WO1996030372A1 - Diazabicyclo[3.3.1]nonane derivatives and intermediates thereof, medicinal use of the same, and processes for producing the same - Google Patents

Diazabicyclo[3.3.1]nonane derivatives and intermediates thereof, medicinal use of the same, and processes for producing the same

Info

Publication number
WO1996030372A1
WO1996030372A1 PCT/JP1996/000742 JP9600742W WO9630372A1 WO 1996030372 A1 WO1996030372 A1 WO 1996030372A1 JP 9600742 W JP9600742 W JP 9600742W WO 9630372 A1 WO9630372 A1 WO 9630372A1
Authority
WO
Grant status
Application
Patent type
Prior art keywords
group
acid
nonane
jiazabishikuro
carboxylic
Prior art date
Application number
PCT/JP1996/000742
Other languages
French (fr)
Japanese (ja)
Inventor
Koji Kobayashi
Kazuhiro Orita
Atsushi Hamada
Takashi Inaba
Hiroyuki Abe
Susumu Miyazaki
Original Assignee
Japan Tobacco Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08Bridged systems

Abstract

Diazabicyclo[3.3.1]nonane derivatives represented by general formula (1), wherein R represents -CONH-(CHR1)m-R2 (wherein R1 represents hydrogen or alkyl; m is 0, 1 or 2; and R2 represents optionally substituted aryl, optionally substituted heterocycle, optionally substituted cycloalkyl, alkyl or alkyenyl) or -CO-R3 [wherein R3 represents alkyl, aralkyloxy or -NR4R5 {wherein R?4 and R5¿ are the same or different and each represents alkyl, or R?4 and R5¿ together with the nitrogen atom to which they are bonded from a group (a) (wherein n is 2 or 3)}]; interm ediates thereof; and a nicotinic cholinergic agent containing the diazabicyclo[3.3.1]nonane derivatives. The compounds have a nicotinic cholinergic effect and a dopamine-releasing effect and are usable as a remeddy for dementia such as Alzheimer's disease, a drug for relieving memory disorders, a remedy for central nerve degeneration diseases, and a drug for relieving cerebral function disorders.

Description

Akira pongee 謇

Jiazabishikuro [3.3.1] nonane derivatives, processes for their intermediates, pharmaceutical use thereof and their preparation

Technical field

The present invention relates to new useful Jiazabishikuro [3.3.1] nonane derivatives as nicotinic cholinergic agonists, the derivative dementia therapeutic agents, such as Alzheimer's disease, memory disorder improving agent, central neurodegenerative diseases agent, is take advantage as cerebral function disorder improving agent. The present invention, said Jiazabinkuro [3.3.1] novel intermediates for the production of nonane derivatives, process for the preparation of preparation and Jiazabishikuro [3.3.1] nonane derivatives of the intermediates.

BACKGROUND

For recent years the elderly, dementia and Parkinson's disease is a major health problem. In particular, Alzheimer's disease is the most treatment in dementia are said to be difficult. According to the report of the US National aging Institute (The National Institute of Aging), more than half of the senile dementia patients in the United States are Alzheimer's disease, also 8 4 0% of the 5 years of age or older population is Alzheimer's disease It rests on.

Mechanisms of brain function deterioration of dementia as typified by Alzheimer's disease, still whole picture is not bright, et al. KaniNatsu. However, some patients with dementia, especially in the brain after death of patients with Alzheimer's disease, the function of cholinergic neurons projecting from the basal ganglia region to the cerebral cortex and hippocampus has been reported to be significantly reduced [ Bigi et. ah. Brain

Cholinergic Systems .. Oxford University Press. 364-386. (1990)]. Conoco and power, et al, for the treatment of dementia, cholinergic agents, acetylcholinesterase inhibitors, choline § acetyltransferase 陚活 drugs are considered to be promising.

Dementia therapeutic agents have been studied on the basis of the pathogenesis is mainly Asechiruko cholinesterase inhibitor [JP-5- 1 9 4 38 7 JP, Hei 6 5 0 0 7 9 4 JP, JP 6 - 1 1 6 2 37 No.] and cholinergic agonists [Patent 2 - 72 1 7 9 JP, Hei 3 - 27 3 77 JP, Hei 3 - 8 6 8 8 3 No.] it is. For these cholinergic drugs, because a large part of the brain 內 acetylcholine receptor is a Mus force phosphoric like, Mus force phosphorus cholinergic drugs have been studied mainly. On the other hand, Parkinson's disease, the substantia nigra - striatum Doha 'Mi emissions nerve path is denatured Dobamin content is believed to be due to the abnormally lowered. Therefore, the treatment of Parkinson's disease, or to activate Dopami down action of reduced or relatively dominant and method for inhibiting cholinergic has decreased have been taken.

However, in Alzheimer's disease patients and brains of Parkinson's patients, whereas no change number of Mus Chikarari down like Asechirukorin receptors, the number of nicotinic Asechiruko Li down receptors are reported to be significantly reduced [ .. Shimohama et al .. J. Neurochem .. Vol 46. 288-293, (1986):.. Whitehouse et al .. Neurol .. Vol 38. 720. (1988)], of the nicotinic acetylcholine receptor the relationship between the change and central neurodegenerative sputum 患発 disease has been attracting attention.

Having a nicotine excellent cognitive function improving effects or central neurodegenerative inhibitory effect, the nicotine contained in 堙中 tobacco promote cognitive function in animal models [Levin et. And a, Behav. Neurol. Biol. , Vol. 53, 269. (1990)], in a pilot study of patients with Alzheimer's disease, to improve nicotine cognitive function that was damaged [Sahakian et. al .. Brit. J. Psych .. . Vol 154. 797. (1989):... Newhouse P. et al .. Psychopharmacol Vol 95. 171, (1988)], that the incidence of § Rutsuhaima one's disease and Parkinson's disease is lower in smokers [van Duijin .. et al .. BMJ Vol 302. 1491-1494 (1991):..... Baron JA NEUROLOGY Vol 36. 1490-1496, (1986)], nicotine rat substantia nigra Dopami down operating neuropathy model ... Uanson et possible to suppress the neurodegenerative al .. Prog Brain Res .. Vol 79. 257, (1989):... 0 誦 an, et and a, Prog Brain Res .. Vol 79. 267. you to understand from the (1989)] . More interestingly, the number of when Renju administration of nicotine to an animal brain nicotinic acetylcholine receptor is increased [Marks et. Al .. J. Pharmacol. Exp. T erap .. Vol. 235. 619- 628. (1985)] have been reported.

Recently, nicotinic cholinergic drugs brain function improving drug, it has been studied as a central neurodegenerative diseases by [Kohyo 6 5 0 8 1 4 3 No., Arneric et. Al .. J.

.. Pharmacol Exp Therap .. Vol 270. 310-318 (1994);....... Decker et al, J. Pharmacol Exp Therap .. Vol 270. 319-328, (1994)]. However, the decrease in body temperature Many of these nicotine cholinergic drugs, sedation, increased blood pressure, for both the action to Oko diarrhea and pull, a living body to exert undesirable side effects [Benowitz et. Al .. Nicotine Psychopharmacology, Oxford University Press. 112-157, (1990) ] o

Disclosure of the Invention

The present inventors have view of the above problems, act selectively on the central nervous, conducted intensive studies in order to explore the side effects are not a brain function improving agent to the peripheral nerves. As a result, have high nicotinic cholinergic receptor binding, yet fewer side effects to the peripheral nerves, and Dopami Jiazabishikuro [3.3.1] having both a down releasing action found nonane derivatives, to complete the present invention It led to. The present invention also provides intermediates useful for the production of Jiazabishikuro [3.3.1] nonane derivatives. Furthermore, the present invention provides a method for producing a Jiazabishikuro [3.3.1] nonane derivative conductor of the present invention using manufacturing methods intermediates, and the intermediate body.

Incidentally, Jiazabishikuro [3.3.1] Examples of the compound having nonane skeleton, the following equation as antiarrhythmics if example embodiment

In compounds and the like are known as shown [US 5 1 1 0 933 Pat]. Substituent in the visible which N-position and is different from the Jiazabinkuro [3.3.1] nonane derivatives of the present invention.

The present invention relates to novel Jiazabishikuro [3.3.1] nonane derivatives and intermediates thereof, Jiazabinkuro [3.3.1] nicotinic cholinergic agonist containing nonane derivatives, intermediates preparation and Jiazabinkuro [3.3 . 1] relates to the method of manufacturing nonane derivatives. Good 0 For more information, is as shown in to the following (1) to (2 8). (1) the general formula [1]

[1]

Wherein, R represents one C0NH - (CHR 1) B - R 2 ( wherein, R 'represents a hydrogen atom or a § alkyl group, m represents 0, 1 or 2, R 2 is substituted good Ariru group, an optionally substituted heterocyclic瓚基,匱換which may be a cycloalkyl group, an alkyl group or an alkenyl group.) or single CO- R 3 (wherein, R 3 is an alkyl group, Araru Kiruokishi group or - NR 4 R 5 (wherein, R * and R 5 are the same or different represent a alkyl Le group, the formula becomes the nitrogen atom and over锗which R 4 and R 5 are adjacent

-N Roh H \ (CH 2) n

H /

(N represents. 2 or 3) to form a group represented by. ) Represents the. ) Represents the. Acceptable Jiazabishikuro [3.3.1] nonane derivative or a pharmacologically represented by]

(2) R gar CONH- (CHR 1) m one R 2 (wherein, R 1, m and R 2 are the same as before Symbol (1).) Jiazabinkuro [3 the (1). 3.1] nonane derivative or pharmacologically acceptable salt thereof.

(3) Jiazabinkuro [3.3.1] non-emission derivative or pharmacologically acceptable salt thereof, wherein R 1 is a hydrogen atom (2).

(4) Jiazabishikuro [3.3.1] nonane derivatives or a pharmaceutically acceptable salt thereof medicine management of the R 2 is an optionally substituted Ariru group or an optionally substituted cycloalkyl Le group (3).

(5) 2-Okiso one 3, 7 - Jiazabishikuro [3-3.1] nonane one 3-Cal Bonn benzyl Ryomi de, 3- [(S) one 1 one-phenylene Rue Ji carbamoyl] - 3, 7 - Jiazabishikuro [3.3.1] nonan one-2-one,

3- [(R) - 1 one-phenylene Rue Chi carbamoyl] 3. 7 Jiazabishikuro [3.3.1] nonan one-2-one,

2 - Okiso one 3, 7 - Jiazabinkuro 3.3.1 nonane one 3 - carboxylic acid i (1 one-naphthyl) § Mi de,

2 Okitsu 3,7 Jiazabishikuro 3.3.1 nonane one 3-force carboxylic acid Feniruami de,

2 Okiso one 3, 7-Jiazabishikuro 3.3.1 nonane one 3-force carboxylic monobasic (2 main Tokishifuweniru) § Mi de,

2 Okifu 3,7 Jiazabishikuro 3.3.1 nonane one 3 - carboxylic acid i (3 main Tokishifue sulfonyl) amino-de,

2 - Okiso one 3, 7-Jiazabishikuro 3.3.1 nonane one three to force carboxylic monobasic (4-menu Tokishifueniru) § Mi de,

2 Okiso one 3, 7 - Jiazabishikuro 3.3.1 nonane one 3-force carboxylic acid Mechiruami de,

2 Okifu 3 - Jiazabinkuro 3.3.1 nonane one 3-force carboxylic acid Echiruami de,

2 Okifu 3 - Jiazabinkuro 3.3.1 nonane one 3 - carboxylic acid

- tert Buchiruami de,

2 Okiso one 3, 7 - Jiazabinkuro 3.3.1 nonane one 3-force carboxylic monobasic Ibb port Piruami de,

2 Okitsu 3,7 Jiazabinkuro 3.3.1 nonane one 3-force carboxylic monobasic (4 one black port benzyl) amino-de,

2 - Okiso one 3, 7 - Jiazabishikuro 3.3.1 nonane one 3-force carboxylic monobasic (3 black port benzyl) amino-de,

2 Okiso one 3, 7 - Jiazabinkuro 3.3.1 nonane one 3-force carboxylic acid - (2-black port benzyl) § Mi de,

2 Okitsu 3,7 Jiazabishikuro [3.3.1] nonane one three to force carboxylic acid

- (4 - Furuorobenjiru) § Mi de,

2 - Okiso 3, 7 - Jiazabishikuro [3.3.1] nonane one-3-carboxylic acid

- (3-Furuorobenjiru) Ami de,

2 Okiso one 3,7 Jiazabishikuro [3 3.1] nonane one 3-force carboxylic acid

- (2-Furuorobenjiru) Ami de,

2 - Okiso one 3,7 Jiazabinkuro [3 3.1] nonane one 3-force carboxylic acid (4-menu Tokishibenjiru) § Mi de,

2 Okiso one 3,7 Jiazabishikuro [3 3.1] nonane one 3-force carboxylic acid (3-main Tokishibenjiru) § Mi de,

2 Okifu 3,7 Jiazabishikuro [3 3 1] nonane 3 Ichiriki carboxylic acid (2-menu Tokishibenjiru) § Mi de,

2 Okitsu 3,7 Jiazabishikuro [3 3 1] nonane 3 Ichiriki carboxylic acid (3, 4-dimethyl Tokishibenjiru) ami de,

2 - Okiso one 3,7 Jiazabishikuro [3 3 1] nonane one-3-carboxylic acid (3, 4, 5 Application Benefits main Tokishibenjiru) ami de,

2 - Okitsu 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid (3, 4-methylenedioxy O alkoxybenzylacetic) ami de,

2 Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid C4 - (Benjiruokishi) benzyl] amino-de,

2 Okitsu 3,7 Jiazabishikuro [3.3.1] nonane 3 Ichiriki carboxylic acid [3, 4-di (Benjiruokishi) benzyl] amino bets "

2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane-3-carboxylic acid (4 one Benjiruokishi 3 main Tokishibenjiru) ami de,

2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid (3-chloro-4-menu Tokishibenjiru) Ami de, 2- Okiso one 3, 7-Jiazabinkuro 3.3.1 nonane one 3-force carboxylic acid '(3-Furuoro 4-menu Tokishibenjizo :) ami de,

2 Okiso one 3, 7-Jiazabishikuro 3.3.1 nonane one 3-force carboxylic acid (2-methylbenzyl) § Mi de,

2 Okiso one 3, 7-Jiazabishikuro 3.3.1 nonane one 3-force carboxylic acid (3 one methylbenzyl) § Mi de,

2 Okitsu 3,7 Jiazabishikuro 3.3.1 nonane one 3-force carboxylic acid (4 one-methylbenzyl) § Mi de,

2 Okiso one 3, 7-Jiazabinkuro 3.3.1 nonane one 3-force carboxylic acid (2-triflate Ruo b methylbenzyl) § Mi de ,,

2 Okiso one 3, 7-Jiazabishikuro 3.3.1 nonane one-3-carboxylic acid (3-triflate Ruo b methylbenzyl) § Mi bets "

2 Okiso one 3, 7-Jiazabinkuro 3.3.1 nonane one-3-carboxylic acid (4 one triflate Ruo b methylbenzyl) § Mi Bok ',,

2 Okiso one 3, 7-Jiazabishikuro 3.3.3 nonane one 3-carboxylic acid (4-dimethylamino § amino benzyl) amino-de

2 - Okiso one 3, 7-Jiazabishikuro 3.3.1 nonane one-3-carboxylic acid (4 one ethoxy Kin benzyl) amino-de,

2 - Okiso one 3, 7-Jiazabishikuro 3.3.1 nonane one 3-carboxylic acid Π- phenylalanine benzyl) amino-de,

2 - Okiso one 3, 7-Jiazabinkuro 3.3.1 nonane one-3-carboxylic acid (3, 4 Jikuro port benzyl) amino-de,

2 Okiso one 3, 7-Jiazabishikuro 3.3.1 nonane one 3-force carboxylic acid (2-thienyl) Mechiruami de,

2 - Okiso one 3, 7-Jiazabishikuro 3.3.1 nonane one-3-carboxylic acid (pyridin-one 3-Irumechiru) amino de

2 - Okiso one 3, 7-Jiazabinkuro 3.3.1 nonane one 3-force carboxylic acid - (pyridin one 4 Irumechiru) Ami de,

2 Okiso one 3,7 Jiazabinkuro [3.3.1 nonane one 3-force carboxylic acid

- (naphthalen one 2-Irumechiru) amino-de,

2 - Okitsu 3, 7 - Jiazabishikuro [3.3.1 nonane one 3-force carboxylic acid

- (2-naphthyl) Ami de,

2 Okiso one 3,7 Jiazabishikuro [3.3.1 nonane one-3-carboxylic acid

- (naphthalen one 1 Irumechiru) § Mi de,

2 Okifu 3,7 Jiazabishikuro [3.3.1 nonane one 3-force carboxylic acid

'Fuenechiruami de,

2 Okiso - 3,7 Jiazabishikuro [3.3.1 nonane one 3-force carboxylic acid (2-menu Tokishifuenechiru) § Mi de,

2 Okiso one 3,7 Jiazabishikuro [3.3.1 nonane one 3-force carboxylic acid (3-main Tokishifuenechiru) § Mi de,

2 Okiso one 3,7 Jiazabishikuro [3.3.1 nonane one 3-force carboxylic acid (4-menu Tokishifu Nechiru) § Mi de,

2 Okiso one 3,7 Jiazabinkuro [3.3.1 nonane - 3-force carboxylic acid Puropirua Mi de,

2 Okiso - 3,7 Jiazabishikuro [3.3.1 nonane one 3-carboxylic acid cycloprothrin building § Mi de,

2 Okiso one 3,7 Jiazabishikuro [3.3.1 nonane one 3-force carboxylic acid Isobuchiruami de,

2 Okiso one 3, 7 - Jiazabinkuro [3.3.1 nonane one 3-force carboxylic acid Shikurobu port Pirumechiruami de,

2 Okiso one 3,7 Jiazabishikuro [3.3.1 nonane one 3-force carboxylic acid (2-Mechiruburo Bae sulfonyl) amino-de,

2 - Okiso one 3,7 Jiazabishikuro [3.3.1 nonane one 3-force carboxylic acid Shikurobuchiruami de, 2- Okiso one 3,7 Jiazabishikuro [3 3.1] nonane one 3-force carboxylic acid over cyclopentyl Rua Mi de,

2 Okiso one 3, 7 - Jiazabinkuro [3 3.1] nonane one 3-force carboxylic monobasic cycloheteroalkyl Kishiruami de,

2 Okiso one 3,7 Jiazabishikuro [3 3.1] nonane one 3-force carboxylic monobasic (2, 2, 3, 3-tetramethyl cyclopropyl blanking opening pill) ami de,

2 - Okiso one 3,7 Jiazabishikuro [3. 3. I] nonane one 3-force carboxylic acid Shikuro hexyl methyl ami de,

2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid - cyclopentylmethyl Ami de,

2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (4-hydroxycarboxylic benzyl) amino-de,

2 - Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (3, 4-dihydroxy-benzyl) ami de,

2 Okitsu 3, 7 - Jiazabinkuro [3.3.1] nonane one 3-force carboxylic monobasic (4-arsenide Dorokishi 3 main Tokishibenjiru) ami de,

3- (N, N-dimethylcarbamoyl) one 3,7-Jiazabishikuro [3.3.1] nonan one-2-one,

3- (Biperijin one 1 one carbonyl) one 3,7-Jiazabishikuro [3.3.1] nonan one-2-one,

3 Asechiru 3, 7 - Jiazabishikuro [3.3.1] nonan one-2-one, 3 _ Bibaroiru 3,7 Jiazabishikuro [3.3.1] nonane one 2 - one, 3- base Nji Ruo propoxycarbonyl two Lou 3, 7-Jiazabinkuro [3.3.1] non Hmm-2-one,

(1 R, 5 S) - (+) - 2- Okiso one 3,7 Jiazabinkuro [3.3.1] nonane one 3-force carboxylic acid over cyclopentyl Rua Mi de,

(1 S, 5 R) - (I) one 2- Okiso one 3,7 Jiazabinkuro [3.3.1] nonane one 3-force carboxylic acid over cyclopentyl ami de,

(1 R, 5 S) - (+) - 2- Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (3, 4-dimethyl Tokishibenjiru) ami de,

(1 S, 5 R) - (-) one 2- Okiso one 3. 7- Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (3, 4-dimethyl Tokishibenjiru) § Mi de,

(1 R, 5 S) - (+) - 2- Okiso one 3,7 Jiazabinkuro [3.3.1] nonane one 3-force carboxylic monobasic (4-menu Tokishibenjiru) § Mi de,

(1 S, 5 R) - (I) one 2- Okiso one 3. 7- Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (4-menu Tokishibenjiru) Y Mi de,

(1 R, 5 S) - (+) - 2- Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3 - carboxylic acid i (3-chloro-4-menu Tokishibenjiru) § Mi de, and

(1 R, 5 S) - (+) - 2- Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (3 Furuo port one 4 - Main Tokishibenjiru) § Mi selected from the group consisting of de (1) according Jiazabinkuro [3.3.1] nonane-induced, or pharmacologically acceptable salts thereof.

(6) the (1) to (5) Jiazabishikuro either in the Ki戴 of [3.3.1] nonane derivatives or medicament containing a pharmacologically acceptable salt thereof.

(7) Jiazabishikuro according to any one of (1) to (5) [3.3.

1] nonane derivative or pharmaceutical composition comprising a free and a pharmacologically acceptable salt thereof and a pharmaceutically acceptable carrier.

(8) Jiazabishikuro according to any one of (1) to (5) [3.3.

1] nonane derivative or nicotinic cholinergic agonist comprising a pharmacologically acceptable salt thereof.

(9) Jiazabishikuro according to any one of (1) to (5) [3.3.

1] nonane derivative or pharmaceutical composition for central nervous disorders treatment with concentrated phosphoric action decreases in brain cell, comprising a pharmacologically acceptable salt thereof. (1 0) (1) to Jiazabishikuro according to any one of (5) [3.3.1] central nervous disorders treatment by Dobami down action decrease comprising nonane derivative or a pharmacologically acceptable salt thereof the pharmaceutical composition for.

(1 1) the Jiazabinkuro [3.3.1] nonane derivatives or central neurodegenerative disease therapeutic agent comprising a pharmacologically acceptable salt thereof according to any one of (1) to (5).

(1 2) wherein Jiazabishikuro [3.3.1] nonane derivatives or dementia therapeutic agent comprising a pharmacologically acceptable salt thereof according to any one of (1) to (5).

(1 3) the Jiazabishikuro [3.3.1] nonane derivatives or cerebral function disorder improving agent comprising a pharmacologically acceptable salt thereof according to any one of (1) to (5).

(1) Jiazabishikuro according to any one of (1) to (5) [3.3.1] nonane derivatives or Parkinson's disease Osamu 療剤 comprising a pharmacologically acceptable salt thereof.

(1 5) the Jiazabishikuro [3.3.1] nonane derivatives or memory disorder improving agent comprising a pharmacologically acceptable salt thereof according to any one of (1) to (5).

(1 6) Jiazabishikuro with nicotinic choline action [3.3.1] nonane derivatives or a medicament for central nervous disorders treatment by cholinergic low down in the brain cell, comprising a pharmacologically acceptable salt thereof Composition.

(1 7; Jiazabishikuro having Dopami emissions release effect [3.3.1] nonane-induced, or a pharmaceutical composition for central nervous disorders treatment by Dobamin effect reduction comprising a pharmacologically acceptable salt thereof.

(1 8) - general formula [1 1]

Wherein, P is an Amino protecting group. Jiazabishikuro [3.3.1] nonane derivatives or salts thereof represented by]. (1 9) formula, characterized in that it comprises the following steps [3 3]

(Wherein, Bn represents a benzyl group.) Represented by (1 R, 5 S) - 7 one base Njiru one 3,7 Jiazabishikuro [3.3.1] nonane - 2 - one method of manufacturing.

(A) a compound of the formula [2 7]

In the 5-bromo-nicotinic acid represented subjected to esterification reaction, the following formula [28]

(Wherein, R 6 represents. Alkyl group) to an ester compound represented by

(B) subjected to the ester compound to the nitrile reaction, the following formula [2 9]

(Wherein, R 6 represents an alkyl group.) And nicotinic acid ester compound represented by, (c) the presence of the nicotinic acid ester compound having an acid, and subjected to catalytic hydrogenation reaction, the following formula [3 0 ]

(Wherein, represents an alkyl group.) And piperidine compounds represented by, (d) Konopipe subjected lysine compound in ring closure reaction of the following formula [3 by further base Njiruharai de and reaction 2]

(Wherein, B n represents a benzyl group.) And Jiazabishikuro [3.3.1] nonane compounds represented by,

(E) the Jiazabinkuro [3.3.1] nonane compound, by optical resolution by Jiasutereoma IchiAkira Oriho of Ru with an optically active acid, the following formula [3

(Wherein the beta eta represents a benzyl group.) Represented by (1 R, 5 S) - 7 one base Njiru one 3, to obtain a 7- Jiazabinkuro [3.3.1] nonan one 2-one.

(2 0) Equation [3 3, characterized in that it comprises the following steps]

(Wherein the beta eta represents a benzyl group.) Represented by (1 R, 5 S) - 7-base Njiru - 3,7 Jiazabishikuro [3.3.1] nonan one 2-one method of manufacturing.

(A) Formula [2 7 '] In nicotinic acid represented the following formula [2 8] [2 8〗

(Wherein, R e represents. Alkyl group) to an ester compound represented by

(B) subjected to the ester compound to the nitrile reaction, the following formula [2 9]

(Wherein, RS represents. Alkyl group) and nicotinic acid ester compound represented by

(C) the presence of an acid The nicotinic acid ester compound is subjected to catalytic hydrogenation, the following formula [3 0]

(Wherein, R 6 represents an alkyl group.) And Piperi Jin compound represented by

And (d) given the Konopipe lysine compound in ring closure reaction, the following equation by further base Njiruharai de and reaction [3 2]

(Wherein, B n represents a benzyl group.) And Jiazabishikuro [3.3.1] nonane compounds represented by,

(E) This Jiazabishikuro [3.3.1] nonane compound, by optical resolution by Jiasutereoma IchiAkira Oriho of Ru with an optically active acid, the following formula [3 3]

(Wherein, Bn represents a benzyl group.) Represented by (1 R, 5 S) - 7-base Njiru one 3, to obtain a 7- Jiazabinkuro [3.3.1] nonan one 2-one.

(2 1) the following formula, characterized in that it comprises the following steps [3 3]

(Wherein, Bn represents. A benzyl group) represented by (1 R, 5 S) one 7-base Njiru one 3,7 Jiazabishikuro [3.3.1] nonan one 2-one method of manufacturing.

(C) formula [2 9]

(Wherein, R 6 represents. An alkyl group) in the presence of an acid nicotinic acid ester compound represented by subjected to catalytic hydrogenation, the following formula [3 0]

(Wherein, R s represents. Alkyl group) and piperidine compounds represented by,

And (d) given the Konopipe lysine compound in ring closure reaction, the following equation by further base Njiruharai de and reaction [3 2]

(Wherein, Bn represents. A benzyl group) and Jiazabishikuro [3.3.1] nonane compounds represented by,

(E> The Jiazabinkuro [3.3.1] nonane compound, by optical resolution by Jiasutereoma IchiAkira Oriho of Ru with an optically active acid, the following formula [33]

(Wherein, Bn represents. A benzyl group) represented by (1 R. 5 S) one 7-base Njiru one 3, to obtain a 7- Jiazabishikuro [3.3.1] nonan one 2-one.

(22) the following formula [27 ']

By nicotinic acid bromine and is chloride Chioniru anti ^ shown in, 5 - to produce a blanking Romonikochin acid Kurori de, which by reacting with an alcohol represented by the following general formula [2 8]

Method for producing a bromo nicotinic acid ester - (wherein, R 6 represents an alkyl group.) 5 represented by.

(23) the following formula [28]

(Wherein, the R s represents. Alkyl group) The Esuchiru compound represented by, after subjecting the nitrile reaction with copper cyanide (I), the complex is treated with sodium hypochlorite solution oxidized, and then the reaction solution was treated with aqueous ammonia to remove the copper ions, the following formula by crystallization [29]

(Wherein, R 6 represents. Alkyl group) method of manufacturing a nicotinic acid ester compound represented by the.

(24) the following formula [29]

(Wherein, R 6 represents. An alkyl group) in the presence of hydrochloric acid to nicotinic acid ester compound represented by ethanol and a solvent selected from isopropyl alcohol, catalytic hydrogenation using platinum oxide or platinum on carbon as catalyst the following formula by subjecting to

[30]

(Wherein, R e represents. Alkyl group) who producing piperidine compound represented by (25) the following formula [30]

(Wherein, R 6 represents. Alkyl group) after subjecting the piperidine compound represented by the閉現reaction Ru with a base, the following formula by a This reaction with benzyl pay de product in Wanbo' Bok [3 2]

(Wherein, B n represents a benzyl group.) 7- base Njiru 3 represented by the 7-Jiaza bicyclo [3.3.1] nonane - process for preparing 2-one.

(2 6) the following formula [3 2]

(Wherein, B n represents. A benzyl group) at indicated are 7-base Njiru 3. 7- Jiaza bicyclo [3.3.1] nonan one-2-one, Jiasutere O Ma one using an optically active acid formula by optical resolution by crystallizer method [3 3]

(Wherein, B n represents a benzyl group.) Represented by (1 R, 5 S) one 7-base Njiru one 3,7 Jiazabishikuro [3.3.1] method for producing nonane one-2-one . (2 7) (a) Formula [2 7]

In the 5-bromo-nicotinic acid represented subjected to esterification reaction, the following formula [2 8]

(Wherein, R 6 represents. Alkyl group) to an ester compound represented by

(B) subjected to the ester compound to the nitrile reaction, the following formula [2 9]

(Wherein, R e is. Represents an alkyl group) and nicotinic acid ester compound represented by, (c) the presence of the nicotinic acid ester compound having an acid, and subjected to catalytic hydrogenation reaction, the following formula [3 0 ]

(Wherein, R 6 represents. Alkyl group) and piperidine compounds represented by,

(D) the Konopibe lysine compound is subjected to ring closure reaction, the following formula by reaction with further base Njiruharaido [3 2]

(Wherein, B n represents a benzyl group.) And Jiazabishikuro [3.3.1] nonane compounds represented by,

(E) This Jiazabishikuro [3.3.1] nonane compound, by optical resolution by Jiasutereoma IchiAkira Oriho of Ru with an optically active acid, the following formula [3 3]

(Wherein, B n represents a benzyl group.) Represented by (1 R. 5 S) - the step of obtaining an on - 7 base Njiru one 3. 7- Jiazabishikuro [3.3.1] nonane one 2 formula characterized that you through [35]

Wherein, R represents in one CONH- (CHR 1) m one R 2 (wherein, R 'represents a hydrogen atom or a § alkyl group, m represents 0, 1 or 2, R 2 is substituted good Ariru group, an optionally substituted heterocyclic group, an optionally substituted cycloalkyl group, an alkyl group or an alkenyl group.) or one C_〇 one R 3 (wherein, R 3 is an alkyl group, Araru Kiruokishi group or - NR 4 R 5 (wherein, R 4 and R 5 are the same or different represent a alkyl Le group, the formula becomes the nitrogen atom and one锗which R 4 and R 5 are adjacent

CH,

One N (CH 2) n

H /

(N represents. 2 or 3) to form a group represented by. ) Represents the. ) Represents the. Jiazabishikuro [3.3.1] The method for producing nonane derivative represented by].

(28) (c) the following formula [2 9]

(Wherein, R 6 represents. An alkyl group) in the presence of an acid nicotinic acid ester compound represented by subjected to catalytic hydrogenation, the following formula [3 0]

Following by (wherein, R 6 represents. Alkyl group) and pin base lysine compound represented by subjected to ring-closing reaction (d) is Konopiperi Gin compound is further base Njiruharai de and reaction equation [3 2]

(Wherein, B n represents. A benzyl group) and Jiazabishikuro C3. 3. 1] nonane compound represented by,

(E) This Jiazabishikuro [3.3.1] nonane compound, by optical resolution by Jiasutereoma IchiAkira Oriho of Ru with an optically active acid, the following formula [3 3]

(Wherein, B n represents a benzyl group.) Represented by (1 R, 5 S) - 7 one base Njiru - 3,7 Jiazabishikuro [3, 3.1] a step of nonane one-2-one formula characterized that you through [35]

Wherein, R represents in one C0NH- (CHR 1) "-R 2 ( wherein, R 1 represents a hydrogen atom or a § alkyl group, m represents 0, 1 or 2, R 2 is substituted good Ariru group, an optionally substituted heterocyclic group, an optionally substituted cycloalkyl group, an alkyl group or an alkenyl group.) or one C_〇 one R 3 (wherein, R 3 is an alkyl group, Araru Kiruokishi group or in one NR * R 5 (wherein R 4 and R 5 represent the same or different alkyl group, wherein together with the nitrogen atom to which R 4 and R 5 are adjacent

CH 2

/ \

One N (CH 2) n

\ «

(N represents. 2 or 3) to form a group represented by. ) Represents the. ) Represents the. Jiazabishikuro [3.3.1] The method for producing nonane derivative represented by].

Next, the meaning of the terms used herein are as follows.

"Alkyl group" refers to a straight-chain or branched technique and an alkyl group optionally having 1 to 6 carbon atoms, such as methyl group, Echiru group, n- propyl group, an isopropyl group, n- Bed butyl group, an isobutyl group , sec- butyl group, tert- butyl group, n- pentyl group, isopentyl group, tert- pentyl group, neopentyl group, 2-pentyl, 3-pentyl group, hexyl group n-, hexyl group or isohexyl 2- hexyl group or the like to, preferably a linear or branched techniques and may be a lower alkyl group having 1 to 4 carbon atoms, such as methyl group, Echiru group, n- Burobiru group, Ibb port propyl group, n- butyl group, a Isobuchiru group, sec one butyl group or tert- butyl group.

The "Ariru group", specifically, Hue group, Bifue group, a naphthyl group, preferably a Fuweniru group. The "heterocyclic group", the nitrogen atom in addition to carbon atoms as atoms constituting the ring, SansoHara element and 1 to 5-membered to 6-membered Kaoru aromatic heterocyclic ring containing three hetero atoms selected from nitrogen atom group means a saturated heterocyclic group or an unsaturated heterocyclic ^ group, specifically thienyl group, a furyl group, a pyrrolyl group, an imidazolyl group, Biraburiru group, a thiazolyl group, I Tsuchiazoriru group, Okisazoriru group, Isookisazoriru group, a morpholino group , pyridine group, a piperazinyl group, a piperidyl group, Biraniru group, a Chiopiraniru group. Preferably a thienyl group, a pyridyl group or a piperidyl group.

The term "cycloalkyl group" is a cyclic alkyl group having 3 to 8 carbon atoms, a cyclopropyl group For example, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc. heptyl group or Shikurootachiru group to cycloalkyl and the like, preferably cyclopropyl group having 3 to 6 carbon, a cyclobutyl group, alkoxy Le group cyclopentyl group or a cycloalkyl.

The Γ alkenyl group ", straight 縝又 from 2 to 6 carbon atoms represents a partial technique and may be alkenyl group, for example Eteniru group, 1 one Purobeniru group, 2-propenyl group, 1 over butenyl group, 2-butenyl, 3-butenyl, 2-methyl - 1 - propenyl, 1 one-pentenyl group, 2-pentenyl group, 3-pentenyl group, 2-methyl-1 over butenyl group, 3-methyl-1 Buteniru group, 1 one hexenyl group, cyclohexenyl group to 2-, 3- hexenyl group, 4 one hexenyl group, cyclohexenyl group to 5-, 2-methyl-1 one base Nteniru group, 3-methyl-1 one-pentenyl group, 4 -methyl-1 one-pentenyl group, 2 - dimethyl-1 Buteniru group or 3, 3-dimethyl-1 Buteniru group. Preferably Ri an alkenyl group Der be straight 鎮又 the minute work of 4 2 -C, e.g. Eteniru group, 1 Buro Bae group, 2-Purobeniru group, 1 Buteniru, 2-butenyl, 3-butenyl a group or a 2-methyl-1 one Purobe alkenyl group, particularly preferably Eteniru group, 1 Buro Bae group, 2-propenyl group, 1 one Buteni group, 2-Buteyuru group or a 3-butenyl group is there.

The Γ Ararukiruokishi group ", Ariru (C, -C S) Arukiruokishi group Der - e.g. Njiruokin group, Fuenechiruokishi group, 1 one-phenylalanine E chill O alkoxy group, 3-phenylpropyl O alkoxy group, 4 one phenyl Buchiruokishi group, 5-phenylene Rupenchiruokishi Kishiruokishi group and the like to the base or 6 Fuweniru, preferably Habe Njiruokishi group, Fuwenechiruokishi group, 1-safe We sulfonyl E chill O alkoxy group, 3-phenylene Ruburobiruokishi group, 4 one-phenylalanine butyl O alkoxy groups such Fuweniru (d ~ C 4) a Arukiruokishi group, particularly preferably a base Njiruokishi group.

4 to 1 and "may also be substituted" preferably means that may be more substituted 1 to 3 substituents, the substituents may be the same or different. Also, position S substituents is optional, and is not particularly limited. Specifically, a methyl group, Echiru group, a propyl group, an isopropyl group, a butyl group, a lower alkyl group such as tert one Petit Le group: hydroxyl; main butoxy group, Etokin group, Purobokishi group, lower pole such butoxy group an alkoxy group: fluorine, chlorine, halogen atom such as bromine; nitro: Shiano group: Ashiru group (e.g. formyl group, Asechiru group, a lower Arukanoiru groups such as propionyl group); Ashiruokishi group (e.g. Horumiruokishi group, Asechiruo Kin group, propionyl Okin lower alkanoyloxy Noi Ruo alkoxy group such as a group): a mercapto group, methylthio group, Echiruchio group, Burobiruchio group, Puchiruchio group, a lower alkylthio group such as Isopuchiruchio group: Amino group: Mechiruamino group, Echiruamino group, pro Piruamino group, Puchiruamino group lower Arukiruamino group such as: di Mechiruamino group, Jechiruami amino group, jib port Piruamino group, a di-lower alkylamino groups such as Jibuchiruamino group; a carboxy group; main butoxycarbonyl group, ethoxy Kin carbonyl group, a lower alkoxycarbonyl group such as a pro-Bo alkoxycarbonyl group; force Rubamoiru group : triflate Ruoromechiru group; Aminosuruhoniru group; a methanesulfonyl group, a lower Arukirusu Ruhoniru groups such as ethanesulfonyl group a cyclopentyl group, cyclohexylene, such as cyclohexyl group (C 3 ~C 8) cycloalkyl group: phenyl group: Asetoami de group , Anruami de group such Puropiona mi de group; Mechirenjiokishi group; Benjiruokin group, and the like Ararukiruokishi groups such Fuenechi Ruokin group, preferably a lower alkyl group (e.g. methyl, Echiru group, a propyl group, Isoburobiru group, butyl Le group, tert one butyl group): a hydroxyl group; a lower alkoxy group (e.g., main butoxy group, an ethoxy group): a halogen atom (e.g. chlorine, fluorine); Amino groups, lower alkylamino groups (for example Mechiruamino group); di lower pole alkylamino group (e.g. Jimechiruamino group); preparative Rifuruoromechiru group:; a Ararukiruokishi group (e.g. downy Nji Ruokishi group) Mechirenjiokishi group. Here 1 to 6 carbon atoms unless otherwise specified The lower, good Mashiku means 1-4 carbon atoms. Examples of substituted Ariru group, 2 main Chirufuweniru, 3-methylphenyl, 4 one-methylphenyl, 2-arsenide Dorokishifue sulfonyl, 3-hydroxyphenyl, 4-arsenide Dorokishifueniru, 3, 4-dihydroxy Shifue sulfonyl, 2 - main Tokishifuweniru, 3 main Tokishifue sulfonyl, 4-main Tokishifue sulfonyl, 2- Etokinfueniru, 3 Etokinfueniru, 4 one ethoxy-phenylalanine, 3, 4 Jime Tokishifue sulfonyl, 3, 4, 5-trimethyl Tokishifue sulfonyl, 4 arsenide mud Kishi 3 main Tokishifue sulfonyl, 2-black port phenyl, 3- black port phenyl, 4 one black port phenyl, 2-fluorophenyl, 3-fluorophenyl, 4 one Furuoro phenyl, 3, 4 Jikuro port phenyl, 3-chloro-4-menu Tokishifue sulfonyl, three to Furuoro 4-menu Tokishifue sulfonyl, 2-methyl § Minofu enyl, 3 Mechirua Minofueniru, 4-methyl § Minofu enyl, 2-dimethyl § Minofu enyl, 3-dimethyl § Minofu enyl, 4-dimethyl § Minofu enyl, 2-Torifuruoromechi Rufueniru, 3-triflate Ruo Russia methyl-phenylalanine, 4 one Torifuruoro Mechirufue two Le, 3, 4-methylenedioxy O carboxymethyl-phenylalanine, 2-base Nji Ruo carboxymethyl-phenylalanine, 3-base Nji Ruo carboxymethyl-phenylalanine, 4 one base Nji Ruo carboxymethyl-phenylalanine, 3, 4-di (Benjiruo alkoxy) phenyl, 4 one Benjiruokishi 3 main Tokishifue two Le, and examples of replacement cycloalkyl group, 2, 2, 3, 3-tetramethyl cyclopropyl and the like.

The "Amino protecting group", a sulfonyl group (e.g., toluenesulfonyl group, benzene Nsuruhoniru group, methanesulfonyl group, benzylsulfonyl group, Fuenashirusuru Honiru group); Ararukiru group (e.g. downy Njiru group, 4-main Tokishibenjiru group, 3 , 4 Jime Tokishibenjiru group, 2-two Torobe Njiru group, 4 twelve Torobe Njiru group, Baie Nzuhi drill group, bis (4-menu Tokishifueniru) methyl group, trityl group); § Shi Le group (e.g. formyl group , Asechiru group, a propionyl group, Puchiriru group, Okisari group, Sukushi group, pivaloyl group, 2-chloroacetyl group, 2-Buromoasechi group, 2-Yodoasechiru group, 2, 2-dichloroacetyl group, 2, 2 , 2-tri-chloro acetyl, 2, 2, 2-triflate Ruo b acetyl group, Fueniruasechiru group, Fuenoki Asechiru group, Benzoiru group, 4 one black port Benzoiru group, 4-main butoxy Benzoiru group, 4 twelve Torobenzoiru group, naphthyl carbonyl group, Adamanchiru carbonyl group): alkoxycarbonyl group (e.g., main-butoxycarbonyl group, ethoxy alkoxycarbonyl group, Bed Robo Kin carbonyl group, said blanking Robo alkoxycarbonyl group, tert one butoxycarbonyl group, pentylene Ruo Kin carbonyl group, Isopenchiruo alkoxycarbonyl group, hexyl O alkoxycarbonyl group cycloheteroalkyl, 2 black port Etokishika Lupo group, 2- ® chromatography de eth Kin carbonyl group, 2, 2, 2-trichloromethyl E butoxycarbonyl group, 2, 2, 2 - tri chloro tert- butoxycarbonyl group, Benzuhi drill O alkoxycarbonyl group, bis one (4-menu Tokishifue sulfonyl) method butoxy carbonyl group, Fuwenashiruo Aryloxycarbonyl group, 2-trimethylsilyl ethoxy Kin carbonyl group, 2-triflate We alkenyl silyl ethoxycarbonyl group, Furuoreniru 9-1 main butoxycarbonyl group); § Luque sulfonyl O alkoxycarbonyl group (e.g. Biniruo alkoxycarbonyl group, 2- propenyl O butoxycarbonyl group, 2-chloro-2-Bro Bae sulfonyl O alkoxycarbonyl group, 3-main Tokishikarubo two Lou 2- propenyl Niruokishi force carbonyl group, 2-methyl-2-Burope sulfonyl O alkoxycarbonyl group, 2- Buteniruo alkoxy carbonyl group, cinnamyl Ruo alkoxycarbonyl group); § Lal kill O propoxycarbonyl sulfonyl group (e.g., base Nji Ruo alkoxycarbonyl group, 4 one-bromobenzyl O propoxycarbonyl group, 2-black port base Nji Ruo alkoxycarbonyl group, 3 - black port Benjiruokishika Lupo group, 3, 5-dimethyl-butoxy-benzyl O carboxymethyl Carbonyl group, 4-main butoxy base Nji Ruo alkoxycarbonyl group, 2-two Toro benzyl O Kin group, 4 twelve preparative port base Nji Ruo alkoxycarbonyl group, 2-two Torrox 4, 5-dimethyl-butoxy-benzyl O key sheet carbonyl group, 3, 4, 5-trimethyl-butoxy-benzyl O alkoxycarbonyl group, Hue phenethyl Ruo alkoxycarbonyl group); low handling alkyl Nriru group (e.g. trimethylsilyl group, tert- heptyl dimethylsilyl group), alkyl thio group (e.g., methylthiocarbonyl group, E Ji thiocarbonyl group, Petit thiocarbonyl group, tert one Petit thiocarbonyl group) § Lal key thiocarbonyl group (Tatoebabe Nji thiocarbonyl group); full enoki Xia cetyl group: phosphoryl group (e.g., the dicyanamide black Kishiruhosuhoriru group, Jifue two Ruhosuhoriru group, Jibenjiruhosu Digging group, di - (4 twelve Torobenjiru) phosphoryl group, full enoki Schiff enyl phosphoryl group): a phosphinyl group (e.g., Jeffrey chill phosphinyl group, a Jifue two Ruhosufiniru group). Preferred Amino protecting groups are, toluenesulfonyl group, a benzyl group, formyl group, Asechiru group, 2-chloroacetyl group, 2, 2, 2-triflate Ruo b acetyl group, Benzoiru group, isopropyl borate alkoxycarbonyl group, tert- butoxy carbonylation group, Furuoreniru 9-1 main butoxycarbonyl group, a benzyl O alkoxycarbonyl group, particularly preferably base Njiru group, tert - a butoxycarbonyl group or Habe Nji Ruo alkoxycarbonyl group.

The Γ halogen atom ", chlorine, bromine, iodine or fluorine.

The Γ alkoxy group j, a linear or branched technique was good an alkoxy group optionally having 1 to 6 carbon atoms, for example, main butoxy group, Etokin group, n- Purobokin group, Isopuroboki sheet group, n- butoxy group, isobutoxy, sec- butoxy group, Kishiruokishi tert- butoxide Kin group, n- Penchiruokishi group, isopentyl Ruo Kin group, tert- Penchiruo alkoxy, neopentyl Ruo Kin group, 2-Penchiruokishi group, 3-Penchiruokishi group, the n one group, Kishiruokishi to I-Soviet group or to Kishiruokishi group 2- elevation Gerare, preferably a lower alkoxy group which may be straight-chain or branched skill having 1 to 4 carbon atoms, such as main butoxy group, Etokin group, n- Burobokin group, Isopurobokishi group, n- butoxy group, Isobutokishi group, sec one butoxy group or tert- butoxide kin group.

"Pharmacologically acceptable salts" Jiazabishikuro [3.3. 1] may be filed any as long as it forms a nonane derivatives and non-toxic salt of formula [1]. Such as hydrochloride, hydrobromide, sulfate, phosphate, inorganic acid addition salts of nitrates; acetate, propionate, succinate, lactate, glycolate, apples, tartrates , Kuen, maleate, fumarate, methanesulfonate, p- toluenesulfonate, organic acid addition salts such as Asukorubin salt: and Asupara Gin salt, acid Amino acids such as glutamic acid salt salt; Natoriu 厶塩, Al force re gold 厲塩 or potassium salts; magnesium salt, Al force Li earth metal salts such as calcium salts; Anmoniumu salts; Torimechiruami emissions salt, Toryechiruamin salt, pyridine salt, pico Li emissions salt , Kishiruami emissions salt dicyclohexyl, N, N '- organic base salts such as dibenzylethylenediammonium § Mi emissions salt; lysine salts, salts with basic amino acids such as arginine salt Ageruko transgression That. Further, it may be a hydrate or ethanol solvate in some cases.

The "Jiazabishikuro [3. 3. 1] nonane derivatives", 2 Okiso one 3, a compound having A one-diazabicyclo [3. 3. 1] nonane skeleton.

The process as "acid" in (c), for example hydrochloric, sulfuric, phosphoric acid, hydrobromic acid, an inorganic acid and nitric acid; acetic, Purobion acid, oxalic acid, malonic acid, Kuen acid, lactic acid, malic acid, succinic acid, tartaric acid, fumaric acid, maleic acid, glycolic acid, methanesulfonic sulfonic acid, P - toluene sulfonic acid, gluconic acid, Asukorubin acid, Asuparagi phosphate, and organic acids such as glutamic acid. Preferably hydrochloric acid, hydrobromic acid, and the like sulfate, ^ acid, particularly preferably hydrochloric acid.

The "benzyl pay de j in the manufacturing method of the step (d) and the (2 5), Benjirukurori de, Benjiruburomi de a Benjiruyojido such a preferred Kuhabe Njirukurori de.

Wherein step (e) and the term "optically active acid" in the manufacturing method of (2 6), for example tartaric acid, Jibenzoiru, ditoluoyltartaric, etc. camphorsulfonic acid or malic acid. Preferably tartaric acid, Jibenzoiru tartaric, a Jitoruoi Le tartaric acid, particularly preferably Jibenzoiru tartaric.

The term "alcohol" in the manufacturing method of (2 2), methanol, ethanol - iso bromide pills alcohol. The (2 5) The "base J in the manufacturing method of the sodium main Tokishido, diisocyanato Liu 厶 Etokindo, potassium tert - such butoxide Al force Li alloy 厲 alkoxy de: Toriechiruamin, organic such as pyridine bases: carbonate power Riu 厶, carbonate Natoriumu, sodium bicarbonate, an inorganic base such as potassium hydrogencarbonate preferably isocyanatoethyl Riumume Tokishido, sodium ethoxide, potassium tert -. a-butoxide, particularly preferably Natoriumume Tokishido or sodium © beam ethoxide in it. the compounds of the present invention can be manufactured by the following method for example, preparation of compounds of the present invention is not limited thereto.

96/30372

Production Method 1

(A)

[twenty three] (C) (D)

[4] [5]

R 6

R 6

PP

[8] [9]

[13] [14] wherein, R 1, R 2 and m are as defined above,

X is a halogen atom (e.g. chlorine, bromine, iodine),

R 6 is an alkyl group (e.g. methyl, Echiru group),

P represents an amino protecting group (e.g. downy Nji Ruo alkoxycarbonyl group, tert- Butokin carbonyl group, 9 one full O Les methylpropenylmethyl O alkoxycarbonyl group). ] Production Method 1

Reaction (A)

Compound [3] can be obtained by subjecting compound [2] to esterification reaction. For example, an alcohol (e.g. methanol, ethanol) indicated the compound [2] with R 'OH (R 8 is an alkyl group) in, using hydrochloric Bruno 1, 4 one Jiokisan, an acid such as sulfuric acid, the reaction at room temperature to reflux temperature by give compound [3]. During this, the compound is a monoester [4] is produced partially, which can be Tan雜. The compound [3], the compound [2] The acid payment de (e.g. chloride Chioniru, Okizarirukurori de) using, as the acid paid de derivative that corresponds by reaction at room temperature to reflux temperature, which R e OH ( R e is also obtained by cowpea to treatment with alcohol represented by the alkyl group) (e.g. methanol, ethanol). Reaction (B)

Compound [3] water, alcohols (e.g. methanol, ethanol) or in their mixed ^ things, from a 20'C Te 4 0, an acid such as hydrochloric acid preferably at 0 to room temperature, or lithium hydroxide, sodium hydroxide to obtain potassium hydroxide, barium hydroxide, compound by hydrolysis in the presence of a base carbonate force Liu 厶等 [4].

Reaction (C)

Compound [4] without solvent or in an inert solvent with an acid payments de (e.g. chloride Chioniru, Okizarirukurori de) and a compound by reacting at room temperature to reflux temperature

Obtain [5]. The inert solvent described herein, is solvent meaning taste without interfering with the reaction. The same is true with the following. It is also possible to use the compound [5] in the next reaction (D) without a single 雜. Reaction (D)

4 Compound [5] from a 2 O'C 0'C, preferably give compound [6] by treatment with an inert solvent containing ammonia § at 0 e C from a 1 O'C.

Reaction (E)

Compound [6] alcohols (e.g. methanol, ethanol), acetic acid, 1, 4 in a suitable solvent, such as one Jiokisan, Raney one nickel, palladium one-carbon, platinum oxide, rhodium - usually used such as alumina, the catalytic hydrogenation the presence of a catalyst which is, as a hydrogen source of hydrogen or Gassin Anmoniumu like, at reflux temperature from 0 to give a compound [7] by reduction under 2 0 0 atmospheres atmospheric pressure. It is also possible to use the compound [7] in the single 雜 be Rukoto without following reaction (F).

Reaction (F)

Compound [7] the compound by introducing an amino-protecting group P by a conventional method to obtain [8]. Here Amino protecting group P as the base Nji Ruo alkoxycarbonyl group, tert one butoxycarbonyl group, 9 one full O but Les methylpropenylmethyl O butoxycarbonyl group and the like, be any Amino protecting group which does not disturb the reaction it may be. For example, if P is tert- butoxycarbonyl group, compound [7] and 4 one Jioki Sun, water, N, N-dimethyl formamidine de or in a solvent such as mixtures thereof, sodium hydroxide reduction, baking soda, Toryechiruami down the presence of a base like, to give compound by reaction with di-tert- butyl carbonate [8].

Reaction (G)

Compound [8 without solvent or in an inert solvent〗, Toryechiruami emissions, presence salt group or the absence of such pyridine, acid payment de (e.g. chloride Chioniru, Okizarirukuro Li de), Okishi chloride Li down, Toshiruku port Rye de , benzenesulfonyl chloride Lai de obtain diphosphorus pentoxide or by connexion compound from room titanium chloride (IV) to react at the reflux temperature [9]. Further, it is possible to obtain carbon tetrachloride compound [8], Torifueniruho ​​Sufui down and be cowpea to react at the reflux temperature from room Compound [9]. . Reaction (H)

Compound [9] the compound by reducing in the same manner as in reaction (E) obtaining the [1 0]. Alternatively an alcohol (e.g. methanol, ethanol), aluminum chloride dihydrate © beam, boron trifluoride, Raney nickel or the presence of cobalt chloride (II), the compound with sodium borohydride [9] compound be cowpea in reducing the can be obtained [10]. It is also possible to use the compound [1 0] in the next reaction (I) without single 雜.

Reaction (I)

Compound [1 0] alcohols (e.g. methanol, ethanol) in a hydrogen Kana Toriu厶, presence or absence of sodium © beam alkoxide (e.g. sodium main Tokishido) such base, the reaction at reflux temperature 50 e C compound by

Get the [1 1].

Reaction (J)

Toluene compound [1 1], Jiokisan, N, N-Jimechiruhoru 厶 inert solvent Ami de like, Toryechiruamin, pyridine, potassium - presence or absence of a base such as tert- butoxide, isocyanate [1 2 〗 and reacted at room temperature to reflux temperature compound is obtained [1 3]. Isoshiana Ichiboku other than commercially available products, (1) corresponding to that C Urtius rearrangement reaction using Jifue two Berlin acid azide from a carboxylic acid, (2) reaction of the corresponding primary amine with phosgene, or (3 ) it can be used to prepare by reaction of the corresponding halide with cyanate Natoriu 厶.

Reaction (K)

Compound [1 3] compound by deprotecting the Amino protecting group P by a known method

[Obtain 1 4〗. If the Amino protecting group P is for example tert one butoxycarbonyl group, no solvent or dichloromethane, in an inert solvent such as black hole Holm, hydrobromic acid / 醉酸, hydrochloride 1, 4 one Jiokisan, 蠖酸, hydrochloric Z acetate, Torifuruoro acetate, using an acid such as tri Furuoro acetate / acetic acid, at 70 from a 30 e C, preferably removing Amino protecting group P by ^ processed from 0 at 30 hand. If Amino protecting group P is, for example, base Njiru group, an alcohol (e.g. methanol, ethanol, isopropyl alcohol), acetic acid, 1.4 one suitable solvent such Jiokisan, palladium over iodine, palladium black, Raney nickel, platinum oxide, Rojiu arm - Usually such as alumina, the presence of a catalyst used in catalytic reduction, as the hydrogen source hydrogen or formic acid-en 乇 Niumu like, O 'at reflux temperature C, to the original place under 1 0 0 atm atmospheric pressure It can be removed Amino protecting group P by.

The compound [1 4] are the basic compound having an amino group may be if necessary, to form a salt with any acid. For example, the case of fumarate, alcohols (e.g. methanol, ethanol, isopropyl Building alcohol), water, acetone in a suitable solvent such as acetic acid Echiru at compound [14] and the reflux temperature of the fumaric acid from 0 e C by mixing, it is possible to obtain the fumaric acid salt of the compound [14]. Production Method 2

[13] [15]

[16]

Wherein, R 1 and m are as defined above,

P is Amino protecting group,

R 2 a is substituted with S conversion has been Ariru group, substituted cycloalkyl group heterocyclic group, or Ararukiruokishi group that is conversion in Ararukiruokishi group, R 2 b is Ariru group substituted with a hydroxyl group, a hydroxyl group at Ararukiruokishi group a heterocyclic group, or a hydroxyl cycloalkyl group substituted with groups. ]

Production Method 2

Reaction (L)

Compound [1 3] of the case of the group R 2 a is substituted with Ararukiruokishi group, compound by deprotecting reductive deprotection, etc. mentioned in the reaction (E), according to a conventional method

Can be obtained [1 5]. The compound [1 5] compound by reaction (K)

It can lead to [1 6].

[11] [18]

[19]

Wherein, R 4 and R 5 are the same as defined above,

P is an amino protecting group,

Y represents a halogen atom (e.g. chlorine, bromine, iodine), alkoxy groups (e.g. main preparative alkoxy group, an ethoxy group) to de-雜基 like. ]

Production Method 3

Reaction (M)

Toluene compound [1 1], black hole Holm, N, N-inert solvent dimethylformamidine de like, Toryechiruami down, pyridine, potassium one tert - presence of a base such as butoxy-de, compound [1 7] ( obtained, for example N, N-dimethylcarbamoyl chloride Lai de, piperidinocarbonyl chloride Lai de) and the reflux temperature from a 2 O'C, preferably the compound by reacting with 4 (TC from 0 e C [1 8] . this compound [18] can be converted into the compound [1 9] by the reaction (K). production method 4

[11] [21]

[twenty two]

Wherein, R 3 is as defined above, P is represents a Amino protecting group

Production Method 4

Reaction (N)

Compound [1 1] The solventless or in an inert solvent, acid anhydride [20] (e.g. anhydrous acetic acid) and the reflux temperature from a 2 0 ° C, preferably by reacting at reflux temperature 4 O'C compound obtain [2 1]. The compound [2 1] can be converted into the compound [22] by reaction (K).

Production Method 5

[twenty two]

Wherein, R 3 is as defined above, X represents a halogen atom, [rho is Amino protecting group manufacturing method 5

Reaction (0)

Dichloromethane compound [1 1], black hole Holm, an inert solvent such as Jiokisan, Toryechiruamin, pyridine, potassium one tert - nucleotide exist under such butoxide, acid pays de [23] (e.g. Viva port Iruku port Rye de, benzyl O carboxymethyl Cal Bonirukurorai de) as one 4 0 e C from reflux temperature, preferably compounds by reacting at room temperature O e C obtaining [2 1]. The compound [2 1] can be led to the reaction (K) Niyotsu Te compound [22].

Li mR:

[11] an optically active form of the optically active substance Π4 13]] optically active form of

(L) R 2 is in Ararukiruokishi group

In the case of substituted groups

[151 optically active form of the optically active complex [16] of the

Production Method 6 - (3)

Optically active form of the optically active substances [22] of [21]

[11] an optically active form of the optically active complex [14] of the optically active substance [13] of the

(L) R 2 is in Ararukiruokishi group

In the case of substituted groups

Π5 optically active form of the optically active substances [161]

Manufacturing method 6- (5)

Optically active form of [19]

Optically active form of the optically active complex [22] of [21]

Wherein, P is represents a Amino protecting group, 1 ^, 1¾ 2, 1 ? 2 1), 1¾ 3, 1 ^, 1¾ 5 and m are as defined above. ]

Production method 6 - (1) - (5)

Reaction (P)

Compound [1 1] to give compound [2 4] is deprotected by a method similar to that reaction (K) a. The compound [2 4], a suitable solvent (e.g., methanol, an alcohol such as ethanol, water) or using a mixture thereof as the recrystallization solvent, using an optically active acid (e.g. L one tartaric acid and D- tartaric acid) Jiasu Tereoma IchiAkira corresponding optically active salt by precipitation, the compound [2 5] and

It can be separated into [2 6]. The compound [2 5] and [2 6] corresponding Amino protected form by reaction (F) from, namely the compound [1 1] can Rukoto give an optically active form. Compound [1 1] corresponding optically active compound from an optically active substance in the same manner as in production method 1-5 of the above [1 4], [1 6〗, can be obtained [1 9] or [22] .

6/30372

Production Method 7

[35] The method for producing 7

Reaction (Q)

Compound [28] can be obtained by subjecting compound [27] in the esterification reaction. For example, in an alcohol represented compound [27] with R e OH (R * is as defined above) (for example, methanol, Etasoru, isopropyl alcohol), using hydrochloric acid, acids such as sulfuric acid, is reacted at room temperature to reflux temperature give compound [28] by. Reaction (Q ')

Compound [28] can also be prepared from nicotinic acid (compound [27 ']). Nicotinic acid, bromine and chloride Chioniru benzene, black hole benzene, 1, 2-dichlorobenzene, benzonitrile, a suitable solvent such as nitrobenzene, or in the absence of a solvent, preferably under nitrogen atmosphere, in 2 0 0 hands from room It reacted to produce 5-Buromonikochi phosphate Kurori de. Here § alcohol represented by R 6 OH (R 8 is as defined above) (for example, methanol, ethanol, iso-Bro pills alcohol) was added, by reacting at room temperature to reflux temperature, compound [28] and the bromide obtaining a salt of hydrogen and a bromine. The reaction mixture carbonate force helium, was made basic with a basic such as sodium hydrogen carbonate, to obtain sodium Chio sulfate, O Ri compound by treatment with a reducing agent such as sodium sulfite [2 8].

The above method, J. Am. C h em. S oc., 70, 23 8 The method described in 1 (1 9 4 8), i.e., a nicotinic acid 5-bromo-nicotinic acid (compound [27]) after obtaining, 5 by reaction with chloride Chioniru - a bromonicotinate Kurori de, is simplified by way of the method of obtaining by reacting it with ethanol 5-bromo nicotinic acid ester (compound [28]) . The method of the first 'step, 5 one-bromo nicotinic acid (compound [27]) without passing through the can be produced directly, compound [28] from nicotinic acid.

Reaction (R)

J. O r. Ch em., 2 6, 25 22 (1 9 6 1) In the same manner as described in the compound [28] and dimethylformamide Ryomi de copper cyanide (I), Jimechirua Setoami de, N- Mechirubirori Don, the hexa methyl phosphoryl Ami de, pyridine in a suitable solvent such as hesitant down, preferably obtained under a nitrogen atmosphere, the compound by reacting at room temperature to reflux temperature [2 9]. Workup of this reaction, oxidizing the complex of nitrile reduction reaction 応後, copper halide the reaction mixture was treated with aqueous sodium hypochlorite solution (the copper bromide) and nitrile compounds of interest, then the reaction the solution was treated with aqueous ammonia solution made by removing copper ions. The resulting crude product, alcohol (e.g., methanol, ethanol, isopropyl alcohol) suitable those solvents, etc. or water, or by crystallization from a mixed solvent thereof, the compound [29] can be obtained.

Alternatively, B ull. C h em. S o c. J ρ n., 4 8, 3 2 9 8 (1 9 7 5) two Bok Lil reduction using a palladium catalyst according to the reaction, or B ui 1. C h em. S o c. J p n., 6 1, 1 9 8 5 by the method of the nitrile reaction or the like using a nickel catalyst according to (1 9 8 8), the two compound [2 8] Bok Lil reduction to give compound [29] can be obtained.

Reaction (S)

Compound [2 9] alcohols (e.g., methanol, ethanol, Isoburopi alcohol) in a suitable solvent, such as, hydrochloric acid, hydrobromic acid, sulfuric acid, the presence of an acid such as acetic acid, and platinum oxide, platinum - carbon, Raney nickel, palladium - carbon, Rojiu beam - normal such as alumina, in the presence of a catalyst used for catalytic hydrogenation, hydrogen or formic acid Anmoniu 厶等 as a hydrogen source, in 2 0 0 ° C from room temperature, normal pressure by performing catalytic hydrogenation from under 1 0 0 atm to give compound [3 0〗. Preferably, ethanol or Ibb opening pill alcohol as a solvent, or hydrochloric acid, platinum oxide or platinum one-carbon is used as the catalyst.

Reaction (T)

Compound [3 0] alcohols (e.g., methanol, ethanol, isopropyl alcohol) in a suitable solvent, such as, sodium main Tokishido, Natoriu 厶 Etokin de, Toryechiruami down, pyridine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, etc. using a base, a compound by reacting at room temperature to reflux temperature

Obtain [3 1].

Compound [3 1] without single 雜, alcohols (e.g., methanol, E ethanol, isopropyl alcohol) in a suitable solvent, such as, potassium carbonate, sodium, sodium bicarbonate, Toryechiruami down, Jiisopurobirue Chiruami presence of a base such as down, Benjirukurori de, Benjiruburomi de, by reaction with Ararukiruharai de such as main Tokishibenjiru Kurori de, it is also possible to give compound [32].

Reaction (U)

Compound [32] alcohols (e.g., methanol, ethanol, Ibburopi alcohol) suitable solvent such as or water, or by using a mixed solvent thereof, optically active acids (e.g., tartaric acid, Jibenbuiru, ditoluoyltartaric obtaining camphor sulfonic acid, by Jiasutereoma crystals 柝法 using malic acid), by dividing light Science, optically active compound [33〗. To produce is Ru (1 R, 5 S) optically active substance represented by the formula [33] can be used ditoluoyltartaric one L one tartaric acid, optically active acid, such as Jibe Nzoiru L one tartrate.

Compound [33] (wherein, Bn is as defined above) (the reaction may be conducted in have guns in reaction (J) (L)) the reaction (J), (M), (N) or (0) and to give compound [34] by carrying out the reaction in the same manner. It is possible to obtain the target compound [35] by subsequently performing the reaction as the reaction (K).

Production process 7, can be produced in good yield intermediate [33] with a small step, 5-bromo-nicotinic acid or nicotinic acid is the starting material is characterized in that it is inexpensive. Therefore, it is Jiazabishikuro [3.3.1] How nonane derivatives may be prepared by efficient low cost of interest.

Single 雜 from the reaction mixture of the compound represented by the thus obtained compound represented by the general formula [1], purification use any means commonly used in organic synthesis chemistry it can be carried out by Rukoto. For example, column chromatography, solvent extraction, and recrystallization. Single 雜, purification may be performed for each reaction, or may be performed after the completion of the reaction. The compounds of the present invention represented by the general formula [1], but stereoisomers due to asymmetric carbon may exist, such isomers and mixtures thereof are included within the scope of the present invention.

Jiazabishiku π [3. 3. 1] nonane derivatives have nicotinic choline action and de dopamine releasing action, is useful as nicotinic choline agonists or Dopami down agonist. Therefore, the Jiazabishikuro [3.3.1] nonane derivatives may be used as medicaments for the central nervous disorder treatment with a pharmaceutically, or Dopami down action decreases for central nervous disorders treatment by cholinergic reduction in brain cells that. In particular, the Jiazabinkuro [3.3.1] nonane derivatives may be utilized one disease Arutsuhaima, Parkinson's disease, Huntington's disease, treatment of central neurodegenerative diseases such as Big disease, the improvement of cerebral dysfunction, it can be used as improving agent of memory disorder typified by dementia since it particularly has a memory disorder improving activity. Such di Azabinkuro [3.3.1] nonane derivatives, the Itto formula [1] is not limited to the compounds represented, 2- Okiso one 3, 7 - Jiazabishikuro [3.3.1] It includes compounds having nonane skeleton. Preferably, a Jiazabishikuro [3.3.1] nonane derivative of the compound represented by the general formula [1].

Jiazabishikuro [3.3.1] When using nonane derivative or a pharmacologically acceptable salt thereof as a pharmaceutical formulation is generally a carrier, 陚 excipient that is acceptable per se known pharmacologically, diluents, bulking agent , disintegrating agents, stabilizers, preservatives, buffers, emulsifiers, fragrances, wearing colorant, sweetening agents, thickening agents, flavoring agents, solubilizers, and other additives, specifically water, vegetable oil, alcohols such as ethanol or base down benzyl alcohol, Boriechiren glycol, glycerol triacetate, gelatin, rata toast, carbohydrates, magnesium stearate, were mixed talc, Rano phosphorus, and vaseline tablets, pills such as starch, powders , granules, suppositories, injections, eye drops, liquids, covering agents, troches, aerosols, elixirs, suspensions, emulsions, shea Oral the form of such-up agent, can be administered by parenteral or external administration (topically). The dosage depends on the type of disease and the extent, compounds and administration routes for administration, the patient's age, sex, may vary by weight, etc., in the case of oral administration, usually, per day per adult Jiazabinkuro [3.3.1] nonane derivative (preferably Ru represented by the general formula [1] Jiazabishikuro [3.3.1] nonane derivatives) to 0. lmg~ 1 000 mg, to administer a particular 1 Mg~30 Omg preferred.

Example

Hereinafter, more detailed description of the present invention to examples, the present invention is not intended to be restricted to these. Abbreviations used in the Examples and in the Tables shows the following meanings.

E NMR Proton nuclear magnetic resonance spectrum

MS mass spectrometry spectrum

FAB MS fast atom collision mass analysis spectrum

DMF N, N-dimethylformamidine de

DMSO dimethyl sulfoxide

Me methyl

E t Echiru

P h phenyl

B n benzyl

Example 1

2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3 - carboxylic acid Benjiruami de hydrochloride

a) pyridine one 3, 5-dicarboxylic acid GETS chill ester

Pyridine one 3, 5-ethanol dicarboxylic acid (200g) (1300ml) suspension 4 N hydrogen chloride - 1, 4 one Jiokisan a (500 ml) and the mixture was heated under reflux for 37 hours. The reaction solution was 饞縮, it poured into saturated aqueous sodium bicarbonate solution, basified with sodium bicarbonate and extracted with acetic acid Echiru. The organic layer was washed with water to give the title compound (219 g) and dried over anhydrous sodium sulfate and concentrated. b) Pyridine one 3, 5-dicarboxylic acid monomethyl E chill ester

Pyridine one 3, in ethanol (1500 ml) solution of 5-dicarboxylic acid GETS chill ester (219 g), under ice-cooling, was added dropwise an aqueous solution of potassium hydroxide (64.8g) (360ml), it was 撹捽 25 hours at room temperature. The reaction was concentrated and washed with Jeffrey chill ether was added water (500 ml). The aqueous layer 齚酸 a (56.2 ml) was added, by standing at 4 hands 4 6 hours to give the title compound (124 g) as crystals.

c) 5- force Luba moil over nicotinic acid Echiruesuteru

Pyridine one 3, 5-dicarboxylic acid monomethyl E chill ester (124 g), under ice-cooling, the salts of Chioniru mixture was heated under reflux for 1 hour. The reaction solution was 澳縮, under ice-cooling the residue, by adding to a mixture of benzene (500 ml) and 2 8% aqueous ammonia (500 ml), to give the title compound (88.5 g) as crystals.

d) 1 - (tert one but-kin carbonyl) Single 5- force Luba Moi ruby ​​Peri Jin one 3 - carboxylic acid Echiruesuteru

5- force Luba moil over nicotinic acid Echiruesuteru acetic acid (88.5 g) (500 ml) platinum oxide U.25g to l® solution) was added, under a hydrogen atmosphere (3 atm) and stirred for 6 hours at 6 O'C. The reaction mixture 據過 and concentrated. Was dissolved in a mixture of the residue 1, 4 one Jiokisan (600 ml) and water (600 ml), under ice-cooling, made basic with sodium bicarbonate, di - tert Buchirukarubone over preparative (84.9 g) was added, 1 for 4 hours at room temperature It stirred. The reaction solution was extracted with acetic acid Echiru, the organic layer washed with water, dried over anhydrous sodium sulfate and then concentrated to give the title compound (118 g).

e) 1 - (tert one butoxycarbonyl) Single 5- Shianobiperijin one 3-Cal Bonn acid Echiruesuteru

1 - (tert one butoxycarbonyl) Single 5- force Luba Moi ruby ​​Peri Gin added Okishi phosphorus chloride (13.2 ml) in pyridine (700 ml) solution of one 3-carboxylic acid Echiruesuteru (70, 0g), 1 hour at 75 hands heated. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with 齚酸 Echiru. The organic layer was washed with water, 5% potassium hydrogen sulfate solution was washed successively with water, to give the title compound (61.2 g) and concentrated after drying with anhydrous sulfate Natoriu 厶. f) 7- (tert-butoxycarbonyl) one 3,7-Jiazabishikuro [3.3.1] nonan one-2-one

1 - (tert-butoxycarbonyl) Single 5- Shianobiperijin one 3-carbonitrile phosphate Echiruesuteru of (61.2 g) 舴酸 (500 ml) was added platinum oxide (3.06 g) was added, under a hydrogen atmosphere (3 atm) at room temperature It stirred in 3 hours. The reaction mixture was concentrated after filtration, the residue was dissolved in methanol (600 ml), under ice-cooling, sodium hydride (60% dispersion in oil 25.0g) and the mixture was heated under reflux for 1 8 hours. Concentration of the anti-IS solution and extracted with black port Holm adding 5% sulfuric acid hydrogen forces potassium water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried and then concentrated in successively washed anhydrous sodium sulphate 厶 with water. The ZanKiyoshi silica gel column chromatography was purified by (eluent black hole Holm one methanol mixed solvent) to obtain the title compound (34. lg).

g) 7- (tert one butoxycarbonyl) one 2 - Okiso one 3.7 - Jiazabishi black [3.3.1] nonane one 3-force carboxylic acid base Njiruami de

7- (tert-butoxycarbonyl) one 3,7-Jiazabishikuro [3.3.1] benzyl iso Xia Natick preparative (0.616Ml) in toluene (10ml) solution of nonane one 2-one (L.OOg), It was heated for 3 hours at 8 0'C. The reaction solution was concentrated by silica gel column chromatography to give the (溶雜 liquid mixture of black hole Holm one methanol) Hand purified title compound (1.60 g).

h) 2 - Okitsu 3,7 Jiazabinkuro [3.3.1] nonane one 3 - carboxylic acid Benjiruami de hydrochloride

7 - (tert one but-kin carbonyl) Single 2 Okitsu 3,7 Jiazabishiku port [3.1, 4-di Okisan (15ml) solution of 3 门 nonane one 3-force carboxylic acid base Njiruami de (1.60 g) in 4 N hydrogen chloride - 1, 4 one Jiokisan a (ml), and the mixture was stirred for 1 hour at room temperature. To give the title compound (985 mg) and recrystallized from a mixture of the reaction mixture was concentrated ZanKiyoshi ethanol and water.

Example 2-5

In the same manner as in Example 1, the following compounds were synthesized. 2 Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid Funiniruami de hydrochloride (Example 2)

2 Okiso one 3,7 Jiazabishikuro [3.3.1 门 nonane one 3-carboxylic acid one Mechiruami de hydrochloride (Example 3)

2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-carboxylic acid one Echiruami de hydrochloride (Example 4)

2 Okiso one 3, 7 - Jiazabinkuro [3.3.1] nonane one 3-force carboxylic acid - tert one butylamine de hydrochloride (Example 5)

Example 6

2 Okiri 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid (2 - main Tokishifue sulfonyl) amino Dofumaru salt

a) 7- (tert-butoxycarbonyl) Single 2- Okiso one 3,7 Jiazabishi black [3.3.1〗 nonane one 3-force carboxylic acid (2-menu Tokishifue sulfonyl) amino-de Example 1 one g ) benzylidene Son § in the same manner as Ne - with 2 main Toki Shifue two Ruisoshiane bets instead of Bok, obtained in example 1 one f) 7 - (tert - butoxycarbonyl) one 3,7-Jiazabishikuro [3.3.1] nonane - give 2-O title compound from emissions (200 mg) and (302 mg).

b) 2- Okitsu 3,7 Jiazabishikuro [3.3.1 门 nonane one 3-force carboxylic acid (2-main Tokishifu X sulfonyl) § Mi Dofumaru salt

7 - (tert one butoxycarbonyl) Single 2- Okiso one 3, 7 - Jiazabishiku port [3.3.1] 1.4 one Jiokisan nonane one 3-force carboxylic acid (2-menu Tokishifueniru) Ami de (295 mg) (5 ml ) was added 4 N hydrogen chloride one 1.4 one Jiokisan (5ml) was added and stirred for 1 hour at room temperature. The reaction mixture was extracted with black port Holm addition of a saturated aqueous sodium bicarbonate solution to the concentrated residue. The organic layer was concentrated, the residue isopropanol - with acme Buropa Nord a (40 ml) solution was added concentrated le (10ml) dissolved fumaric acid (241 mg), and recrystallized from a mixture of ethanol and water ZanKiyoshi to give the title compound (198 mg). In the same manner as in Example 7-1 2 Example 6, the following compounds were synthesized.

3- C (S) one 1 monounsaturated We sulfonyl E Ji carbamoyl] one 3,7 Jiazabishikuro [3.3.1] nonane one 2- one fumarate (Example 7)

3- [(R) - 1 one-phenylene Rue Chi carbamoyl] one 3,7 Jiazabishikuro [3.3.1] nonane one 2- one fumarate (Example 8)

2 - Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3 - carboxylic acid i (1 one-naphthyl) amino Dofumaru salt (Example 9)

2 Okifu 3,7 Jiazabishikuro [3.3.1] nonane - 3 - carboxylic acid i (3 main Tokishifue sulfonyl) amino Dofumaru salt (Example 1 0)

2 Okifu 3. 7- Jiazabishikuro [3.3.1] nonane one 3 - carboxylic acid i (4-menu Tokishifuweniru) § Mi Dofumaru salt (Example 1 1)

2 Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3 - carboxylic monobasic isopropyl amine Dofumaru salt (Example 1 2)

Example 1 3

2 Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid (4 one black port benzyl) amino Dofumaru salt

a) 7 - (tert - but-Kin carbonyl) Single 2 Okitsu 3, 7 Jiazabishi black [3.3.1] nonane one 3 - carboxylic acid (4 - black port benzyl) amino-de

4 Kurorofuweniru toluene acetate (850mg) (10ml) was added diphenyl two ruri phosphate azide (1.18ral), Toryechiruami down the (0.764ml) was added, and stirred for 1 hour at room temperature, stirred for 1 hour at 8 0 e C did.

The reaction mixture obtained in Example 1 one f) to 7 (tert - butoxycarbonyl) one 3,7-Jiazabishikuro [3.3.1] nonan one 2-one (400 mg) was added 3 at 8 0 Hand and the mixture was stirred time. The reaction solution acetic Echiru (30ml) was added 5% aqueous solution of potassium hydrogensulfate, a saturated aqueous sodium bicarbonate solution, and washed and dried after S condensed over anhydrous sodium sulfate and saturated brine. The ZanKiyoshi silica gel column chromatography - obtain purified by (eluent: click c mouth Holm one methanol Le mixed solvent) to give the title compound (670 mg). b) 2 - Okiso one 3,7 Jiazabishikuro [3-3.1] nonane one 3-force carboxylic acid (4 one black port benzyl) § Mi Dofumaru salt

7- (tert one butoxycarbonyl) Single 2- Okiso one 3,7 Jiazabishiku port [3.3.1] than nonane one 3-force carboxylic acid (4 one black port benzyl) amino-de (664 mg), Example 6 - to give the title compound (343 mg) in b) and the same method.

Example 1 4-6 0

In the same manner as in Example 1 3, the following compounds were synthesized.

2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane - 3 Power carboxylic acid - (3 - chloro port benzyl) Ryomi Dofumaru salt (Example 1 4)

2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid - (2 - chloro port benzyl) amino Dofumaru salt (Example 1 5)

2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (4 one Furuorobenjiru) amino Dofumaru salt (Example 1 6)

2 Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (3 Furuorobenjiru) amino Dofumaru salt (Example 1 7)

2 Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (2 Furuorobenjiru) amino Dofumaru salt (Example 1 8)

2 - Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane - 3-carboxylic acid - (4 - Main Tokishibenjiru) amino Dofumaru salt (Example 1 9)

2 - Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (3 - Main Tokishibenjiru) Ryomi Dofumaru salt (Example 2 0)

2 - Okiso - 3,7 Jiazabishikuro [3.3.1] nonane one 3-carboxylic acid i (2 main Tokishibenjiru) amino Dofumaru salt (Example 2 1)

2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (3, 4 Jime Tokishibenjiru) amino Dofumaru salt (Example 2 2)

2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (3, 4,. 5-trimethyl Tokishibenjiru) amino Dofumaru salt (Example 2 3) 2- Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid

(3, 4-methylenedioxy O alkoxybenzylacetic) § Mi Dofumaru salt (Example 24) - Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid

[4 one (Benjiruokin) benzyl] amino Dofumaru salt (Example 2 5)

- Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid

[3, 4-di (Benjiruokishi) benzyl] § Mi Dofumaru salt (Example 2 6) - Okiso one 3,7 Jiazabinkuro [3.3.1] nonane one 3-force carboxylic acid

(4 one Benjiruokishi 3 main Tokishibenjiru) § Mi Dofumaru salt (Example 27) - Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid

(3-chloro 4-menu Tokishibenjiru) § Mi Dofumaru salt (Example 28) - Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid

(3 Furuoro 4-menu Kishibenjiru) § Mi Dofumaru salt (Example 2 9) - Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid

(2-methylbenzyl) amino Dofumaru salt (Example 3 0)

- Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3 - carboxylic acid

(3-methylbenzyl) § Mi Dofumaru salt (Example 3 1)

- Okiso one 3,7 Jiazabinkuro [3.3.1] nonane one 3-force carboxylic acid

(4 one-methylbenzyl) § Mi Dofumaru salt (Example 3 2)

- Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3 - carboxylic acid

(2-triflate Ruo b methylbenzyl) § Mi Dofumaru salt (Example 3 3)

- Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one-3-carboxylic acid

(3-triflate Ruo b methylbenzyl) § Mi Dofumaru salt (Example 3 4)

- Okitsu 3,7 Jiazabinkuro [3.3.1] nonane one-3-carboxylic acid

(4 one triflate Ruo b methylbenzyl) § Mi Dofumaru salt (Example 3 5)

- Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid

(4-dimethyl § amino benzyl) § Mi Dofumaru salt (Example 3 6)

- Okiso one 3,7 Jiazabinkuro [3.3.1] nonane - 3-force carboxylic monobasic (4-E butoxy benzyl) amino Dofumaru salt (Example 3 7)

2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (one Fuwenirupenjiru) § Mi Dofumaru salt (Example 3 8)

2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (3, 4 Jikuro port benzyl) § Mi Dofumaru salt (Example 3 9)

2 Okitsu 3, 7 - Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (2-thienyl) Mechiruami Dofumaru salt (Example 4 0)

2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3 - carboxylic acid i (pyridin - 3-Irumechiru) § Mi Dofumaru salt (Example 4 1)

2 Okiso one 3. 7- Jiazabinkuro [3.3.1] nonane - 3-carboxylic acid i (pyridin one 4-I le - methyl) A Mi Dofumaru salt (Example 4 2)

2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid - (naphthalen one 2-Irumechiru) amino Dofumaru salt (Example 4 3)

2 Okiso one 3,7 Jiazabinkuro [3.3.1] nonane one 3-force carboxylic monobasic (2-naphthyl) amino Dofumaru salt (Example 4 4)

2 Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid - (naphthalen one 1 Irumechiru) amino Dofumaru salt (Example 4 5)

2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid - Fuwenechiruami Dofumaru salt (Example 4 6)

2 Okiso - 3,7 Jiazabinkuro [3.3.1] nonane one 3-carboxylic acid - (2-menu Tokishifuenechiru) amino Dofumaru salt (Example 4 7)

2 Okiso one 3, 7 - Jiazabinkuro [3.3.1 门 nonane one 3-carboxylic acid i (3 main Tokishifuenechiru) amino Dofumaru salt (Example 4 8)

2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid - (4-menu Tokishifuenechiru) Ryomi Dofumaru salt (Example 4 9)

2 Okiso one 3. 7- Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid - Puropiruami Dofumaru salt (Example 5 0) 2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid Shikurobu port Piruami Dofumaru salt (example 5 1)

2 Okiso one 3,7 Jiazabishikuro [3.3.1 nonane one 3-force carboxylic monobasic Isopuchiruami Dofumaru salt (Example 5 2)

2 Okiso one 3,7 Jiazabinkuro [3.3.1] nonane one 3-force carboxylic acid Shikurobu port Pirumechiruami Dofumaru salt (Example 5 3)

2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (2 Mechiruburo Bae sulfonyl) amino Dofumaru salt (Example 5 4)

2 - Okitsu 3, 7 - Jiazabishikuro [3.3.1] nonane one 3 - carboxylic acid over cyclobutyl amine Dofumaru salt (Example 5 5)

2 - Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid over cyclopentyl Ami Dofumaru salt (Example 5 6)

2 - Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid Shikuro to Kishiruami Dofumaru salt (Example 5 7)

2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid - (2, 2.3, 3-tetramethyl cyclopropyl) amino Dofumaru salt (Example 5 8)

2 - Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid - hexyl methyl amino Dofumaru salt cyclohexane (Example 5 9)

2 Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid over cyclopentylmethyl § Mi Dofumaru salt (Example 6 0)

Example 6 1

2 Okiso one 3,7 Jiazabinkuro [3.3.1] nonane one 3-force carboxylic acid (4-hydroxycarboxylic benzyl) amino Dofumaru salt

a) 7 - (tert one butoxycarbonyl) Single 2 Okitsu 3, 7 - Jiazabishi black [3.3.1] nonane one 3-force carboxylic acid (4 one base Nji 儿 Okishibenjiru) § Mi de, Example 1 3 - in the same way as a), using the 4 one black port full sulfonyl ^ 4 one base Nji Ruo carboxymethyl off We sulfonyl S acid instead of acid (820 mg), example 1 one: obtained in f) 7- (tert- butoxyethyl Kin carbonyl) one 3,7-Jiazabishikuro [3.3.1] nonane one 2 - was obtained from the oN (409 mg) to give the title compound (805 mg).

b) 7- (tert one butoxycarbonyl) Single 2 Okitsu 3, 7 - Jiazabishi black [3.3.1] nonane one-3-carboxylic acid (4 - arsenate mud Kin benzyl) amino-de-7 - (tert one butoxycarbonyl ) Single 2 Okitsu 3,7 Jiazabishiku port [3.3.1] nonane one 3-force carboxylic acid (4 one-benzyl O alkoxybenzylacetic) Ami de (533 mg) in methanol (10 ml) 1 solution 0% palladium one added carbon (lOmg), under a hydrogen atmosphere and stirred at room temperature for 1 hour. The reaction mixture was concentrated after 澳過 to give the title compound (354 mg).

c) 2-Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid (4-hydroxycarboxylic benzyl) § Mi Dofumaru salt

7 - (tert one butoxycarbonyl) Single 2 Okifu 3,7 Jiazabishiku port [3.3.1] than nonane one 3-force carboxylic acid (4-hydroxycarboxylic benzyl) amino-de (340 mg), Example 6 - to give the title compound (llOmg) with b) and the same method.

Example 6 2, 6 3

In the same manner as in Example 6 1, the following compounds were synthesized.

2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-carboxylic acid i (3, 4 dihydric mud alkoxybenzylacetic) Ami de hydrochloride (Example 6 2)

2 - Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3 - carboxylic acid i (4-arsenide Dorokishi 3 main Tokishibenjiru) Ryomi Dofumaru salt (Example 6 3) Example 6 4

3- (N, N-dimethylcarbamoyl) one 3,7-Jiazabishikuro [3.3.1] nonane - 2-one fumarate

a) 7- (tert Butokinkarubo sulfonyl) - 3- (N, N-dimethyl carbamyl model I Le) Single 3 ... 7 - Jiazabishikuro [3.3.1] nonan one 2-one Example 1 one: f ) obtained in 7 - (tert one but-kin carbonyl) one 3, 7 - Jiazabishikuro [3.3.1] nonane one 2 - N oN (600 mg), N-Jimechiruho ​​Le 厶 § mi de solution (12Ral) to under ice-cooling, potassium one tert - was stirred for 20 minutes at room temperature was added butoxide (841 mg). The reaction mixture was ice-cooled, N. N-dimethyl carbamyl mode Iruku port Lai de a (0.690ml) was added, followed by stirring for 2 0 minutes. The reaction mixture Note technique into water, and extracted with black port Holm and 囊縮 dried over anhydrous sodium sulfate, the ZanKiyoshi silica gel column chromatography and purified by (eluent black hole Holm first mixing solvent of methanol) to give the title compound (549 mg).

b) 3 - (N, N-dimethylcarbamoyl) one 3,7-Jiazabishikuro [3.3.1] nonane one 2- one fumarate

7 - (tert one butoxycarbonyl) Single 3- (N, N-dimethyl carbamoylthiopheno Le) one 3, 7 - Jiazabishikuro [than 3. 3. 门 nonan one 2-one (540 mg), Example 6 - b) and to give the title compound (66.0 mg) in a similar manner.

Example 6 5

In a similar manner to Example 64, 3- (Biperijin one 1 one carbonyl) one 3,7-Jiazabishikuro [3.3.1] nonane one 2 - was synthesized fumarate.

Example 6 6

3- Asechiru one 3,7 Jiazabinkuro [3.3.1] nonane one 2 - one hydrochloride

a) 3 - Asechiru 7- (tert-but Kin carbonyl) one 3, 7 - Jiazabi cyclo [3.3.1] nonan one-2-one

Example 1 one: 7 obtained in f) - a (tert one but-kin carbonyl) one 3,7-Jiazabishikuro [3.3.1] anhydrous nonane one 2-one (2.30 g) 齚酸 (Loral) It was added and heated at 1 2 0 hands. Methanol (15ml) was added to the reaction solution, followed by extraction with concentrated 齚酸 Echiru addition of a saturated aqueous sodium bicarbonate solution. The organic layer 5% potassium hydrogen sulfate solution, saturated sodium bicarbonate solution, successively washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated to give the title compound (2.45 g). b) 3- Asechiru 3, 7 - Jiazabishikuro [3.3.1] nonan one-2-one salt salt

Three to Asechiru 7 - (tert-butoxycarbonyl) one 3, 7 - Jiazabin black [3.3.1] in dichloromethane (8 ml) solution of nonane one 2-one (L.OOg), under ice-cooling, Torifuruoro acetate ( 8ml) was added and stirred for 30 minutes to. The reaction was 囊縮, basified with potassium carbonate added saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane. The organic layer was 澳縮 dried over anhydrous sulfate Na preparative potassium. The residue was dissolved in acetic acid Echiru (lOral), 0. 2 N hydrogen chloride - concentrated after stirring for 1 hour was added dropwise acetic acid Echiru (12 ml). To give the title compound (395 mg) by recrystallizing the residue from ethanol.

Example 6 7

3 - Bibaroiru 3,7 Jiazabishikuro [3.3.1] nonane one 2 - one salt salt

a) 7- (tert one butoxycarbonyl) Single 3 Bibaroiru 3,7 Jiaza bicyclo [3.3.1] nonan one-2-one

Example 1 - f) obtained in 1 - (tert - but-Kin carbonyl) one 3, 7-Jiazabinkuro [3.3.1] dichloromethane nonane one 2-one (1.20 g) (12 ml) solution, under ice-cooling, and the mixture was stirred for 2 0 min at room temperature was added a Bok Riechiruami emissions (2.09 ml) and Pibaroiruku port Lai de (1.23 ml). 5% potassium bisulfate water (15ml) was added to the reaction solution, and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried and concentrated over anhydrous sodium sulfate to give the title compound (1.57 g).

b) 3 - Bibaroiru 3,7 Jiazabishikuro [3. 3. I] nonane one 2 - one Example a 1 one h) similar to the method 7- (tert-butoxycarbonyl) Single 3 - pivaloyl one 3, 7 - Jiazabinkuro [3.3.1 门 nonane one 2 - was obtained from oN (1.57 g) to give the title compound (685 mg).

Example 6 8

3 base Nji Ruo carboxymethyl carbonylation Lou 3,7 Jiazabishikuro [3.3.1] non Hmm 2- one fumarate

a) 3 one base Nji Ruo carboxymethyl carbonylation Lou 7- (tert-butoxycarbonyl) one 3,7-Jiazabishikuro [3.3.1] nonan one-2-one

Example 64 - by a) similarly to the method, N, with benzyl O butoxycarbonyl chloride Lai de (0.891ml) in place of N- dimethylcarbamoyl chloranil I de, Example 1 - obtained in f) 7- (tert- butoxycarbonyl) one 3,7-Jiazabi cyclo [3.3.1] nonane one 2 - to give the title compound than on (500 mg) and (399 mg). b) 3- base Nji Ruo carboxymethyl carbonylation route 3, 7 - Jiazabishikuro [3.3.1] nonane one 2- one fumarate

Three to benzyl O Kin carbonylation Lou 7- (tert-butoxycarbonyl) one 3,7-Jiazabinkuro [3.3.1] dichloromethane nonane one 2-one (389 mg)

To (3 ml) solution, under ice-cooling, and the mixture was stirred added 3 0 minutes Torifuruoro acetate (3rol). The reaction was 瘻縮, basified with potassium carbonate was added saturated sodium bicarbonate water, issued extracted with dichloromethane. The organic layer was dried and concentrated over anhydrous sodium sulfate. The ZanKiyoshi acme Bro Banoru

Was dissolved in (5 ml), iso-Bro Banoru (20ml) solution was added concentrated fumarate (80 mg), to give the title compound (175 mg) The residue was recrystallized from acme Bro Banoru.

Example 6 9, 7 0

(1 R, 5 S) - (+) - 2-Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid cyclopentyl Rua Mi Dofumaru salt (Example 6 9) and (1 S, 5 R) - (I) one 2- Okiso one 3. 7- Jiazabinkuro [3.3.1] nonane one 3-force carboxylic acid cyclopentyl Rua Mi Dofumaru salt (example 7 0) a) 3, 7 - Jiazabishikuro [3.3.1] nonane-one-2-one

Example 1 one f) obtained in 7- (tert one butoxycarbonyl) one 3, 7 - Jiazabinkuro [3.3.1] 1 nonane one 2-one (6.40 g), 4 - Jiokisan (50ml) solution in 4 N hydrogen chloride one 1, 4 - Jiokisan (50ml) was added and stirred for one hour at room temperature. Potassium carbonate to the reaction solution was concentrated, and the residue (5.51 g) aqueous solution was extracted sequentially added 5% ethanol one black port Holm sulfuric anhydride Na Toriu 厶 to give the title compound Ri by the concentrating the (2.98 g).

b) (1 R, 5 S) - 3, 7- Jiazabinkuro [3.3.1] nonan one-2-one L- tartrate and (1 S. 5 R) - 3, 7- Jiazabinkuro [3.3. 1] non Hmm-2-one D- tartrate

3,7 Jiazabishikuro [3.3.1] nonane one 2 - ethanol on L one tartrate in water bath Te 8 0 to ethanol solution (30ml) of (2.98g) (1.60g) (35ml) - water ( 7ml) mixed solution and the mixture was left for 1 at room temperature for 20 hours. The crystals were collected by filtration to precipitate recrystallized from a mixture of methanol and water (1 R. 5 S) - 3, 7 - Jiaza bicyclo [3.3.1] nonan one-2-one L one-tartrate a (1.20g) was obtained. Further, potassium carbonate to the residue and concentrating the filtrate (996 mg) aqueous solution, leaving the oil sequentially pressurizing example 5% ethanol over chloroform anhydrous sodium sulfate, concentrated, and dissolved Zan'niwatazumi in ethanol (20ml) 8 0 ° C on a water bath in D- ethanol tartrate (1.06g) (30ml) - it was allowed to stand at room temperature added water (6 ml) mixed solution for 48 hours. By then 據取 precipitated crystals recrystallized from a mixture of methanol and water (1 S, 5 R) - 3. 7- Jiazabishikuro [3.3.1] nonane - 2 - one D- tartrate (771 mg) It was obtained.

c) (1 R, 5 S) - 7- (tert - but-Kin carbonyl) one 3,7-Jiaza bicyclo [3.3.1] nonan one 2-one and (1 S, 5 R) - 7 - ( tert one but-kin carbonyl) one 3,7-Jiazabishikuro [3.3.1] nonan one-2-one

(1 R, 5 S) - 3, 7- Jiazabishikuro [3-3.1] nonane one 2 - On-L one-tartrate 1, 4 one Jiokisan (20nil) - water (20ml) mixture, under ice-cooling the baking soda (1.36 g) and di-tert- butyl carbonate (832 mg) was added and stirred for 1 8 h at room temperature. The reaction solution was extracted with black port Holm, washed with water, dried and concentrated over anhydrous sodium sulphate 厶, (1 R. 5 S) - 7- (tert- butoxycarbonyl) - 3, 7 - Jiazabishikuro [3 . 3.1] nonane one-2-one (892 mg). Similarly (1 S, 5 R.) - 3, 7 - Jiazabishiku port [3.3.1] than nonan one-2-one D- tartrate (751mg) (IS, 5 R) - 7 - (tert one Butokinkarubo two Le) one 3,7-Jiazabishikuro [3.3.1] nonane one 2 - was obtained on (583 mg). d) (1 R, 5 S) - 7- (tert- butoxycarbonyl) Single 2- Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3 - carboxylic acid cyclopropyl ventile ami de and (1 S , 5 R) - 7 - (tert one butoxycarbonyl) Single 2- Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3-carboxylic acid cyclopentyl ami de

Using Shikurobe Ntankarubon acid instead of 4 one Kurorofuweniru acetate in Example 1 3- a) and the same method, (1 R, 5 S) - 7- (tert- butoxycarbonyl two Le) one 3,7 Jiazabinkuro than [3.3.1] nonane-one-2-one (240mg)

(1 R, 5 S) - 7- (tert- butoxycarbonyl) Single 2 Okitsu 3, 7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid cyclopentyl ami de

The (350mg) was obtained. Further, (1 S, 5 R) - from (tert- butoxycarbonyl two Le) one 3,7-Jiazabishikuro [3.3.1] nonan one 2-one (200 mg) - 7

(1 S, 5 R) - 7- (tert- butoxide Kin carbonyl) Single 2 Okitsu 3, 7 one Jiazabinkuro [3.3.1] nonane one 3-force carboxylic acid cyclopentyl ami de

The (253mg) was obtained.

e) (1 R, 5 S) - (+) - 2- Okiso one 3, 7 - Jiazabinkuro [3.3.

1] nonane one 3-force carboxylic acid cyclopentyl amino Dofumaru acid salt and (1 S. 5 R) Single (one) one 2- Okiso one 3, 7 - Jiazabinkuro [3.3.1] nonane one 3-force carboxylic acid cyclopentyl Ami Dofumaru salt

(1 R, 5 S) - 7- (tert- butoxycarbonyl) Single 2- Okiso one 3,7 Jiazabishikuro than [3.3.1] nonane one 3-force carboxylic acid cyclopentyl ami de (345 mg), Example 6 - b) in the same manner as in (1 R. 5 S) - (+) - 2 - Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid cyclopropyl Penchiruami Dofumaru salt ( 17½g) was obtained. Further, (IS, 5 R) - 7 - than (tert one butoxycarbonyl) Single 2- Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid cyclopentyl Rua mi de (250 mg) ( 1 S, 5 R) Single (one) one 2- Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3 - to obtain a force carboxylic acid cyclopentyl Ami Dofumaru salt (130 mg).

Example 7 1-76

In the same manner as in Example 6 9, 70, the following compounds were synthesized.

(1 R. 5 S) - (+) - 2 - Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (3, 4-dimethyl Tokishibenjiru) § Mi Dofumaru salt (example 7 1)

(1 S, 5 R) - (-) one 2 - Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3 - carboxylic monobasic (3, 4-dimethyl Tokishibenjiru) A Mi Dofumaru salt ( example 72)

(1 R, 5 S) - (+) - 2 - Okiso one 3,7 Jiazabinkuro [3.3.1] nonane one 3-force carboxylic monobasic (4 Ichime Tokishibenjiru) § Mi Dofumaru salt (embodiment example 73)

(1 S, 5 R) - (I) one 2 - Okiso one 3,7 Jiazabishikuro [3.3.1] nonane - 3-carboxylic acid (4-menu Tokishibenjiru) § Mi Dofumaru salt (Example 74)

(1 R, 5 S) - (+) - 2 - Okitsu 3, 7 - Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (3-chloro-4 Ichime Tokishibenjiru) amino Dofumaru salt ( example 75)

(1 R, 5 S) - (+) - 2- Okitsu 3, 7 - Jiazabinkuro [3.3.1] nonane one 3-force carboxylic monobasic (3 Furuoro 4-menu Tokishibenjiru) Ami Dofuma Le salt (example 76)

Example 7 7

(1 R, 5 S) - 2 -. Okiso one 3. 7- Jiazabishikuro L3 3. 1] nonane one three to force carboxylic acid (4-menu Tokishibenjiru) Ami de 'fumarate

Prepared from a) 5-Bromo-nicotinic acid Echiru (1) 5-bromo-nicotinic acid

H00C B EtOOC Br In ethanol (375 ml) solution of hydrochloric acid (about 18 g) 5 - bromo nicotinic acid (LOOG.

After refluxing for 2 4 hours added 495 mmol), the reaction solution was vacuum Umichijimi. Water to ZanKiyoshi

After addition of hexane (400ral) (150ml) and to, it was neutralized with sodium hydrogen carbonate (36 g). The organic layer was washed min 雜後 in hexane fart aqueous layer (15 (kl, each once with 100ml) again extracted. The organic layer were combined and saturated brine (100ml). Anhydrous sodium sulfate (30 g) and was heated for 10 minutes at 50'C with addition of active charcoal (10 g). insoluble material was removed by filtration through Celite bets, blink pressure combined and concentrated washed. 滤液 and washings with hexane (250 ml) to it the 5 -. bromonicotinate Echiru (97. 8 g give † this yields 865 as colorless crystals.

'H-NMR (CDC) 1. 42C3H. T. J = 7Hz), 4. 43 (2H. Q. J = 7Hz), 8. 43 (1H. T. J = 2Hz). 8, 84 (1H, d. J = 2Hz). 9. 13 (1H. d. J = 2Hz)

Mp 40-4 l e C,

(2) Production of nicotinic acid

H00C EtOOC Br i) a method that does not use a solvent

Nicotinic acid (2. 0 g), bromine (3. 11g), a mixture of Chioniru chloride (2. 32 g), 0 "C After stirring for 4 hours at (external temperature), add bromine (1. 30 g) further, after stirring for 13 hours at the same temperature. within the temperature was cooled to 40 e C, ethanol was added dropwise (0. 90 g). after攆拌20 minutes at the same temperature, at an internal temperature of 80 hands and 擾拌 30 minutes. the reaction solution was returned to room temperature, the butane (13. 0 ml) and water (7. 6 ml) was. with stirring under ice-cooling, sodium bicarbonate was added added and the reaction solution was made basic after separation was decolorized by adding Chio sodium sulfate. the organic layer was re-extracted with butane f water S (1.5mlx 2). the combined organic layer was washed with saturated brine (5 ml), anhydrous dried over sodium sulfate, filtered, the Rukoto to concentrate, obtained by 5-bromo-nicotinic acid Echiru (3.30 g, 88% yield) as light yellow crystals.

Methods using ii) a solvent

1. 2-dichloroethane port benzene suspension of nicotinic acid (100 g), under a nitrogen atmosphere at 70 e C (external temperature) under擾拌, bromine (41.9 g) and chloride Chioniru (71. lg) It was successively dropped. After completion of the dropwise addition, 0.99 'C after 1.5 hours 攬拌 at (external temperature) was added bromine (41.9 g). 180. After 13 hours 攢拌 at C (external temperature) was further added bromine (12.5 g). After stirring for 3 hours, the reaction solution was cooled to 50 hands. After ethanol was added dropwise (44.9 g) to the reaction solution, followed by stirring for 30 minutes at 80 ° C. The reaction solution was returned to room temperature, acetic acid Echiru (100 ml), were successively added butane (75 ml) and ethanol (5ml) to and 攙拌 between 12 at room temperature. The precipitate was 澳取, and lavage with acetic acid Echiru (300 ml), air dried. Obtained was suspended in butane f salt of the desired product (221g) (750ml) and water (750 ml), under 擾拌, it was added sequentially carbonate force potassium (95.5 g) and Chio sodium sulfate (I07g). After confirming that the salt was completely dissolved, the layers were separated. It was re-extracted with butane fart and the aqueous layer (100ml). The combined organic layer was successively washed with water (500 ml X2) and brine (500 ml), dried over anhydrous sodium sulfate, filtered after, and concentrated to 5-bromo-nicotinic acid Echiru (123 g, yield: 67%) as a pale yellow crystal.

b) 5- Shianonikochin acid Echiru

CN

(1) Nitrile reduction by copper cyanide

Cyanide (I) (98%, 45.68g. 500 Yuzuru ol) and the step a) obtained in 5 pro Monikochin acid Echiru (100g. 435mmol) dimethylformamidine de (500 ml) suspension of nitrogen atmosphere, and refluxed for 4 hours. Acetic acid Echiru The reaction solution was cooled to an inner temperature of 50'C (500ml), were added sequentially 5 potassium carbonate solution (100ml). The 3.25N sodium hypochlorite aqueous solution (360 ml) was added dropwise over 25 minutes to keep the ~ a 內温 Te 30 40'C, and stirred for 1 hour at the same temperature. Thereafter, it was slowly added 28% aqueous ammonia 內温 the a (45ral) so as to maintain the at ~ on 20 30, and separated. The Mizu屨 was re-extracted with acetic acid Echiru (lOOnil). The combined organic layers 10¾ brine (200 ml), washed successively with saturated brine (450 ml). The organic layer activated carbon (6 g) was added to 攬拌 30 minutes at room temperature, after 據去 insolubles, and the filtrate was concentrated under reduced pressure. The ZanKiyoshi methanol (200 ml) - by crystallization from water (500 ml), 5 - the Shianonikochin acid Echiru (. 58.83g 77% yield) as pale yellow crystals.

Ή-NM (CDCh) 1.44C3H, t. J = 7Hz). 4.46C2H. Q. J = 7Hz). 8.57 (1H. T. J = 2Hz). 9.04 (1H, t. J = 2Hz). 9.40 ( 1H. t. J = 2Hz)

FAB MS (m / z) 177 (MH +), 149. 136

Te melting point 85-87

(2) Nitrile reduction by nickel catalyst

Bu ll. C h em. S o c. J p n., Was Nitrile reduction in the same manner as described in 6 1, 1 9 8 5 (1 9 8 8). Nickel bromide () (2.85 g, 13.1 strokes ol), zinc dust (2.56 g. 39.2 mmol) and Application Benefits Fueniruhosufi down (13.7 g, 52.2 mmol) in mixed compounds of under argon atmosphere, Asetonitoriru (300ml ), and the mixture was stirred for 1 hour at an internal temperature of 60 hands. Sodium cyanide in the reaction mixture (23.5 g, 479 瞧 ol) was added and after 攬拌 20 minutes, the obtained in step a) 5-bromo-nicotinic acid Echiru (LOOG. 435 瞧 ol) of Asetonitoriru (100ml) It was added, followed by stirring while the inner temperature 60 e C. After 22 hours, the reaction solution was allowed to cool, acetic acid Echiru (200ml) and 5 aqueous potassium carbonate (100ml) was added and 攙拌 30 minutes at room temperature. Further ice-cooled and stirred for 30 minutes by adding 10% aqueous sodium hypochlorite solution to (150 ml), the layers were separated. The Mizuyatoi was re-extracted with acetic acid Echiru (100ml). The organic layers were combined, mixed solution of saturated aqueous sodium chloride solution (50ml) and consisting of water (50ml), and washed sequentially with 3N hydrochloric acid a50ml). The aqueous layer separated in washing with 3N hydrochloric acid and re-extracted with acetic acid Echiru (100ml). The combined organic layer was washed with saturated brine (50ml) and consisting of water (50ml) mixture, was washed with saturated brine (100ml). The organic layer was Drying over anhydrous sodium sulfate, after Omonbakayogi and vacuum S reduced. Methanol Zan'niwatazumi (150 ml) - by crystallization from water (Oral), 5-Shianonikochin acid Echiru (59.1 g, yield 77D as a white crystalline.

(3) Nitrile reduction by a palladium catalyst

Bu ll. Ch em. S o c. J p n., Was Nitrile reduction in the same manner as described in 4 8, 329 8 (1 9 7 5). Step a) above obtained 5-bromo nicotine acid Echiru (800 mg), iodine Kaka potassium (58 mg), palladium acetate (77 mg :), Xia emissions potassium (453 mg) and potassium t- butoxide (78 mg) 1.3-dimethyl-2-imino Dazorijinon suspension was stirred for 4 hours at an inner temperature of 120 hands under an argon atmosphere. Pour reaction solution into water and extracted with toluene. The organic layer was dried over anhydrous sodium sulfate, after 濂過, and concentrated under reduced pressure. ZanKiyoshi by silica gel column chromatography (acetic E Chi le: hexane = 1: 3) to give 5-Shianonikochin acid Echiru (438 mg, yield 71) as white crystals.

c) 5- amino Mechirubi base Li Jin one 3-force carboxylic acid Echiru dihydrochloride

EtOOC CN EtOOC

Autoclave obtained in the above step b) 5 -.. Shianonikochin acid Echiru (20.0 g U4 strokes ol), platinum oxide (l.OOg, 5% wt) and hydrochloric acid (16.6 g 4 eq) / ethanol

The (300 ml) was added, under an atmosphere of hydrogen (5kg / cm 2), after 8 hours攬拌at 50 hands, and stirred for 1 hour at 70 e C. After the product was dissolved by adding methanol (200ml) to the reaction solution, it was filtered off catalysts.濂液 was concentrated under reduced pressure and the residue toluene (50 ml X 2) at by azeotropic 5 amino Mechirubiperijin one 3-force carboxylic acid Echiru dihydrochloride crude product as a main component a (32.3 g) It was obtained as a yellow amorphous solid.

• H-NM (D S0- d 6) 1.24C3H. T. J = 7.5Hz), 1.73 (1H. M). 1.98 (1H. M). 2.20 (2H. M). 2.5-3.4 (6H, m ). 4.11 (2H, q. J = 7.5Hz)

FAB S (m / z) 187. 136

Mp 240-247 (dec.)

d) 7- base Njiru one 3, 7 - Jiazabishikuro [3.3.1] nonan one-2-one

EtOOC The crude product obtained in the above step c) to (32.3 g), methanol (300 ml) and 28% Na Toriumume Tokishido methanol (66.0 g, 342 mmol) and the mixture was refluxed for 2 hours. To the reaction solution of that, it was added dropwise acetic acid (6.57tnl. L mmol), potassium carbonate (15.8 g. 114 mmol), Benjirukurori de (17.1 ml. 149 mmol) was added and refluxed again for 4 hours. To the reaction solution of its acetate (13. lml, 228mraol) was added followed by vacuum S reduced. 10% click E phosphate aqueous ZanKiyoshi (100 ml) - it was partitioned 醉酸 Echiru (80 ml). It was further extracted with the organic layer with 10% Kuen acid water solution (60ral. 40ml once each). The combined aqueous 曆 added 攙拌 Shinano grounds potassium carbonate at room temperature to a pH 9~l 0, and extracted with acetic acid Echiru (160 ml, 60 ml each once). The organic layers were combined, washed with saturated brine (50ml), dried over anhydrous sulfate Ma Guneshiumu, filtered, and concentrated under reduced pressure. Crystallization from acetic acid Echiru (60 ml) and ZanKiyoshi, 7- base Njiru 3, 7 - Jiazabishikuro [3.3.1] yield from Nona Hmm 2-one (16.3 g) (5-Shianonikochin acid Echiru 62%) as a pale yellow binding.

Ή-NR CCDCh) 1.7K1H. D. J = 12.5Hz). 1.98 (lH.d. J = 12.5Hz). 2.10 (lH.br s), .20C1H. D. J = 12Hz). 2.24 (1H. dd. J = 2.5 and 11Hz). 2.53 (1H, br s).

.79 (1H. D. J = llHz). 3.19 (1H, d. J = 12Hz), 3.23 (1H, d. J = 12Hz).

.36 (lH.d. J = 13.5Hz). 3.48 (lH.dd. J = 6.5 and 12Hz). 3.60 (1H. D. J = 13.5Hz), .00dH.br s), 7.1-7.3C5H. m)

FAB MS (m / z) 231 Jiazabishikuro [3.3.1] Roh

The step d) obtained in 7- base Njiru 3,7 Jiazabishikuro [3.3.

1] nonane - 2-one in methanol (1.0 1) solution of (200 g), at room temperature, (I) over di Benzoiru L one tartrate (L one DBTA) - methanol hydrate (326.8g) (2.0

1) was added, seed crystals (7 mg) was added and stirred for 1 8 h at room temperature. Were collected ¾ The precipitated crystals were washed with ethanol (600 ml). Was dissolved by the resulting crystals are refluxed in ethanol (4.0 1), it was returned S 拌下, to room temperature. Were collected filtration of the separated crystals washed with ethanol (400 ml), and dried (1 R, 5 S) - 7 - benzyl-3,7-Jiazabinkuro [3.3.1] nonane one 2 - On one L one DB TA salt (180.26g, 35.3% yield, 99.5% ee, or higher) was obtained as colorless crystals.

Ή-NMR (DMS0-d e ) 1.59C1H. D. J = 13Hz). 1.82 (lH.d. J = 13Hz). 2.06 (lH, br s). 2.13C1H. D. J = llHz). 2.22 ( 1H. d. J = llHz). 2.25C1H. br s). 2.79 (1H, d. J = llHz). 2.93 (1H. d. J = llHz). 3.05 (1H. d. J = 12Hz). 3.32 C1H. dd. J = 6.5 and 12Hz),

3.46C1H. D. J = 13Hz). 3.5K1H. D. J = 13Hz). 5.86 (2H. S), 7.2-8. K15H, m)

FAB MS (m / z) 231

Mp 177-179'C (dec.)

[A] D = -92.6. (C = 1.09. DMF)

(1 R, 5 S) - 7 - benzyl-3, 7 - Jiazabinkuro [3.3.1] non Hmm 2-one one L-DBTA salt (75.0 g, 127 Yuzuru ol) in toluene (375 ml) and water (225 ml suspended in a mixture of), under 攬拌 was added dropwise aqueous potassium carbonate (potassium carbonate 35.22g water 75 ml). The mixture was partitioned and the aqueous layer was re-extracted with toluene (150ral). The organic layer ^ combined, dried over anhydrous magnesium sulfate, filtered, by enrichment reduced pressure to a volume of about 1/3 (1 R, 5 S) - 7- base Njiru 3,7 Jiazabishikuro [3.3. 1] nonane one-2-one in toluene (156 g). This solution was used as it is next reaction.

'.eta. Anonymous (CDC) 1.7K1H. D. J = 12.5Hz). 1.98C1H. D. J = 12.5Hz). 2.10ClH.br s). 2.20C1H. D. J = 12Hz). 2.24 (1H. dd. J = 2.5 and 11Hz). 2.53 (1H. br s),

2.79C1H. D. J = llHz). 3.19C1H. D, J = 12Hz). 3.23 (1H. D. J = 12Hz).

3.36C1H. D. J = 13.5Hz). 3.48 (1H, dd. J = 6.5 and 12Hz). 3.60 (1H. D. J = 13.5Hz). 6.00ClH.br s). 7.1-7.3C5H. M)

FAB MS (m / z) 231

Mp 108-110 e C

[A] D = -42.7 ° (c-1.02. DMF)

f) (1 R, 5 S) - 7- benzyl one 2- Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid (4-menu Tokishibenjiru) § Mi de

The step e) obtained in (1 R, 5 S) - 7- base Njiru 3, 7 - Jiazabishi black 3.3.1] 4-toluene solution U56g) nonane one-2-one main Tokishiben Jiruison'ana one DOO (18.40ml. 127 noodles ol) and Toryechiruamin (1.78 ml, 12.7 hidden ol) was added reflux. After 30 min, to calculate the deficiency of the 4-main Bok alkoxybenzylacetic Lee knot holes one Bok by high performance liquid chromatography analysis, after 1 hour, added the shortfall of (0.87 ml. 6.03mmol). After refluxing for further 30 minutes, the reaction solution was cooled with ice. The insolubles were 據去 using Serai door, which was washed with cold toluene (100ml). ¾ solution 5¾ Beautique phosphate solution, saturated sodium hydrogen Natoriumu solution, and a saturated brine (each 50ml). The c insoluble matter was stirred at room temperature for 30 minutes over anhydrous magnesium sulfate and activated carbon (1.47 g) was 據去 was concentrated ¾ solution. The residue ethanol (60ml) are added to, and vacuum enrichment again (1 R, 5 S) - 7- benzyl one 2 - Okiso one 3, 7 - Jiazabishikuro

Was obtained - (main Tokishibenjiru 4) Ami de (51.4 g 103% yield.) Pale yellow oil saphenous composed mainly of [3.3.1] nonane one 3-force carboxylic acid. Which was used in the next reaction c 1 H-NMR (CDCh) 1.72C1H. D. J = 13Hz). 1.97 (1H. D. J = 13Hz). 2.20-2.30 (3H. M).

2.65 (1H. Br s). 2.86C1H. D. J = 10Hz). 3.12 (1H. D. J = llHz). 3.4K1H. D. J = 13.5Hz).

3.50 (lH.d. J = 13.5Hz). 3.70-3.90C5H. M), 4.46 (1H. Dd. J = 5.5 and 14.5Hz).

4.52 (lH, dd. J = 5.5 and 14.5Hz). 6.85-6.90 (2H.m). 7.10-7.35 (7H. M),

9.83 (1H, br s)

FAB MS (m / z) 394, 272. 229, 121

[] D = +17.5 ° (c = 1.08. DF)

g) (1 R, 5 S) - 2- Okiso one 3,7 Jiazabishikuro [3.3.1] non Hmm 3- force carboxylic acid (4-menu Tokishibenjiru) § Mi de

Obtained in the above step f) (1 R, 5 S) - 7- base Njiru 2 Okitsu 3, 7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic acid (4-menu Tokishibenji Le) ami de of 5% palladium one carbon of ethanol (490 ml) solution of the crude product (51.40g)

(Water content 55) a (7.36 g) was added, under hydrogen atmosphere (5 kgf / cm 2), it was at an internal temperature of 60 for 5.5 hours攬拌. The catalyst was filtered off, the way to push washed with ethanol (283ml), (1 R, 5 S) one 2- Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-carbonitrile phosphate (4- main Tokishibenjiru) to give Ami de ethanol solution (652.7g).

'H-NMR (CDCh) 1.87C1H. D. J = 13Hz). 2.02C1H. D. J = 13Hz). 2.19 (lH.br s),

2.6K1H. Br s), 2.89 (1H. Dd. J = 2 and 12Hz), 2.95 (1H. Dd. J = 2 and 12Hz).

3.05C1H. D. J = 12Hz). 3.24C1H. D. J = 12Hz). 3.79 (3H.s). 3.84 (lH.s).

3.85C1H. S). 4.39 (1H. Dd. J = 5.5 and 14,5Hz), 4.48C1H. Dd. J = 5.5 and 14.5Hz). 6.86C1H. D. J = 8.5Hz). 7.27 (1H. D . J = 8.5Hz). 9.80C1H, br s)

FAB MSCm / z) 304. 261. 195. 121

[A] D = +42.0. (C-0.545. DMF)

Melting point 93-95'C

h) (1 R, 5 S) - 2- Okiso one 3,7 Jiazabishikuro [3.3 1] non Hmm 3- force carboxylic acid (4-menu Tokishibenjiru) Ami de 'fumarate

Fumarate

Obtained in the above step g) (1 R. 5 S) - 2- Okiso one 3,7 Jiazabishiku port [3, 3.1] nonane one 3-force carboxylic acid (the 4-menu Tokishibenjiru) ami de heating the 620. lg of E ethanol solution 63-65 hands, it was added dropwise over ethanol (550.8ml) solution 1.5 hours there fumaric acid (14.05g. 121 mmol). Under 攙拌, after returning to room temperature, and 濂取 the precipitated crystals, by drying (1 R, 5 S) - 2- old Kiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3 - power carboxylic acid (4-menu Tokishibenjiru) Ami de fumarate (42.65g, (1 R. 5 S) - 7 - benzyl-3, 7 - Jiazabishikuro [3.3.1] nonan one-2-one - 84% yield) from L -DBTA salt as pale yellow crystals.

Ή-NMR (DMS0-d «) L77C1H. D, J = 12.5Hz). 1.97C1H. D. J = 12.7Hz).

2.20 (lH.br s), 2.54 (1H. Br s), 2.81-2.85 (2H.m). 2.96-3.07C2H. M).

3.64-6.68C2H. M). 3.73 (3H. S), 4.3K2H. D. J = 5.69Hz). 6.57 (2H, s).

6.89C2H. D. J = 8.57Hz). 7.24 (2H. D. J = 8.48Hz). 9.64-9.68C1H. M)

FAB S (m / z) 30 Translation +). 121

[A] D = +33.1. (C-0.61, DMF)

Mp 176-177 e C

The structural formulas and physicochemical properties of the compounds of Examples 1 7 6 shown in Table 1 to 2 6. Support

εοε / 96 θΛλ Him 00 / 96dT / XD «l 00 / 9_

oϋ zx "

LL

ZLZ0 £ i96 OAV

ZPLQ0 / 96d £ ilDd 6L

Him 00 / 96dT / JDd 08

Him 00 / 96dT / XDd 18

Z LQ0 / 96dr / JLDd P 72

V8

"Εοε / 96 o / A 58

ZL £ 0 £ / 96 O / A

ZPL00f96drilDd LB

ZPL0O / 96driIDd

Z LOOI96dr / J d 68

ZPLO 16

Shed 厶 00 / 96df / XDd 36

ZL £ 0 £ J96 OA \

ZPLQOI96driJDd Sa 6

ZL £ 0 £ I96 O

ZPL0QI96d £ IIDd

ZPLQ0l96d £ IJDd ≠ 3

ZL € 0 £ I96 OAV monument 00 / 96dT / XDd 96/30372

66

ZPL00f96d £ IIDd Experimental Example 1 (binding test of the nicotinic acetylcholine receptor)

To demonstrate the binding properties of the nicotinic Asechirukorin receptor of the compounds of the present invention, binding was measured inhibitory effect of the present invention compound [3 H] Saichishin and the nicotinic acetylcholine receptor.

Male Wi star rats - buffer (200 350g) 1 0-fold volume of a brain obtained was ice-cooled from (vZw) (.... 50mM Tris one HCI 120mM NaCl 5mM KC1 lm gCl 2 2.5mM CaCl 2) It was homogenized in the middle. Homojine Sorted 2 0 min centrifugal雜at 50000 xg, keeping the 4 e C and resuspended Perez preparative obtained in distilled water 1 0-fold volume (VZW). After 1 hour standing in ice-cold, centrifuged at 5 0 0 0 0 xg 20 minutes while maintaining the 4 hand, was Nigosa resuspend in buffer further resulting Perez Bok 1 0-fold volume (VZW) after, the method of L OWR y etc. the protein concentration of the suspension [J. Biol. Chem., Vol.193, 265-275, (1951)] was measured with.

C 3 H] - binding Saichishin was measured by modified method CMolecular Pharmacology, such as P abreza Vol.39, 9 one 12. (1991)].. For the measurement, 90 0 suspension protein, the solution containing 6 nM [3 H] Saichishin (45nCi / tube) and test compound at various Umido, in 1 2mmx 75 mm Helsingborg styrene tubes 550 using 4 'those 2 hours Inkyubeto at C 1 of the last fin incubation volume. Binding reactions, 0.3% on Helsingborg ethylene I glass O維 filter one that had been soaked in Min solution was terminated by aspirating the suspension S liquid protein. After washing 4 times with each filter with buffer 2m 1, solubilized with Clearsol (manufactured by Nacalai Tesque), and radioactivity was measured by scintillation counter one. Non-specific binding was determined using a fin incubation containing wit thin 1 mM. By test compounds [3 H] - binding inhibition of Saichishin was measured similarly using the fin incubation containing 0. 1 nM to 1 mM of the test compound.

Table 2 7 shows the results. IC 5 0 values specific [3 H] - the concentration of Saichishin binding Test compound 50% inhibition. Reference compound in Table A BT- 4 1 8 is a 3- methyl-5- (1 Mechirubi port Rijiniru 2 I le) Isookisazoru. Table 2

Experimental Example 2 (dopamine release effect)

Dopami emissions release effect, a method such as Na gy [Neuroc em .. Vol. 3, 1114-1123. (1984)] was measured in accordance with.

Brain striatal region was obtained from Sprague-Dawley species rats, N-2-Hidorokishechi Rubiperajin one N '- 2-ethanesulfonic acid (HE PE S) (pH 7. 5) 0. 3 buffered with 5 mM 2M in sucrose 搪 2m 1 of the glass - and homogenized using a Teflon tissue grinder. The homogenate was diluted to 5 m 1 with additional homogenization solution and centrifuged for 10 minutes at 1000X g. Returns Ri pellet Nikanshiteku obtained this procedure, combined supernatant the supernatant obtained in the previous in here, and further 1 20 0 0 X g for 2 0 min centrifugation separation. The resulting Perez preparative dispersed in HE PE S buffer sucrose solution, three-layer discontinuous P erc the P erc 0 1 1 concentration made to another consisting of 1 6% 1 0% and 7.5% 0 1 It was laminated on top of the 1 gradient. After this was 1 5 0 0 0 X g 2 0 min centrifugal at 雜, the Shinabutosomu was integrated on a 6 percent layer was collected by Basutsurubipe' Bok, perfusion buffer (128mM Na C l, 2. 4 mM KC 1, 3. 2mM C a C 1 2. lo 1 1. 2mM KH 2 P0 4. 1. 2mM Mg SCK, 2 5mM HE PE S, 1 OmM glucose, 1 mM Asukorubin salt, 0. 0 1 mM pargyline ) was diluted with 8m l, it was further centrifuged for 2 0 min at 1 5 0 0 O xg. The resulting Perez preparative resuspended in perfusion buffer, and incubated for 10 minutes at 37 hand. Then, [3 H] Dopami emissions (Amersham, 40-60 Ci / m) was added to the suspension, and the suspension 0.1 final澳度, Dopami by incubation further 3 7 by hand for 5 minutes It was absorbed on to Shinabutozomu.

Filtering the suspension liquid obtained above at 0.5% of Boriechireni glass O維 filter the Mi emissions infiltrated (Gelman type A / E), were added Shinabutoso 厶 on the filter. The filters dropwise before 2 0 minutes or more test substances were washed (0. 2- 0. 3ml / min) by a perfusion buffer while Aspirate with peristaltic pump is dropped on the filter. 1 0 ^ solution 0. 2 m 1 of the test substance, was added dropwise to washed fill evening one above were collected at 1 minute intervals perfusate scintillation vial. The released Dopami emission amount was measured by scintillation one Deployment counter Bok. Total radioactivity released beak over a background, subtracting the average group bottom emission in the same time from the sum, S equal concentrations resulting release value - (I) release is obtained in one nicotine detection value It expressed as a percentage (% nicotine) against. Table 2 8 shows the results.

Table 2 8 Example No.% nicotine Saichishin 6 4

Nicotine 1 0 0

4 3 4

2 0 2 6

5 1 6 3

5 2 3 8

5 3 8 7

5 5 3 2

5 8 2 8

6 4 4 3

6 6 5 2 Experimental Example 3 (Note billion disorder improving action)

As an indicator of the central action, to measure the serial «disorder improving action by using the Sukoborami down processing rats. A male Wi star rats (170 -200g) for the experiment, Akira喑 two rooms as a device (喑室: Width 30cmx30cmx height 30 cm, bright room: width 25cmx Depth lOcmx height 25 cm) Passive avoidance training box consisting of ( step-through) was used.

First, placed in a light room to 1 hour before acquisition trial the rat as habituation trial, the time was measured (the response latency) of the partition plate from the open only by until rats from entering the darkroom. Then, the rats were placed in a bright room as acquisition attempt, when the rack Bok open the partition plate has given the electrical stimulation of 0. 25 mA on the floor grid of (1 second) when entering the dark room the response latency was recorded. Performed retention trial 24 hours later was measured response latency. 3 0 minutes before the acquisition trial, Sukoporami emissions (0.5 mg / kg) and test compound dissolved in saline (0.1. 0.3. One kind of l.Orag / kg) was administered subcutaneously. Response latency of retention trial was recorded up to 3 0 0 seconds, and more than the 3 0 0 seconds. The retention trial response latency of each group were assayed using U - test the Mann-Whitney, at significantly longer latencies than 5% of the risk rate than the group treated with saline and Sukoboramin without test compound It was effective and decipher test compounds having a.

Table 2 9 show the results. Of dose of the active and determined test compound group was the minimum effective dose dosage most small (MED).

Experimental Italy .4 (measurement of blood pressure change)

To measure the changes in blood pressure as an indicator of the peripheral action. Male Wi star rats (220 - 300 g) were anesthetized with pentobarbital sodium (25mg / kg, ip) and anesthetized with Barubitaruna thorium (. 300mg / kg ip), the PE 1 0 Teflon tube in the crotch vein for the drug administration after 揷入 the PE 3 0 Teflon tube in femoral artery for the blood pressure measurement to measure the changes in blood pressure before and after drug administration by connecting the femoral artery force two Yure the pressure transducer scratch. Drug was dissolved in physiological saline dosing from the crotch vein force Nyure by RenMitsuru to the highest dose (10 mg / kg) at intervals of more than 2 0 minutes from the lowest dose (0.1mg / kg). Doses blood pressure change before and after drug administration reached 3 OmmHg was the minimum effective dose (EC 3 0). Table 2 9 show the results. The central effects Z peripheral effects ratios of each compound shown in Table 2 9.

Table 2 9

The compound of the present invention has a higher affinity to nicotinic Asechirukorin receptor showed excellent improvement effect in the test of the memory disorder improving action of in vi vo with Sukoborami emissions treatment rats. The compounds are reference compounds Saichishin, compared to nicotine and ABT- 4 1 8, acting central selectivity for high peripheral nerves has the feature that has low.

Jiazabinkuro [3.3. 1] nonane derivatives of the present invention has a high nicotinic choline receptor binding, also because it has also Dopami down releasing action, as nicotinic co Li down agonist or dopamine agonists it is useful. Therefore, the compounds of the present invention Alzheimer's disease, Parkinson's disease, Huntington's disease, the treatment of the central nervous degeneration diseases such as Pick's disease, can be used for improvement of cerebral dysfunction, since in particular having a storage disorder improving work as possible out it is used as a drug for improving memory impairment typified by dementia. The compound of the present invention due to the low effect on peripheral nerves, boosting found in conventional cholinergic Doyaku, has a characteristic that side effects such as diarrhea is small.

The Ichiko compound of ¾ [1 1] is Jiazabishikuro one crotch formula [1] [3.3. 1] is useful as an intermediate for the production of nonane derivatives.

According to the method shown in the production method 7 L 0 4 present invention, an inexpensive starting material 5 - it can be produced in high yield from bromo nicotinic acid or nicotinic acid intermediate compound [33]. Accordingly Through these steps, can be prepared in Jiazabishi black [3.3.1] nonane derivatives efficiently low cost general formula of interest [35].

Claims

The scope of the claims
1. the general formula [1]
Wherein, R represents in one C0NH- (CHR 1) "one R 2 (wherein, R 1 represents a hydrogen atom or a § alkyl group, m represents 0, 1 or 2, R 2 is substituted good Ariru group, an optionally substituted heterocyclic group, an optionally substituted cycloalkyl group, an alkyl group or an alkenyl group), or -. CO- R 3 (wherein, R 3 is an alkyl group, Araru Kiruokishi during group or one NR 4 R 5 (wherein and R 5 are the same or different represent a alkyl Le group, the formula becomes the nitrogen atom and one緖which R 4 and R 5 are adjacent
(N represents. 2 or 3) to form a group represented by. ) Represents the. ) Represents the. Acceptable Jiazabishikuro [3.3.1] nonane derivative or a pharmacologically represented by]
2. R gar CONH- (CHR 1) m -R 2 ( wherein, R 1, m and R 2 are the same as請Motomeko 1.) A Jiazabishikuro according to claim 1, wherein the [3.3. I] nonane derivatives or pharmacologically acceptable salts thereof.
3. Jiazabishikuro of claim 2 wherein R 1 is a hydrogen atom [3.3.1] nonane derivatives or a pharmacologically acceptable salt thereof.
4. Jiazabishikuro [3.3.1] nonane derivatives or pharmacologically acceptable salt thereof according to claim 3, wherein R 2 is an optionally substituted Ariru group or an optionally substituted cycloalkyl Le group.
5. 2-Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3 - local bon acid Benjiruami de,
3- C (S) one 1 one-phenylene Rue Chi carbamoyl] one 3,7 Jiazabinkuro [3.3.1] nonan one-2-one,
3- [(R) - 1 - phenylene Rue Chi carbamoyl] one 3,7 Jiazabishikuro [3.3.1] nonan one-2-one,
2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (1 one-naphthyl) § Mi de,
2 Okiso one 3,7 Jiazabinkuro [3.3.1] nonane one 3 - carboxylic acid Fueniruami de,
2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-carboxylic acid i (2 main Tokishifueniru) § Mi de,
2 Okiso one 3. 7- Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (3 main Tokishifue sulfonyl) § Mi de,
2 - Okiso one 3. 7- Jiazabinkuro [3.3.1] nonane one 3-force carboxylic monobasic (4-menu Tokishifue sulfonyl) Ryomi de,
2 Okitsu 3, 7 - Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic Mechiruami de,
2 - Okiso one 3,7 Jiazabinkuro [3.3.1] nonane one 3-force carboxylic acid Echiruami de,
2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic tert- butylamine de,
2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic Ibb port Piruami de,
2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3 - carboxylic monobasic (4 one black port benzyl) amino-de,
2 Okiso one 3, 7 - Jiazabinkuro [3.3.1] nonane one 3-force carboxylic acid - (3 - chloro port benzyl) § Mi de,
1 0 2 - Okitsu 3,7 Jiazabishikuro [3.3.3 nonane - 3 - carboxylic acid - (2 - chloro port benzyl) § Mi de,
2 - Okiso one 3,7 Jiazabishikuro [3.3.1 nonane one 3-force carboxylic acid - (4 one Furuorobenjiru) ami de,
2 Okiso one 3,7 Jiazabishikuro [3.3.1 nonane - 3 Power carboxylic acid
(3 Furuorobenjiru) Ami de,
2 - Okiso one 3, 7 - Jiazabishikuro [3.3.1 nonane one 3-force carboxylic acid
(2 Furuorobenjiru) Ami de,
2 Okiso one 3,7 Jiazabishikuro [3.3.1 nonane one 3-force carboxylic acid
(4-menu Tokishibenjiru) § Mi de,
2 Okiso one 3,7 Jiazabishikuro [3.3.1 nonane one 3-force carboxylic acid
(3 main Tokishibenjiru) Ryomi de,
2 Okiso one 3,7 Jiazabishikuro [3.3.3 nonane one 3 - carboxylic acid
(2 main Tokishibenjiru) § Mi de,
2 Okiso one 3,7 Jiazabishikuro [3.3.3 nonane one 3 - carboxylic acid
(3, 4 Jime Tokishibenjiru) Ami de,
2 Okiso one 3,7 Jiazabishikuro [3.3.3 nonane one 3 - carboxylic acid
(3, 4, 5-trimethyl Tokishibenjiru) Ami de,
2 Okiso one 3,7 Jiazabishikuro [3.3.3 nonane one 3 - carboxylic acid
(3, 4-methylenedioxy O alkoxybenzylacetic) ami de,
2 Okiso one 3,7 Jiazabishikuro [3.3.3 nonane one 3 - carboxylic acid
[4 one (Benjiruokin) benzyl] amino-de,
2 Okiso one 3,7 Jiazabishikuro [3.3.1 nonane one 3-force carboxylic acid
[3, 4-di (Benjiruokishi) benzyl] amino
2 Okiso one 3, 7 - Jiazabishikuro [3.3.1 nonane one 3-force carboxylic acid
(4 one Benjiruokishi 3 main Tokishibenjiru) § de ,,
2 - Okiso one 3,7 Jiazabishikuro [3.3.3 nonane one 3 - carboxylic acid - (3-chloro 4-menu Tokishibenjiru) ami de,
2 Okiso one 3,7 Jiazabishikuro [3.3.3 nonane one three to force carboxylic monobasic (3 Furuoro 4-menu Tokishibenjiru) ami de
2 Okiso one 3,7 Jiazabishikuro [3.3.3 nonane one three to force carboxylic monobasic (2-methylbenzyl) amino-de,
2 - Okiso one 3, 7 - Jiazabinkuro [3.3.1 nonane one 3-force carboxylic monobasic (three to methylbenzyl) § Mi de,
2 Okiso one 3,7 Jiazabishikuro [3.3.1 nonane one 3-force carboxylic monobasic (4 one-methylbenzyl) § Mi de,
2 Okiso one 3,7 Jiazabishikuro [3.3.1 nonane one 3-force carboxylic monobasic (2-triflate Ruo b methylbenzyl) § Mi de,
2 Okiso one 3,7 Jiazabishikuro [3.3.1 nonane one 3-force carboxylic monobasic (3-triflate Ruo b methylbenzyl) § Mi de,
2 - Okiso one 3, 7 - Jiazabinkuro [3.3.1 nonane one 3-carboxylic acid i (4 one triflate Ruo b methylbenzyl) § Mi de,
2 Okitsu 3,7 Jiazabishikuro [3.3.1 nonane one 3-carboxylic acid i (4-dimethyl § amino benzyl) § Mi de,
2 Okiso one 3,7 Jiazabinkuro [3.3.1 nonane one 3-carboxylic acid i (4 one ethoxy benzyl) amino-de,
2 Okiso one 3,7 Jiazabinkuro [3.3.1 nonane one 3-force carboxylic monobasic (4 one-phenylalanine benzyl) § Mi de,
2 Okitsu 3,7 Jiazabinkuro [3.3.1 nonane one 3-force carboxylic acid - (3, 4 Jikuro port benzyl) amino-de,
2 Okiso one 3,7 Jiazabishikuro [3.3.1 nonane one 3-force carboxylic acid i (2 - thienyl) Mechiruami de,
2 Okiso one 3,7 Jiazabishikuro [3.3.1 nonane one 3-force carboxylic monobasic (pyridin one 3- Irumechiru) amino-de, 2 - Okiso one 3, 7-Jiazabishikuro 3.3.1 nonane one 3- force carboxylic acid - (pyridin one 4 Irumechiru) Ami
2 Okiso one 3, 7 - Jiazabishikuro 3.3.3 nonane one 3 - carboxylic acid - (naphthalen one 2-Irumechiru) § de ',
2 Okitsu 3,7 Jiazabishikuro 3.3.1 nonane one 3-force carboxylic acid - (2-naphthyl) § Mi de,
2 Okiso one 3, 7-Jiazabishikuro 3.3.1 nonane one 3-force carboxylic acid - (naphthalen one 1 Irumechiru) Ami de ',
2 Okitsu 3,7 Jiazabishikuro 3.3.3 nonane one 3 - carboxylic acid Fuwenechiruami de,
2 Okiso one 3, 7-Jiazabinkuro 3.3.1 nonane one-3-carboxylic acid (2-menu Tokishifuenechiru) ami de,
2 Okiso one 3, 7-Jiazabishikuro 3.3.1 nonane one 3-force carboxylic acid (3-main Tokishifuenechiru) § Mi de,
2 Okiso one 3, 7-Jiazabishikuro 3.3.1 nonane one-3-carboxylic acid (4-menu Tokishifuwenechiru) § Mi de,
2 Okiso one 3, 7-Jiazabinkuro 3.3.1 nonane one 3-force carboxylic acid Purobiruami de,
2 Okitsu 3,7 Jiazabishikuro 3.3.1 nonane - 3-carboxylic acid Shikurobu port Piruami de,
2 Okifu 3,7 Jiazabinkuro 3.3.3 nonane one 3 - carboxylic acid Isobuchiruami de,
2 Okiso one 3, 7-Jiazabishikuro 3.3.1 nonane one 3-force carboxylic acid cyclopropylmethyl § Mi de,
2 Okiso one 3, 7-Jiazabishikuro 3.3.1 nonane one 3-force carboxylic acid (2-Mechirupuro base sulfonyl) amino-de,
2 Okiso one 3, 7-Jiazabishikuro 3.3.1 nonane one 3-force carboxylic acid - Shikurobuchiruami de,
2 Okiso one 3,7 Jiazabishikuro [3 3.1] nonane one 3-carboxylic acid - cyclopentyl ami de,
2 Okiso one 3,7 Jiazabishikuro [3.3 1] nonane one 3-carboxylic acid Shikuro to Kishiruami de,
2 Okitsu 3,7 Jiazabishikuro [3.3 1] nonane one 3 - carboxylic acid - (2, 2, 3, 3-tetramethyl-cyclo pro building) ami de,
2 Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-carboxylic acid Shikuro hexyl methyl ami de,
2 Okiso one 3,7 Jiazabinkuro [3.3 1] nonane one 3-force carboxylic acid over cyclopentylmethyl Ami de,
2 Okiso one 3,7 Jiazabishikuro [3.3 1] nonane one 3-force carboxylic monobasic (4-hydroxycarboxylic benzyl) amino-de,
2 Okiso one 3,7 JiRyo Zabinkuro [3.3 1] nonane one 3-carboxylic acid i (3, 4 dihydric mud alkoxybenzylacetic) ami de,
2 Okiso one 3,7 Jiazabishikuro [3.3 1] nonane one 3-carboxylic acid i (4-arsenide Dorokishi one 3- main Tokishibenjiru) ami de,
3- (N, N-dimethylcarbamoyl) one 3,7-Jiazabishikuro [3.3.1] nonan one-2-one,
3 - (piperidin-one 1 one carbonyl) one 3,7-Jiazabishikuro [3.3.1] nonan one-2-one,
3 Asechiru 3,7 Jiazabishikuro [3.3.1] nonane one 2 one-one, 3- Bibaroiru 3,7 Jiazabinkuro [3.3.1] nonane one 2 - one, 3- base Nji Ruo propoxycarbonyl two Lou 3, 7 - Jiazabishikuro [3.3, 1] non Hmm 2-one,
(1 R, 5 S) - (+) - 2 - Okiso one 3,7 Jiazabishikuro [3.3.1] nonane, 3-carboxylic acid over cyclopentyl Ami de, (IS, 5 R) - (-) one 2 Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3 - carboxylic acid over cyclopentyl ami de,
(1 R, 5 S) - (+) - 2- Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (3, 4-dimethyl Tokishibenjiru) § Mi de,
(1 S, 5 R) - (-) one 2 - Okiso one 3,7 Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (3, 4 Jime Tokishibenjiru) ami de,
(1 R, 5 S) - (+) - 2- Okitsu 3, 7 - Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (4-menu Tokishibenjiru) ami de,
(1 S, 5 R) - (I) one 2- Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (4-menu Tokishibenjiru) Ryomi de,
(1 R, 5 S) - (+) - 2- Okiso one 3, 7 - Jiazabishikuro [3.3.1] nonane one 3 - carboxylic acid i (3 - Black port one 4 - Main Bok Kishibenjiru) § Mi de , as well as
(1 R, 5 S) - (+) - 2- Okiso one 3, from 7-Jiazabishikuro [3.3.1] nonane one 3-force carboxylic monobasic (3 Furuoro 4-menu Tokishibenjiru) § Mi de Jiazabishikuro of claim 1 wherein is selected from the group consisting [3.3.1] nonane derivative conductor or a pharmacologically acceptable salt thereof.
6. Jiazabishikuro according to any one of claims 1 to 5, [3.3.1] nonane derivatives or medicament containing a pharmacologically acceptable salt thereof.
7. according to any one of claims 1 to 5 Jiazabishikuro [3.3.1] nonane derivative or pharmaceutical composition comprising a pharmacologically acceptable salt thereof and a pharmaceutically acceptable carrier Stuff.
8. Jiazabishikuro according to any one of claims 1 to 5, [3.3.1] nonane derivatives or nicotinic cholinergic agonist comprising a pharmacologically acceptable salt thereof.
9. according to any one of claims 1 to 5 Jiazabishikuro [3.3.1] nonane derivatives or central nervous disorders due to a reduction for cholinergic in brain cell, comprising a pharmacologically acceptable salt thereof the pharmaceutical composition for the treatment.
1 0. Jiazabishikuro as claimed in any one of claims 1 to 5 [3.3.1] central nervous disorder treatment that by the Dobami down action decrease comprising nonane derivative or a pharmacologically acceptable salt thereof the pharmaceutical composition for.
1 1. Jiazabishikuro according to any one of claims 1 to 5, [3.3.1] nonane derivatives or central neurodegenerative diseases Chi麼 agent comprising a pharmacologically acceptable salt thereof.
1 2. Jiazabishikuro according to any one of claims 1 to 5, [3.3.1] nonane derivatives or dementia therapeutic agent comprising a pharmacologically acceptable salt thereof.
1 3. Jiazabishikuro according to any one of claims 1 to 5, [3.3.1] nonane derivatives or cerebral function disorder improving agent comprising a pharmacologically acceptable salt thereof.
1 4. Jiazabishikuro according to any one of claims 1 to 5, [3.3.1] nonane derivatives or Parkinson's disease agent comprising a pharmacologically acceptable salt thereof.
1 5. Jiazabishikuro according to any one of claims 1 to 5, [3.3.1] nonane derivatives or serial billion disorder improving agent comprising a pharmacologically acceptable salt thereof.
1 6. Jiazabishikuro with nicotinic choline action [3.3.1] nonane derivatives or pharmaceutically acceptable for central nervous disorders treatment by cholinergic low down in the brain cell, comprising a pharmacologically acceptable salt thereof Stuff.
1 7. Jiazabinkuro [3.3.1] nonane-induced, or a pharmaceutical composition for central nervous disorders treatment with dopaminergic decline comprising a pharmacologically acceptable salt thereof having a Dopami emissions release effect.
1 8. - crotch formula [1 1]
[11]
Wherein, P is an Amino protecting group. Jiazabishikuro [3.3.1] nonane derivatives or salts thereof represented by].
1 9. formula which comprises the following steps [3 3]
(Wherein, B n represents a benzyl group.) Represented by (1 R, 5 S) - 7 one base Njiru one 3, '7 Jiazabishikuro [3.3.1] The method for producing nonane one-2-one .
(A) a compound of the formula [2 7]
In the 5-bromo-nicotinic acid represented subjected to esterification reaction, the following formula [2 8]
(Wherein, R 6 represents. Alkyl group) to an ester compound represented by
(B) subjected to the ester compound to the nitrile reaction, the following formula [2 9]
[2 9]
(Wherein, RS represents an alkyl group.) And nicotinic acid ester compound represented by, (c) the presence of the nicotinic acid ester compound having an acid, and subjected to catalytic hydrogenation - following formula [3 0]
R
(Wherein, represents an alkyl group.) And piperidine compounds represented by, (d) are denoted by the bi pane lysine compound in ring closure reaction, the following equation by further base Njiruharai de and reaction [32 ]
(Wherein, Bii represents. A benzyl group) and Jiazabinkuro [3.3.1] nonane compounds represented by,
(E) This Jiazabishikuro [3.3.1] nonane compound, by optical resolution by Jiasutereoma IchiAkira precipitation of Ru with an optically active acid, the following formula [3 3]
(Wherein, Bn represents a benzyl group.) Represented by (1 R, 5 S) - 7 one base Njiru - 3, to obtain a 7- Jiazabishikuro [3.3.1] nonan one 2-one.
Expression, characterized in that it comprises a 2 0. The following steps [3 3]
(Wherein, Bn represents a benzyl group.) (1 R, 5 S) one 7 represented by - benzyl - 3,7 Jiazabishikuro [3.3.1] nonan one 2-one method of manufacturing.
(A) formula [27 '] In formula nicotinic acid represented [2 8]
(Wherein, R e represents. Alkyl group) to an ester compound represented by
(B) subjected to the ester compound to the nitrile reaction, the following formula [2 9]
(Wherein, R e represents. Alkyl group) and nicotinic acid ester compound represented by
(C) the presence of an acid The nicotinic acid ester compound is subjected to catalytic hydrogenation, the following formula [3 0]
(Wherein, R 6 represents. Alkyl group) and pin base lysine compound represented by
And (d) given the Konopipe lysine compound in ring closure reaction, the following equation by further base Njiruharai de and reaction [3 2]
(Wherein, B n represents a benzyl group.) And Jiazabishikuro [3.3.1] nonane compounds represented by,
(E) This Jiazabishikuro [3.3.1] nonane compound, by optical resolution by Jiasutereoma crystallization method Ru using an optically active acid, the following formula [3 3]
Obtained 7 one base Njiru one 3,7 Jiazabishikuro [3.3.1] nonan one-2-one - (wherein, B n represents a benzyl group.) Represented by (1 R, 5 S).
2 1. formula which comprises the following steps [3 3]
(Wherein, B n represents a benzyl group.) Represented by (1 R, 5 S) one 7 - benzyl one 3,7 Jiazabishikuro [3.3.1] nonan one 2-one method of manufacturing.
(C) formula [2 9]
(Wherein, R e represents. An alkyl group) in the presence of an acid nicotinic acid ester compound represented by subjected to catalytic hydrogenation, the following formula [3 0]
(Wherein, R e represents. Alkyl group) and pin base lysine compound represented by
And (d) given the Konopibe lysine compound in ring closure reaction, the following equation by further base Njiruharai de and reaction [3 2]
1 1
(Wherein, Bn represents. A benzyl group) and Jiazabinkuro [3.3.1] nonane compounds represented by,
(E) This Jiazabishikuro [3.3.1] nonane compound, by optical resolution by Jiasutereoma IchiAkira Oriho of Ru with an optically active acid, the following formula [3 3]
(Wherein, Bn represents a benzyl group.) Represented by (1 R, 5 S) - 7 one base Njiru one 3, to obtain a 7- Jiazabishikuro [3.3.1] nonan one 2-one.
2 2. the following formula [2 7 ']
By reacting nicotinic acid with bromine and chloride Chioniru shown in, to produce a 5-Bed Romonikochin acid Kurori de, by reacting it with an alcohol, the following one crotch formula [2 8]
(Wherein, R e represents. Alkyl group) A method for producing a 5-bromo nicotinic acid ester represented by.
2 3. the following formula [2 8]
(Wherein, R e represents. Alkyl group) an ester compound represented by, after subjecting the nitrile reaction with copper cyanide (I), the complex is treated with hypochlorite Natoriumu solution oxidized, and then the reaction solution was treated with aqueous ammonia to remove the copper ions, the following formula by crystallization [29]
(Wherein, R e represents. Alkyl group) method of manufacturing a nicotinic acid ester compound represented by the.
24. the following formula [29]
[29]
(Wherein, R e represents. An alkyl group) in the presence of hydrochloric acid to nicotinic acid ester compound represented by a solvent chosen from ethanol and Ibb port buildings alcohol, catalytic hydrogenation using a platinum oxide or platinum on carbon as catalyst formula by subjecting the addition reaction
C30]
(Wherein, R, represents an alkyl group.) Who 25. formula for producing a bi Bae lysine compound of the formula [30]
(Wherein, R * represents. Alkyl group) after subjecting the bi Bae lysine compound represented by the ring closure reaction Ru with a base, the following formula by the this to the product in Wanbo' preparative reaction with benzyl pay de [ 32]
(Wherein, B n represents. A benzyl group) A method for producing a 7-base Njiru three to Jiaza bicyclo represented by [3.3.1] nonan one 2-one.
2 6. the following formula [3 2]
(Wherein, B n represents a benzyl group.) 7- base Njiru 3 represented by the 7-Jiaza bicyclo [3.3.1] nonane one 2 - ON, Jiasutere Oma crystallization using an optically active acid formula by optical resolution by law [3 3]
(Wherein, B n represents a benzyl group.) Represented by (1 R, 5 S) - 7 one base Njiru - 3,7 Jiazabishikuro [3.3.1] method for producing nonane one-2-one . 2 (a) Formula [2 7]
In the 5-bromo-nicotinic acid represented subjected to esterification reaction, the following formula [2 8]
R'00C
(Wherein, R 6 represents. Alkyl group) to an ester compound represented by
(B) The ester compound denoted nitrile reaction ^, the following formula [2 9]
(Wherein, R e is. Represents an alkyl group) and nicotinic acid ester compound represented by, (c) the presence of the nicotinic acid ester compound having an acid, and subjected to catalytic hydrogenation reaction, the following formula [3 0 ]
(Wherein, R e represents. Alkyl group) and bi Bae lysine compound represented by
(D) the Konopipe lysine compound is subjected to ring closure reaction, the following formula by reaction with further base Njiruharaido [3 2]
(Wherein, B n represents a benzyl group.) And Jiazabishikuro [3.3.1] nonane compounds represented by,
(E) This Jiazabishikuro [3.3.1] nonane compound, by optical resolution by Jiasutereoma IchiAkira Oriho of Ru with an optically active acid, the following formula [3 3]
(Wherein, Bn represents a benzyl group.) Represented by (1 R, 5 S) - 7-base Njiru one 3, via a 7-Jiazabishikuro [3.3.1] step nonane one-2-one the following formula, wherein be Rukoto [35]
Wherein, R represents in one CONH- (CHR 1) β -R 2 ( wherein, R 1 represents a hydrogen atom or a § alkyl group, m represents 0, 1 or 2, also R 2 is is conversion good Ariru group, substituted with heterocyclic group which may, conversion is cycloalkyl group which may be an alkyl group or an alkenyl group.) or single CO- R 3 (wherein, R 3 is an alkyl group, Araru Kiruokishi during group or one NR 4 R 5 (wherein, R <and R 5 are taken same or different represent a alkyl group, the nitrogen atom and one緖the RS adjacent formula
(N represents. 2 or 3) to form a group represented by. ) Represents the. ) Represents the. Jiazabishikuro [3.3.1] The method for producing nonane derivative represented by].
2 8. (c) the following formula [2 9]
(Wherein, R 6 represents. An alkyl group) in the presence of an acid nicotinic acid ester compound represented by subjected to catalytic hydrogenation, the following formula [3 0]
R e 00
(Wherein, R e represents. Alkyl group) and piperidine compounds represented by,
(D) the Konopipe lysine compound is subjected to ring closure reaction, the following formula by reaction with further base Njiruharaido [3 2]
(Wherein, B n represents a benzyl group.) And Jiazabishikuro [3.3.1] nonane compounds represented by,
(E) This Jiazabishikuro [3.3.1] nonane compound, by optical resolution by Jiasutereoma crystallization method Ru using an optically active acid, the following formula [3 3]
(Wherein, B n represents a benzyl group.) Represented by (1 R, 5 S) one 7-base Njiru one 3, 7 - the Jiazabinkuro [3.3.1] step nonane one-2-one formula characterized that you through [35]
Wherein, R represents one C0NH- (CHR 1). One R 2 (wherein, R 1 represents a hydrogen atom or a § alkyl group, m represents 0, 1 or 2, also R 2 is is conversion good Ariru group, substituted with heterocyclic group which may, conversion is cycloalkyl group which may be an alkyl group or an alkenyl group.) or single CO- R 3 (wherein, R 3 is an alkyl group, Araru Kiruokishi during group or one NR * R 5 (wherein, R <and R 5 represent a same or different alkyl group, wherein Bruno H \ together with the nitrogen atom to which R 4 and R 5 are adjacent
-N (CH 2) n
H /
(N represents. 2 or 3) to form a group represented by. ) Represents the. ) Represents the. Jiazabinkuro [3.3.1] The method for producing nonane derivative represented by].
PCT/JP1996/000742 1995-03-24 1996-03-21 Diazabicyclo[3.3.1]nonane derivatives and intermediates thereof, medicinal use of the same, and processes for producing the same WO1996030372A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP7/66497 1995-03-24
JP6649795 1995-03-24

Publications (1)

Publication Number Publication Date
WO1996030372A1 true true WO1996030372A1 (en) 1996-10-03

Family

ID=13317519

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1996/000742 WO1996030372A1 (en) 1995-03-24 1996-03-21 Diazabicyclo[3.3.1]nonane derivatives and intermediates thereof, medicinal use of the same, and processes for producing the same

Country Status (1)

Country Link
WO (1) WO1996030372A1 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2786770A1 (en) * 1998-12-04 2000-06-09 Synthelabo Derivatives of 1,4-diazabicyclo [3.2.2.] Nonane, their preparation and their application in therapeutic
WO2003000261A1 (en) * 2001-06-25 2003-01-03 Elan Pharmaceuticals, Inc. Use of bicyclo compounds for treating alzheimer's disease
EP1415651A1 (en) * 2001-08-06 2004-05-06 Mitsubishi Pharma Corporation Preventives/remedies for cholinergic neuropathy
US6852721B2 (en) 2000-05-25 2005-02-08 Targacept, Inc. Pharmaceutical compositions and methods for use
US7214686B2 (en) 1997-06-30 2007-05-08 Targacept, Inc. Pharmaceutical compositions and methods for effecting dopamine release
US7402592B2 (en) 2003-10-15 2008-07-22 Targacept, Inc. Pharmaceutical compositions and methods for relieving pain and treating central nervous system disorders
EP2018874A2 (en) 1998-08-07 2009-01-28 Targacept, Inc. Pharmaceutical compositions for the prevention and treatment of central nervous system disorders comprising a nicotinic compound and an acetylcholinesterase inhibitor

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0588917A1 (en) * 1991-05-29 1994-03-30 Abbott Laboratories Isoxazole and isothiazole compounds that enhance cognitive function

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0588917A1 (en) * 1991-05-29 1994-03-30 Abbott Laboratories Isoxazole and isothiazole compounds that enhance cognitive function

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7214686B2 (en) 1997-06-30 2007-05-08 Targacept, Inc. Pharmaceutical compositions and methods for effecting dopamine release
EP2018874A2 (en) 1998-08-07 2009-01-28 Targacept, Inc. Pharmaceutical compositions for the prevention and treatment of central nervous system disorders comprising a nicotinic compound and an acetylcholinesterase inhibitor
FR2786770A1 (en) * 1998-12-04 2000-06-09 Synthelabo Derivatives of 1,4-diazabicyclo [3.2.2.] Nonane, their preparation and their application in therapeutic
US6407095B1 (en) 1998-12-04 2002-06-18 Sanofi-Synthelabo 1,4-diazabicylo[3,2,2]nonane derivatives, their preparation and their therapeutic application
WO2000034279A1 (en) * 1998-12-04 2000-06-15 Sanofi-Synthelabo 1,4-diazabicyclo[3.2.2]nonane derivatives, their preparation and therapeutic application
USRE41439E1 (en) 2000-05-25 2010-07-13 Targacept, Inc. Pharmaceutical compositions and methods for use
US6852721B2 (en) 2000-05-25 2005-02-08 Targacept, Inc. Pharmaceutical compositions and methods for use
WO2003000261A1 (en) * 2001-06-25 2003-01-03 Elan Pharmaceuticals, Inc. Use of bicyclo compounds for treating alzheimer's disease
EP1415651A4 (en) * 2001-08-06 2005-11-09 Mitsubishi Pharma Corp Preventives/remedies for cholinergic neuropathy
EP1415651A1 (en) * 2001-08-06 2004-05-06 Mitsubishi Pharma Corporation Preventives/remedies for cholinergic neuropathy
US7402592B2 (en) 2003-10-15 2008-07-22 Targacept, Inc. Pharmaceutical compositions and methods for relieving pain and treating central nervous system disorders
US7897611B2 (en) 2003-10-15 2011-03-01 Targacept, Inc. Pharmaceutical compositions and methods for relieving pain and treating central nervous system disorders

Similar Documents

Publication Publication Date Title
US5718912A (en) Muscarine agonists
US6790854B2 (en) Diphenylalkylamine derivatives useful as opioid receptor agonists
US7718666B2 (en) Pyrido [2,1-a] isoquinoline derivatives
US5756508A (en) Muscarine antagonists
US6150376A (en) Bi- and tri-cyclic aza compounds and their uses
US5574044A (en) Muscarine antagonists
US5241065A (en) 2,3,4,5-tetrahydro-1h-3-benzazepines having anti-psychotic activity
US5691323A (en) Muscarine antagonists
US6288079B1 (en) Tropane-derivatives, their preparation and use
US6727261B2 (en) Pyrido[2,1-A]Isoquinoline derivatives
US20020037886A1 (en) Muscarinic agonists
WO1996013262A1 (en) Muscarine antagonists
WO2001085693A1 (en) N-acyltetrahydroisoquinoline derivatives
WO2007101270A1 (en) MODULATORS OF 11-β HYDROXYL STEROID DEHYDROGENASE TYPE 1, PHARMACEUTICAL COMPOSITIONS THEREOF, AND METHODS OF USING THE SAME
WO2014031167A1 (en) Compounds and methods for treatment of hypertension
WO2002051809A1 (en) Piperidine mch antagonists and their use in the treatment of obesity
JP2000256358A (en) Pyrazole derivative
US20110034455A1 (en) Inhibitors of 11beta-hydroxysteroid dehydrogenase type 1
WO1998014447A1 (en) Novel indole-2,3-dione-3-oxime derivatives
WO1995021820A1 (en) Novel carbamate derivative and medicinal composition containing the same
WO1997016192A1 (en) Muscarine antagonists
US6395738B1 (en) Benzofuran derivatives
WO2000053600A1 (en) Novel piperidine derivatives
WO2005007644A1 (en) Heteroaryloxy nitrogenous saturated heterocyclic derivative
WO1993020077A1 (en) Fused quinoxalinone derivative and pharmaceutical composition containing the same

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AU BB BG BR CA CN CZ EE GE HU IS KR LK LR LT LV MG MK MN MX NO NZ PL RO SG SI SK TR TT UA US UZ VN AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: CA