JPH0761940A - Azabicycloheptane derivative - Google Patents

Abstract

PURPOSE:To obtain a new azacycloheptane derivative, not having narcotic properties like habit forming and indulgence, while keeping a sharp potency of morphine, useful as a non opioid analgesic with a clinically high safety and usefulness. CONSTITUTION:A compound of formula (wherein, R is H, a lower alkyl, a lower alkoxy; Y is NH, CH2, O S; Z is either non substituted or substituted phenyl, pyridyl, N-oxypyridyl, pyrazyl, N-oxypyrazyl, pyrimidyl, N-oxypyrimidyl, pyridazyl, N-oxypyridazyl, quinolyl, N-oxyquinolyl, isoquinolyl, N-oxyisoquinolyl, indolyl, N-oxy -indolyl, furyl, tetrahydrofuryl, pyranyl, tetrahydropyranyl, thienyl, tetrahydrothienyl; n is 0-5; except that Z is 6-chloro-3- -pyridyl), e.g. exo-2-(6-bromo-3-pyridyl)-7- -azabicyclo[2.2.1]heptane.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a clinically useful analgesic agent having a non-opioid analgesic action, a muscle relaxant, an antihypertensive agent, an anti-Parkinson's disease agent, an anti-Alzheimer's disease agent,
It relates to an anti-ulcerative colitis agent or an anti-tobacco addictive agent.

[0002]

BACKGROUND ART Morphine has an excellent analgesic effect, but it has a limitation in handling as a narcotic, and when treating cancer pain and the like, it is necessary to gradually increase the dose to maintain its effect for a long period of time. However, it has drawbacks such as easy occurrence of constipation. Therefore, a new analgesic having a non-opioidergic analgesic action, which has a different action point from that of morphine and is highly clinically useful and safe, is expected.

However, few compounds are known to have such a mechanism of action. For example DE-410
1325 and Japanese Patent Publication No. 5-866 disclose that isoxazolecarboxylic acid amide derivatives have the same action.

[0004] In WO-9304675, tramadol, which is a phenylcyclohexanol derivative, is disclosed as a non-opioid analgesic.

Further, Psychophacology
rmacology, 91 (3), 273-8, 1987. discloses the non-opioid analgesic action of nefopam, a tetrahydrobenzoxazocine derivative.

[0006]

DISCLOSURE OF THE INVENTION PROBLEM TO BE SOLVED BY THE INVENTION As described above, few compounds are known to have a non-opioidergic analgesic action, and among these compounds, those actually used clinically are It wasn't there yet.

The analgesic action of the isoxazolecarboxylic acid amide derivative disclosed in DE-4101325 or Japanese Examined Patent Publication No. 5-866 has the acetylsalicylic acid (as described in Japanese Examined Patent Publication No. 5-866). Almost the same as the trivial name; aspirin), and strong and reliable effects cannot be expected.

The tramadol disclosed in WO-9304675 is a drug development research (D
rug Dev. Res.), 28 (2), 176-82, 1993., a slight effect was observed with intradural (d) administration to mice, but a more direct effect was observed. Intracerebroventricular (icv) administration, which should have been observed, was ineffective even if the dose exceeded the level of toxicity. Therefore, it is difficult to expect clinical efficacy.

[0009] Furthermore, Psychopharmacology (Psychopha
rnecology, 91 (3), 273-8, 1987. Nefopam has many pharmacological activities such as anti-Parkinson's disease action and muscle relaxant action in addition to the target non-opioid analgesic action. Therefore, the occurrence of side effects is predicted in humans, and it can be said that clinical use is difficult.

Further, conventionally, a muscle relaxant having high clinical utility,
There were no anti-hypertensive, anti-Parkinson's, anti-Alzheimer's, anti-ulcerative colitis or anti-tobacco addicts.

[0011]

[Means for Solving the Problems] Therefore, the inventors of the present invention have high clinical safety and usefulness while maintaining the sharp drug effect of morphine and not having narcotics such as addiction and addiction. We have conducted extensive research on opioid analgesics. As a result, the novel azabicycloheptane derivative having the following general formula (I) or a pharmacologically acceptable salt thereof has an excellent non-opioid analgesic effect and is also excellent in safety. The inventors have completed the present invention by finding that the above problems can be solved.

Accordingly, an object of the present invention is to provide a clinically useful analgesic which has improved the drawbacks of morphine and is a novel muscle relaxant, antihypertensive agent, antiparkinsonian agent,
The present invention provides an anti-Alzheimer's disease drug, an anti-ulcerative colitis drug, or an anti-tobacco dependence drug.

[0013]

[Chemical 2]

In the formula, R is the same or different groups selected from hydrogen atom, lower alkyl group or lower alkoxy group, Y is> NH group,> CH ₂ group, oxygen atom or sulfur atom, and Z is unsubstituted. Or optionally substituted, phenyl group, pyridyl group, N-oxypyridyl group, pyrazyl group,
N-oxypyrazyl group, pyrimidyl group, N-oxypyrimidyl group, pyridazyl group, N-oxypyridazyl group, quinolyl group, N-oxyquinolyl group, isoquinolyl group, N-oxyisoquinolyl group, indolyl group, N-oxyindolyl group,
Furyl group, tetrahydrofuryl group, pyranyl group, tetrahydropyranyl group, thienyl group or tetrahydrothienyl group, and n means 0 or an integer of 1 to 5. However, Z does not include a 6-chloro-3-pyridyl group.

More specifically, the substituent of Z is, for example, a halogen atom, a lower alkyl group, a lower alkoxy group, an aryl group, an aryloxy group, an aralkyl group, an aralkyloxy group, a cyano group, a carboxy group or a lower alkoxycarbonyl. Group, one or more selected from an aminocarbonyl group optionally substituted with a nitrogen atom, a lower aliphatic acyl group, an aromatic acyl group, a hydroxyl group, a nitro group or an optionally substituted amino group. it can.

Further, as the halogen atom, more specifically, a chlorine atom, a fluorine atom, a bromine atom or an iodine atom can be mentioned, but a chlorine atom is more preferable. Next, as a lower alkyl group, more specifically, a methyl group, an ethyl group, n-
Propyl group, i-propyl group, n-butyl group, i-butyl group,
C1-C6 such as t-butyl group, pentyl group, hexyl group
More specifically, the alkyl group of is a lower alkoxy group, more specifically a group in which an oxygen atom is bonded to the lower alkyl group, and the aryl group is more specifically a phenyl group, tolyl group, xylyl group, dimethylphenyl group, trimethylphenyl group, ethylphenyl group. Group, chlorophenyl group, bromophenyl group, fluorophenyl group, nitrophenyl group, cyanophenyl group and the like, more specifically as an aryloxy group, more specifically a group having an oxygen atom bonded to the aryl group, and more specifically as an aralkyl group, a benzyl group Further, a methylbenzyl group, a phenethyl group, a phenylpropyl group and the like can be mentioned as the aralkyloxy group, more specifically, a group in which an oxygen atom is bonded to the aralkyl group.

Specific examples of the lower alkoxycarbonyl group include a group having the above lower alkoxy group in the molecule such as a methoxycarbonyl group, an ethoxycarbonyl group and a propoxycarbonyl group, and an aminocarbonyl group which may be substituted with a nitrogen atom. The group is, for example, a group represented by the formula-C
A group represented by ONH ₂ , a group represented by the formula —CONHR ^′ ,
The group represented by the formula -CONHR ^" R ^" (R ^' , R ^" mean the same or different lower alkyl groups), and the lower aliphatic acyl group is specifically a group such as acetyl group- C
A group represented by OR ^' (R ^' has the same meaning as described above) is specifically defined as a group represented by the formula -COR ^'" such as benzoyl group (R ^'"means an aryl group.), and substituted in particular the also an amino group optionally example methylamino group, formula -NR such as dimethyl amino group ^'R' groups represented by (R ^{', "} R ^" has the same meaning as described above.).

The substituent of the bicyclo skeleton of the compound of the present invention has a sterically exo (exo) configuration and an endo (endo).
Although there is a configuration, the compound of the present invention is not limited and may have any configuration, but the exo configuration is more preferred. The compound of the present invention may have stereoisomers, but the present invention is not limited thereto, and either one of the stereoisomers may be used, or a mixture thereof may be used.

The pharmacologically acceptable salt of the azabicycloheptane derivative (I) in the present invention specifically includes, for example, hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, Addition salts of inorganic acids such as perchlorates and phosphates, addition salts of organic acids such as oxalates, maleates, fumarates and succinates, methanesulfonates, ethanesulfonates, benzene Examples thereof include addition salts of sulfonic acids such as sulfonic acid salts, p-toluenesulfonic acid salts and camphorsulfonic acid salts.

The following compounds may be mentioned as specific examples of the azabicycloheptane derivative (I), but the azabicycloheptane derivative (I) in the present invention is not limited thereto. (1) Exo-2- (6-bromo-3-pyridyl) -7-
Azabicyclo [2.2.1] heptane (2) Exo-2- (6-iodo-3-pyridyl) -7-
Azabicyclo [2.2.1] heptane (3) Exo-2- (6-fluoro-3-pyridyl) -7
-Azabicyclo [2.2.1] heptane (4) exo-2- (6-chloro-2-pyridyl) -7-
Azabicyclo [2.2.1] heptane (5) Exo-2- (6-bromo-2-pyridyl) -7-
Azabicyclo [2.2.1] heptane (6) Exo-2- (6-iodo-2-pyridyl) -7-
Azabicyclo [2.2.1] heptane (7) Exo-2- (6-fluoro-2-pyridyl) -7
-Azabicyclo [2.2.1] heptane (8) exo-2- (6-chloro-4-pyridyl) -7-
Azabicyclo [2.2.1] heptane (9) Exo-2- (5-chloro-3-pyridyl) -7-
Azabicyclo [2.2.1] heptane (10) Exo-2- (2-chloro-3-pyridyl) -7
-Azabicyclo [2.2.1] heptane (11) exo-2- (4-chlorophenyl) -7-azabicyclo [2.2.1] heptane (12) exo-2- (2-bromophenyl) -7- Azabicyclo [2.2.1] heptane (13) Exo-2- (4-chlorobenzyl) -7-azabicyclo [2.2.1] heptane (14) Exo-2- (4-fluorophenethyl) -7-
Azabicyclo [2.2.1] heptane (15) Exo-2- (6-chloro-3-pyridyl) -1
-Methyl-7-azabicyclo [2.2.1] heptane (16) exo-2- (6-chloro-3-pyridyl)-
1,4-Dimethyl-7-azabicyclo [2.2.1] heptane (17) Exo-2- (6-chloro-3-pyridyl) -3
-Methyl-7-azabicyclo [2.2.1] heptane (18) exo-2- (6-chloro-3-pyridyl) -5
-Methyl-7-azabicyclo [2.2.1] heptane (19) exo-2- (6-chloro-3-pyridyl)-
5,6-Dimethyl-7-azabicyclo [2.2.1] heptane (20) exo-2- (6-chloro-3-pyridyl) -3
-Methoxy-7-azabicyclo [2.2.1] heptane (21) exo-2- (6-bromo-3-pyridyl)-
1,4-dimethoxy-7-azabicyclo [2.2.1]
Heptane (22) Exo-2- (6-chloro-3-pyridyl)-
5,6-dimethoxy-7-azabicyclo [2.2.1]
Heptane (23) Exo-2-phenyl-7-azabicyclo [2.
2.1] Heptane (24) Exo-2-toluyl-7-azabicyclo [2.
2.1] Heptane (25) exo-2-xylyl-7-azabicyclo [2.
2.1] Heptane (26) exo-2- (6-cyano-3-pyridyl) -7
-Azabicyclo [2.2.1] heptane (27) exo-2- (5-pyrazyl) -7-azabicyclo [2.2.1] heptane (28) exo-2- (5-pyrimidyl) -7-azabicyclo [2.2.1] Heptane (29) Exo-2- (5-pyridazyl) -7-azabicyclo [2.2.1] heptane (30) Exo-2- (2-pyridyl) -7-azabicyclo [2 1.2.1] heptane (31) exo-2- (3-pyridyl) -7-azabicyclo [2.2.1] heptane (32) exo-2- (4-pyridyl) -7-azabicyclo [2.2] .1] heptane (33) exo-2- (2-pyrimidyl) -7-azabicyclo [2.2.1] heptane (34) exo-2- (2-quinolyl) -7-azabicyclo [2.2.1] ] Heptane (35) Exo-2- (2-isoquinolyl) -7-azabi Black [2.2.1] heptane (36) exo-2- (2-chloro-3-pyridyl) -7
-Bicyclo [2.2.1] heptane (37) exo-2- (2-chloro-3-pyridyl) -7
-Oxabicyclo [2.2.1] heptane (38) exo-2- (2-chloro-3-pyridyl) -7
-Thiobicyclo [2.2.1] heptane (39) exo-2- (3-furyl) -7-azabicyclo [2.2.1] heptane (40) exo-2- (3-tetrahydrofuryl) -7-
Azabicyclo [2.2.1] heptane (41) Exo-2- (3-thienyl) -7-azabicyclo [2.2.1] heptane (42) Exo-2- (3-tetrahydrothienyl) -7
-Azabicyclo [2.2.1] heptane

Next, preparation examples for producing the starting materials necessary for carrying out the present invention will be listed prior to the examples. The starting material in the present invention is Organometal.Chem Synthesis (Organometal.Che).
m.Syn.), 1 , 145, 1970. Tosyl acetylene and the like produced by the method described in Angevante Chemie International Edition English (Angew.
Chem. Int. Ed. Engl.), 21 , 778, 1982., N-protected pyrrole, cyclopentadiene, furan,
It is obtained by reacting with thiophene or the like.

Production Example 2-Tosyl-7-ethoxycarbo
Nilazabicyclo [2.2.1] -1,4-heptadie
Synthesis

[0023]

[Chemical 3]

Organometal.Chem.Syn., 1 , 145, 1970.
Tosylacetylene synthesized by the method described in 41.
0 g (0.226 mol) and 1-ethoxycarbonylpyrrole 15.
7 g (0.113 mol) was heated at 100 ° C. for 4 hours under a nitrogen stream.
After cooling, the reaction solution was purified by silica gel column chromatography (ethyl acetate: n-hexane system) to obtain 27 g of the title compound as a colorless oil. (Yield: 75%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ 1.0-1.2 (3 H,
m), 2.4 (3H, s), 3.7-4.0 (1H, m), 5.2 (1H, s), 5.4 (1H, s), 6.9
(1H, s), 7.0 (1H, s), 7.4 (2H, s), 7.6 (1H, s), 7.8 (2H, s)

Next, in order to specifically describe the present invention,
Examples will be given below, but it goes without saying that the present invention is not limited thereto.

EXAMPLES Example 1 2-Tosyl-7-ethoxycarbonylazabi
Synthesis of cyclo [2.2.1] -4-heptene

[0027]

[Chemical 4]

[In the formula, Ts represents a tosyl group (p-toluenesulfonyl group). ] 2-Tosyl-7-ethoxycarbonylazabicyclo [2.2.1] -1,4-heptadiene
34.0 g (0.106 mol) was dissolved in ethanol (300 ml), sodium borohydride 4.0 g (0.105 mol) was added under ice-cooling, and the mixture was reacted for 1 hour. After adding acetone to the reaction solution, the mixture was poured into water and extracted with ethyl ether to obtain a crude product of the title compound (exo form: endo form = mixture of about 4: 3). The crude product has a sufficient purity for the next reaction without purification.

¹ H-NMR (400 MHz, CDCl ₃ ); Exo body δ (ppm) 1.1-1.3 (3H, br-t), 1.6 (1H, br-s), 2.
4 (3H, br-s), 3.0 (1H, br-s), 4.1 (2H, br-q), 4.8 (1H, br-s),
5.1 (1H, br-s), 6.3 (1H, br-s), 6.4 (1H, br-s), 7.4 (2H, d, J =
8.2Hz), 7.8 (2H, br-d) End body δ (ppm) 1.2 (3H, t, J = 7.1Hz), 1.7 (1H, m), 2.2
(1H, m), 2.4 (3H, s), 3.7 (1H, m), 4.0 (2H, q, J = 7.1Hz), 4.8 (2
H, m), 6.4 (1H, m), 6.5 (1H, m), 7.4 (2H, d, J = 8.2Hz), 7.8 (2H,
(d, J = 8.2Hz)

Example 2 7-Ethoxycarbonyl azabi
Synthesis of cyclo [2.2.1] -4-heptene

[0031]

[Chemical 5]

2-tosyl-7-ethoxycarbonylazabicyclo [2.2.1] -4-heptene 10.0 g (0.0311 m
ol) and sodium hydrogen phosphate (Na ₂ HPO ₄ ) 17.6 g (0.124 mol)
Is dissolved in methanol (100 ml) and cooled to 0 ° C. 5% under stirring-sodium amalgam 200.0 g (0.894 mol)
Was added and the reaction was allowed to proceed for 3 hours. The reaction solution was poured into water, extracted with ethyl ether, washed with water and dried to obtain a crude product of the title compound. The concentrated residue was purified by silica gel column chromatography (ethyl acetate: n-hexane system) to give 2.0 g of the title compound. (Yield; 38%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.1 (2H,
d, J = 8.8Hz), 1.2 (3H, t, J = 7.1Hz), 1.8 (2H, d, J = 8.8Hz), 4.0
(2H, q, J = 7.1Hz), 4.7 (2H, s), 6.2 (2H, s)

Example 3 Exo-2- (3-pyridyl)
-7-Ethoxycarbonylazabicyclo [2.2.1]
Heptane synthesis

[0035]

[Chemical 6]

7-Ethoxycarbonylazabicyclo [2.2.1] -4-heptene 4.0 g (23.8 mmol), 3-
Pyridine bromide 3.76 g (23.8 mmol), tetra-n-butylammonium chloride 6.62 g (23.8 mmol), potassium formate 6.0 g (71.4
mmol) and 280 mg (1.25 mmol) of palladium (II) acetate were dissolved in N, N-dimethylformamide (50 ml) and reacted at 60 ° C. for 24 hours. After cooling the reaction solution, it was poured into water and extracted with ethyl acetate. After drying, it was concentrated to give a crude product of the title compound. The concentrated residue was purified by silica gel column chromatography (toluene: ethyl acetate system) to give the title compound 3.1.
got g. (Yield; 53%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.2 (3 H,
m), 1.6 (2H, m), 1.8 (3H, m), 2.0 (1H, m), 2.9 (1H, m), 4.1 (2H, m)
q, J = 7.3Hz), 4.3 (1H, s), 4.5 (1H, s), 7.2 (1H, m), 7.6 (1H, d,
J = 7.9Hz), 8.5 (2H, m)

The following compounds were obtained in the same manner as in Example 3. (All oily substances) Example 4 Exo-2-phenyl-7-ethoxycarbo
Synthesis of Nilazabicyclo [2.2.1] heptane

[0039]

[Chemical 7]

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.05-1.
25 (3H, br-s), 1.30-2.02 (6H, m), 2.93 (1H, dd, J = 5.2,8.8H
z), 4.03-4.18 (2H, br-s), 4.21-4.33 (1H, br-s), 4.35-4.48
(1H, br), 7.17-7.42 (5H, m)

Example 5 Exo-2- (2-pyridyl)
-7-Ethoxycarbonylazabicyclo [2.2.1]
Heptane synthesis

[0042]

[Chemical 8]

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.02-1.
29 (3H, br-s), 1.50-2.22 (6H, m), 3.16 (1H, dd, J = 5.2,8.8H
z), 3.92-4.27 (2H, br-s), 4.32-4.52 (2H, br-s), 7.11 (1H, d
dd, J = 7.6,4.8,1.2Hz), 7.26-7.38 (1H, m), 7.61 (1H, td, J =
7.6,1.2Hz), 8.49 (1H, dd, J = 4.8,1.2Hz)

Example 6 Exo-2- (5-pyrimidi
) -7-Ethoxycarbonylazabicyclo [2.2.
1] Synthesis of heptane

[0045]

[Chemical 9]

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.23 (3
H, t, J = 7.2Hz), 1.55-1.94 (5H, m), 2.06 (1H, dd, J = 12.4,8.8
Hz), 2.89 (1H, dd, J = 8.8,4.8Hz), 4.12 (2H, q, J = 7.2Hz), 4.2
8 (1H, br-d), 4.49 (1H, br-t), 8.66 (2H, s), 9.08 (1H, s)

Example 7 Exo-2- (3-quinonyl)
-7-Ethoxycarbonylazabicyclo [2.2.1]
Heptane synthesis

[0048]

[Chemical 10]

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.00-1.
33 (3H, br-s), 1.57-2.13 (6H, m), 3.12 (1H, dd, J = 8.4,7.2H
z), 3.99-4.18 (2H, br-s), 4.31-4.45 (1H, br-s), 4.48-4.57
(1H, br-s), 7.53 (1H, t, J = 8.4Hz), 7.67 (1H, td, J = 8.0,1.2H
z), 7.78 (1H, d, J = 8.0Hz), 7.99-8.05 (1H, br-s), 8.06 (1H, J
= 8.4Hz), 8.82 (1H, d, J = 1.2Hz)

Example 8 Exo-2- (2-picolyl)
-7-Ethoxycarbonylazabicyclo [2.2.1]
Heptane synthesis

[0051]

[Chemical 11]

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.28 (3
H, t, J = 7.2Hz), 1.35-1.82 (5H, m), 2.24-2.33 (1H, m), 2.63
(1H, dd, J = 13.6,8.4Hz), 2.82 (1H, dd, J = 13.6,8.4Hz), 3.98
-4.08 (1H, br-s), 4.15 (2H, q, J = 7.2Hz), 4.27-4.357.09-7.
23 (2H, m), 7.60 (1H, td, J = 7.2,1.2Hz), 8.54 (1H, dd, J = 5.2,
(1.2Hz)

Example 9 Exo-2- (4-pyridyl)
-7-Ethoxycarbonylazabicyclo [2.2.1]
Heptane synthesis

[0054]

[Chemical 12]

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.15-1.
28 (3H, br-s), 1.51-2.05 (6H, m), 2.87 (1H, dd, J = 8.4,7.2H
z), 4.11 (2H, br-q), 4.27-2.35 (1H, br-s), 4.42-4.49 (1H, b
rs), 7.18 (2H, dd, J = 6.0,1.2Hz), 8.49 (2H, dd, J = 6.0,1.2H
z)

Example 10 Exo-2- (3-furyl)
-7-Ethoxycarbonylazabicyclo [2.2.1]
Heptane synthesis

[0057]

[Chemical 13]

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.10-1.
28 (3H, br-s), 1.40-1.93 (6H, m), 2.81 (1H, dd, J = 8.4,7.2H
z), 3.96-4.14 (2H, br-s), 4.16-4.25 (1H, br-s), 4.37-4.42
(1H, br-s), 6.29 (1H, m), 7.22 (1H, m), 7.33 (1H, t, J = 1.6Hz)

Example 11 Exo-2- (3-N-Oki)
Cypyridyl) -7-ethoxycarbonylazabicyclo
[2.2.1] Synthesis of heptane

[0060]

[Chemical 14]

Exo-2- (3-pyridyl) -7-ethoxycarbonylazabicyclo [2.2.1] heptane
5.82 g (23.6 mmol) was dissolved in methylene chloride (50 ml), 7.64 g (35.4 mmol) of 80% m-chloroperbenzoic acid was added under ice cooling, and the reaction was continued for 24 hours. Return the reaction solution to room temperature,
The product was directly purified by silica gel column chromatography (methylene chloride: ethanol system) to obtain 4.8 g of the title compound. (Yield; 77%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.2 (3H,
t, J = 7.1Hz), 1.6 (2H, m), 1.8 (3H, m), 2.0 (1H, m), 2.8 (1H, m
m), 4.1 (2H, m), 4.3 (1H, s), 4.5 (1H, s), 7.2 (1H, m), 7.4 (1H, s
m), 8.2 (1H, d, J = 7.9Hz), 8.3 (1H, s)

Example 12 Exo-2- (6-chloro-)
3-pyridyl) -7-ethoxycarbonylazabicyclo
[2.2.1] Synthesis of heptane

[0064]

[Chemical 15]

Exo-2- (3-N-oxypyridyl)
-7-Ethoxycarbonylazabicyclo [2.2.1]
4.8 g (18.3 mmol) of heptane was added with 10.0 ml of phosphorus oxychloride (108
mmol), heated to 80 ° C. and reacted for 1 hour. The reaction solution was cooled and then poured into ice water for neutralization. The pH was adjusted to weakly basic and extracted with ethyl acetate. After drying, it was concentrated to give a crude product of the title compound. The concentrated residue was purified by silica gel column chromatography (ethyl acetate: n-hexane system) to give the title compound (1.5 g). (Yield; 29%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.2 (3H,
t, J = 7.2Hz), 1.6 (3H, m), 1.8 (3H, m), 2.0 (1H, m), 2.9 (1H, q,
J = 5.2Hz), 4.1 (1H, q, J = 7.2Hz), 4.2 (1H, s), 4.4 (1H, s), 7.2
(1H, s), 7.6 (1H, d, J = 8.4Hz), 8.2 (1H, s) FAB-MS; m / e 283 ( ³⁷ Cl) / 281 ( ³⁵ Cl), (M + H ⁺ )

Example 13 Exo-2- (2-chloro-
3-pyridyl) -7-ethoxycarbonylazabicyclo
[2.2.1] Heptane and exo-2- (4-chloro
R-3-pyridyl) -7-ethoxycarbonylazabisi
Synthesis of Kuro [2.2.1] heptane

[0068]

[Chemical 16]

[0069]

[Chemical 17]

When the crude product of Example 12 was purified by silica gel column chromatography, two title compounds were obtained as by-products.

(1) Exo-2- (2-chloro-3-pyridyl) -7-ethoxycarbonylazabicyclo [2.
2.1] Heptane (yield; 28%) ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.2 (3H, br-t), 1.6-2.
2 (6H, m), 3.3 (1H, br-s), 4.1 (2H, br-q), 4.4 (1H, br-s), 7.2
(1H, dd, J = 7.9, 4.8Hz), 7.8 (1H, br-s), 8.2 (1H, dd, J = 4.8,
1.8Hz) FAB-MS; m / e 283 ( ³⁷ Cl) / 281 ( ³⁵ Cl), (M + H ⁺ )

(2) Exo-2- (4-chloro-3-pyridyl) -7-ethoxycarbonylazabicyclo [2.
2.1] Heptane (yield; 10%) ¹ H-NMR (400MHz, CDCl ₃ ); δ (ppm) 1.2 (3H, t, J = 7.2Hz),
1.6-2.0 (5H, m), 2.1 (1H, dd, J = 12.2, 9.7Hz), 3.3 (1H, dd, J
= 9.7, 4.8Hz), 4.1 (2H, q, J = 7.2Hz), 4.4-4.5 (2H, m), 7.3 (1
H, d, J = 5.4Hz), 8.4 (1H, d, J = 5.4Hz), 8.6 (1H, br-s) FAB-MS; m / e 283 ( ³⁷ Cl) / 281 ( ³⁵ Cl), ( M + H ⁺ )

Example 14 Exo-2- (6-chloro-)
3-Pyridyl) -7-azabicyclo [2.2.1] hep
Synthesis of tan dihydrochloride

[0074]

[Chemical 18]

Exo-2- (6-chloro-3-pyridyl) -7-ethoxycarbonylazabicyclo [2.2.
1] Heptane (820 mg, 2.91 mmol) was added to 5N-hydrochloric acid (5 ml), and the mixture was heated under reflux for 24 hours. The reaction liquid was cooled and then concentrated under reduced pressure to obtain 780 mg of the title compound. (Yield: 95%)

¹ H-NMR (400 MHz, D ₂ O); δ (ppm) 1.7-2.1 (5
H, m), 2.3 (1H, dd, J = 13.6, 9.6Hz), 3.3 (1H, dd, J = 9.6, 6.0
Hz), 4.2 (1H, t, J = 4.4Hz), 4.4 (1H, d, J = 4.4Hz), 7.3 (1H, d, J
= 8.4Hz), 7.7 (1H, dd, J = 8.4, 2.8Hz), 8.2 (1H, d, J = 2.8Hz) FAB-MS; m / e 211 ( ³⁷ Cl) / 209 ( ³⁵ Cl), ( M + H ⁺ )

Example 15 Exo-2- (2-chloro-)
3-Pyridyl) -7-azabicyclo [2.2.1] hep
Synthesis of tan dihydrochloride

[0078]

[Chemical 19]

Exo-2-
(2-Chloro-3-pyridyl) -7-ethoxycarbonylazabicyclo [2.2.1] heptane 82 mg (0.29 mmo
78 mg of the title compound was obtained from (l). (Yield: 95%)

¹ H-NMR (400 MHz, D ₂ O); δ (ppm) 1.7-2.0 (5
H, m), 2.4 (1H, dd, J = 13.6, 9.2Hz), 3.5 (1H, dd, J = 9.2, 6.0
Hz), 4.2 (1H, t, J = 4.4Hz), 4.4 (1H, d, J = 4.4Hz), 7.3 (1H, dd,
J = 8.0,4.8Hz), 7.8 (1H, dd, J = 8.0Hz, 1.6Hz), 8.1 (1H, dd, J
= 4.8, 1.6Hz) MS; m / e 208 (M + H ⁺ ) FAB-MS; m / e 211 ( ³⁷ Cl) / 209 ( ³⁵ Cl), (M + H ⁺ )

Example 16 Exo-2- (4-chloro-)
3-Pyridyl) -7-azabicyclo [2.2.1] hep
Synthesis of tan dihydrochloride

[0082]

[Chemical 20]

In the same manner as in Example 14, exo-2-
(4-Chloro-3-pyridyl) -7-ethoxycarbonylazabicyclo [2.2.1] heptane 82 mg (0.29 mmo
76 mg of the title compound was obtained from (l). (Yield; 93%)

¹ H-NMR (400 MHz, D ₂ O); δ (ppm) 1.5-1.8 (5
H, m), 2.0 (1H, dd, J = 13.5, 9.0Hz), 3.0 (1H, s), 3.2 (1H, m),
3.8 (1H, m), 3.9 (1H, m), 7.3 (1H, m), 8.3 (1H, m), 8.8 (1H, s) MS; m / e 208 (M + H ⁺ ) FAB-MS; m / e 211 ( ³⁷ Cl) / 209 ( ³⁵ Cl), (M + H ⁺ )

Example 17 Exo-2- (3-pyridy
) -7-Azabicyclo [2.2.1] heptane di-salt
Acid salt synthesis

[0086]

[Chemical 21]

In the same manner as in Example 14, exo-2-
78 mg of the title compound was obtained from 96 mg (0.39 mmol) of (3-pyridyl) -7-ethoxycarbonylazabicyclo [2.2.1] heptane. (Yield; 81%)

¹ H-NMR (400 MHz, D ₂ O); δ (ppm) 1.7-2.1 (5
H, m), 2.4 (1H, dd, J = 14.0, 10.0Hz), 3.6 (1H, dd, J = 10.0,
6.0Hz), 4.3 (1H, t, J = 4.4Hz), 4.6 (1H, d, J = 4.4Hz), 7.9 (1H,
dd, J = 8.4, 5.6Hz), 8.4 (1H, d, J = 8.4Hz), 8.6 (1H, d, J = 5.
6), 8.7 (1H, s) FAB-MS; m / e 174 (M + H ⁺ )

Example 18 3- (3-pyridyl) -4-
Synthesis of acetamido-2-cyclohexen-1-one

[0090]

[Chemical formula 22]

[In the formula, Ac means an acetyl group. ] 3
− Acetamide acetylpyridine 2.1 g (11.8 mmol) in ethanol (20 ml) was added with sodium ethylate 0.8 g at 0 ° C.
After adding g (1.88 mmol) and stirring for 5 minutes, 1 ml (12 mmol) of methyl vinyl ketone was added dropwise at 0 ° C. over 30 minutes. After stirring as such for 1 hour, the mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was washed with water, dried and then concentrated under reduced pressure, and the residue was recrystallized from ethanol-ether to obtain 0.464 g of light brown crystals of the title compound. The recrystallized mother liquor was purified by silica gel column chromatography (methylene chloride: methanol system) to collect 0.28 g of crystals of the title compound. (Total yield; 28%)

Melting point: 185-187 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.93 (3 H, s), 2.17-2.2
6 (1H, m), 2.30-2.40 (1H, m), 2.50-2.66 (2H, m), 5.44 (1H, dd
d, J = 8.8, 4.4, 4.4Hz), 6.36 (1H, d, J = 1.2Hz), 6.50 (1H, d,
J = 9.2Hz), 7.35 (1H, dd, J = 8.0, 4.8Hz), 7.80 (1H, ddd, J = 8.
0, 1.8, 1.8Hz), 8.55-8.60 (2H, m)

Example 19 3- (3-pyridyl) -4-
Synthesis of acetamide-2-cyclohexan-1-ol

[0094]

[Chemical formula 23]

3- (3-pyridyl) -4-acetamide-
0.52 g (2.26 mmol) of 2-cyclohexen-1-one was dissolved in methanol (30 ml), and at room temperature in the presence of a platinum oxide catalyst.
Catalytic reduction was carried out at normal pressure for 4 hours. The catalyst was filtered off and then concentrated under reduced pressure to give an oily crude product of the title compound. This crude product has a sufficient purity to be used in the next reaction without purification.

Example 20 3- (3-pyridyl) -4-
Synthesis of aminocyclohexan-1-ol

[0097]

[Chemical formula 24]

3- (3-pyridyl) -obtained in Example 19
20% -Sodium hydroxide aqueous solution (50 ml) was added to the crude product of 4-acetamido-2-cyclohexan-1-ol to give 1
The mixture was heated under reflux for 0 hours. The reaction solution was cooled and then extracted with methylene chloride. The organic layer was washed with water, dried, and concentrated under reduced pressure to give 0.357 g of an oily crude product of the title compound. This crude product has a sufficient purity to be used in the next reaction without purification.

Example 21 3- (3-pyridyl) -4-
Benzoxycarbamidocyclohexan-1-ol
Success

[0100]

[Chemical 25]

3- (3-pyridyl) -obtained in Example 20
Crude product of 4-aminocyclohexan-1-ol 0.3
Dissolve 57 g in methylene chloride (10 ml), and under ice cooling, 1N-sodium hydroxide aqueous solution (12 ml) and carbobenzoxy chloride 1.0
ml (7.0 mmol) was added. After stirring at room temperature for 1 hour, the reaction solution was extracted with methylene chloride. The organic layer was washed with water, dried, and concentrated under reduced pressure to give an oily crude product of the title compound.
This crude product has a sufficient purity to be used in the next reaction without purification.

Example 22 1-Methanesulfonyloxy
-3- (3-pyridyl) -4-benzoxycarbamide
Crohexane synthesis

[0103]

[Chemical formula 26]

[In the formula, Ms means a methanesulfonyl group. ] 3- (3-Pyridyl) -4-benzoxycarbamidocyclohexan-1-ol obtained in Example 21 was dissolved in pyridine (30 ml), and methanesulfonyl chloride 0.7
ml (9.0 mmol) was added and the mixture was stirred as it was for 17 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with methylene chloride. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (ethyl acetate).
The title compound (0.11 mg) was obtained. (Yield; 3- (3
-Pyridyl) -4-acetamido-2-cyclohexene-
1-on to 12.0%)

Example 23 1-Methanesulfonyloxy
Of 3- (3-pyridyl) -4-aminocyclohexane
Synthesis

[0106]

[Chemical 27]

0.31 g (0.77 mmol) of 1-methanesulfonyloxy-3- (3-pyridyl) -4-benzoxycarbamidocyclohexane obtained in Example 22 was added to methanol (40 ml).
And was subjected to catalytic reduction for 8 hours at room temperature and atmospheric pressure in the presence of 10% -palladium carbon catalyst. After filtering off the catalyst, it was concentrated under reduced pressure,
A crude product of the title compound was obtained. This crude product has a sufficient purity to be used in the next reaction without purification.

Example 24 End-2- (3-pyridy
Ru) -7-azabicyclo [2.2.1] heptane and
Exo-2- (3-pyridyl) -7-azabicyclo
[2.2.1] Synthesis of heptane

[0109]

[Chemical 28]

[0110]

[Chemical 29]

1-Methanesulfonyloxy-3- (3-pyridyl) -4-aminocyclohexane obtained in Example 23 was dissolved in 80% -ethanol water (20 ml) to prepare a 1N-sodium hydroxide aqueous solution (0.8 ml). Was added, and the mixture was heated with stirring at 50 to 55 ° C for 15 hours. The reaction mixture was cooled, concentrated under reduced pressure, water was added, and the mixture was extracted with methylene chloride. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is purified by preparative thin layer chromatography (methylene chloride: methanol: aqueous ammonia system) and endo-2- (3-pyridyl) -7-azabicyclo [2.2]. .1] heptane (45 mg, yield: 34%) and exo-2- (3-pyridyl) -7-azabicyclo [2.
2.1] Heptane (2 mg, yield: 1.5%) was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ); (1) endo-2- (3-pyridyl) -7-azabicyclo [2.2.1] heptane δ (ppm) 1.40-1.74 (5H, m) , 2.10
-2.19 (1H, m), 3.35-3.44 (1H, m), 3.82 (2H, t, J = 4.8Hz), 7.2
5 (1H, dd, J = 7.6, 4.8Hz), 7.51 (1H, d, J = 8.0Hz), 8.46 (1H, d
d, J = 4.8, 1.6Hz), 8.49 (1H, d, J = 2.4Hz)

(2) Exo-2- (3-pyridyl) -7-
Azabicyclo [2.2.1] heptane δ (ppm) 1.50-2.0
5 (5H, m), 2.20-2.32 (1H, m), 2.85 (1H, dd, J = 8.8, 5.2Hz),
3.64 (1H, d, J = 4.0Hz), 3.84 (1H, t, J = 3.8Hz), 7.22 (1H, dd, J
= 8.0, 4.8Hz), 7.73 (1H, dt, J = 8.0, 1.6Hz), 8.43 (1H, dd, J
= 4.8, 1.6Hz), 8.51 (1H, d, J = 2.4Hz)

Example 25 End-2- (3-pyridy
) -7-Acetylazabicyclo [2.2.1] hepta
Synthesis

[0115]

[Chemical 30]

45 m of endo-2- (3-pyridyl) -7-azabicyclo [2.2.1] heptane obtained in Example 24
g (0.26 mmol) was dissolved in pyridine (5 ml), and acetic anhydride 0.05
ml (0.5 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (methylene chloride: methanol: ammonia water system) to give 0.056 g of the title compound as an oil. (Yield: 10
0%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.43-
1.93 (5H, m), 2.10 (3H, s), 2.13 (3H, s), 2.10-2.22 (1H, m),
2.28-2.38 (1H, m), 3.46-3.55 (1H, m), 4.26 (1H, t, J = 5.20H
z), 4.28 (1H, t, J = 5.20Hz), 4.77 (1H, t, J = 5.20, 4.80Hz),
4.83 (1H, t, J = 5.20, 4.80Hz), 7.25-7.34 (1H, m), 7.51-7.5
7 (1H, m), 8.52 (1H, br-s)

Example 26 End-2- (3-pyridy
) -7-Acetylazabicyclo [2.2.1] hepta
Synthesis of N-oxide

[0119]

[Chemical 31]

0.135 g (0.62 mmol) of endo-2- (3-pyridyl) -7-acetylazabicyclo [2.2.1] heptane obtained in Example 25 was dissolved in methylene chloride (7 ml) to give 80%. - metachloroperbenzoic acid 0.15 g (0.69 mmol) and disodium hydrogen phosphate · dodecahydrate _{(Na 2 HPO 4 · 12H 2} O) 0.12
5 g (0.35 mmol) was added, and the mixture was stirred at room temperature for 19 hours. The insoluble material was filtered off, concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (methylene chloride: methanol system) to give the title compound (0.132 g). (Yield: 91%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.40-1.
70 (1H, m), 1.82-1.95 (1H, m), 2.09 (3H, s), 2.11 (3H, s), 2.2
5-2.38 (1H, m), 3.40-3.49 (1H, m), 4.27 (1H, t, J = 5.20, 3.6
0Hz), 4.28 (1H, t, J = 5.20, 3.60Hz), 4.77 (1H, t, J = 4.80H
z), 4.83 (1H, t, J = 4.80Hz), 7.16 (1H, d, J = 8.0Hz), 7.25-7.3
3 (1H, m), 8.12-8.20 (2H, m)

Example 27 End-2- (6-chloro-
3-pyridyl) -7-acetoxyazabicyclo [2.
2.1] Heptane and endo-2- (2-chloro-3
-Pyridyl) -7-acetoxyazabicyclo [2.2.
1] Synthesis of heptane

[0123]

[Chemical 32]

[0124]

[Chemical 33]

To 0.07 g (0.3 mmol) of endo-2- (3-pyridyl) -7-acetoxyazabicyclo [2.2.1] heptane N-oxide obtained in Example 26 was added phosphorus oxychloride (3 ml). The mixture was stirred at 80 ° C for 10 minutes. After cooling, the reaction solution was poured into ice water, made basic with 5N-sodium hydroxide aqueous solution, and extracted with methylene chloride. The organic layer was washed with water, dried and concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (methylene chloride: methanol system) to give a mixture of the title compounds (4 mg).

Example 28 End-2- (6-chloro-
3-Pyridyl) -7-azabicyclo [2.2.1] hep
Tan and endo-2- (2-chloro-3-pyridyl)
Synthesis of -7-azabicyclo [2.2.1] heptane

[0127]

[Chemical 34]

[0128]

[Chemical 35]

Endo-2- (6-chloro-3-pyridyl) -7-acetoxyazabicyclo [2.2.1] heptane obtained in Example 27 and endo-2- (2-chloro-
3-pyridyl) -7-acetoxyazabicyclo [2.
2.1] 5N-hydrochloric acid (3 ml) was added to 4 mg of the heptane mixture, and the mixture was heated under reflux for 3 hours. After cooling the reaction solution, it was concentrated under reduced pressure,
The residue was purified by preparative thin layer chromatography (methylene chloride: methanol: aqueous ammonia system), and 0.6 mg of endo-2- (6-chloro-3-pyridyl) -7-azabicyclo [2.2.1] heptane ( Yield: 18%)
And endo-2- (2-chloro-3-pyridyl) -7-
0.4 mg of azabicyclo [2.2.1] heptane (yield;
12%) obtained.

¹ H-NMR (400 MHz, CDCl ₃ ); (1) endo-2- (6-chloro-3-pyridyl) -7-
Azabicyclo [2.2.1] heptane δ (ppm) 1.50-2.48 (6H, m), 3.64-3.71 (1H, m), 4.09 (2H, t,
J = 4.8Hz), 7.33 (1H, d, J = 8.4Hz), 7.49 (1H, dd, J = 8.2, 2.4H
z), 8.27 (1H, d, J = 2.4Hz) IR (neat): 3400,2924,1461,1105 cm ^-1 FAB-MS; m / e 211 ( ³⁷ Cl) / 209 ( ³⁵ Cl): (MH ⁺ )

(2) Endo-2- (2-chloro-3-pyridyl) -7-azabicyclo [2.2.1] heptane δ (ppm) 1.62-2.27 (6H, m), 3.79-3.86 (1H, m), 3.96 (1H, t,
J = 4.8Hz), 4.15 (1H, t, J = 4.8Hz), 7.26 (1H, dd, J = 7.8, 4.8H
z), 7.64 (1H, dd, J = 7.8, 1.6Hz), 8.30 (1H, dd, J = 4.8, 1.6H
z) IR (neat): 3400,3200,2961,1406,1074 cm ^-1 FAB-MS; m / e 211 ( ³⁷ Cl) / 209 ( ³⁵ Cl): (MH ⁺ ).

Example 29 Exo-2- (3-pyridy
) -7-oxabicyclo [2.2.1] heptane
Success

[0133]

[Chemical 36]

Journal of Organic Chemistry (J.Org.Chem.), 50 , 4340-4345, 1985. 7-oxabicyclo [2.2.
1] hept-2-ene 538 mg (5,60 mmol), 3-bromopyridine 885 mg, tetra-n-butylammonium chloride 1.56
g, palladium (II) acetate 31 mg and potassium formate 1.41 g N,
A suspension of N-dimethylformamide (5 ml) was stirred at 60 ° C. for 24 hours under an argon gas stream. The reaction solution was extracted with ethyl acetate, the organic layer was washed with water, dried and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (toluene: ethyl acetate system) to give the title compound (6.0 mg). (Yield: 0.61%)

¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.47-1.
67 (5H, m), 2.11 (1H, dd, J = 12.8, 9.2Hz), 3.18 (1H, dd, J = 9.
2, 4.4Hz), 4.45 (1H, d, J = 3.6Hz), 4.71 (1H, t, J = 3.6Hz), 7.
81 (1H, dd, J = 8.0, 6.0Hz), 8.36 (1H, dt, J = 8.4, 1.6Hz), 8.
44 (1H, d, J = 6.0Hz), 8.50 (1H, d, J = 1.6Hz) FAB-MS; m / e 176 (MH ⁺ )

Example 30 Exo-2- (3-pyridy
Synthesis of ru) -7-bicyclo [2.2.1] heptane

[0137]

[Chemical 37]

Norbornylene 1.0 g (10.6 mmol), 3-bromopyridine 1.67 g, tetra-n-butylammonium chloride
2.95 g, 60 mg of palladium (II) acetate and potassium formate 2.67
A suspension of g of N, N-dimethylformamide (15 ml) was stirred at 60 ° C. for 10 hours under an argon gas stream. The reaction solution was extracted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate system) to give 763 mg of the title compound. (Yield: 42%)

Melting point: 122-124 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ); δ (ppm) 1.08-1.17 (2H, m), 1.2
0-1.30 (2H, m), 1.36-1.52 (3H, m), 1.74 (1H, td, J = 9.2,2.0H
z), 2.24 (1H, br-t), 2.28 (1H, d, J = 3.6Hz), 2.84 (1H, dd, J =
9.2, 5.2Hz), 7.78 (1H, dd, J = 8.0, 5.6Hz), 8.32 (1H, d, J =
8.4Hz), 8.38 (1H, d, J = 5.6Hz), 8.46 (1H, s) FAB-MS; m / e 174 (MH ⁺ )

The following compounds were obtained in the same manner as in Example 12. Example 31 Exo-2-phenyl-7-azabicyclo
[2.2.1] Synthesis of heptane hydrochloride

[0141]

[Chemical 38]

¹ H-NMR (400 MHz, D ₂ O); δ (ppm) 1.67-2.01
(5H, m), 2.24 (1H, dd, J = 14.0, 10.0Hz), 3.27 (1H, dd, J = 9.
6, 5.6Hz), 4.19 (1H, t, J = 4.4Hz), 4.35 (1H, d, J = 4.4Hz), 7.
15 (1H, t, J = 7.6Hz), 7.16 (2H, d, J = 7.6Hz), 7.26 (2H, td, J =
7.6, 1.2Hz) FAB-MS; m / e 174 (MH ⁺ )

Example 32 Exo-2- (4-pyridyl)
) -7-Azabicyclo [2.2.1] heptane di-salt
Acid salt synthesis

[0144]

[Chemical Formula 39]

¹ H-NMR (400 MHz, D ₂ O); δ (ppm) 1.74-2.04
(5H, m), 2.46 (1H, dd, J = 13.6, 10.0Hz), 3.62 (1H, dd, J = 10.
0, 6.0Hz), 4.26 (1H, t, J = 4.4Hz), 4.65 (1H, d, J = 4.4Hz), 7.
86 (2H, d, J = 7.2Hz), 8.58 (2H, d, J = 7.2Hz) FAB-MS; m / e 175 (MH ⁺ )

Example 33 Exo-2- (2-pyridy
) -7-Azabicyclo [2.2.1] heptane di-salt
Acid salt synthesis

[0147]

[Chemical 40]

¹ H-NMR (400 MHz, D ₂ O); δ (ppm) 1.76-2.16
(5H, m), 2.45 (1H, dd, J = 13.6, 9.6Hz), 3.72 (1H, dd, J = 10.
0, 6.0Hz), 4.31 (1H, t, J = 4.4Hz), 4.63 (1H, d, J = 4.4Hz), 7.
79 (1H, t, J = 7.2Hz), 7.90 (1H, d, J = 8.0Hz), 8.41 (1H, td, J =
8.0, 1.6Hz), 8.57 (1H, dd, J = 5.6,1.6Hz) FAB-MS; m / e 175 (MH ⁺ )

Example 34 Exo-2- (3-quinoli
) -7-Azabicyclo [2.2.1] heptane di-salt
Acid salt synthesis

[0150]

[Chemical 41]

¹ H-NMR (400 MHz, D ₂ O); δ (ppm) 1.76-2.06
(5H, m), 2.49 (1H, dd, J = 13.6, 9.6Hz), 3.70 (1H, dd, J = 9.6,
6.0Hz), 4.32 (1H, t, J = 4.4Hz), 4.64 (1H, d, J = 4.4Hz), 7.81
(1H, t, J = 8.0Hz), 7.98 (1H, t, J = 7.2Hz), 8.05 (1H, d, J = 8.4H
z), 8.11 (1H, d, J = 8.0Hz), 8.96 (1H, s), 8.98 (1H, s) FAB-MS; m / e 221 (MH ⁺ )

Example 35 Exo-2- (5-pyrimidi
) -7-Azabicyclo [2.2.1] heptane di-salt
Acid salt synthesis

[0153]

[Chemical 42]

¹ H-NMR (400 MHz, D ₂ O); δ (ppm) 1.70-2.06
(5H, m), 2.36 (1H, dd, J = 13.6, 9.6Hz), 3.43 (1H, dd, J = 9.6,
6.0Hz), 4.25 (1H, t, J = 4.4Hz), 4.51 (1H, d, J = 4.4Hz), 8.69
(1H, s), 8.93 (1H, s) FAB-MS; m / e 176 (MH ⁺ )

Example 36 Exo-2- (3-picoli)
) -7-Azabicyclo [2.2.1] heptane di-salt
Acid salt synthesis

[0156]

[Chemical 43]

¹ H-NMR (400 MHz, D ₂ O); δ (ppm) 1.49-1.64
(3H, m), 1.78-1.84 (2H, m), 1.93 (1H, dd, J = 13.6, 9.2Hz),
2.46 (1H, m), 2.94 (1H, dd, J = 15.2, 8.4Hz), 3.12 (1H, dd, J =
15.2, 8.0Hz), 3.97 (1H, d, J = 4.0Hz), 4.16 (1H, t, J = 4.0H)
z), 7.76 (1H, td, J = 6.0, 1.2Hz), 7.80 (1H, d, J = 7.6Hz), 8.3
8 (1H, td, J = 8.4, 2.0Hz), 8.52 (1H, d, J = 6.0Hz) FAB-MS; m / e 189 (MH ⁺ )

Example 37 Exo-2- (3-furyl)
Of -7-azabicyclo [2.2.1] heptane hydrochloride
Synthesis

[0159]

[Chemical 44]

¹ H-NMR (400 MHz, D ₂ O); δ (ppm) 1.60-1.89
(6H, m), 2.09 (1H, dd, J = 13.2, 3.6Hz), 3.05 (1H, dd, J = 8.8,
3.6Hz), 4.09-4.17 (2H, m), 6.27 (1H, br-s), 7.24 (1H, br-
s), 7.32 (1H, br-s) FAB-MS; m / e 164 (MH ⁺ )

Next, in order to show the excellent non-opioid analgesic action of the compound of the present invention, experimental examples will be given as the effects of the invention.

The following compounds were selected as typical examples of the compound of the present invention, and morphine was selected as the activity control drug. (1) Exo-2- (2-pyridyl) -7-azabicyclo [2.2.1] heptane (2) Exo-2- (5-pyrimidyl) -7-azabicyclo [2.2.1] heptane (3 ) Morphine

[0162] The method using the mouse of eight mice in each group, measure the time extension of up to Keru yo waving his tail when given the heat stimulus to the tail, the tail - evaluate the analgesic effect by the flick (tail-flick) method did.

Results The results of evaluating each compound are shown in Table 1.

[0164]

[Table 1]

From Table 1, it is clear that the compound of the present invention exerts an analgesic effect at a dose lower than that of morphine, showing the excellent non-opioid analgesic effect of the compound of the present invention.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/395 AAH 9454-4C 31/40 ABV ACL 9454-4C 31/44 AAB 9454-4C 31 / 47 AAM 9454-4C 31/505 AAS 9454-4C C07C 43/188 C07D 213/16 487/08 7019-4C 493/08 A 495/08

Claims (4)

[Claims] 1. An azabicycloheptane derivative (I) having the following general formula or a pharmaceutically acceptable salt thereof. [Chemical 1] [Wherein R represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, which are the same or different, and Y is> N
H group,> CH ₂ group, oxygen atom or sulfur atom, Z may be unsubstituted or substituted, phenyl group, pyridyl group, N-oxypyridyl group, pyrazyl group, N-oxypyrazyl group, pyrimidyl group, N-oxypyrimidyl group, pyridazyl group, N-oxypyridazyl group, quinolyl group, N-oxyquinolyl group, isoquinolyl group, N-oxyisoquinolyl group, indolyl group, N-oxyindolyl group, furyl group,
A tetrahydrofuryl group, a pyranyl group, a tetrahydropyranyl group, a thienyl group or a tetrahydrothienyl group,
n means 0 or an integer of 1 to 5. However, Z does not include a 6-chloro-3-pyridyl group. ] 2. The substituent of Z is substituted with a halogen atom, a lower alkyl group, a lower alkoxy group, an aryl group, an aryloxy group, an aralkyl group, an aralkyloxy group, a cyano group, a carboxy group, a lower alkoxycarbonyl group and a nitrogen atom. The aza according to claim 1, which is one or more selected from an optionally substituted aminocarbonyl group, a lower aliphatic acyl group, an aromatic acyl group, a hydroxyl group, a nitro group or an optionally substituted amino group. Bicycloheptane derivative
(I) or a pharmaceutically acceptable salt thereof. 3. An analgesic containing an azabicycloheptane derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient. 4. A muscle relaxant, an anti-hypertensive agent, an anti-Parkinson's disease agent, an anti-Alzheimer's disease agent, an anti-ulcerative large intestine containing an azabicycloheptane derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient. Anti-inflammatory or anti-tobacco drug.