1H), 3.66-3.49 (m, 4H), 3.43-3.31 (m, 1H), 2.36-2.21 (m, 2H), 2.17-2.06 (m, 2H), 1.99-1.85 (m, 3H), 1.77-1.66 (m, 1H), 1.68-1.25 (m, 9H)。 Example 38: (R) -1-[(2,6-difluoro-phenylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] Octane bromide

2-Bromo-N- (2,6-difluoro-phenyl) -acetamide (Example 38a) (42 mg) and 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] A mixture of oct-3-yl) ester (Example 14e) (50 mg) in MeCN (1 mL) was stirred at room temperature for 19 hours. An additional 20 mg 2-bromo-N- (2,6-difluoro-phenyl) -acetamide was added and stirring was continued for another 22 hours. Volatiles were evaporated and the residue was purified by silica gel chromatography eluting with 0-10% MeOH / dichloromethane to give the title compound (41 mg) as a colorless foam.
m / e 497 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 10.40 (s, 1H), 7.42-7.35 (m, 1H), 7.31-7.25 (m, 4H), 7.22-7.16 (m, 3H), 5.12- 5.05 (m, 1H), 4.32-4.27 (m, 2H), 4.10-4.02 (m, 1H), 3.66-3.49 (m, 4H), 3.43-3.31 (m, 1H), 2.36-2.21 (m, 2H ), 2.17-2.06 (m, 2H), 1.99-1.85 (m, 3H), 1.77-1.66 (m, 1H), 1.68-1.25 (m, 9H).

Ｎ−メチルアニリン(５mL)および炭酸カリウム(９.６ｇ)の１００mL ジクロロメタン中の混合物にブロモアセチルブロマイド(８.１mL)を添加した(発熱)。混合物を４.５時間撹拌し、次いで水を添加した。相を分離し、有機層を濃縮した。粗生成物を０−１００％ＥｔＯＡｃ／シクロヘキサンで溶出するシリカゲルクロマトグラフィーで精製した。関連フラクションを合わせ、蒸発させ、残留物をジクロロメタンに取り込み、水で洗浄した。有機層をさらなる水と数分間撹拌し、次いで層を分離した。有機層の蒸発により、副題化合物(１０.２ｇ)を麦わら色固体として得た。
¹H NMR (400 MHz, CDCl₃):δ 7.50-7.36 (m, 3H), 7.31-7.26 (m, 2H), 3.67 (s, 2H), 3.31 (s, 3H)。 Example 39: (R) -1-[(methyl-phenyl-carbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octaneformate a) 2-Bromo-N-methyl-N-phenyl-acetamide

Bromoacetyl bromide (8.1 mL) was added (exotherm) to a mixture of N-methylaniline (5 mL) and potassium carbonate (9.6 g) in 100 mL dichloromethane. The mixture was stirred for 4.5 hours and then water was added. The phases were separated and the organic layer was concentrated. The crude product was purified by silica gel chromatography eluting with 0-100% EtOAc / cyclohexane. The relevant fractions were combined and evaporated and the residue was taken up in dichloromethane and washed with water. The organic layer was stirred with additional water for several minutes and then the layers were separated. Evaporation of the organic layer gave the subtitle compound (10.2 g) as a straw solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 7.50-7.36 (m, 3H), 7.31-7.26 (m, 2H), 3.67 (s, 2H), 3.31 (s, 3H).

２−ブロモ−Ｎ−メチル−Ｎ−フェニル−アセトアミド((実施例３９ａ)(３８mg)および１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(５０mg)の１mL ＭｅＣＮ中の混合物を室温で４８時間撹拌した。揮発物を蒸発させ、残留物を０−１０％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製した。０.１％ギ酸含有２０−９０％ＭｅＣＮ／Ｈ_２Ｏで溶出する逆相ＨＰＬＣでさらに精製して、表題化合物(１７mg)を無色ガム状物として得た。
m/e 475 [M]^+
1H NMR (400 MHz, DMSO-D₆ with a drop of TFA-D):δ 8.08 (s, 1H), 7.47 (t, 2H), 7.39 (dd, 3H), 7.32-7.23 (m, 4H), 7.20-7.15 (m, 1H), 5.09-4.98 (m, 1H), 4.01-3.83 (m, 3H), 3.61-3.34 (m, 5H), 3.16-3.09 (s, 3H) 2.37-2.21 (m, 2H), 2.16-2.05 (m, 2H), 1.96-1.75 (m, 3H), 1.71-1.36 (m, 10H)。 Example 39: (R) -1-[(methyl-phenyl-carbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octaneformate

2-Bromo-N-methyl-N-phenyl-acetamide (Example 39a) (38 mg) and 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] octo- A mixture of 3-yl) ester (Example 14e) (50 mg) in 1 mL MeCN was stirred for 48 h at room temperature The volatiles were evaporated and the residue chromatographed on silica gel eluting with 0-10% MeOH / dichloromethane. Further purification by reverse phase HPLC eluting with 20-90% MeCN / H ₂ O containing 0.1% formic acid gave the title compound (17 mg) as a colorless gum.
m / e 475 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ with a drop of TFA-D): δ 8.08 (s, 1H), 7.47 (t, 2H), 7.39 (dd, 3H), 7.32-7.23 (m, 4H) , 7.20-7.15 (m, 1H), 5.09-4.98 (m, 1H), 4.01-3.83 (m, 3H), 3.61-3.34 (m, 5H), 3.16-3.09 (s, 3H) 2.37-2.21 (m , 2H), 2.16-2.05 (m, 2H), 1.96-1.75 (m, 3H), 1.71-1.36 (m, 10H).

４−(３−ブロモ−プロポキシ)−ベンゾニトリル(４１mg)および１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(５２mg)のＭｅＣＮ(１mL)中の混合物を室温で１６時間撹拌し、次いで窒素下、８０℃でさらに１６時間加熱した。揮発物を蒸発させ、残留物をエーテルで摩砕して、灰白色固体を得て、それをＥｔＯＡｃで摩砕し、真空下で乾燥させて、表題化合物(６１mg)を白色固体として得た。
m/e 487 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 7.78-7.73 (m, 2H), 7.33-7.26 (m, 4H), 7.22-7.17 (m, 1H), 7.09-7.04 (m, 2H), 5.05-4.99 (m, 1H), 4.08 (t, 2H), 3.82 (ddd, 1H), 3.43-3.26 (m, 5H), 3.21-3.08 (m, 1H), 3.02-2.90 (m, 1H), 2.39-2.22 (m, 2H), 2.17-2.00 (m, 4H), 1.99-1.78 (m, 3H), 1.68-1.43 (m, 10H)。 Example 40: (R) -1- [3- (4-Cyano-phenoxy) -propyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

4- (3-Bromo-propoxy) -benzonitrile (41 mg) and 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (implemented) Example 14e) A mixture of (52 mg) in MeCN (1 mL) was stirred at room temperature for 16 hours and then heated at 80 ° C. under nitrogen for an additional 16 hours. The volatiles were evaporated and the residue was triturated with ether to give an off-white solid that was triturated with EtOAc and dried under vacuum to give the title compound (61 mg) as a white solid.
m / e 487 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 7.78-7.73 (m, 2H), 7.33-7.26 (m, 4H), 7.22-7.17 (m, 1H), 7.09-7.04 (m, 2H), 5.05-4.99 (m, 1H), 4.08 (t, 2H), 3.82 (ddd, 1H), 3.43-3.26 (m, 5H), 3.21-3.08 (m, 1H), 3.02-2.90 (m, 1H), 2.39-2.22 (m, 2H), 2.17-2.00 (m, 4H), 1.99-1.78 (m, 3H), 1.68-1.43 (m, 10H).

副題化合物(３.６ｇ、９０％、オレンジ色固体を、実施例３８ａの製造に使用した方法に準じる方法により、２,５−ジフルオロアニリンを２,６−ジフルオロアニリンの代わりに使用して、製造した。
¹H NMR (400 MHz, CDCl₃):δ 8.42 (s, 1H), 8.13 (ddd, 1H), 7.08 (ddd, 1H), 6.82-6.75 (m, 1H), 4.04 (s, 2H)。 Example 41: (R) -1-[(2,5-difluoro-phenylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] Octane bromide a) 2-Bromo-N- (2,5-difluoro-phenyl) -acetamide

Subtitle compound (3.6 g, 90%, orange solid, prepared according to the method used for the preparation of Example 38a, using 2,5-difluoroaniline instead of 2,6-difluoroaniline did.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.42 (s, 1H), 8.13 (ddd, 1H), 7.08 (ddd, 1H), 6.82-6.75 (m, 1H), 4.04 (s, 2H).

２−ブロモ−Ｎ−(２,５−ジフルオロ−フェニル)−アセトアミド(実施例４１ａ)(４７mg)および１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(５６mg)のＭｅＣＮ(１mL)中の混合物を室温で３０時間撹拌した。得られた沈殿を濾取し、エーテルで洗浄し、５０℃で、真空下に一夜乾燥させて、表題化合物(６５mg)を無色固体として得た。
m/e 497 [M]^+
1H NMR (400 MHz, DMSO-d₆):δ 10.51 (s, 1H), 7.82-7.75 (m, 1H), 7.38-7.26 (m, 5H), 7.21-7.16 (m, 1H), 7.09-7.01 (m, 1H), 5.12-5.06 (m, 1H), 4.25 (s, 2H), 4.05 (ddd, 1H), 3.61-3.48 (m, 4H), 3.42-3.29 (m, 1H), 2.36-2.23 (m, 2H), 2.17-2.06 (m, 2H), 1.98-1.85 (m, 3H), 1.76-1.67 (m, 1H), 1.66-1.41 (m, 9H)。 Example 41: (R) -1-[(2,5-difluoro-phenylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] Octane bromide

2-Bromo-N- (2,5-difluoro-phenyl) -acetamide (Example 41a) (47 mg) and 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] A mixture of oct-3-yl) ester (Example 14e) (56 mg) in MeCN (1 mL) was stirred at room temperature for 30 hours. The resulting precipitate was collected by filtration, washed with ether and dried overnight at 50 ° C. under vacuum to give the title compound (65 mg) as a colorless solid.
m / e 497 [M] ^+
1 H NMR (400 MHz, DMSO-d ₆ ): δ 10.51 (s, 1H), 7.82-7.75 (m, 1H), 7.38-7.26 (m, 5H), 7.21-7.16 (m, 1H), 7.09- 7.01 (m, 1H), 5.12-5.06 (m, 1H), 4.25 (s, 2H), 4.05 (ddd, 1H), 3.61-3.48 (m, 4H), 3.42-3.29 (m, 1H), 2.36- 2.23 (m, 2H), 2.17-2.06 (m, 2H), 1.98-1.85 (m, 3H), 1.76-1.67 (m, 1H), 1.66-1.41 (m, 9H).

４−(２−ブロモ−エトキシメチル)−ベンゾニトリル(４１mg、０.１７mmol)および１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(５１mg)のＭｅＣＮ(１mL)中の混合物を室温で１６時間撹拌し、次いで８０℃で、窒素下、一夜加熱した。得られた固体を濾取し、エーテルで洗浄し、真空下で乾燥させて、表題化合物(７０mg)を白色固体として得た。
m/e 487 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 7.80 (dd, 2H), 7.48 (d, 2H), 7.31-7.22 (m, 4H), 7.22-7.16 (m, 1H), 5.06-4.96 (m, 1H), 4.57 (s, 2H), 3.94-3.78 (m, 3H), 3.56-3.35 (m, 5H), 3.27-3.18 (m, 1H), 3.11-3.00 (m, 1H), 2.36-2.18 (m, 2H), 2.08 (d, 2H), 1.98-1.77 (m, 3H), 1.72-1.60 (m, 1H), 1.60-1.38 (m, 9H)。 Example 42: (R) -1- [2- (4-cyano-benzyloxy) -ethyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] Octane bromide

4- (2-Bromo-ethoxymethyl) -benzonitrile (41 mg, 0.17 mmol) and 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3- Yl) ester (Example 14e) (51 mg) in MeCN (1 mL) was stirred at room temperature for 16 hours and then heated at 80 ° C. under nitrogen overnight. The resulting solid was collected by filtration, washed with ether and dried under vacuum to give the title compound (70 mg) as a white solid.
m / e 487 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 7.80 (dd, 2H), 7.48 (d, 2H), 7.31-7.22 (m, 4H), 7.22-7.16 (m, 1H), 5.06-4.96 ( m, 1H), 4.57 (s, 2H), 3.94-3.78 (m, 3H), 3.56-3.35 (m, 5H), 3.27-3.18 (m, 1H), 3.11-3.00 (m, 1H), 2.36- 2.18 (m, 2H), 2.08 (d, 2H), 1.98-1.77 (m, 3H), 1.72-1.60 (m, 1H), 1.60-1.38 (m, 9H).

副題化合物(１.１ｇ、定量的、白色固体)を、実施例１４ｆの製造に使用した方法に準じる方法により、２−アミノ−６−(トリフルオロメチル)ピリジンを２−アミノ−ピリジンの代わりに使用し、クロロアセチルクロライドを０℃ではなく室温で添加して、製造した。
¹H NMR (300 MHz, CDCl₃):δ 8.90 (s, 1H), 8.42 (d, 1H), 7.92 (t, 1H), 7.48 (d, 1H), 4.22 (s, 2H)。 Example 43: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-[(6-trifluoromethyl-pyridin-2-ylcarbamoyl) -methyl] -1-azonia-bicyclo [2. 2.2] Octane chloride a) 2-Chloro-N- (3-trifluoromethyl-phenyl) -acetamide

The subtitle compound (1.1 g, quantitative, white solid) was replaced with 2-amino-6- (trifluoromethyl) pyridine instead of 2-amino-pyridine by a method analogous to that used for the preparation of Example 14f. Used to make chloroacetyl chloride added at room temperature rather than 0 ° C.
¹ H NMR (300 MHz, CDCl ₃ ): δ 8.90 (s, 1H), 8.42 (d, 1H), 7.92 (t, 1H), 7.48 (d, 1H), 4.22 (s, 2H).

表題化合物(６６mg、７６％、白色固体)を、実施例１４の製造に使用した方法に準じる方法により、２−クロロ−Ｎ−(３−トリフルオロメチル−フェニル)−アセトアミド(実施例４３ａ)を２−クロロ−Ｎ−ピリジン−２−イル−アセトアミドの代わりに使用して、製造した。
m/e 530 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 11.48 (s, 1H), 8.25 (d, 1H), 8.14 (t, 1H), 7.67 (d, 1H), 7.33-7.26 (m, 4H), 7.22-7.17 (m, 1H), 5.12-5.05 (m, 1H), 4.28 (s, 2H), 4.11-4.03 (m, 1H), 3.66-3.49 (m, 4H), 3.41-3.29 (m, 1H), 2.36-2.23 (m, 2H), 2.18-2.06 (m, 2H), 2.00-1.82 (m, 3H), 1.79-1.66 (m, 1H), 1.66-1.40 (m, 9H)。 Example 43: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-[(6-trifluoromethyl-pyridin-2-ylcarbamoyl) -methyl] -1-azonia-bicyclo [2. 2.2] Octane chloride

The title compound (66 mg, 76%, white solid) was prepared according to the method used for the preparation of Example 14 to give 2-chloro-N- (3-trifluoromethyl-phenyl) -acetamide (Example 43a). Prepared using 2-chloro-N-pyridin-2-yl-acetamide instead.
m / e 530 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 11.48 (s, 1H), 8.25 (d, 1H), 8.14 (t, 1H), 7.67 (d, 1H), 7.33-7.26 (m, 4H) , 7.22-7.17 (m, 1H), 5.12-5.05 (m, 1H), 4.28 (s, 2H), 4.11-4.03 (m, 1H), 3.66-3.49 (m, 4H), 3.41-3.29 (m, 1H), 2.36-2.23 (m, 2H), 2.18-2.06 (m, 2H), 2.00-1.82 (m, 3H), 1.79-1.66 (m, 1H), 1.66-1.40 (m, 9H).

副題化合物(１.３ｇ、７４％、固体)を、実施例１４ｆの製造に使用した方法に準じる方法により、２−アミノ−４−メチルピリジンを２−アミノ−ピリジンの代わりに使用し、そしてクロロアセチルクロライドを０℃ではなく室温で添加して、製造した。
¹H NMR (400 MHz, CDCl₃):δ 8.77 (s, 1H), 8.17 (d, 1H), 8.03 (s, 1H), 6.93 (d, 1H), 4.19 (s, 2H), 2.39 (s, 3H)。 Example 44: (R) -1-[(4-Methyl-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride a) 2-Chloro-N- (4-methyl-pyridin-2-yl) -acetamide

The subtitle compound (1.3 g, 74%, solid) was prepared according to the method used for the preparation of Example 14f using 2-amino-4-methylpyridine in place of 2-amino-pyridine and chloro Produced by adding acetyl chloride at room temperature rather than 0 ° C.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.77 (s, 1H), 8.17 (d, 1H), 8.03 (s, 1H), 6.93 (d, 1H), 4.19 (s, 2H), 2.39 (s , 3H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(１００mg)の１mL ＭｅＣＮ溶液に、２−クロロ−Ｎ−(４−メチル−ピリジン−２−イル)−アセトアミド(実施例４４ａ)(６２mg)、混合物を室温で２１時間撹拌した。沈殿を濾取し、５０℃で真空下乾燥させて、表題化合物(８０mg)を白色固体として得た。
ｍ／ｅ ４７６ [Ｍ]^＋
1H NMR (400 MHz, DMSO-D₆):δ 10.98 (s, 1H), 8.18 (d, 1H), 7.85 (s, 1H), 7.33-7.26 (m, 4H), 7.22-7.17 (m, 1H), 7.02-7.00 (m, 1H), 5.11-5.04 (m, 1H), 4.24 (s, 2H), 4.10-4.02 (m, 1H), 3.64-3.50 (m, 4H), 3.40-3.29 (m, 1H), 2.42-2.20 (m, 5H), 2.17-2.06 (m, 2H), 1.98-1.84 (m, 3H), 1.79-1.67 (m, 1H), 1.73-1.31 (m, 9H)。 Example 44: (R) -1-[(4-Methyl-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride

1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e) (100 mg) in 1 mL MeCN solution was added 2-chloro- N- (4-Methyl-pyridin-2-yl) -acetamide (Example 44a) (62 mg), the mixture was stirred at room temperature for 21 hours. The precipitate was collected by filtration and dried under vacuum at 50 ° C. to give the title compound (80 mg) as a white solid.
m / e 476 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 10.98 (s, 1H), 8.18 (d, 1H), 7.85 (s, 1H), 7.33-7.26 (m, 4H), 7.22-7.17 (m, 1H), 7.02-7.00 (m, 1H), 5.11-5.04 (m, 1H), 4.24 (s, 2H), 4.10-4.02 (m, 1H), 3.64-3.50 (m, 4H), 3.40-3.29 ( m, 1H), 2.42-2.20 (m, 5H), 2.17-2.06 (m, 2H), 1.98-1.84 (m, 3H), 1.79-1.67 (m, 1H), 1.73-1.31 (m, 9H).

副題化合物(０.３３ｇ、２０％)を、実施例１４ｆの製造に使用した方法に準じる方法により、２−アミノ−５−クロロピリジンを２−アミノ−ピリジンの代わりに使用して、製造し、クロロアセチルクロライドを０℃ではなく室温で添加して、製造した。
¹H NMR (400 MHz, CDCl₃):δ 8.80 (s, 1H), 8.28 (d, 1H), 8.19 (d, 1H), 7.70 (dd, 1H), 4.20 (d, 2H)。 Example 45: (R) -1-[(5-chloro-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride a) 2-chloro-N- (5-chloro-pyridin-2-yl) -acetamide

The subtitle compound (0.33 g, 20%) was prepared by a method analogous to that used for the preparation of Example 14f, using 2-amino-5-chloropyridine instead of 2-amino-pyridine, Produced by adding chloroacetyl chloride at room temperature rather than 0 ° C.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.80 (s, 1H), 8.28 (d, 1H), 8.19 (d, 1H), 7.70 (dd, 1H), 4.20 (d, 2H).

表題化合物(１０３mg、６３％、白色固体)を、実施例４４の製造に使用した方法に準じる方法により、２−クロロ−Ｎ−(５−クロロ−ピリジン−２−イル)−アセトアミド(実施例４５ａ)を２−クロロ−Ｎ−(４−メチル−ピリジン−２−イル)−アセトアミドの代わりに使用して、製造した。
m/e 496 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 11.26 (s, 1H), 8.41-8.39 (m, 1H), 8.02-7.94 (m, 2H), 7.32-7.25 (m, 4H), 7.22-7.17 (m, 1H), 5.12-5.03 (m, 1H), 4.27 (s, 2H), 4.09-4.02 (m, 1H), 3.63-3.50 (m, 4H), 3.42-3.32 (m, 1H), 2.37-2.23 (m, 2H), 2.17-2.05 (m, 2H), 1.99-1.84 (m, 3H), 1.78-1.65 (m, 1H), 1.65-1.39 (m, 9H)。 Example 45: (R) -1-[(5-chloro-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride

The title compound (103 mg, 63%, white solid) was prepared according to the method used for the preparation of Example 44 by 2-chloro-N- (5-chloro-pyridin-2-yl) -acetamide (Example 45a ) Was used in place of 2-chloro-N- (4-methyl-pyridin-2-yl) -acetamide.
m / e 496 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 11.26 (s, 1H), 8.41-8.39 (m, 1H), 8.02-7.94 (m, 2H), 7.32-7.25 (m, 4H), 7.22- 7.17 (m, 1H), 5.12-5.03 (m, 1H), 4.27 (s, 2H), 4.09-4.02 (m, 1H), 3.63-3.50 (m, 4H), 3.42-3.32 (m, 1H), 2.37-2.23 (m, 2H), 2.17-2.05 (m, 2H), 1.99-1.84 (m, 3H), 1.78-1.65 (m, 1H), 1.65-1.39 (m, 9H).

ｐ−トルイジン(２.３５ｇ)の１００mL ジクロロメタン輸液に、炭酸カリウム(６.２１ｇ)を添加した。反応混合物をアルゴンでフラッシュし、次いでブロモアセチルブロマイド(１.６mL)を滴下し、次いで反応混合物を１７時間撹拌した。水を添加し、層を分離した。有機層をシクロヘキサンで処理し、体積を減らして固体を沈殿させ、それを濾取して、副題化合物(２.６７ｇ)を灰白色固体として得た。
¹H NMR (400 MHz, CDCl₃):δ 8.06 (s, 1H), 7.40 (d, 2H), 7.16 (d, 2H), 4.01 (s, 2H), 2.33 (s, 3H)。 Example 46: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (p-tolylcarbamoyl-methyl) -1-azonia-bicyclo [2.2.2] octane bromide a) 2- Bromo-Np-tolyl-acetamide

To a 100 mL dichloromethane infusion of p-toluidine (2.35 g), potassium carbonate (6.21 g) was added. The reaction mixture was flushed with argon, then bromoacetyl bromide (1.6 mL) was added dropwise and then the reaction mixture was stirred for 17 hours. Water was added and the layers were separated. The organic layer was treated with cyclohexane and the volume was reduced to precipitate a solid that was filtered off to give the subtitle compound (2.67 g) as an off-white solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.06 (s, 1H), 7.40 (d, 2H), 7.16 (d, 2H), 4.01 (s, 2H), 2.33 (s, 3H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(５１mg)のアセトニトリル(１mL)に２−ブロモ−Ｎ−ｐ−トリル−アセトアミド(実施例４６ａ)(３９mg)を添加した。反応を室温で一夜撹拌し、アセトニトリルを減圧下除去した。物質をアセトニトリル／酢酸エチルから再結晶して、表題化合物を無色固体として得た(１６mg)。
m/e 475 [M]^+
1H NMR (400MHz, DMSO-D₆):δ 10.40 (s, 1H), 7.40 (d, 2H), 7.33-7.25 (m, 4H), 7.21-7.16 (m, 1H), 7.13 (d, 2H), 5.11-5.04 (m, 1H), 4.13 (q, 2H), 4.09-4.00 (m, 1H), 3.64-3.48 (m, 4H), 3.42-3.36 (m, 1H), 2.37-2.23 (m, 2H), 2.23 (s, 3H), 2.17-2.04 (m, 2H), 1.95-1.86 (m, 3H), 1.78-1.66 (m, 1H), 1.65-1.40 (m, 9H)。 Example 46: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (p-tolylcarbamoyl-methyl) -1-azonia-bicyclo [2.2.2] octane bromide

1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e) (51 mg) in acetonitrile (1 mL) with 2-bromo- Np-tolyl-acetamide (Example 46a) (39 mg) was added. The reaction was stirred at room temperature overnight and acetonitrile was removed under reduced pressure. The material was recrystallized from acetonitrile / ethyl acetate to give the title compound as a colorless solid (16 mg).
m / e 475 [M] ^+
1 H NMR (400MHz, DMSO-D ₆ ): δ 10.40 (s, 1H), 7.40 (d, 2H), 7.33-7.25 (m, 4H), 7.21-7.16 (m, 1H), 7.13 (d, 2H ), 5.11-5.04 (m, 1H), 4.13 (q, 2H), 4.09-4.00 (m, 1H), 3.64-3.48 (m, 4H), 3.42-3.36 (m, 1H), 2.37-2.23 (m , 2H), 2.23 (s, 3H), 2.17-2.04 (m, 2H), 1.95-1.86 (m, 3H), 1.78-1.66 (m, 1H), 1.65-1.40 (m, 9H).

ｍ−トルイジン(５.３５ｇ)の１５０mL ジクロロメタン溶液に、炭酸カリウム(１７.３ｇ)を添加した。反応混合物をアルゴンでフラッシュし、次いでブロモアセチルブロマイド(３.６mL)を〜１５分間にわたり滴下し、反応混合物を２.５時間撹拌した。水を添加し、層を分離した。有機層を蒸発させ、残留物をＥｔＯＡｃ／シクロヘキサンで処理した。沈殿を濾取し、廃棄した。母液を蒸発させ、０−１００％ＥｔＯＡｃ／シクロヘキサンで溶出するシリカゲルクロマトグラフィーで精製して、副題化合物(６.１３ｇ)を灰白色固体として得た。
¹H NMR (400 MHz, CDCl₃):δ 8.06 (s, 1H), 7.38-7.28 (m, 2H), 7.27-7.21 (t, 1H), 6.98 (d, 1H), 4.02 (s, 2H), 2.36 (s, 3H)。 Example 47: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (m-tolylcarbamoyl-methyl) -1-azonia-bicyclo [2.2.2] octane bromide a) 2- Bromo-Nm-tolyl-acetamide

To a 150 mL dichloromethane solution of m-toluidine (5.35 g) was added potassium carbonate (17.3 g). The reaction mixture was flushed with argon, then bromoacetyl bromide (3.6 mL) was added dropwise over ˜15 minutes and the reaction mixture was stirred for 2.5 hours. Water was added and the layers were separated. The organic layer was evaporated and the residue was treated with EtOAc / cyclohexane. The precipitate was collected by filtration and discarded. The mother liquor was evaporated and purified by silica gel chromatography eluting with 0-100% EtOAc / cyclohexane to give the subtitle compound (6.13 g) as an off-white solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.06 (s, 1H), 7.38-7.28 (m, 2H), 7.27-7.21 (t, 1H), 6.98 (d, 1H), 4.02 (s, 2H) , 2.36 (s, 3H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(５０mg)のアセトニトリル(１mL)溶液に、２−ブロモ−Ｎ−ｍ−トリル−アセトアミド(実施例４７ａ)(３８mg)を添加した。反応を室温で２６時間撹拌し、アセトニトリルを減圧下除去した。物質を０−１０％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製して、表題化合物(３７mg)を無色泡状物として得た。
m/e 475 [M]^+
1H NMR (400MHz, DMSO-D₆):δ 10.40 (s, 1H), 7.39 (s, 1H), 7.32-7.25 (m, 5H), 7.22-7.15 (m, 2H), 6.92 (d, 1H), 5.11-5.05 (m, 1H), 4.14 (q, 2H), 4.11-4.01 (m, 1H), 3.64-3.48 (m, 4H), 3.42-3.30 (m, 1H), 2.39-2.21 (m, 5H), 2.18-2.05 (m, 2H), 1.97-1.84 (m, 3H), 1.77-1.66 (m, 1H), 1.65-1.39 (m, 9H)。 Example 47: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (m-tolylcarbamoyl-methyl) -1-azonia-bicyclo [2.2.2] octane bromide

A solution of 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e) (50 mg) in acetonitrile (1 mL) was added 2- Bromo-Nm-tolyl-acetamide (Example 47a) (38 mg) was added. The reaction was stirred at room temperature for 26 hours and acetonitrile was removed under reduced pressure. The material was purified by silica gel chromatography eluting with 0-10% MeOH / dichloromethane to give the title compound (37 mg) as a colorless foam.
m / e 475 [M] ^+
1 H NMR (400MHz, DMSO-D ₆ ): δ 10.40 (s, 1H), 7.39 (s, 1H), 7.32-7.25 (m, 5H), 7.22-7.15 (m, 2H), 6.92 (d, 1H ), 5.11-5.05 (m, 1H), 4.14 (q, 2H), 4.11-4.01 (m, 1H), 3.64-3.48 (m, 4H), 3.42-3.30 (m, 1H), 2.39-2.21 (m , 5H), 2.18-2.05 (m, 2H), 1.97-1.84 (m, 3H), 1.77-1.66 (m, 1H), 1.65-1.39 (m, 9H).

ブロモアセチルブロマイド(０.４４mL)の乾燥ＣＨＣｌ_３(５mL)溶液を、２−アミノ−１,３−オキサゾール(０.３９ｇ)およびトリエチルアミン(０.９６mL)の乾燥ＣＨＣｌ_３(９２mL)懸濁液に室温で滴下した。褐色混合物を１６時間撹拌し、次いでＨ_２Ｏ(２mL)でクエンチし、２０分間撹拌し、その後減圧下で濃縮して、明褐色固体を得た。粗生成物を１−３％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製して、表題化合物(０.５６ｇ)を灰白色固体として得た。
¹H NMR (400 MHz, DMSO-D₆):δ 11.61 (s, 1H), 7.89 (s, 1H), 7.12 (s, 1H), 4.11 (s, 2H)。 Example 48: (R) -1- (oxazol-2-ylcarbamoylmethyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide a) 2 -Bromo-N-oxazol-2-yl-acetamide

Bromoacetyl bromide (0.44 mL) in dry CHCl ₃ (5 mL) was added to a suspension of 2-amino-1,3-oxazole (0.39 g) and triethylamine (0.96 mL) in dry CHCl ₃ (92 mL). Added dropwise at room temperature. The brown mixture was stirred for 16 hours, then quenched with H ₂ O (2 mL), stirred for 20 minutes and then concentrated under reduced pressure to give a light brown solid. The crude product was purified by silica gel chromatography eluting with 1-3% MeOH / dichloromethane to give the title compound (0.56 g) as an off-white solid.
¹ H NMR (400 MHz, DMSO-D ₆ ): δ 11.61 (s, 1H), 7.89 (s, 1H), 7.12 (s, 1H), 4.11 (s, 2H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(０.３１mmol)および２−ブロモ−Ｎ−オキサゾール−２−イル−アセトアミド(実施例４８ａ)(０.３１mmol)を、無水ＭｅＣＮ中、室温で１８時間撹拌した。反応混合物を真空で濃縮し、黄色固体を、０−１５％ＭｅＯＨ／ジクロロメタンで溶出するフラッシュシリカゲルカラムクロマトグラフィーで精製して、表題化合物(１００mg)を白色固体として得た。
m/e 452 [M]^+
1H NMR (400 MHz, DMSO-D_6, 353K):δ 7.67 (s, 1H), 7.35-7.29 (m, 4H), 7.26-7.18 (m, 1H), 7.02 (s, 1H), 5.14-5.05 (m, 1H), 4.17-4.04 (m, 3H), 3.66-3.56 (m, 4H), 3.52-3.40 (m, 1H), 2.42-2.29 (m, 2H), 2.24-2.12 (m, 2H), 2.10-1.86 (m, 3H), 1.82-1.70 (m, 1H), 1.70-1.47 (m, 9H)。 Example 48: (R) -1- (oxazol-2-ylcarbamoylmethyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane bromide

1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e) (0.31 mmol) and 2-bromo-N-oxazole 2-yl-acetamide (Example 48a) (0.31 mmol) was stirred in anhydrous MeCN at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the yellow solid was purified by flash silica gel column chromatography eluting with 0-15% MeOH / dichloromethane to give the title compound (100 mg) as a white solid.
m / e 452 [M] ^+
1 H NMR (400 MHz, DMSO-D _6, 353K): δ 7.67 (s, 1H), 7.35-7.29 (m, 4H), 7.26-7.18 (m, 1H), 7.02 (s, 1H), 5.14- 5.05 (m, 1H), 4.17-4.04 (m, 3H), 3.66-3.56 (m, 4H), 3.52-3.40 (m, 1H), 2.42-2.29 (m, 2H), 2.24-2.12 (m, 2H ), 2.10-1.86 (m, 3H), 1.82-1.70 (m, 1H), 1.70-1.47 (m, 9H).

ブロモアセチルブロマイド(０.２２mL)の乾燥ＣＨＣｌ_３(４mL)溶液を、３−アミノ−６−メチルピリダジン(０.２４ｇ)およびトリエチルアミン(０.４７mL)の乾燥ＣＨＣｌ_３(４５mL)の懸濁液に室温で添加した。褐色混合物を３.５時間撹拌し、次いでＨ_２Ｏ(１.５mL)でクエンチし、２０分間撹拌し、その後減圧下で濃縮して、褐色固体を得た。粗生成物を１−２％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製した。関連フラクションを合わせ、蒸発させて、表題化合物(０.２０ｇ)をピンク色がかった／ベージュ色固体として得た。
¹H NMR (400 MHz, DMSO-D₆):δ 11.41 (s, 1H), 8.18 (d, 1H), 7.59 (d, 1H), 4.17 (s, 2H), 2.57 (s, 3H)。 Example 49: (R) -1-[(6-Methyl-pyridazin-3-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane bromide a) 2-Bromo-N- (6-methyl-pyridazin-3-yl) -acetamide

Bromoacetyl bromide (0.22 mL) in dry CHCl ₃ (4 mL) was added to a suspension of 3-amino-6-methylpyridazine (0.24 g) and triethylamine (0.47 mL) in dry CHCl ₃ (45 mL). Added at room temperature. The brown mixture was stirred for 3.5 hours, then quenched with H ₂ O (1.5 mL), stirred for 20 minutes, and then concentrated under reduced pressure to give a brown solid. The crude product was purified by silica gel chromatography eluting with 1-2% MeOH / dichloromethane. The relevant fractions were combined and evaporated to give the title compound (0.20 g) as a pinkish / beige solid.
¹ H NMR (400 MHz, DMSO-D ₆ ): δ 11.41 (s, 1H), 8.18 (d, 1H), 7.59 (d, 1H), 4.17 (s, 2H), 2.57 (s, 3H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(０.２０mmol)および２−ブロモ−Ｎ−(６−メチル−ピリダジン−３−イル)−アセトアミド(実施例４９ａ)(０.２０mmol)を、一緒に、無水ＭｅＣＮ中、室温で１８時間撹拌した。反応混合物を真空で濃縮し、黄色固体を、０−１５％ＭｅＯＨ／ジクロロメタンで溶出するフラッシュシリカゲルカラムクロマトグラフィーで精製して、表題化合物(６５mg)を黄褐色固体として得た。
m/e 477 [M]^+
1H NMR (400 MHz, CDCl₃):δ 8.19 (d, 1H), 7.38 (d, 1H), 7.27 (d, 4H), 7.20-7.12 (m, 1H), 5.18-4.96 (m, 3H), 4.41 (dd, 1H), 4.11-3.95 (m, 3H), 3.81 (d, 1H), 3.47-3.37 (m, 1H), 2.66 (s, 3H), 2.45-2.27 (m, 2H), 2.26-2.13 (m, 2H), 2.08-1.96 (m, 3H), 1.81-1.68 (m, 1H), 1.69-1.30 (m, 9H)。 Example 49: (R) -1-[(6-Methyl-pyridazin-3-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane bromide

1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e) (0.20 mmol) and 2-bromo-N- ( 6-Methyl-pyridazin-3-yl) -acetamide (Example 49a) (0.20 mmol) was stirred together in anhydrous MeCN at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the yellow solid was purified by flash silica gel column chromatography eluting with 0-15% MeOH / dichloromethane to give the title compound (65 mg) as a tan solid.
m / e 477 [M] ^+
1 H NMR (400 MHz, CDCl ₃ ): δ 8.19 (d, 1H), 7.38 (d, 1H), 7.27 (d, 4H), 7.20-7.12 (m, 1H), 5.18-4.96 (m, 3H) , 4.41 (dd, 1H), 4.11-3.95 (m, 3H), 3.81 (d, 1H), 3.47-3.37 (m, 1H), 2.66 (s, 3H), 2.45-2.27 (m, 2H), 2.26 -2.13 (m, 2H), 2.08-1.96 (m, 3H), 1.81-1.68 (m, 1H), 1.69-1.30 (m, 9H).

２−アミノ−ピリミジン(２.０ｇ)の乾燥ジクロロメタン(１７mL)溶液を、窒素下、０℃で、トリエチルアミン(２.６mL)で処理し、続いてクロロアセチルクロライド(１.５mL、１８.４mmol)をゆっくり添加した。反応混合物を室温に温めた。２時間後、混合物をジクロロメタンおよび水に分配した。相を分離し、水性層をジクロロメタン(×２)で抽出した。合わせた有機層を塩水で洗浄し、硫酸ナトリウムで乾燥させ、濾取し、濃縮して、粗生成物を得て、それを１０％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製した。関連フラクションを合わせ、蒸発させて、表題化合物(１.２０ｇ)を緑色固体として得た。
¹H NMR (400 MHz, CDCl₃):δ 8.84 (s, 1H), 8.65 (d, 2H), 7.09 (t, 1H), 4.46 (s, 2H)。 Example 50: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- (pyrimidin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride a) 2 -Chloro-N-pyrimidin-2-yl-acetamide

A solution of 2-amino-pyrimidine (2.0 g) in dry dichloromethane (17 mL) was treated with triethylamine (2.6 mL) at 0 ° C. under nitrogen followed by chloroacetyl chloride (1.5 mL, 18.4 mmol). Was added slowly. The reaction mixture was warmed to room temperature. After 2 hours, the mixture was partitioned between dichloromethane and water. The phases were separated and the aqueous layer was extracted with dichloromethane (x2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product which was purified by silica gel chromatography eluting with 10% MeOH / dichloromethane. The relevant fractions were combined and evaporated to give the title compound (1.20 g) as a green solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.84 (s, 1H), 8.65 (d, 2H), 7.09 (t, 1H), 4.46 (s, 2H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ、０.３０mmol)および２−クロロ−Ｎ−ピリミジン−２−イル−アセトアミド(実施例５０ａ)(０.３６mmol)のＭｅＣＮ(１.５mL)溶液を、一緒に室温で一夜撹拌した。反応混合物を真空で濃縮し、残留物を、０−１０％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製して、表題化合物を白色固体として得た(９０mg)。
m/e 463 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 11.19 (s, 1H), 8.66 (d, 2H), 7.32-7.24 (m, 4H), 7.23-7.14 (m, 2H), 5.09-5.03 (m, 1H), 4.48 (s, 2H), 4.06 (ddd, 1H), 3.65-3.51 (m, 4H), 3.45-3.34 (m, 1H), 2.37-2.21 (m, 2H), 2.15-2.07 (m, 2H), 1.96-1.80 (m, 3H), 1.75-1.64 (m, 1H), 1.63-1.38 (m, 9H)。 Example 50: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyrimidin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride

1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e, 0.30 mmol) and 2-chloro-N-pyrimidine- A solution of 2-yl-acetamide (Example 50a) (0.36 mmol) in MeCN (1.5 mL) was stirred together at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography eluting with 0-10% MeOH / dichloromethane to give the title compound as a white solid (90 mg).
m / e 463 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 11.19 (s, 1H), 8.66 (d, 2H), 7.32-7.24 (m, 4H), 7.23-7.14 (m, 2H), 5.09-5.03 ( m, 1H), 4.48 (s, 2H), 4.06 (ddd, 1H), 3.65-3.51 (m, 4H), 3.45-3.34 (m, 1H), 2.37-2.21 (m, 2H), 2.15-2.07 ( m, 2H), 1.96-1.80 (m, 3H), 1.75-1.64 (m, 1H), 1.63-1.38 (m, 9H).

２−アミノ−５−シアノピリジン(２.０ｇ)の乾燥ジクロロメタン(１７mL)溶液を、窒素下、０℃で、トリエチルアミン(２.６mL)で処理し、続いてクロロアセチルクロライド(１.５mL)をゆっくり添加した。反応混合物を室温に温めた。２時間後、混合物をジクロロメタンおよび水に分配した。相を分離し、水性層をジクロロメタン(×２)で抽出した。合わせた有機層を塩水で洗浄し、硫酸ナトリウムで乾燥させ、濾取し、濃縮して、粗生成物を得て、それを５０％ＥｔＯＡｃ／シクロヘキサンで溶出するシリカゲルクロマトグラフィーで精製した。関連フラクションを合わせ、蒸発させて、表題化合物(２.１７ｇ)を明褐色固体として得た。
¹H NMR (400 MHz, CDCl₃):δ 8.99 (s, 1H), 8.61 (dd, 1H), 8.36 (dd, 1H), 8.00-7.97 (m, 1H), 4.23 (s, 2H)。 Example 51: (R) -1-[(5-Cyano-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride a) 2-Chloro-N- (5-cyano-pyridin-2-yl) -acetamide

A solution of 2-amino-5-cyanopyridine (2.0 g) in dry dichloromethane (17 mL) was treated with triethylamine (2.6 mL) at 0 ° C. under nitrogen, followed by chloroacetyl chloride (1.5 mL). Slowly added. The reaction mixture was warmed to room temperature. After 2 hours, the mixture was partitioned between dichloromethane and water. The phases were separated and the aqueous layer was extracted with dichloromethane (x2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product which was purified by silica gel chromatography eluting with 50% EtOAc / cyclohexane. The relevant fractions were combined and evaporated to give the title compound (2.17 g) as a light brown solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.99 (s, 1H), 8.61 (dd, 1H), 8.36 (dd, 1H), 8.00-7.97 (m, 1H), 4.23 (s, 2H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(０.３０mmol)および２−クロロ−Ｎ−(５−シアノ−ピリジン−２−イル)−アセトアミド(実施例５１ａ)(０.３６mmol)のＭｅＣＮ(１.５mL)溶液を、一緒に室温で一夜撹拌した。反応混合物を真空で濃縮し、残留物を、０−１０％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製して、表題化合物を白色固体として得た(６０mg)。
m/e 487 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 11.56 (s, 1H), 8.81 (dd, 1H), 8.31 (dd, 1H), 8.09 (d, 1H), 7.32-7.25 (m, 4H), 7.23-7.17 (m, 1H), 5.11-5.04 (m, 1H), 4.32 (s, 2H), 4.10-4.01 (m, 1H), 3.63-3.50 (m, 4H), 3.42-3.29 (m, 1H), 2.37-2.23 (m, 2H), 2.17-2.05 (m, 2H), 2.00-1.82 (m, 3H), 1.78-1.65 (m, 1H), 1.65-1.40 (m, 9H)。 Example 51: (R) -1-[(5-Cyano-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride

1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e) (0.30 mmol) and 2-chloro-N- ( A solution of 5-cyano-pyridin-2-yl) -acetamide (Example 51a) (0.36 mmol) in MeCN (1.5 mL) was stirred together at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography eluting with 0-10% MeOH / dichloromethane to give the title compound as a white solid (60 mg).
m / e 487 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 11.56 (s, 1H), 8.81 (dd, 1H), 8.31 (dd, 1H), 8.09 (d, 1H), 7.32-7.25 (m, 4H) , 7.23-7.17 (m, 1H), 5.11-5.04 (m, 1H), 4.32 (s, 2H), 4.10-4.01 (m, 1H), 3.63-3.50 (m, 4H), 3.42-3.29 (m, 1H), 2.37-2.23 (m, 2H), 2.17-2.05 (m, 2H), 2.00-1.82 (m, 3H), 1.78-1.65 (m, 1H), 1.65-1.40 (m, 9H).

５−アミノピリミジン(４５０mg)をＤＣＥ(２mL)およびアセトニトリル(２mL)に、マイクロ波バイアル中で懸濁させた。クロロアセチルクロライド(０.３７７mL)を撹拌しながら添加した。バイアルを密閉し、反応混合物をマイクロ波中、８０℃で５分間加熱した。固体を濾取し、アセトニトリル(２×５mL)、ＤＣＥ(２×５mL)およびペンタン(２×３０mL)で洗浄し、次いで飽和重炭酸ナトリウムおよびＤＣＥ(５０mL／５０mL)に分配し、水性層がなお塩基性であることを確実にした。有機層を分離し、水性層をＤＣＥ(２×７５mL)で抽出した。合わせた有機層を硫酸マグネシウムで乾燥させ、蒸発させて、副題化合物(２００mg)を黄色固体として得た。
¹H NMR (400 MHz, DMSO-D₆):δ 10.71 (s, 1H), 9.00 (s, 2H), 8.93 (s, 1H), 4.35 (s, 2H)。 Example 52: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- (pyrimidin-5-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride a) 2 -Chloro-N-pyrimidin-5-yl-acetamide

5-Aminopyrimidine (450 mg) was suspended in DCE (2 mL) and acetonitrile (2 mL) in a microwave vial. Chloroacetyl chloride (0.377 mL) was added with stirring. The vial was sealed and the reaction mixture was heated in the microwave at 80 ° C. for 5 minutes. The solid was filtered off and washed with acetonitrile (2 × 5 mL), DCE (2 × 5 mL) and pentane (2 × 30 mL), then partitioned between saturated sodium bicarbonate and DCE (50 mL / 50 mL) and the aqueous layer still Ensured that it was basic. The organic layer was separated and the aqueous layer was extracted with DCE (2 × 75 mL). The combined organic layers were dried over magnesium sulfate and evaporated to give the subtitle compound (200 mg) as a yellow solid.
¹ H NMR (400 MHz, DMSO-D ₆ ): δ 10.71 (s, 1H), 9.00 (s, 2H), 8.93 (s, 1H), 4.35 (s, 2H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(１１５mg)のアセトニトリル(２mL)を２−クロロ−Ｎ−ピリミジン−５−イル−アセトアミド(実施例５２ａ)(６６mg)で処理して、暗色褐色溶液を得て、それを室温で一夜撹拌した。得られた固体を濾取し、冷アセトニトリル(２mL)およびペンタン(３mL)で洗浄し、真空下、４５℃で乾燥させて、表題化合物を黄褐色固体として得た(１５１mg)。
m/e 463 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 11.70 (s, 1H), 9.01 (s, 2H), 8.93 (s, 1H), 7.33-7.26 (m, 4H), 7.22-7.16 (m, 1H), 5.11-5.05 (m, 1H), 4.34 (s, 2H), 4.12-4.04 (m, 1H), 3.67-3.52 (m, 4H), 3.43-3.31 (m, 1H), 2.37-2.22 (m, 2H), 2.17-2.06 (m, 2H), 1.99-1.83 (m, 3H), 1.79-1.67 (m, 1H), 1.65-1.40 (m, 9H)。 Example 52: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyrimidin-5-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane chloride

1-Phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e) (115 mg) in acetonitrile (2 mL) was added 2-chloro- Treatment with N-pyrimidin-5-yl-acetamide (Example 52a) (66 mg) gave a dark brown solution which was stirred at room temperature overnight. The resulting solid was collected by filtration, washed with cold acetonitrile (2 mL) and pentane (3 mL) and dried under vacuum at 45 ° C. to give the title compound as a tan solid (151 mg).
m / e 463 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 11.70 (s, 1H), 9.01 (s, 2H), 8.93 (s, 1H), 7.33-7.26 (m, 4H), 7.22-7.16 (m, 1H), 5.11-5.05 (m, 1H), 4.34 (s, 2H), 4.12-4.04 (m, 1H), 3.67-3.52 (m, 4H), 3.43-3.31 (m, 1H), 2.37-2.22 ( m, 2H), 2.17-2.06 (m, 2H), 1.99-1.83 (m, 3H), 1.79-1.67 (m, 1H), 1.65-1.40 (m, 9H).

２−アミノ−３−フルオロピリジン(１.５ｇ)をＤＣＥ(１５mL)に溶解し、クロロアセチルクロライド(１.１mL)を滴下した。反応をマイクロ波中、８０℃で５分間加熱した。反応混合物を冷却し、得られた固体を濾取し、ＤＣＥ、ＭｅＣＮおよびペンタンで洗浄し、次いでジクロロメタンに懸濁し、水性ＮａＨＣＯ_３(飽和)を添加した。有機相を分離し、水性層をジクロロメタン(×２)で抽出した。合わせた有機層を硫酸ナトリウムで乾燥させ、濃縮した。粗生成物を０−１００％ＥｔＯＡｃ／シクロヘキサンで溶出するシリカゲルクロマトグラフィーで精製して、表題化合物を白色固体として得た(８００mg)。
¹H NMR (400 MHz, DMSO-D₆):δ 10.61 (s, 1H), 8.27 (dt, 1H), 7.83-7.77 (m, 1H), 7.41-7.35 (m, 1H), 4.37 (s, 2H)。 Example 53: (R) -1-[(3-Fluoro-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride a) 2-chloro-N- (3-fluoro-pyridin-2-yl) -acetamide

2-Amino-3-fluoropyridine (1.5 g) was dissolved in DCE (15 mL), and chloroacetyl chloride (1.1 mL) was added dropwise. The reaction was heated in the microwave at 80 ° C. for 5 minutes. The reaction mixture was cooled and the resulting solid was collected by filtration, washed with DCE, MeCN and pentane, then suspended in dichloromethane and aqueous NaHCO ₃ (saturated) was added. The organic phase was separated and the aqueous layer was extracted with dichloromethane (x2). The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography eluting with 0-100% EtOAc / cyclohexane to give the title compound as a white solid (800 mg).
¹ H NMR (400 MHz, DMSO-D ₆ ): δ 10.61 (s, 1H), 8.27 (dt, 1H), 7.83-7.77 (m, 1H), 7.41-7.35 (m, 1H), 4.37 (s, 2H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(０.３０mmol)および２−クロロ−Ｎ−(３−フルオロ−ピリジン−２−イル)−アセトアミド(実施例５３ａ)(０.３６mmol)のＭｅＣＮ(１.５mL)溶液を室温で一夜撹拌した。反応混合物を真空で濃縮し、残留物を、０−１０％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製して、表題化合物を白色固体として得た(８６mg)。
m/e 480 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 11.07 (s, 1H), 8.25 (dt, 1H), 7.81 (ddd, 1H), 7.39 (ddd, 1H), 7.31-7.24 (m, 4H), 7.22-7.15 (m, 1H), 5.11-5.04 (m, 1H), 4.36 (s, 2H), 4.11-4.04 (m, 1H), 3.66-3.52 (m, 4H), 3.44-3.32 (m, 1H), 2.37-2.21 (m, 2H), 2.19-2.06 (m, 2H), 1.99-1.82 (m, 3H), 1.77-1.65 (m, 1H), 1.65-1.38 (m, 9H)。 Example 53: (R) -1-[(3-Fluoro-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride

1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e) (0.30 mmol) and 2-chloro-N- ( A solution of 3-fluoro-pyridin-2-yl) -acetamide (Example 53a) (0.36 mmol) in MeCN (1.5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography eluting with 0-10% MeOH / dichloromethane to give the title compound as a white solid (86 mg).
m / e 480 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 11.07 (s, 1H), 8.25 (dt, 1H), 7.81 (ddd, 1H), 7.39 (ddd, 1H), 7.31-7.24 (m, 4H) , 7.22-7.15 (m, 1H), 5.11-5.04 (m, 1H), 4.36 (s, 2H), 4.11-4.04 (m, 1H), 3.66-3.52 (m, 4H), 3.44-3.32 (m, 1H), 2.37-2.21 (m, 2H), 2.19-2.06 (m, 2H), 1.99-1.82 (m, 3H), 1.77-1.65 (m, 1H), 1.65-1.38 (m, 9H).

３−フルオロ−ピリジン−４−イルアミン(０.２ｇ)の乾燥ジクロロメタン(２mL)溶液を、窒素下、０℃で、トリエチルアミン(０.２８mL)で処理し、続いてクロロアセチルクロライド(０.１６mL)をゆっくり添加した。反応混合物を室温に温めた。２時間後、混合物をジクロロメタンおよび水に分配した。相を分離し、水性層をジクロロメタン(×２)で抽出した。合わせた有機層を塩水で洗浄し、硫酸ナトリウムで乾燥させ、濾取し、濃縮して、粗生成物を得て、それを０−１００％ＥｔＯＡｃ／シクロヘキサンで溶出するシリカゲルクロマトグラフィーで精製した。関連フラクションを合わせ、蒸発させて、表題化合物(０.１１ｇ)をピンク色固体として得た。
¹H NMR (400 MHz, DMSO-D₆):δ 10.55 (s, 1H), 8.56 (d, 1H), 8.35 (d, 1H), 8.16 (dd, 1H), 4.44 (s, 2H)。 Example 54: (R) -1-[(3-Fluoro-pyridin-4-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride a) 2-Chloro-N- (3-fluoro-pyridin-4-yl) -acetamide

A solution of 3-fluoro-pyridin-4-ylamine (0.2 g) in dry dichloromethane (2 mL) was treated with triethylamine (0.28 mL) at 0 ° C. under nitrogen followed by chloroacetyl chloride (0.16 mL). Was added slowly. The reaction mixture was warmed to room temperature. After 2 hours, the mixture was partitioned between dichloromethane and water. The phases were separated and the aqueous layer was extracted with dichloromethane (x2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product which was purified by silica gel chromatography eluting with 0-100% EtOAc / cyclohexane. The relevant fractions were combined and evaporated to give the title compound (0.11 g) as a pink solid.
¹ H NMR (400 MHz, DMSO-D ₆ ): δ 10.55 (s, 1H), 8.56 (d, 1H), 8.35 (d, 1H), 8.16 (dd, 1H), 4.44 (s, 2H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(０.３０mmol)および２−クロロ−Ｎ−(３−フルオロ−ピリジン−４−イル)−アセトアミド(実施例５４ａ)(０.３６mmol)のＭｅＣＮ(１.５mL)溶液を、一緒に室温で一夜撹拌した。反応混合物を真空で濃縮し、残留物を、０−１０％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製して、表題化合物を白色固体として得た(１１０mg)。
m/e 480 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 10.92 (s, 1H), 8.56 (d, 1H), 8.35 (d, 1H), 8.03 (dd, 1H), 7.32-7.26 (m, 4H), 7.21-7.16 (m, 1H), 5.11-5.05 (m, 1H), 4.41-4.29 (m, 2H), 4.10-4.02 (m, 1H), 3.63-3.50 (m, 4H), 3.42-3.30 (m, 1H), 2.36-2.23 (m, 2H), 2.17-2.06 (m, 2H), 1.98-1.82 (m, 3H), 1.78-1.65 (m, 1H), 1.66-1.40 (m, 9H)。 Example 54: (R) -1-[(3-Fluoro-pyridin-4-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride

1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e) (0.30 mmol) and 2-chloro-N- ( A solution of 3-fluoro-pyridin-4-yl) -acetamide (Example 54a) (0.36 mmol) in MeCN (1.5 mL) was stirred together at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography eluting with 0-10% MeOH / dichloromethane to give the title compound as a white solid (110 mg).
m / e 480 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 10.92 (s, 1H), 8.56 (d, 1H), 8.35 (d, 1H), 8.03 (dd, 1H), 7.32-7.26 (m, 4H) , 7.21-7.16 (m, 1H), 5.11-5.05 (m, 1H), 4.41-4.29 (m, 2H), 4.10-4.02 (m, 1H), 3.63-3.50 (m, 4H), 3.42-3.30 ( m, 1H), 2.36-2.23 (m, 2H), 2.17-2.06 (m, 2H), 1.98-1.82 (m, 3H), 1.78-1.65 (m, 1H), 1.66-1.40 (m, 9H).

２−ピラジンカルボン酸(１ｇ)のジクロロメタン(３０mL)をトリエチルアミン(１.２７mL)およびＨＡＴＵ(３.６ｇ)で処理し、混合物を１０分間撹拌した。２−ブロモエチルアミンヒドロブロマイド(１.５ｇ)およびトリエチルアミン(１.２７mL)のジクロロメタン(２０mL)溶液を添加し、反応混合物を３時間撹拌した。水(５０mL)を添加し、有機層を分離しおよび水で洗浄した(３×５０mL)。有機層を硫酸マグネシウムで乾燥させ、蒸発させて、粗生成物を得て、それを０−１００％ＥｔＯＡｃ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製した。関連フラクションを合わせ、蒸発させて、残留物を得て、それをＥｔＯＡｃ(４０mL)に溶解し、飽和炭酸水素ナトリウムで洗浄し、水性層が塩基性であることを確実にした。有機層を硫酸マグネシウムで乾燥させ、蒸発させて、副題化合物(１.０ｇ)を白色固体として得た。
¹H NMR (400 MHz, DMSO-D₆):δ 9.21 (d, 1H), 9.14 (t, 1H), 8.90 (d, 1H), 8.75 (dd, 1H), 3.75-3.69 (m, 2H), 3.66-3.60 (m, 2H)。 Example 55: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- {2-[(pyrazine-2-carbonyl) -amino] -ethyl} -1-azonia-bicyclo [2.2 .2] Octane bromide a) Pyrazine-2-carboxylic acid (2-bromo-ethyl) -amide

2-Pyrazinecarboxylic acid (1 g) in dichloromethane (30 mL) was treated with triethylamine (1.27 mL) and HATU (3.6 g) and the mixture was stirred for 10 minutes. A solution of 2-bromoethylamine hydrobromide (1.5 g) and triethylamine (1.27 mL) in dichloromethane (20 mL) was added and the reaction mixture was stirred for 3 hours. Water (50 mL) was added and the organic layer was separated and washed with water (3 × 50 mL). The organic layer was dried over magnesium sulfate and evaporated to give the crude product that was purified by silica gel chromatography eluting with 0-100% EtOAc / dichloromethane. The relevant fractions were combined and evaporated to give a residue that was dissolved in EtOAc (40 mL) and washed with saturated sodium bicarbonate to ensure that the aqueous layer was basic. The organic layer was dried over magnesium sulfate and evaporated to give the subtitle compound (1.0 g) as a white solid.
¹ H NMR (400 MHz, DMSO-D ₆ ): δ 9.21 (d, 1H), 9.14 (t, 1H), 8.90 (d, 1H), 8.75 (dd, 1H), 3.75-3.69 (m, 2H) , 3.66-3.60 (m, 2H).

ピラジン−２−カルボン酸(２−ブロモ−エチル)−アミド(実施例５５ａ)(８７mg)を、１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(１１３mg)のアセトニトリル(２mL)溶液に添加した。反応混合物を室温で１６時間撹拌した。固体が析出し、濾取し、冷アセトニトリルで洗浄し、真空下、４０℃で乾燥させて、表題化合物(９６mg)を白色固体として得た。
m/e 477 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 9.22 (t, 1H), 9.17 (d, 1H), 8.88 (d, 1H), 8.72 (dd, 1H), 7.33-7.25 (m, 4H), 7.22-7.16 (m, 1H), 5.01-4.96 (m, 1H), 3.89 (ddd, 1H), 3.73-3.57 (m, 2H), 3.51-3.28 (m, 5H), 3.22 (dt, 1H), 3.13-3.02 (m, 1H), 2.38-2.30 (m, 1H), 2.30-2.20 (m, 1H), 2.17- 2.06 (m, 2H), 1.97-1.76 (m, 3H), 1.69-1.37 (m, 10H)。 Example 55: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- {2-[(pyrazine-2-carbonyl) -amino] -ethyl} -1-azonia-bicyclo [2.2 .2] Octane bromide

Pyrazine-2-carboxylic acid (2-bromo-ethyl) -amide (Example 55a) (87 mg) was converted to 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2]. Oct-3-yl) ester (Example 14e) (113 mg) was added to a solution of acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 16 hours. A solid precipitated out, was collected by filtration, washed with cold acetonitrile and dried under vacuum at 40 ° C. to give the title compound (96 mg) as a white solid.
m / e 477 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 9.22 (t, 1H), 9.17 (d, 1H), 8.88 (d, 1H), 8.72 (dd, 1H), 7.33-7.25 (m, 4H) , 7.22-7.16 (m, 1H), 5.01-4.96 (m, 1H), 3.89 (ddd, 1H), 3.73-3.57 (m, 2H), 3.51-3.28 (m, 5H), 3.22 (dt, 1H) , 3.13-3.02 (m, 1H), 2.38-2.30 (m, 1H), 2.30-2.20 (m, 1H), 2.17- 2.06 (m, 2H), 1.97-1.76 (m, 3H), 1.69-1.37 ( m, 10H).

[１,２,４]−チアジアゾール−５−イルアミン(３.０ｇ)の乾燥ジクロロメタン(３０mL)溶液を、窒素下、０℃で、トリエチルアミン(４.６mL)で処理し、続いてクロロアセチルクロライド(２.６mL)をゆっくり添加した。反応混合物を室温に温めた。２時間後、混合物をジクロロメタンおよび水に分配した。相を分離し、水性層をジクロロメタン(×２)で抽出した。合わせた有機層を塩水で洗浄し、硫酸ナトリウムで乾燥させ、濾取し、濃縮して、粗生成物を得て、それを５０−７５％ＥｔＯＡｃ／シクロヘキサンで溶出するシリカゲルクロマトグラフィーで精製して、表題化合物(１.００ｇ)を黄色固体として得た。
¹H NMR (400 MHz, DMSO-D₆):δ 13.32 (s, 1H), 8.51 (s, 1H), 4.52 (s, 2H)。 Example 56: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-([1,2,4] thiadiazol-5-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2. 2] Octane chloride a) 2-Chloro-N- [1,2,4] thiadiazol-5-yl-acetamide

A solution of [1,2,4] -thiadiazol-5-ylamine (3.0 g) in dry dichloromethane (30 mL) was treated with triethylamine (4.6 mL) at 0 ° C. under nitrogen, followed by chloroacetyl chloride ( 2.6 mL) was added slowly. The reaction mixture was warmed to room temperature. After 2 hours, the mixture was partitioned between dichloromethane and water. The phases were separated and the aqueous layer was extracted with dichloromethane (x2). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product which is purified by silica gel chromatography eluting with 50-75% EtOAc / cyclohexane. The title compound (1.00 g) was obtained as a yellow solid.
¹ H NMR (400 MHz, DMSO-D ₆ ): δ 13.32 (s, 1H), 8.51 (s, 1H), 4.52 (s, 2H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(０.３０mmol)および２−クロロ−Ｎ−[１,２,４]チアジアゾール−５−イル−アセトアミド(０.３６mmol)(実施例５６ａ)のＭｅＣＮ(１.５mL)溶液を室温で一夜撹拌した。反応混合物を濾過し、得られた固体を冷ＭｅＣＮで洗浄して、表題化合物(３０mg)を固体として得た。
m/e 469 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 13.70 (s, 1H), 8.51 (s, 1H), 7.34-7.27 (m, 4H), 7.22-7.17 (m, 1H), 5.11-5.05 (m, 1H), 4.54-4.43 (m, 2H), 4.12-4.05 (m, 1H), 3.67-3.53 (m, 4H), 3.45-3.33 (m, 1H), 2.38-2.24 (m, 2H), 2.18-2.05 (m, 2H), 1.99-1.83 (m, 3H), 1.80-1.67 (m, 1H), 1.67-1.40 (m, 9H)。 Example 56: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-([1,2,4] thiadiazol-5-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2. 2] Octane chloride

1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e) (0.30 mmol) and 2-chloro-N- [ A solution of 1,2,4] thiadiazol-5-yl-acetamide (0.36 mmol) (Example 56a) in MeCN (1.5 mL) was stirred at room temperature overnight. The reaction mixture was filtered and the resulting solid was washed with cold MeCN to give the title compound (30 mg) as a solid.
m / e 469 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 13.70 (s, 1H), 8.51 (s, 1H), 7.34-7.27 (m, 4H), 7.22-7.17 (m, 1H), 5.11-5.05 ( m, 1H), 4.54-4.43 (m, 2H), 4.12-4.05 (m, 1H), 3.67-3.53 (m, 4H), 3.45-3.33 (m, 1H), 2.38-2.24 (m, 2H), 2.18-2.05 (m, 2H), 1.99-1.83 (m, 3H), 1.80-1.67 (m, 1H), 1.67-1.40 (m, 9H).

イソブチルクロロホルメート(３.３５mL)を、２−ピリジンカルボン酸(２.１０ｇ)およびＮ−メチルモルホリン(２.８２mL)の乾燥ＴＨＦ(８５mL)溶液に０℃で添加した。１５分間後、３−アミノ−１−プロパノール(１.３１mL)を添加し、混合物を一夜撹拌した。反応混合物を真空濃縮してピンク色固体を得て、シリカのパッド(１−５％ＭｅＯＨ／ジクロロメタン)を通した。得られた褐色油状物をジクロロメタン(８５mL)に取り込み、０℃に冷却した。この溶液に、Ｅｔ_３Ｎ(４.７５mL)およびメタンスルホニルクロライド(２.０mL)を添加した。３０分後、反応を室温に温め、２.５時間撹拌し、その後Ｈ_２Ｏ(５０mL)でクエンチした。層を分離し、有機相を飽和ＮａＨＣＯ_３(水性)で洗浄し、乾燥させた(ＭｇＳＯ_４)。減圧濃縮により、オレンジ色油状物を得て、それを９０％ＥｔＯＡｃ／シクロヘキサンで溶出するシリカゲルクロマトグラフィーにより精製して、副題化合物(２.０６ｇ)をオレンジ色油状物として得た。
¹H NMR (400 MHz, CDCl₃):δ 8.55 (ddd, 1H), 8.29 (s, 1H), 8.17 (dt, 1H), 7.88-7.83 (m, 1H), 7.45 (ddd, 1H), 4.35 (t, 2H), 3.63 (q, 2H), 3.07 (s, 3H), 2.11 (p, 2H)。 Example 57: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- {3-[(pyridine-2-carbonyl) -amino] -propyl} -1-azonia-bicyclo [2.2 .2] Octane bromide a) Methanesulfonic acid 3-[(pyridine-2-carbonyl) -amino] -propyl ester

Isobutyl chloroformate (3.35 mL) was added to a solution of 2-pyridinecarboxylic acid (2.10 g) and N-methylmorpholine (2.82 mL) in dry THF (85 mL) at 0 ° C. After 15 minutes, 3-amino-1-propanol (1.31 mL) was added and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo to give a pink solid that was passed through a pad of silica (1-5% MeOH / dichloromethane). The resulting brown oil was taken up in dichloromethane (85 mL) and cooled to 0 ° C. To this solution was added Et ₃ N (4.75 mL) and methanesulfonyl chloride (2.0 mL). After 30 minutes, the reaction was warmed to room temperature and stirred for 2.5 hours before being quenched with H ₂ O (50 mL). The layers were separated and the organic phase was washed with saturated NaHCO _{3 (aq)} and dried (MgSO ₄ ). Concentration in vacuo gave an orange oil which was purified by silica gel chromatography eluting with 90% EtOAc / cyclohexane to give the subtitle compound (2.06 g) as an orange oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.55 (ddd, 1H), 8.29 (s, 1H), 8.17 (dt, 1H), 7.88-7.83 (m, 1H), 7.45 (ddd, 1H), 4.35 (t, 2H), 3.63 (q, 2H), 3.07 (s, 3H), 2.11 (p, 2H).

メタンスルホン酸３−[(ピリジン−２−カルボニル)−アミノ]−プロピルエステル(実施例５７ａ)(１.９６ｇ)およびリチウムブロマイド(３.２９ｇ)のアセトン(１９mL)中の混合物を２時間加熱還流した。反応混合物を室温に冷却し、真空で濃縮し、残留物をＥｔＯＡｃ／Ｈ_２Ｏ(６０mL、１：１)に分配した。相を分離し、水性相さらにＥｔＯＡｃ(２×２５mL)で抽出した。合わせた有機物を乾燥させ(ＭｇＳＯ_４)、真空で濃縮して、褐色油状物を得て、それは静置により固化した。０−１００％ＥｔＯＡｃ／シクロヘキサンで溶出するシリカゲルクロマトグラフィーでの精製により、副題化合物(１.５ｇ)を白色固体として得た。
¹H NMR (400 MHz, CDCl₃):δ 8.55 (ddd, 1H), 8.25-8.12 (s, 1H), 8.19 (dt, 1H), 7.85 (td, 1H), 7.43 (ddd, 1H), 3.64 (q, 2H), 3.50 (t, 2H), 2.22 (p, 2H)。 b) Pyridine-2-carboxylic acid (3-bromo-propyl) -amide

A mixture of methanesulfonic acid 3-[(pyridine-2-carbonyl) -amino] -propyl ester (Example 57a) (1.96 g) and lithium bromide (3.29 g) in acetone (19 mL) was heated to reflux for 2 hours. did. The reaction mixture was cooled to room temperature, concentrated in vacuo, and the residue was partitioned between EtOAc / H ₂ O (60 mL, 1: 1). The phases were separated and the aqueous phase was further extracted with EtOAc (2 × 25 mL). The combined organics were dried (MgSO ₄ ) and concentrated in vacuo to give a brown oil that solidified upon standing. Purification by silica gel chromatography eluting with 0-100% EtOAc / cyclohexane gave the subtitle compound (1.5 g) as a white solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 8.55 (ddd, 1H), 8.25-8.12 (s, 1H), 8.19 (dt, 1H), 7.85 (td, 1H), 7.43 (ddd, 1H), 3.64 (q, 2H), 3.50 (t, 2H), 2.22 (p, 2H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(０.３１mmol)およびピリジン−２−カルボン酸(３−ブロモ−プロピル)−アミド(実施例５７ｂ)(０.３１mmol)を、一緒に、無水ＭｅＣＮ(３mL)中、室温で１６日間撹拌した。反応混合物を真空で濃縮し、固体を、０−１５％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製して、表題化合物(１４５mg)を白色固体として得た。
m/e 490 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 8.94 (t, 1H), 8.62 (ddd, 1H), 8.03-7.95 (m, 2H), 7.58 (ddd, 1H), 7.31-7.24 (m, 4H), 7.19-7.13 (m, 1H), 5.01-4.95 (m, 1H), 3.76 (ddd, 1H), 3.51-3.09 (m, 7H), 3.09-3.01 (m, 1H), 2.93-2.82 (m, 1H), 2.36-2.22 (m, 2H), 2.14-2.06 (m, 2H), 1.99-1.90 (m, 1H), 1.92-1.71 (m, 4H), 1.68-1.39 (m, 10H)。 Example 57: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- {3-[(pyridine-2-carbonyl) -amino] -propyl} -1-azonia-bicyclo [2.2 .2] Octane bromide

1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e) (0.31 mmol) and pyridine-2-carboxylic acid ( 3-Bromo-propyl) -amide (Example 57b) (0.31 mmol) was stirred together in anhydrous MeCN (3 mL) at room temperature for 16 days. The reaction mixture was concentrated in vacuo and the solid was purified by silica gel chromatography eluting with 0-15% MeOH / dichloromethane to give the title compound (145 mg) as a white solid.
m / e 490 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 8.94 (t, 1H), 8.62 (ddd, 1H), 8.03-7.95 (m, 2H), 7.58 (ddd, 1H), 7.31-7.24 (m, 4H), 7.19-7.13 (m, 1H), 5.01-4.95 (m, 1H), 3.76 (ddd, 1H), 3.51-3.09 (m, 7H), 3.09-3.01 (m, 1H), 2.93-2.82 ( m, 1H), 2.36-2.22 (m, 2H), 2.14-2.06 (m, 2H), 1.99-1.90 (m, 1H), 1.92-1.71 (m, 4H), 1.68-1.39 (m, 10H).

２−メチル−ピリミジン−４−イルアミン(５４５mg)をＤＣＥ(５mL)に懸濁し、クロロアセチルクロライド(０.４mL)を滴下した。反応をマイクロ波中、８０℃で５分間加熱した。反応混合物を冷却して、固体を得て、それを濾過し、ジクロロメタンで洗浄し、次いでジクロロメタンに懸濁し、飽和ＮａＨＣＯ_３(水性)を添加した。有機相を冷却し、水性層をジクロロメタン(×２)で抽出した。合わせた有機層を硫酸ナトリウムで乾燥させ、濃縮した。粗生成物を０−１０％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製して、副題化合物を黄色固体として得た(７０mg、７.５％)。
¹H NMR (400 MHz, DMSO-D₆):δ 11.16 (s, 1H), 8.58 (d, 1H), 7.84 (d, 1H), 4.37 (s, 2H), 2.53 (s, 3H)。 Example 58: (R) -1-[(2-Methyl-pyrimidin-4-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride a) 2-Chloro-N- (2-methyl-pyrimidin-4-yl) -acetamide

2-Methyl-pyrimidin-4-ylamine (545 mg) was suspended in DCE (5 mL), and chloroacetyl chloride (0.4 mL) was added dropwise. The reaction was heated in the microwave at 80 ° C. for 5 minutes. The reaction mixture was cooled to give a solid that was filtered, washed with dichloromethane, then suspended in dichloromethane and saturated NaHCO ₃ (aq) was added. The organic phase was cooled and the aqueous layer was extracted with dichloromethane (x2). The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography eluting with 0-10% MeOH / dichloromethane to give the subtitle compound as a yellow solid (70 mg, 7.5%).
¹ H NMR (400 MHz, DMSO-D ₆ ): δ 11.16 (s, 1H), 8.58 (d, 1H), 7.84 (d, 1H), 4.37 (s, 2H), 2.53 (s, 3H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ、０.２９mmol)および２−クロロ−Ｎ−(２−メチル−ピリミジン−４−イル)−アセトアミド(実施例５８ａ)(０.３５mmol)のＭｅＣＮ(２.０mL)溶液を、一緒に、室温で１６時間撹拌した。反応混合物を真空で濃縮し、残留物を、０−１０％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製して、表題化合物を白色固体として得た(５５mg)。
m/e 477 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 11.40 (s, 1H), 8.61 (d, 1H), 7.75 (d, 1H), 7.32-7.25 (m, 4H), 7.23-7.17 (m, 1H), 5.10-5.03 (m, 1H), 4.28 (s, 2H), 4.09-4.01 (m, 1H), 3.62-3.48 (m, 4H), 3.40-3.30 (m, 1H), 2.50 (s, 3H), 2.36-2.24 (m, 2H), 2.17-2.05 (m, 2H), 1.98-1.84 (m, 3H), 1.78-1.65 (m, 1H), 1.64-1.41 (m, 9H)。 Example 58: (R) -1-[(2-Methyl-pyrimidin-4-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride

1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e, 0.29 mmol) and 2-chloro-N- (2 A solution of -methyl-pyrimidin-4-yl) -acetamide (Example 58a) (0.35 mmol) in MeCN (2.0 mL) was stirred together at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography eluting with 0-10% MeOH / dichloromethane to give the title compound as a white solid (55 mg).
m / e 477 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 11.40 (s, 1H), 8.61 (d, 1H), 7.75 (d, 1H), 7.32-7.25 (m, 4H), 7.23-7.17 (m, 1H), 5.10-5.03 (m, 1H), 4.28 (s, 2H), 4.09-4.01 (m, 1H), 3.62-3.48 (m, 4H), 3.40-3.30 (m, 1H), 2.50 (s, 3H), 2.36-2.24 (m, 2H), 2.17-2.05 (m, 2H), 1.98-1.84 (m, 3H), 1.78-1.65 (m, 1H), 1.64-1.41 (m, 9H).

６−メチル−ピリミジン−４−イルアミン(５４５mg)をＤＣＥ(５mL)に懸濁し、クロロアセチルクロライド(０.４mL)を滴下した。反応をマイクロ波中、８０℃で５分間加熱した。反応混合物を冷却し、濾取し、固体を得た。第２回目の反応を繰り返し、両方のバッチの固体を合わせ、ジクロロメタンで洗浄し、次いでジクロロメタンに懸濁し、飽和ＮａＨＣＯ_３(水性)を添加した。有機相を回収し、水性層をジクロロメタン(×２)で抽出した。合わせた有機層を硫酸ナトリウムで乾燥させ、濃縮した。粗生成物を０−１０％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製して、副題化合物を黄色固体として得た(１２０mg)。
¹H NMR (400 MHz, DMSO-D₆):δ 11.11 (s, 1H), 8.76 (d, 1H), 7.91 (s, 1H), 4.38 (s, 2H), 2.44 (s, 3H)。 Example 59: (R) -1-[(6-Methyl-pyrimidin-4-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride a) 2-Chloro-N- (6-methyl-pyrimidin-4-yl) -acetamide

6-Methyl-pyrimidin-4-ylamine (545 mg) was suspended in DCE (5 mL), and chloroacetyl chloride (0.4 mL) was added dropwise. The reaction was heated in the microwave at 80 ° C. for 5 minutes. The reaction mixture was cooled and filtered to give a solid. The second reaction was repeated and both batches of solids were combined, washed with dichloromethane, then suspended in dichloromethane and saturated NaHCO ₃ (aq) was added. The organic phase was collected and the aqueous layer was extracted with dichloromethane (x2). The combined organic layers were dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography eluting with 0-10% MeOH / dichloromethane to give the subtitle compound as a yellow solid (120 mg).
¹ H NMR (400 MHz, DMSO-D ₆ ): δ 11.11 (s, 1H), 8.76 (d, 1H), 7.91 (s, 1H), 4.38 (s, 2H), 2.44 (s, 3H).

１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(０.３０mmol)および２−クロロ−Ｎ−(６−メチル−ピリミジン−４−イル)−アセトアミド(実施例５９ａ)(０.３６mmol)のＭｅＣＮ(２mL)を、一緒に室温で１６時間撹拌した。反応混合物を真空で濃縮し、残留物を、０−１０％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製して、表題化合物を白色固体として得た(１２５mg)。
m/e 477 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 11.39 (s, 1H), 8.76 (d, 1H), 7.83 (s, 1H), 7.34-7.26 (m, 4H), 7.22-7.17 (m, 1H), 5.10-5.04 (m, 1H), 4.32 (s, 2H), 4.10-4.01 (m, 1H), 3.64-3.50 (m, 4H), 3.43-3.31 (m, 1H), 2.42 (s, 3H), 2.37-2.23 (m, 2H), 2.18-2.06 (m, 2H), 1.98-1.81 (m, 3H), 1.78-1.66 (m, 1H), 1.65-1.39 (m, 9H)。 Example 59: (R) -1-[(6-Methyl-pyrimidin-4-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane chloride

1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 14e) (0.30 mmol) and 2-chloro-N- ( 6-Methyl-pyrimidin-4-yl) -acetamide (Example 59a) (0.36 mmol) in MeCN (2 mL) was stirred together at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography eluting with 0-10% MeOH / dichloromethane to give the title compound as a white solid (125 mg).
m / e 477 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 11.39 (s, 1H), 8.76 (d, 1H), 7.83 (s, 1H), 7.34-7.26 (m, 4H), 7.22-7.17 (m, 1H), 5.10-5.04 (m, 1H), 4.32 (s, 2H), 4.10-4.01 (m, 1H), 3.64-3.50 (m, 4H), 3.43-3.31 (m, 1H), 2.42 (s, 3H), 2.37-2.23 (m, 2H), 2.18-2.06 (m, 2H), 1.98-1.81 (m, 3H), 1.78-1.66 (m, 1H), 1.65-1.39 (m, 9H).

ピコリン酸(０.９９ｇ)のジクロロメタン(３０mL)をトリエチルアミン(１.２７mL)およびＨＡＴＵ(３.６ｇ)で処理した。混合物を１０分間撹拌し、次いで２−ブロモエチルアミンヒドロブロマイド(１.５ｇ)およびトリエチルアミン(１.２７mL)のジクロロメタン(２０mL)溶液を添加した。反応混合物を３時間撹拌した。水(５０mL)を添加し、層を分離した。有機層を水(３×５０mL)で洗浄し、硫酸マグネシウムで乾燥させ、蒸発させて、粗生成物を得て、それを０−１００％ＥｔＯＡｃ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製した。関連フラクションを合わせ、蒸発させ、ＥｔＯＡｃ(４０mL)に溶解し、飽和炭酸水素ナトリウム溶液で洗浄し、水性層が塩基性のままであることを確実にした。有機層を硫酸マグネシウムで乾燥させ、蒸発させて、副題化合物(０.８８ｇ)を白色固体として得た。
¹H NMR (400 MHz, DMSO-D₆):δ 9.01 (t, 1H), 8.66 (ddd, 1H), 8.07-7.98 (m, 2H), 7.62 (ddd, 1H), 3.70 (q, 2H), 3.62 (t, 2H)。 Example 60: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- {2-[(pyridine-2-carbonyl) -amino] -ethyl} -1-azonia-bicyclo [2.2 .2] Octane bromide a) Pyridine-2-carboxylic acid (2-bromo-ethyl) -amide

Picolinic acid (0.99 g) in dichloromethane (30 mL) was treated with triethylamine (1.27 mL) and HATU (3.6 g). The mixture was stirred for 10 minutes and then a solution of 2-bromoethylamine hydrobromide (1.5 g) and triethylamine (1.27 mL) in dichloromethane (20 mL) was added. The reaction mixture was stirred for 3 hours. Water (50 mL) was added and the layers were separated. The organic layer was washed with water (3 x 50 mL), dried over magnesium sulfate and evaporated to give the crude product that was purified by silica gel chromatography eluting with 0-100% EtOAc / dichloromethane. The relevant fractions were combined, evaporated, dissolved in EtOAc (40 mL) and washed with saturated sodium bicarbonate solution to ensure that the aqueous layer remained basic. The organic layer was dried over magnesium sulfate and evaporated to give the subtitle compound (0.88 g) as a white solid.
¹ H NMR (400 MHz, DMSO-D ₆ ): δ 9.01 (t, 1H), 8.66 (ddd, 1H), 8.07-7.98 (m, 2H), 7.62 (ddd, 1H), 3.70 (q, 2H) , 3.62 (t, 2H).

ピリジン−２−カルボン酸(２−ブロモ−エチル)−アミド(実施例６０ａ)(７５mg)を、１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１４ｅ)(９８mg)のアセトニトリル(２mL)溶液に添加した。反応混合物を室温で１６時間撹拌した。さらに１０mgのピリジン−２−カルボン酸(２−ブロモ−エチル)−アミドを添加し、反応混合物を８時間撹拌した。揮発物を蒸発させ、残留物を０−１０％ＭｅＯＨ／ジクロロメタンで溶出するシリカゲルクロマトグラフィーで精製して、表題化合物(５５mg)を白色固体として得た。
m/e 476 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 9.12 (t, 1H), 8.64-8.62 (m, 1H), 8.05-7.97 (m, 2H), 7.61 (ddd, 1H), 7.32-7.25 (m, 4H), 7.22-7.15 (m, 1H), 5.02-4.96 (m, 1H), 3.88 (ddd, 1H), 3.71-3.55 (m, 2H), 3.49-3.27 (m, 5H), 3.22 (dt, 1H), 3.12-3.02 (m, 1H), 2.38-2.20 (m, 2H), 2.17-2.07 (m, 2H), 1.96-1.75 (m, 3H), 1.69-1.38 (m, 10H)。 Example 60: (R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- {2-[(pyridine-2-carbonyl) -amino] -ethyl} -1-azonia-bicyclo [2.2 .2] Octane bromide

Pyridine-2-carboxylic acid (2-bromo-ethyl) -amide (Example 60a) (75 mg) was converted to 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2]. Oct-3-yl) ester (Example 14e) (98 mg) was added to a solution of acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 16 hours. An additional 10 mg of pyridine-2-carboxylic acid (2-bromo-ethyl) -amide was added and the reaction mixture was stirred for 8 hours. Volatiles were evaporated and the residue was purified by silica gel chromatography eluting with 0-10% MeOH / dichloromethane to give the title compound (55 mg) as a white solid.
m / e 476 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 9.12 (t, 1H), 8.64-8.62 (m, 1H), 8.05-7.97 (m, 2H), 7.61 (ddd, 1H), 7.32-7.25 ( m, 4H), 7.22-7.15 (m, 1H), 5.02-4.96 (m, 1H), 3.88 (ddd, 1H), 3.71-3.55 (m, 2H), 3.49-3.27 (m, 5H), 3.22 ( dt, 1H), 3.12-3.02 (m, 1H), 2.38-2.20 (m, 2H), 2.17-2.07 (m, 2H), 1.96-1.75 (m, 3H), 1.69-1.38 (m, 10H).

３−ピリジン−４−イル−プロパン−１−オール(２.８８mL)の臭化水素酸(１６mL、１４１.４３mmol)溶液を、１３５℃で１８時間加熱還流した。冷却した溶液を真空下濃縮し、残留物をイソプロパノールに再溶解し、再濃縮した(この工程をさらに３回繰り返した)。残留物をイソプロパノールに溶解し、活性炭と沸騰させることにより脱色し、濾過し、透明溶液は冷凍庫に４８時間放置することにより結晶化した。得られた結晶を濾過により除去し、イソプロパノール／ジエチルエーテル(１：１)、続いてジエチルエーテルで洗浄し、次いで真空下、４０℃および室温で乾燥させて、副題化合物を薄褐色固体として得た(３.５５ｇ)。
¹H NMR (400 MHz, D₂O):δ 8.64 (d, 2H), 7.96 (d, 2H), 3.52 (t, 2H), 3.12 (t, 2H), 2.30 (quint., 2H)。 Example 61: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (3-pyridin-4-yl-propyl) -1-azonia-bicyclo [2.2.2] octane bromide a 4- (3-Bromo-propyl) -pyridine hydrobromide

A solution of 3-pyridin-4-yl-propan-1-ol (2.88 mL) in hydrobromic acid (16 mL, 141.43 mmol) was heated to reflux at 135 ° C. for 18 hours. The cooled solution was concentrated under vacuum and the residue was redissolved in isopropanol and reconcentrated (this process was repeated three more times). The residue was dissolved in isopropanol, decolorized by boiling with activated carbon, filtered, and the clear solution crystallized by leaving it in the freezer for 48 hours. The resulting crystals were removed by filtration and washed with isopropanol / diethyl ether (1: 1) followed by diethyl ether and then dried under vacuum at 40 ° C. and room temperature to give the subtitle compound as a light brown solid. (3.55 g).
¹ H NMR (400 MHz, D ₂ O): δ 8.64 (d, 2H), 7.96 (d, 2H), 3.52 (t, 2H), 3.12 (t, 2H), 2.30 (quint., 2H).

４−(３−ブロモ−プロピル)−ピリジンヒドロブロマイド(実施例６１ａ)(０.２１０ｇ)を、分液漏斗中のジエチルエーテル(１０mL)および水酸化ナトリウム溶液(４mL)(１０％)に添加し、混合物を振盪し、分離した。エーテル層を水(２×１０mL)で洗浄し、乾燥させ(ＭｇＳＯ_４)、蒸発させて、遊離塩基を油状物として得た。残留物に１−フェニル−シクロヘプタンカルボン酸(Ｒ)−(１−アザ−ビシクロ[２.２.２]オクト−３−イル)エステル(実施例１ｅ)(０.２４５ｇ)およびアセトニトリル(２mL)を添加し、２日間静置した。ジエチルエーテル(２０mL)の添加により油状物を得て、上清を傾捨し、残留物を酢酸エチル(２×２０mL)で洗浄した。油状物をジエチルエーテル(２０mL)との撹拌により固化し、固体を２回ジエチルエーテル(２×２０mL)で洗浄して、表題化合物を固体として得た(０.０９４ｇ)。
m/e 447 [M]^+
1H NMR (400 MHz, DMSO-D₆):δ 8.51 (d, 2H), 7.35 - 7.30 (m, 4H), 7.30 - 7.27 (m, 2H), 7.24 - 7.18 (m, 1H), 5.07 - 5.01 (m, 1H), 3.81 (ddd, 1H), 3.43 - 3.27 (m, 2H), 3.21 - 3.14 (m, 1H), 3.10 (d, 1H), 2.97 - 2.88 (m, 2H), 2.59 (t, 2H), 2.40 - 2.27 (m, 3H), 2.18 - 2.10 (m, 2H), 2.04 - 1.76 (m, 5H), 1.72 - 1.43 (m, 10H)。 Example 61: (R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (3-pyridin-4-yl-propyl) -1-azonia-bicyclo [2.2.2] octane bromide

4- (3-Bromo-propyl) -pyridine hydrobromide (Example 61a) (0.210 g) was added to diethyl ether (10 mL) and sodium hydroxide solution (4 mL) (10%) in a separatory funnel. The mixture was shaken and separated. The ether layer was washed with water (2 × 10 mL), dried (MgSO ₄ ) and evaporated to give the free base as an oil. To the residue was added 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo [2.2.2] oct-3-yl) ester (Example 1e) (0.245 g) and acetonitrile (2 mL). Was added and allowed to stand for 2 days. Addition of diethyl ether (20 mL) gave an oil, the supernatant was decanted and the residue was washed with ethyl acetate (2 × 20 mL). The oil solidified by stirring with diethyl ether (20 mL) and the solid was washed twice with diethyl ether (2 × 20 mL) to give the title compound as a solid (0.094 g).
m / e 447 [M] ^+
1 H NMR (400 MHz, DMSO-D ₆ ): δ 8.51 (d, 2H), 7.35-7.30 (m, 4H), 7.30-7.27 (m, 2H), 7.24-7.18 (m, 1H), 5.07- 5.01 (m, 1H), 3.81 (ddd, 1H), 3.43-3.27 (m, 2H), 3.21-3.14 (m, 1H), 3.10 (d, 1H), 2.97-2.88 (m, 2H), 2.59 ( t, 2H), 2.40-2.27 (m, 3H), 2.18-2.10 (m, 2H), 2.04-1.76 (m, 5H), 1.72-1.43 (m, 10H).

Pharmacological analysis
M3 affinity for _{M 3} receptor receptor activity assay compound _{(pIC 50),} scintillation proximity assay (SPA) format, CHO-K1 (Chinese expressing human muscarinic acetylcholine _{M 3} receptor _(M 3 -ACh) It was determined by competitive binding of [ ³ H] N-methylscopolamine (NMS) to the hamster ovary) cell membrane.
SPA beads were precoated with membranes, then serial dilutions of compounds of the invention in 2 mg beads / well, 0.2 nM [ ³ H] NMS, half Kd (experimentally determined dissociation constant) and assay buffer (5 mM). MgCl ₂ containing 20 mM HEPES pH 7.4) and incubated. The assay was performed in a final volume of 200 μL in the presence of 1% (v / v) dimethyl sulfoxide (DMSO). ^{[3 H]} The total binding of NMS, determined in the absence competing compounds was determined in the presence of 1μM atropine non-specific binding of ^{[3 H]} NMS. Plates were incubated for 16 hours at room temperature and then read on the Wallac Microbeta ^™ using a normalized ³ H protocol. The pIC ₅₀ , defined as the negative logarithm of the concentration of compound required for 50% reduction in specific [ ³ H] -NMS binding, was determined. Table 1 shows the pIC ₅₀ values for some representative examples.

Ｍ３結合ＩＣ_５０ ＜２nM “＋＋＋”；ＩＣ_５０ ２−１０nM “＋＋”；ＩＣ_５０ ＞１０nM “＋”；ＮＴ − 試験せず。 Table 2 lists the IC ₅₀ intensities of the example compounds.

M3 binding _{IC 50 <2nM "+++";} IC 50 2-10nM "++"; IC 50> 10nM "+"; NT - not tested.

Measurement of plasma protein binding The extent of plasma protein binding was determined by equilibrium dialysis of the compound at 37 ° C. between human plasma and aqueous buffer and determination of the concentration of the compound in plasma and buffer by HPLC-MS / MS. ,Were determined.

Method A dialysis cell (molecular weight cut-off 5000) was prepared by rinsing with water followed by immersion in dialysis buffer for a minimum of 1 hour. The dialysis buffer was isotonic buffered saline pH 7.4. A stock solution of the compound in dimethyl sulfoxide was prepared at a concentration of 0.5 mM. Frozen pooled human plasma was obtained from volunteers.
Stock solution of compound in DMSO was added to plasma at a ratio of 10 μl DMSO per ml of plasma. This resulted in 1% DMSO in plasma solution containing each compound at a concentration of 5 μM.
A dialysis cell was then prepared, half of the cell was filled with 750 μl of dialysis buffer and the other half of the cell was filled with 750 μl of a plasma solution of the compound. Once ready, the cell was sealed and placed in a 37 ° C. incubator box. The cells were then rotated for a minimum of 4 hours to equilibrate.

After equilibration, a 500 μl buffer sample is taken and added to the HPLC vial with 100 μl plasma (sample in 6-fold diluted plasma), and 100 μl plasma sample is taken and 500 μl dialysis buffer (6-fold diluted plasma) in the HPLC vial. Middle sample).
Samples were then analyzed using HPLC-MS / MS. A four-point calibration curve was obtained at concentrations of 0.013 μM, 0.05 μM, 0.25 μM and 1.25 μM by diluting a 6-fold diluted plasma stock solution, which in this order followed by the buffer sample And then infused with plasma samples.

Calculation The compound concentration in the sample was determined using a calibration curve and MassLynx version 4.1 software (manufactured by Waters / Micromass) which automatically calculates the concentration of the compound in the cell. Plasma protein binding was determined as the percentage of compound that bound to human plasma (% binding) using the following formula:

Table 3 shows the measured human plasma protein binding values using the methods described above for some representative example compounds.

Metacholine-induced bronchoconstriction in vivo
Dunkin-Hartley guinea pigs (300-600 g) were procured from designated breeding tissues. Animals were administered either test compound or vehicle by inhalation into conscious guinea pigs or by intratracheal infusion (0.5 ml / kg) under recoverable gas anesthesia (5% halothane). The animals were allowed to recover from anesthesia before measuring bronchoconstriction. By 48 hours after dosing, guinea pigs were final anesthetized with sodium pentobarbital (60 mg / kg), the trachea was cannulated for artificial ventilation, and the jugular vein was cannulated for intravenous administration of methacholine. Guinea pigs were ventilated during surgery using a constant volume respiratory pump (Harvard Rodent Ventilator model 683) with a tidal volume of 5 ml / kg at a rate of 60 breaths / minute. Lung function (pulmonary resistance and compliance) was measured in anesthetized and ventilated guinea pigs using a pulmonary measurement Flexivent system (SCIREQ, Montreal, Canada) connected to a tracheal cannula. The animals were ventilated (quasi-sinusoidal ventilation pattern) and ventilated at a tidal volume of 5 ml / kg at a rate of 60 breaths / minute. A positive and expiratory pressure of 2-3 cmH ₂ O was applied. Respiratory resistance was measured using a Flexivent “snapshot” facility (1 second, 1 Hz frequency). Lung resistance and compliance were measured before and after intravenous administration of methacholine (3, 10 and 30 ug / kg). The peak increase in resistance after methacholine challenge was calculated and the effect of the test compound on methacholine-induced lung function conversion was calculated.
The percent inhibition of bronchoconstriction was calculated for each methacholine as follows:

Inhibition of pilocarpine-induced saliva by administered compounds.
Guinea pigs (450-550 g) were procured from Harlan UK or David Hall, Staffs UK and acclimated to in-house equipment for a minimum of 3 days prior to use. Guinea pigs were randomly divided into treatment groups and weighed. Each animal was lightly anesthetized (4% halothane) and compound or vehicle (0.5 ml / kg) was administered intranasally up to 24 hours prior to pilocarpine challenge. At the time of testing, guinea pigs were final anesthetized with urethane (25% solution in H ₂ O, 1.5 g / kg). When fully anaesthetized (pinch toes and no reflexes), each animal is placed with an absorbent pad in the mouth for 5 minutes to dry the remaining saliva, this pad is removed and a new pre-weighed pad 5 In a minute, a basal saliva production reading was established. At the end of this 5 minute period, the pad was removed and weighed. A new pre-weighed pad was placed in the oral cavity, after which each animal was given sc pilocarpine subcutaneously on the back of the neck (0.6 mg / kg @ 2 ml / kg). Every 5 minutes up to 15 minutes, the pad was removed and weighed and replaced with a new pre-weighed pad.

For saliva production, the weight of the pre-weighed pad was subtracted from the weight after weighing for each 5 minute period, and this value was added to obtain the accumulated amount of saliva over 15 minutes. Each 5 minute period could be analyzed in addition to the total 15 minute recording period. Assuming that the basal production of saliva is constant, it was tripled to obtain a 15 minute basal saliva production reading.
Inhibition of saliva production by this compound could be calculated using the following formula:
(1- (Test-Base) / (Medium-Base)) * 100.

Claims (8)

A compound selected from the group consisting of:
(R) -1-[(6-Methyl-pyridin-3-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -1-[(6-Methyl-pyrazin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1-[(6-trifluoromethyl-pyridazin-3-ylcarbamoyl) -methyl] -1-azonia-bicyclo [2.2.2] Octane X;
(R) -1- (benzo [d] isoxazol-3-ylcarbamoylmethyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1- (pyridazin-3-ylcarbamoylmethyl) -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(5-Methyl-isoxazol-3-ylcarbamoyl) -methyl] -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane X;
(R) -1-[(3-Methyl-isoxazol-5-ylcarbamoyl) -methyl] -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane X;
(R) -1-[(3-Fluoro-phenylcarbamoyl) -methyl] -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -1-[(5-Methyl-pyrazin-2-ylcarbamoyl) -methyl] -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2. 2] Octane X;
(R) -1- (Benzo [d] isoxazol-3-ylcarbamoylmethyl) -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1- (pyrazin-2-ylcarbamoylmethyl) -3- (1-thiophen-2-yl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -3- [1- (3-Fluoro-phenyl) -cycloheptanecarbonyloxy] -1- (pyrazin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -3- [1- (3-Fluoro-phenyl) -cycloheptanecarbonyloxy] -1- (isoxazol-3-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyridin-4-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(5-Fluoro-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -1-[(5-Methyl-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyridin-3-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(2-Methyl-pyridin-4-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -1-phenylcarbamoylmethyl-3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyrimidin-4-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(2-fluoro-phenylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(2,3-difluoro-phenylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1- [2- (2,3-Dihydro-benzofuran-5-yl) -ethyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2 ] Octane X;
(R) -1- [2- (4-Fluoro-phenoxy) -ethyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyridazin-4-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(5-Fluoro-pyridin-3-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- [2- (pyridin-3-yloxy) -ethyl] -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(6-Methyl-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (o-tolylcarbamoyl-methyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (2-pyrazin-2-yl-ethyl) -1-azonia-bicyclo [2.2.2] octane X;
(S) -1- (3-phenoxy-propyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-{[2- (3-Fluoro-phenoxy) -ethylcarbamoyl] -methyl} -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] Octane X;
(R) -1-[(3,5-difluoro-phenylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1- [2- (4-Methoxy-benzyloxy) -ethyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1- (2-phenethyloxy-ethyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(2,6-difluoro-phenylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(methyl-phenyl-carbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1- [3- (4-Cyano-phenoxy) -propyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(2,5-difluoro-phenylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1- [2- (4-cyano-benzyloxy) -ethyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1-[(6-trifluoromethyl-pyridin-2-ylcarbamoyl) -methyl] -1-azonia-bicyclo [2.2.2] Octane X;
(R) -1-[(4-Methyl-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -1-[(5-Chloro-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (p-tolylcarbamoyl-methyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (m-tolylcarbamoyl-methyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1- (oxazol-2-ylcarbamoylmethyl) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(6-Methyl-pyridazin-3-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyrimidin-2-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(5-Cyano-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (pyrimidin-5-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(3-Fluoro-pyridin-2-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -1-[(3-Fluoro-pyridin-4-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- {2-[(pyrazine-2-carbonyl) -amino] -ethyl} -1-azonia-bicyclo [2.2.2] octane X;
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1-([1,2,4] thiadiazol-5-ylcarbamoylmethyl) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- {3-[(pyridine-2-carbonyl) -amino] -propyl} -1-azonia-bicyclo [2.2.2] octane X;
(R) -1-[(2-Methyl-pyrimidin-4-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -1-[(6-Methyl-pyrimidin-4-ylcarbamoyl) -methyl] -3- (1-phenyl-cycloheptanecarbonyloxy) -1-azonia-bicyclo [2.2.2] octane X ;
(R) -3- (1-Phenyl-cycloheptanecarbonyloxy) -1- {2-[(pyridine-2-carbonyl) -amino] -ethyl} -1-azonia-bicyclo [2.2.2] octane X; and
(R) -3- (1-phenyl-cycloheptanecarbonyloxy) -1- (3-pyridin-4-yl-propyl) -1-azonia-bicyclo [2.2.2] octane X;
(Wherein X is a pharmaceutically acceptable anion of a monovalent or polyvalent acid). 2. The compound of claim 1 selected from the group consisting of:

(Wherein X is a pharmaceutically acceptable anion of a monovalent or polyvalent acid).   A pharmaceutical composition comprising a compound according to claim 1 or 2 together with a pharmaceutically acceptable adjuvant, diluent or carrier.   A method for producing a pharmaceutical composition according to claim 3, comprising mixing the compound according to claim 1 or 2 with a pharmaceutically acceptable adjuvant, diluent or carrier.   3. A compound according to claim 1 or 2 for use in therapy.   Use of a compound according to claim 1 or 2 in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease.   A method of treating chronic obstructive pulmonary disease in a warm-blooded animal, such as a human, comprising administering to a mammal in need of such treatment an effective amount of a compound according to claim 1 or 2. A first active ingredient which is a compound according to claim 1 or 2, and:-
Phosphodiesterase inhibitors,
Β2 adrenergic receptor agonist,
A modulator of chemokine receptor function,
An inhibitor of kinase function,
Protease inhibitors,
A pharmaceutical comprising, in combination, a steroidal glucocorticoid receptor agonist, and at least one further active ingredient selected from non-steroidal glucocorticoid receptor agonists.

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