JPH045289A - Amide compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R<1> is H or lower alkyl; m is 2 or 3; R<2> is -COOR<3> (R<3> is lower alkyl), (CH2)nCOOR<4> (R<4> is H or lower alkyl; n is 1-7) or -(CH2)po(CH2)qCOOR<4> (p and q are 1 or 2)]. EXAMPLE:Ethyl endo-[3-[(1-methyl-1H-indazol-3-yl) carbonylamino]-9-azabicyclo [3,3,1] non-9-yl] acetate. USE:A serotonin (5-hydroxytryptamine) antagonist. PREPARATION:A compound shown by formula II is reacted with a halogen compound shown by the formula X-COOR<3>, the formula X-(CH2)n COOR<5> or the formula X-(CH2)pO(CH2J)q COOR<6> (X is halogen) in an organic solvent in the presence of a base as a dehydrohalogenating agent.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel amide compound having an antagonistic effect and useful as a pharmaceutical, and a pharmacologically acceptable salt thereof.

Conventional technology JP-A-59-3-6-6-7-5 and JP-A-59-
No. 67284 discloses an indole derivative having an azabicyclo side chain, and JP-A No. 61-275276 discloses an indazole derivative, which have been shown to have serotonin antagonistic activity.

Problems to be Solved by the Invention When using these compounds as medicines, there is a strong desire in clinical practice to develop new drugs that are more effective and have fewer side effects.

Means for Solving the Problems As a result of intensive research in view of the above-mentioned circumstances, the present inventors discovered excellent effects in the novel amide compound according to the present invention, and completed the present invention.

That is, the present invention relates to the following general formula (I) (wherein, R1 is a hydrogen atom or a lower alkyl group, and m is 2
or an integer of 3, and R2 is a -COOR3 group.

(CH2). C0OR' group or -(CH2), O(CH
2).

represents a C0OR' group, where R3 is a lower alkyl group,
R4 represents a hydrogen atom or a lower alkyl group, n represents an integer of 1 to 7, and p and q independently represent an integer of 1 or 2. ) and its pharmacologically acceptable salts.

In the general formula (I) of the present invention, the lower alkyl groups represented by R', R3 and R4 include, for example, a methyl group,
Examples include ethyl group, n-propyl group, isopropyl, cyclopropyl group, n-butyl group, isobutyl group, and tert-butyl group.

Examples of the pharmacologically acceptable salts of the compound represented by the general formula (I) of the present invention include alkali addition salts and acid addition salts. Examples of the alkali addition salts include:
Inorganic alkali salts such as sodium, potassium, calcium, and ammonium, or ethylenediamine and ethanolamine.

Salts of organic bases such as N,N-dialkylethanolamine and triethanolamine, and acid addition salts include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid,
Mineral acid salts such as phosphoric acid, or acetic acid, maleic acid, fumaric acid, citric acid, and oxalic acid.

Succinic acid, tartaric acid, malic acid, methanesulfonic acid.

Examples include organic acid salts such as 10-camphorsulfonic acid and mandelic acid.

Different steric configurations exist in the compounds represented by the above general formula (I) of the present invention. For example, the piperidine ring to which the amide moiety is attached may have a chair, boat, or intermediate configuration.

The amide moiety also has two different configurations. That is, if the carbon part of the piperidine ring is drawn as a plane,
The nitrogen atom at position 1 of the piperidine ring can be drawn above the plane, and the alkylene bridge can be drawn below the plane, or the amide moiety or the alkylene bridge, like the alkylene bridge, can be drawn below the plane. -Has a configuration. This configuration is an endo configuration and corresponds to the configuration of tropin and the like. The other case is when the amide moiety is located above the plane, like the nitrogen atom of the piperidine ring, and has a β-configuration. This configuration is an exo configuration and corresponds to the configuration of pseudotropin and the like.

The exo/endo nomenclature will be used below.

The novel amide derivative represented by the general formula (I) of the present invention can be produced by various methods.

According to the first mode of the method for producing the compound of the present invention, R2 in the general formula (I) is a -COOR'' group.

-(CH2)ゎCOOR5 group or -(CH2),○(C
H2).

A compound having a C0OR' group (R", n, p, and q have the same meanings as above, and R5 represents a lower alkyl group) has the following general formula (I[) (wherein R1 and m represents the same meaning as above.), the following general formulas (I[) and (IV).

Or (V)X-COOR” (I)X-(CH
2)ゎC00R5(IV)X-(CH2),O(CH
2), COOR6(V) (wherein R'', R5,n, p
and q represent the same meanings as above, and X represents a halogen atom. ) can be produced by reacting the halogen compound shown in the following in an organic solvent in the presence of a base as a dehydrogenating agent.

Examples of the organic solvent used in this production method include alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, and n-butanol, tetrahydrofuran, acetonitrile, and N,N-dimethylformamide.

Examples include aprotic polar solvents such as N-methyl-2-pyrrolidone and dimethyl sulfoxide, and examples of bases used include sodium metal, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, and carbonic acid. Storium.

Examples include potassium carbonate, and the reaction is carried out at a temperature ranging from water cooling to the reflux temperature of the solvent.

In addition, in this production method, the above general formula (
The compound represented by II) is a known compound described in JP-A-2-85253, and can be produced as follows.

(In the formula, R' and m represent the same meanings as described above.) According to the second mode of the method for producing the compound of the present invention, in the general formula (I), R2(CH2)2COOR5 group (R5 is The compound represented by the general formula ([) has the same meaning as the above.
Michael addition of an acrylic acid ester represented by the following general formula (VI) CH2=CH-COOR' (VI) (wherein R5 represents the same meaning as above) to the compound represented by It can be produced by reaction.

This Michael addition reaction is a method known per se, and the organic solvents used include alcoholic solvents such as methanol, 7ethanol, isopropanol, and n-butanol;
Examples include aromatic hydrocarbon solvents such as benzene, toluene, and xylene; aprotic polar solvents such as tetrahydrofuran, 1,4-dioxane, and acetonitrile;
The reaction is carried out at a temperature ranging from room temperature to the reflux temperature of the solvent.

According to the third mode of the method for producing the compound of the present invention, in the general formula (I), R2 or -(CH2), C○OH group or =
(CH, ), O(CH2), C00H group (n, p and q represent the same meanings as above), in the general formula (I), R2 or -(CH2), COOR5 group or −
(CH2), 0 (CH2), COOR5 group (R5+n
+p and q represent the same meanings as above. ) can be produced by hydrolyzing a compound.

This hydrolysis is carried out in a manner known per se using acids or alkalis, for acidic hydrolysis hydrochloric acid.

An acid such as sulfuric acid is used for alkaline hydrolysis, and an alkali such as sodium hydroxide or potassium hydroxide is used for alkaline hydrolysis.
- It can be used in the reaction as a solution such as butanol or a solution in a water-containing organic solvent, and the reaction is carried out at a temperature ranging from room temperature to the reflux temperature of the solvent.

The novel amide compound represented by the general formula (I) and its pharmacologically acceptable salts produced in this manner are:
Tablets, powders, capsules, injections 9 eye drops 2
It can be made into formulations such as nasal drops, inhalants, or external preparations, and is clinically administered by oral or parenteral administration. The dosage depends on the condition to be treated and the method of administration, and is usually 1 to 1000 g per day for adults.

Examples Hereinafter, the present invention will be explained by reference examples and examples.
The invention is not limited to the specific details of these examples.

Reference example 1 Endo-N-C9-benzyl-9-asabicyclo[3,
3,1conon-3-yl)-1-methyl-IH-indazole-3-carboxamide endo-3-amino-9-
Benzyl-9-azabicyclo[3,3,1]nonane 13
．． 8 g,) ethylamine 6.6 g dichloromethane 1
10.2 g of 1-methyl-1H-indazole-3-carbonyl chloride was added little by little to the 50 ml suspension while stirring under water cooling. After stirring at room temperature for 2 hours, the reaction solution was washed with water and dried over anhydrous sodium sulfate. The reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: chloroform) to obtain 14.75 g of colorless crystals. The obtained crystals were recrystallized from methanol to a melting point of 161.
Colorless needles at ~162°C were obtained.

Elemental analysis value C2, H2, N, 0 Theoretical value C, 74, 20; H, 7, 26; N, 14
．． 42 experimental value C, 74, 15; H, 7, 32; N
, 14.41 Reference Example 2 Endo-N-(9-azabicyclo[3,3,1]non-
3-yl)-1-methyl-IH-indazole-3-carboxamide hydrochloride endo-N-(9-benzyl-9-asabicyclo[3,
3,1]non-3-yl)-1-methyl IH-indazole-3-carboxamide i 2.9 g, acetic acid 25 rn
I! Bahlmann's catalyst (20% palladium hydroxide on carbon) in a mixture of 2. Og was added and hydrogen reduction was performed at room temperature and pressure for 3 hours. The catalyst was removed and the filtrate was concentrated under reduced pressure. Water and 10% hydrochloric acid were added to the residue, and insoluble materials were removed by filtration. Add potassium carbonate to the filtrate, p
After reaching H10, the precipitated crystals were collected by filtration to obtain 9.9 g of a colorless amorphous solid. The obtained solid was converted into hydrochloride by a conventional method,
Recrystallization from ethanol gave colorless needle crystals with a melting point of over 300°C.

Elemental analysis value C17H2□N, O・HCI theoretical value C,
60,98; H, 6,92; N, 16.73 Experimental value C160°77; H, 7,01, N, 16.55 Example 1 Endo-[3-[(1-methyl-1H-indazole-
3-yl) carbonylaminoco-9-azabicyclo[3
,3,1]non-9-yl]ethyl acetate-N-(9-azabicyclo[3,3,11non-
2.50 g of 3-yl)-1-methyl-IH-indazole-3-carboxamide, 1.54 g of ethyl bromoacetate
A mixture of 1.16 g of potassium carbonate and 20 d of N,N-dimethylformamide was heated and stirred at 70°C for 4.5 hours. After cooling, water was added to the reaction mixture and extracted with ether. The extract was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: dichloromethane) to obtain 2.69 g of a pale yellow liquid.

IR spectrum ν (liquid film method) cF': 1748, 1
662 NMR spectrum δ(CDC12)I)pl :0,
93-2.22 (8H, m), 1.28 (3H, t,
J=7.3Hz), 2.282, 81 (2H, m)
, 3.06-3.43 (2H, m), 3.49 (2
H,s).

4,08(3H,s), 4.17(2H,q, J=
7.3Hz), 4.20-4.80 (IH, Il+)
, 6.67-6, 93 (IH, m), 7.10-7
．． 60 (3H, l11).

8, 23-8.51 (IH, m) High resolution mass spectrum: C2, H2, N402 theoretical value m/z: 384.2161 experimental value m/z:
384.2173 Example 2 Endo-3-[3-[(1-methyl=lH-indazol-3-yl)carbonylaminoco-9azabicyclo[
3,3,1]non-9-yl]propionic acid ethylendo-N-(9-asabicyclo[3,3,11non-
To a solution of 2.98 g of 3-yl)-1-methyl-IH-indazole-3-carboxamide in 24 rILl ethanol was added 1.35 ml of ethyl acrylate, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: dichloromethane-methanol (30:1)) to obtain 2.64 g of brown crystals.
I got it. The obtained crystals were recrystallized from isopropyl ether to obtain pale brown needles with a melting point of 102.5-103.5°C.

Elemental analysis value C2□Hs o N 40-theoretical value C,
66,31; H, 7,59; N, 14.06 Experimental value C, 66,33, H, 7,70; N, 14.02 According to the method of Example 1, the following Ibi compound was obtained. Ta.

Example 3 Endo-4-[3-[(1-methyl-1H-indazol-3-yl)carbonylaminoco9-azabicyclo[
3,3,1]Non-9-yl]ethyl butyrate hydrochloride Properties Colorless crystals (1so-PrOH) Melting point 187.
5-190℃ Elemental analysis value (: HH22NnCh・HCI theoretical value C
961,53, H, 7,41; N, 12.48 Experimental value C, 61,43; H, 7,47, N, 12.75 Example 4 Endo-5-[3-[(1-methyl- IH-indazol-3-yl)carbonylaminoco-9-azabicyclo[3,3,1]non-9-yl]ethyl valerate Properties Pale yellow liquid IR spectrum ν (liquid film method) cm 1734, 166O NMR spectrum δ (CDCI3) ppm: 0, 8
5-2.85 (18H, m), 1.27 (3H, t,
J=7.0Hz).

3, 00-3.41 (2H, m), 4.09 (3H,
S), 4.13 (2H, q.

J=7.0Hz), 4. ．． 27-4.81 (IH, m
), 6.61-6.93 (IH, m).

7, 11-7.59 (3H, m), 8.27-8.5
0(IH,m) high resolution mass spectrum: C24H2
4N 402 Theoretical value m/z: 426.2631 Experimental value m/z: 426.2629 Example 5 Endo-6-[3-[(1-methyl-IH-indazol-3-yl)carbonylaminoco-9azabicyclo [
3,3,1] Methyl non-9-ylcohexanoate/hydrochloride Properties Colorless needle crystals (MeOH) Melting point 238-240°C Elemental analysis value Ca 4Hs 4N 402/MCI theoretical value c, 62.26; )(,7 ,62+N,12
．． 10 Experimental values C, 61,94; H, 7,60; N
, 12.17 Example 6 Endo-7-[3-[(1-methyl-IH-indazol-3-yl)carbonylaminoco-9 asabicyclo[3,3,1]non-9-yl]methyl hebutanoate Properties Colorless crystal Melting point 61-63°C Elemental analysis values C2, H,, N, Ch Theoretical values C68,15; H, 8,24; N, 12.
72 experimental value C67,79; H,8,22,N,12
．． 83 Example 7 Methyl endo-8-[3-[(1-methyl-IH-indazol-3-yl)carbonylaminoco-9-azabicyclo[3,3,1conon-9-yl]octoate Properties Colorless liquid IR Spectrum ν (liquid film method) cm 1738, 1664 NMR spectrum δ (CDCI3) ppm: 0, 8
5-2.77 (24H, m), 2.99-3.31 (
2H, m), 3.67 (3H, s), 4.07 (3
H, s), 4.35-4.77 (IH, m), 6.
676, 93 (IH, m), 7.15-7.49 (3
H, m), 8.29-8.51 (IH, [11) High resolution mass spectrum: C2, H3, N, O.

Theoretical value m/z: 454.2944 Experimental value m/z
: 454.2935 Example 8 Endo-[2-[3-[(1-methyl-I H-indazol-3-yl)carbonylaminoco-9-azabicyclo[3,3,1]non-9-yl] Methyl ethoxyacetate Properties Pale yellow liquid IR spectrum ν (liquid film method) cF': 1754, 1
658 NMR spectrum δ (CDCI) pm: 0, 8
1-2.76 (IOH, m), 2.93 (2H, t,
J=6.0Hz).

3, 05-3.43 (2H, m), 3.62 (2H,
t, J=6.0Hz).

3.76 (3H, s), 4.08 (3H, s), 4
．． 13 (2H, s), 4.164.81 (LH, m)
, 6.58-6.95 (IH, m), 7.10-7
．． 55(3)1. m), 8.26-8.50 (IH
,rn) High-resolution mass spectrum: C22H,,N,
O.

Theoretical value m/z: 414.2267 Experimental value m/z
・414.2279 Example 9 Endo-[3-[(1-methyl-IH-indazole-
3-yl) carbonylaminoco-9-azabicyclo[3
,3,1]Non-9-yl]ethyl formate Properties Colorless prism crystals (toluene) Melting point 193-195°C Elemental analysis value C1°H2,N,02 Theoretical value C,64,85,H,7,07; N , 15.
12 Experimental values C, 64, 93; H, 7, 24; N,
15.07 Example 10 Endo-[3-[(1-methyl=lH-indazol-3-yl)carbonylaminoco-9-azabicyclo[3
,3,1]Non-9-ylcoacetic acid hydrochloride dihydrate endo-[3~[(1-methyl-IH-indazole-
3-yl) carbonylaminoco-9-azabicyclo[3
,3,,1] To a solution of 2.0 g of ethyl non-9-ylcoacetate in 20 yd of methanol was added a 2N aqueous sodium hydroxide solution 5. 2rnl was added and heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in a small amount of water, and then adjusted to pH 2 with 10% hydrochloric acid.

After cooling, the precipitated crystals were collected by filtration to obtain a colorless amorphous solid of 1.5
Obtained 0g.

IR spectrum v (KBr) cm-'1744, 2
652 NMR spectrum δ(DMSO-da)llpml,
29-2.70 (IOH, m), 3.70-4.0
5 (2H, m), 4.14 (3H, s), 4.18
(2H, s), 4.39-5.03 (IH, m),
7.127, 85 (3H, m), 8.02-8.50
(2H, m) Elemental analysis value C,, H24N40.・HC
I・ 2H20 Theoretical value C, 53, 21; H, 6, 81; N, 13
．． 06 experimental value C, 53, 34, H, 6, 66, N, 1
3.04 According to the method of Example 10, the following compound was obtained.

Example 11 Endo-3-[3-[(1-methyl-1H-indazol-3-yl)carbonylaminoco-9-azabi 22 units [3,3,1]non-9-ylcobropionic acid hydrochloride. Monohydrate properties Colorless prism (LO) Melting point 207-212°C (decomposition) Elemental analysis value C1°H□N402 ・MCI・H20 Theoretical value C, 56, 53, H, 6, 88; N, 13.
19 Experimental values C, 56,47; H, 6,89; N,
13.22 Example 12 Endo-4-[3-[(1-methyl-IH-indazol-3-yl)carbonylaminoco-9-azabicyclo[3,3,1]non-9-yl]butyric acid/hydrochloric acid Salt properties Colorless crystals (MeOH-iPrzO) Melting point 243
~248°C (decomposed) IR spectrum v (KBr) cm-': 1722
, 1662 NMR spectrum δ (DMSO-dg) ppm: 1
, 28-2.88 (14H, m), 2.99-3.4
7 (2H, m), 3.573, 95 (2H, m),
4.13 (3H, S), 4.37-5.01 (IH,
m).

7, 12-7.87 (3H, m), 8.05-8.4
8 (2H, m) high resolution mass spectrum: C2, H2
, N40° Theoretical value m/z: 384.2161 Experimental value m/z: 384.2163 Example 13 Endo-5-[3-[(1-methyl-IH-indazol-3-yl)carbonylaminoco-9 -Azabicyclo[3,3,1conon-9-yl]valeric acid hydrochloride monohydrate Properties Colorless needle crystals (MeOH-Et20) Melting point 28
3~285°C (decomposition) Elemental analysis value C22H-o N 403・HCI・H,
0 Theoretical value C, 58, 33; H, 7, 34; N, 12
．． 37 experimental value C, 58, 57, H, 7, 05; N,
12.27 Example 14 Endo-6-[3-[(1-methyl-1H-indazol-3-yl)carbonylaminoco-9azabicyclo[
3,3,1]Non-9-ylcohexanoic acid hydrochloride 1
/dihydrate Properties Colorless needle crystals (H2O) Melting point 125-130°C 265-267°C Elemental analysis value C22H3□N403 ・HCI・1/2H20 Theoretical value C, 60, 32; H, 7, 48; N, 12
．． 23 Experimental value C, 60, 24; H, 7, 40; N
, 12.16 Example 15 Endo-7-[3-[(1-methyl-IH-indazol-3-yl)carbonylaminoco-9-asabicyclo[3,3,1]non-9-yl]heptanoic acid・Hydrochloride・
l Hydrate Properties Colorless needle crystals (H2O) Melting point 116-123°C 264-266°C Elemental analysis C24H34N,O.

-HCl-H2O Theoretical value C, 59,93; H, 7,75; N, 11
．． 65 experimental value C, 59,72; H, 7,51; N
, 11.86 Example 16 Endo-8-[3-[(1-methyl-IH-indazol-3-yl)carbonylaminoco-9-azabicyclo[3,3,1]non-9-yl]octanoic acid. Hydrochloride/L hydrate Properties Colorless needle crystals (H2O) Melting point 107-112°C 252-254°C Elemental analysis C25H3,N,O.

-HCl-820 Theoretical value C, 60, 65; H, 7, 94; N, 11
．． 32 experimental value C, 60, 44; H, 7, 68; N
, 11.31 Example 17 Endo-[2-[3-[(1-methyl-IH-indazol-3-yl)carbonylamino]=9-azabicyclo[3,3,1]non-9-yl]ethoxy ] Acetic acid/hydrochloride properties Pale yellow amorphous solid IR spectrum v (KBr) cm-': 1738
, 1656 NMR spectrum δ(DMSO-do)ppm: 1
, 28-2.77 (IOH, m), 3.11-4.9
9 (7H, m), 4.13 (5H, S), 7.17
-7, 84 (3H, m), 8.08-8.49 (2H
, m) High resolution mass spectrum: C2, H2, N, O
.

Theoretical value m/z: 400.2111 Experimental value m/z
: 400.2097 Effects of the Invention The novel amide derivative shown in the above-mentioned ship stock (I) and its pharmacologically acceptable salt produced in this way are as follows:
It has a serotonin antagonistic effect and is useful as a medicine.

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 is a hydrogen atom or a lower alkyl group, m is an integer of 2 or 3, R^2 is -COOR^3 group, -(C
H_2)_nCOOR^4 group or -(CH_2)_pO
(CH_2)_qCOOR^4 group, here R^3
represents a lower alkyl group, R^4 represents a hydrogen atom or a lower alkyl group, n represents an integer of 1 to 7, and p and q independently represent an integer of 1 or 2. ) An amide compound and a pharmacologically acceptable salt thereof.