JPH09278749A - Heterocyclic derivatives - Google Patents

Abstract

(57) [Abstract] [Purpose] To provide a compound having a smooth muscle contraction inhibitory action, a secretion inhibitory action and the like and selectively reducing side effects by selectively blocking muscarinic receptor subtype m3. . [Constitution] Formula [Formula 1] (In the formula, R ¹ and R ² each represent a hydrogen atom or a methoxy group, or R ¹ and R ² together represent a methylenedioxy group, and n represents 2 or 3.) A heterocyclic derivative or a pharmaceutically acceptable acid addition salt thereof.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a heterocyclic derivative having a muscarinic receptor blocking activity.

[0002]

2. Description of the Related Art Muscarinic receptor blockers antagonize muscarinic receptors widely existing in the living body and exhibit smooth muscle contraction inhibitory action, secretion inhibitory action and mydriatic action. Therefore, they are used as therapeutic agents for many diseases, for example, as a therapeutic agent for neuropathic bladder disorders, unstable bladder, irritable bowel syndrome, spastic colitis, hypertension, asthma and peptic ulcer, etc. Or it is prescribed as a mydriatic drug. Such muscarinic receptor blockers include:
Atropine, pirenzepine, oxybutynin, propiverine, etc. are known.

However, since conventional muscarinic receptor blockers have a wide range of actions, they may be clinically unfavorable because they have side effects due to the action other than the treatment of the target disease. As muscarinic receptor subtypes, m1, m2, m3, m4 and m5 are known, and it has been confirmed that the subtype distribution ratios differ among tissues in the living body. Furthermore, various possibilities have been suggested regarding the phenomenon that is caused by the action of each receptor subtype, and there are many reports regarding m1, m2, and m3 in particular. For example, m1 is mainly distributed in the central nervous system and is involved in memory and learning, m2 is involved in negative chronotropic action in the heart, and m1 is
It has been suggested that 3 is involved in smooth muscle contraction and distribution of the bladder, ileum, and bronchus. From this, it is considered that the selective inhibition of the target receptor subtype can reduce the side effects resulting from the inhibition of other receptor subtypes.

[0004]

The object of the present invention is to provide a compound having a smooth muscle contraction inhibitory action or a secretory inhibitory action by selectively blocking the muscarinic receptor subtype m3 and having reduced side effects. To provide.

[0005]

Means for Solving the Problems As a result of intensive studies to achieve the above-mentioned objects, the present inventors have found that certain pyrrolidine derivatives or piperidine derivatives block muscarinic receptors and muscarinic receptor Type m
Found that m3 has higher selectivity than 1, m2,
The present invention has been completed.

That is, the present invention provides

[0007]

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(In the formula, R ¹ and R ² each represent a hydrogen atom or a methoxy group, or R ¹ and R ² together represent a methylenedioxy group, and n represents 2 or 3.) Or a pharmaceutically acceptable acid addition salt thereof. The pharmaceutically acceptable acid addition salt of the compound of formula (I) means a salt to which an inorganic acid or an organic acid is added, and examples thereof include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid,
Examples thereof include acetic acid, propionic acid, glycolic acid, fumaric acid, succinic acid, tartaric acid, ascorbic acid, salicylic acid, lactic acid, malic acid, methanesulfonic acid, and paratoluenesulfonic acid. The present invention includes all optical isomers, racemates and hydrates of the compound represented by the formula (I). Further, a preferable compound is a compound in which n is 2,
More preferably, n is 2 and R ¹ and R ² are taken together to form a methylenedioxy group.

The compound of the present invention can be produced, for example, according to the method shown below. That is, the expression

[0010]

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And the formula

[0012]

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(Wherein R ¹ and R ² have the same meanings as described above, and X represents a halogen atom such as chlorine, bromine or iodine), and the compound represented by the formula ( A compound of formula I) can be obtained.

Here, as the solvent, a benzene solvent (toluene, benzene), dimethylformamide, acetonitrile or the like can be used. The reaction temperature is 0 to 150 ° C., and the reaction time is 10 minutes to 48 hours. In this reaction, a base (for example, potassium carbonate,
It is also possible to use metal iodide (eg, sodium iodide, potassium iodide, etc.) and, if necessary, triethylamine and the like.

[0015]

EFFECTS OF THE INVENTION The compound of the present invention selectively blocks muscarinic receptor subtype m3, as is clear from the test examples described below, and therefore, it is expected to reduce the side effects resulting from the inhibition of m1 and m2. Is useful as

[0016]

The present invention will be described below in more detail with reference to examples and test examples. (Example 1) 3-diphenylmethoxy-1- [2- (3,4-methylene)
( Dioxyphenoxy ) ethyl] pyrrolidine (compound
1) To a solution of 0.51 g of 3- (diphenylmethoxy) pyrrolidine in 15 ml of acetonitrile was added 0.45 g of 2- (3,4-methylenedioxyphenoxy) ethyl bromide and 0.30 ml of triethylamine, and the mixture was heated under reflux for 4 hours. After evaporating the solvent under reduced pressure, ethyl acetate was added, and the mixture was washed successively with water and saturated brine. After drying over magnesium sulfate, filtration and evaporation of the solvent under reduced pressure, the residue was subjected to silica gel chromatography (developing solvent: hexane: ethyl acetate = 1: 5) to obtain 0.32 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ ppm;
1.82 to 2.17 (2H, m), 2.58 to 2.97
(6H, m), 3.99 (2H, t, J = 7Hz),
4.06 to 4.21 (1H, m), 5.38 (1H,
s), 5.91 (2H, s), 6.30 (1H, dd,
J = 3,9 Hz), 6.49 (1H, d, J = 3H
z), 6.69 (1H, d, J = 9 Hz), 7.17-
7.45 (10H, m).

The following compounds were synthesized in the same manner.

3-diphenylmethoxy-1- (2-phenoxyethyl) pyrrolidine ¹ H-NMR (CDCl ₃ ) δppm; 1.85-2.
17 (2H, m), 2.63 to 3.03 (5H, m),
4.05 to 4.22 (1H, m), 4.08 (2H,
t, J = 7 Hz), 5.38 (1H, s), 6.82-
7.01 (3H, m), 7.17 to 7.43 (12H,
m).

3-diphenylmethoxy-1- [2- (2
-Methoxyphenoxy) ethyl] pyrrolidine ¹ H-NMR (CDCl ₃ ) δppm; 1.85-2.
16 (2H, m), 2.60 to 3.03 (6H, m),
3.83 (3H, s), 4.07 to 4.21 (1H,
m), 4.12 (2H, t, J = 7Hz), 5.38
(1H, s), 6.81 to 6.98 (4H, m), 7.
16-7.38 (10H, m).

3-diphenylmethoxy-1- [2- (3
-Methoxyphenoxy) ethyl] pyrrolidine ¹ H-NMR (CDCl ₃ ) δ ppm; 1.82-2.
16 (2H, m), 2.59 to 2.98 (6H, m),
3.76 (3H, s), 4.05 (2H, t, J = 7H
z), 4.06 to 4.21 (1H, m), 5.38 (1
H, s), 6.43 to 6.55 (3H, m), 7.10
~ 7.38 (11H, m).

3-diphenylmethoxy-1- [2- (4
-Methoxyphenoxy) ethyl] pyrrolidine ¹ H-NMR (CDCl ₃ ) δ ppm; 1.82-2.
18 (2H, m), 2.58 to 2.98 (6H, m),
3.76 (3H, s), 4.02 (2H, t, J = 7H
z), 4.07 to 4.21 (1H, m), 5.38 (1
H, s), 6.83 (4H, s), 7.17 to 7.42.
(10H, m).

3-diphenylmethoxy-1- [2-
(3,4-Dimethoxyphenoxy) ethyl] pyrrolidine ¹ H-NMR (CDCl ₃ ) δppm; 1.85-2.
18 (2H, m), 2.61 to 3.00 (6H, m),
3.83 (3H, s), 3.85 (3H, s), 4.0
3 (2H, t, J = 7Hz), 4.08 to 4.22 (1
H, m), 5.38 (1H, s), 6.38 (1H, d)
d, J = 3,9 Hz), 6.54 (1H, d, J = 3H
z), 6.77 (1H, d, J = 9 Hz), 7.18-
7.38 (10H, m).

(R) -3-diphenylmethoxy-1-
[2- (3,4-Methylenedioxyphenoxy) ethyl] pyrrolidine [α] _D = -5.3 (c = 1.0, methanol) ¹ H-NMR (CDCl ₃ ) δppm; 1.82-2.
17 (2H, m), 2.58 to 2.97 (6H, m),
3.99 (2H, t, J = 7Hz), 4.06-4.2
1 (1H, m), 5.38 (1H, s), 5.91 (2
H, s), 6.30 (1H, dd, J = 3,9Hz),
6.49 (1H, d, J = 3Hz), 6.69 (1H,
d, J = 9 Hz), 7.17 to 7.45 (10H,
m).

(Example 2) 3-diphenylmethoxy-1- [2- (3,4-methylene)
Nji oxy-phenoxy) ethyl] piperidine 3- (diphenyl-methoxy) acetonitrile 15ml solution of piperidine 0.50 g 2-(3,4-methylenedioxy phenoxy) ethyl bromide 0.42g and triethylamine 0.29ml was added heated to reflux for 4 h did. After evaporating the solvent under reduced pressure, ethyl acetate was added, and the mixture was washed successively with water and saturated brine. After drying over magnesium sulfate, filtration and evaporation of the solvent under reduced pressure, the residue was subjected to silica gel chromatography (developing solvent: hexane: ethyl acetate = 1: 5) to obtain 0.43 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ ppm;
1.26 to 1.82 (3H, m), 1.92 to 2.21
(3H, m), 2.72 to 2.84 (1H, m), 2.
76 (2H, t, J = 7Hz), 3.00 to 3.14
(1H, m), 3.47 to 3.62 (1H, m), 3.
97 (2H, t, J = 7Hz), 5.52 (1H,
s), 5.91 (2H, s), 6.30 (1H, dd,
J = 3,9 Hz), 6.48 (1H, d, J = 3H
z), 6.69 (1H, d, J = 9 Hz), 7.16-
7.42 (10H, m).

The following compounds were synthesized in the same manner.

3-diphenylmethoxy-1- (2-phenoxyethyl) piperidine ¹ H-NMR (CDCl ₃ ) δppm; 1.26-2.
23 (6H, m), 2.70 to 2.87 (1H, m),
2.79 (2H, t, J = 7Hz), 3.02-3.1
7 (1H, m), 3.46 to 3.62 (1H, m),
4.05 (2H, t, J = 7Hz), 5.52 (1H,
s), 6.82 to 7.01 (3H, m), 7.05
7.42 (12H, m).

3-diphenylmethoxy-1- [2- (2
- methoxyphenoxy) ethyl] piperidine _{^{1 H-NMR (CDCl 3)}} δppm; 1.21~2.
25 (6H, m), 2.73 to 2.85 (1H, m),
2.83 (2H, t, J = 7 Hz), 3.07 to 3.1
7 (1H, m), 3.47 to 3.62 (1H, m),
3.82 (3H, s), 4.12 (2H, t, J = 7H
z), 5.53 (1H, s), 6.83 to 6.99 (4
H, m), 7.14 to 7.43 (10H, m).

3-diphenylmethoxy-1- [2- (3
- methoxyphenoxy) ethyl] piperidine _{^{1 H-NMR (CDCl 3)}} δppm; 1.21~1.
82 (3H, m), 1.92 to 2.23 (3H, m),
2.72 to 2.87 (1H, m), 2.79 (2H, m
t, J = 7 Hz), 3.02 to 3.13 (1H, m),
3.48 to 3.62 (1H, m), 3.77 (3H,
s), 4.03 (2H, t, J = 7Hz), 5.53
(1H, s), 6.42 to 6.56 (3H, m), 7.
13-7.40 (11H, m).

3-diphenylmethoxy-1- [2- (4
- methoxyphenoxy) ethyl] piperidine _{^{1 H-NMR (CDCl 3)}} δppm; 1.21~1.
60 (2H, m), 1.65 to 1.81 (1H, m),
1.93 to 2.23 (3H, m), 2.75 to 2.86
(1H, m), 2.76 (2H, t, J = 7Hz),
3.02 to 3.13 (1H, m), 3.46 to 3.63
(1H, m), 3.76 (3H, s), 4.01 (2
H, t, J = 7 Hz), 5.53 (1H, s), 6.8
2 (4H, s), 7.16-7.40 (10H, m).

1- [2- (3,4-dimethoxyphenoxy) ethyl] -3- (diphenylmethoxy) piperidine ¹ H-NMR (CDCl ₃ ) δppm; 1.21-1.
80 (3H, m), 1.92 to 2.23 (3H, m),
2.76 to 2.88 (1H, m), 2.76 (2H, m
t, J = 7 Hz), 3.02 to 3.16 (1H, m),
3.44 to 3.63 (1H, m), 3.83 (6H,
s), 4.02 (2H, t, J = 7Hz), 5.03
(1H, s), 6.37 (1H, dd, J = 3,9H
z), 6.52 (1H, d, J = 3 Hz), 6.77
(1H, d, J = 9 Hz), 7.16 to 7.38 (10
H, m).

(Test Example) [Muscarinic Receptor Binding Test] The recombinant human muscarinic receptor binding reaction was performed in Wall
[J.Pharmacol.Exp.Ther., Vol40, 783 (1991)], Pep
itoni et al. [Biochem.Biophs.Res.Commun., vol.176, 453
(1991)] and the like. Recombinant human muscarinic receptor subtype m purchased from RBI
1, m2, m3 0.5ml each 24.5ml incuba
dilution buffer [50 mM Tris-hydrochloric acid buffer (containing 10 mM MgCl ₂ and 1 mM EDTA, pH 7.4)] was used as a membrane preparation of each subtype.

0.2 nM in 0.5 ml of each receptor membrane preparation
Add [ ³ H] NMS and various concentrations of specimens, 27 ℃
And reacted for 60 minutes. After the reaction was completed, suction filtration was performed with a glass filter (Whatman GF / C), and the filter was 3 ml in
It was washed 3 times with the cubation buffer. Radioactivity on the filter was measured by liquid scintillation counter. The radioactivity obtained in the presence of 1 μM of atropine was subtracted from the radioactivity when no sample was added, and this was used as the specific binding of the control. From the radioactivity obtained at the time of adding the sample, the ratio to the control was calculated, and from the curve fitting by the computer plotted against the sample concentration, 50% for each subtype of each sample
The inhibitory concentration (IC ₅₀ value) was determined and the subtype selectivity was examined. The results are shown in Table 1.

[0035]

[Table 1]

Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical indication location A61K 31/445 ABL A61K 31/445 ABL ABU ABU ACF ACF ACL ACL C07D 211/42 C07D 211/42 405/12 207 405/12 207 211 211 // (C07D 405/12 207: 12 317: 48) (C07D 405/12 211: 42 317: 48) (72) Inventor Tomoki Ota 3-24-1 Takada, Toshima-ku, Tokyo In Taisho Pharmaceutical Co., Ltd. (72) Inventor Ichiyuki Tomizawa 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd.

Claims (1)

[Claims] (1) Formula (1) (In the formula, R ¹ and R ² each represent a hydrogen atom or a methoxy group, or R ¹ and R ² together represent a methylenedioxy group, and n represents 2 or 3.) A heterocyclic derivative or a pharmaceutically acceptable acid addition salt thereof.