JPS63301881A - Indolylpiperidine derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> represents amino or acylamino; A represents lower alkylene; Q represents =N- or =C(R<2>)-(R<2> represents carboxyl, esterified carboxyl or hydroxy lower alkyl)] and salt there of. EXAMPLE:5-Amino-3-[4-(3-indolyl)piperidinomethyl]-1,2,4-thiadiazole. USE:An antiallergic agent. PREPARATION:For example, a compound expressed by formula II or salt thereof is reacted with a compound expressed by formula III or salt thereof normally in an inert solvent such as water, alcohols or ethers, and, as necessary, in the presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] This invention relates to novel indolylpiperidine derivatives. More specifically, the present invention relates to a novel indolylpiperidine derivative and its salt having excellent antiallergic effects, a method for producing the same, and an antiallergic agent containing the same.

[Prior Art] Until now, as a certain type of indolylpiperidine compound having anti-allergic effect, Japanese Patent Application Laid-Open No. 57-156484
The one described in the publication No. 1 is known.

[Means for solving the problems] The indolylpiperidine derivative of the present invention has the following general formula [
1] and its salt.

[In the formula, R1 means an amino group or an acylamino group, A means a lower alkylene group, (wherein R2 means a carboxyne group, an esterified carboxy group, or a hydroxy (lower) alkyl group)] Purpose The moiety in compound CI] also exists as its tautomer as shown in the following formula.

[1[] [11] [wherein, R1
' is an imino group or an acylimino group, and R1 and Q have the same meanings as before.] Although any of the above tautomers can be included within the scope of this invention, for convenience in this invention, they are expressed as the formula [r1 do.

The indolylpiperidine derivative [I] of the present invention can be synthesized by various methods, and for example, can be produced by the above-mentioned production method.

Production method 1 or its salt production method 2 or its salt production method 3 or its salt production method 4 or its salt or its salt [wherein, X is a leaving group, R1 is an acylamino group, R1 is an amino group, and R2 is carboxy group or esterified carboxy group, Rb means hydroxymethyl group, f? , 1. A and Q each have the same meaning as before] Details of the various definitions mentioned in this specification and preferred examples thereof are explained below.

As used herein, "lower" shall mean groups having 1 to 6 carbon atoms, unless otherwise specified.

As used in this specification, unless otherwise specified, "1-higher" shall mean a group having 7 to 20 hydrogen atoms.

Examples of suitable 1-hydroxy (lower) alkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, and the like.

Examples of suitable "esterified carboxy groups" include lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc. etc.

Examples of suitable "lower alkylene groups" include methylene,
Ethylene, trimethylene, methylethylene, tetramethylene, ethylethylene, propylene, pentamethylene,
Examples include hexamethylene.

Examples of suitable acyl moieties in the 1-acylamino group include straight-chain and branched acyl moieties such as formyl, acetyl, propionyl, butyryl, imbutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, and 3-dimethylbutyryl. Alkanoyl groups such as lower alkanoyl groups, higher alkanoyl groups such as heptanoyl, octanoyl, myristoyl, balmitoyl, and stearoyl;
Acryloyl, crotonoyl, isocrotonoyl, 3-
Straight-chain and branched lower alkenoyl groups such as methacryloyl, lower alkinoyl groups such as propionylyl, 2-butynoyl, and 3-butynoyl, and mono-, di-, or trihalo(lower) alkanoyl groups such as chloroacetyl and trifluoroacetyl. , cyclo(lower) alkylcarbonyl such as cyclopropylcarbonylbutylcarbonyl, cyclopentylcarbonylcyclohexylcarbonyl, cyclo( fff
i class) alkenylcarbonyl group, methoxycarbonyl,
I-class alkoxycarbonyl groups such as ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, imbutoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyluroxycarbonyl, glycoloyl, lactoyl, 3-hydroquinepropionyl, glycoloyl, etc. hydroxy (lower) alkanoyl group, methoxyacetyl, ethoxyacetyl, methoxypropionyl, ethquinzolopioni L,
Lower alkoxy(lower)alkanoyl groups such as methoxybutyryl and profoxib-butyryl, lower alkanoyloxy(lower)alkanoyl groups such as acetyloxyacetyl, acetyloxypropionyl, propionyloxyacetyl, carbamoyl group, methylcarbamoyl, ethylcarbamoyl , lower alkylcarbamoyl groups such as propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, tertiary butylcarbamoyl, glycyl, alanyl, β
- Amino-substituted alkanoyl groups such as alanyl, 4-aminobutyryl, 4-aminovaleryl, 5-aminovaleryl, leucyl, and baryl; carboxy-substituted (lower) alkanoyl groups such as oxa-butyryl, carboxyacetylpionylboxybutyryl, and 4-carboxyvaleryl; , methoxalyl, lower alkoxycarbonyl carbonyl groups such as ethoxalyl,
Lower alkoxycarbonyls such as methoxycarbonylacetyl, carbonylacetyl, methoxycarponyl, ethoxycarbonyl, etc.
Esterified carboxy-substituted (lower) alkanoyl groups such as lower) alkanoyl groups, lower alkanoylcarbonyl groups such as glyoxyloyl and pyruvoyl, and f-class alkanoyl groups such as acetoacetyl and acetopropionyl.
(lower) alkanoyl groups, amines and carboxy-substituted alkanoyl groups such as α-aspartyl, β-aspartyl, α-glutamyl, and 7-glutamyl, aroyl groups such as benzoyl, toluoyl, xyloyl, and naphthoyl, furoyl, thenoyl, nicotinoyl, and innicotinoyl. Heterocyclic carbonyl groups such as phenylacetyl, tolylacetyl, naphthylacetyl, 2-phenylpropionyl, 3
- Aralkayl groups such as phenylpropionyl, 4-phenylbutyryl, tritylcarbonyl, cinnamoyl-terminated aralkayl groups, morpholinoacetyl, morpholinopropionyl, piperidinoprobionyl, pyrrolidinylacetyl, pyrrolidinylpropionyl, imidazolidinylpropionyl groups Heterocyclic-substituted (lower) alkanoyl groups such as diyl, lower furkylsulfonyl groups such as mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tertiary butylsulfonyl, pentylsulfonyl, arylsulfonyl groups such as tosyl, phenylsulfonyl, etc. can be mentioned.

Examples of suitable leaving groups include chlorine, bromine, fluorine,
Examples include acid residues such as halogen atoms such as iodine, and sulfonyloxy groups such as phenylsulfonyloxy, tosyloxy, and mesyloxy.

The salt of the target compound [1] is not particularly limited, but for example,
Maleic acid, fumaric acid, tartaric acid, citric acid, acetic acid, benzoic acid, hydrochloric acid, sulfuric acid, nitric acid, hydroiodic acid, hydrobromic acid,
In addition to salts with organic or inorganic acids such as phosphoric acid, salts with metals such as sodium, potassium, calcium, and magnesium, and salts with organic bases such as triethylamine and dicyclohexylamine, intramolecular salts are also used as salts. Illustrated.

In this regard, compounds [Ia] to
[I d] can be included in the range of compound [11, so
Suitable salts of these compounds include the target compound [
I].

The method for producing the object compound [I] of the present invention will be explained in detail below.

a-adic method 1 The target compound [1] or a salt thereof can be produced by reacting a compound [IV] or a salt thereof with a compound [V] or a salt thereof.

Examples of suitable salts for compounds [IV] and [vco] include the same salts as exemplified for compound [I].

This reaction usually involves water, alcohols such as methanol, ethanol, and isopropyl alcohol, ethers such as dioxane and tetrahydrofuran, and halogenated hydrocarbons such as N,N-dimethylformamide, methylene chloride, chloroform, and carbon tetrachloride. , or other conventional solvents that do not adversely affect the reaction.

The reaction temperature is not particularly limited, and the reaction is carried out at room temperature or under heating.

This reaction can be carried out using alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and inorganic metal carbonates such as potassium hydrogen carbonate. Bases such as triethylamine, pyridine, N, N-
The reaction can also be carried out in the presence of an organic base such as tertiary amines such as dimethylaniline.

This reaction can also be carried out in the presence of an alkali metal halide such as sodium iodide or potassium iodide.

Production method 2 Target compound [Ib] or its salt is compound [I a]
Alternatively, it can be produced by subjecting a salt thereof to a solvolysis reaction.

This solvolysis reaction can be carried out in the same manner as ordinary hydrolysis, amitrilysis, and the like.

Amicilysis can be carried out, for example, using hydrazine or ammonia in conventional solvents such as water, alcohols as mentioned above, halogenated hydrocarbons.

Hydrolysis is carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, or a base such as sodium hydroxide or sodium ethoxide. The reaction can be carried out in any other solvent that does not adversely affect the reaction.

The reaction temperature is not particularly limited, and the reaction can be carried out under cooling, at room temperature, or under heating.

Production method 3 Target compound [Ia] or its salt is compound [I b]
Alternatively, it can be produced by reacting a salt thereof with an acylating agent.

Suitable acylating agents are carboxylic or sulfonic acid compounds and their reactive derivatives and corresponding isocyanate compounds of the formula R3-OH, where R3 represents an acyl group.

Suitable reactive derivatives as mentioned above include acid halides,
Examples include acid anhydrides, activated amides, activated esters, and the like. Suitable examples thereof include acid halides such as acid chlorides and acid bromides, and mixed acid anhydrides with various acids (for example, substituted phosphoric acids such as dialkyl phosphoric acids, sulfuric acid, aliphatic carboxylic acids, aromatic carboxylic acids, etc.). , symmetric acid anhydrides, activated amides with various imidazoles, such as cyan methyl ester, methoxy methyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, hentachlorophenyl ester, phenylazophenyl ester,
Activated esters such as carboxymethyl thioester and N-hydroxysuccinimide ester are included. These reactive derivatives can be appropriately selected depending on the type of acyl group to be introduced.

The reaction is usually carried out using halogenated hydrocarbons such as those mentioned above, aromatic solvents such as benzene, toluene, and pyridine, ether solvents such as diethyl ether, dioxane, and tetrahydrofuran, acetone, acetonitrile, ethyl acetate, N,
The reaction is carried out in a conventional solvent such as N-dimethylformamide which does not adversely affect the reaction. Furthermore, when the acylating agent used is a liquid, it can be used also as a solvent.

When the carboxylic acid or sulfonic acid compound used as an acylating agent can be reacted in the form of the free acid or its salt, it is preferable to carry out the reaction in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide. preferable.

The reaction temperature is not particularly limited, and the reaction can be carried out under cooling, at room temperature, or under heating.

This reaction can be carried out using alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal salts or hydrogen carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc. inorganic bases such as triethylamine, pyridine, N, N-
The reaction can also be carried out in the presence of an organic base such as tertiary amines such as dimethylaniline.

In this reaction, depending on the reaction conditions, a compound represented by the formula H[Ia'co [where Acyl means an acyl group, and A and Q each have the same meanings as before] can be obtained as a by-product. Sometimes. In this case, compound [Ia] can be easily produced by subjecting compound [I'a'] to a conventional hydrolysis reaction, and these steps are also included in the scope of this production method.

Production method 4 Target compound [Id] or its salt is compound [I c]
Alternatively, it can be produced by subjecting its salt to a reduction reaction.

This reaction can be carried out in a conventional manner, ie by chemical reduction.

Suitable reducing agents used in the chemical reduction include aluminum hydride compounds [e.g. lithium aluminum hydride, sodium aluminum hydride, aluminum hydride, lithium trimethoxyaluminum hydride, lithium tri-t-butoxyaluminum hydride, etc. Hydrogenated boronate compounds [e.g. sodium borohydride, lithium borohydride, sodium borohydride, tetramethylammonium borohydride, etc., borane, diborane, etc. Examples include metal compounds.

This reaction usually involves water, alcohol [e.g. methanol,
[ethanol, propatool, etc.], acetic acid, diethyl ether, dioxane, tetrahydrofuran, etc., or a mixture thereof.

The reaction is carried out under cooling or heating.

The compounds produced by the above production methods 1 to 4 and their salts can be isolated and purified by conventional methods such as recrystallization, column chromatography, and reprecipitation.

The target compound [1] and the starting compound may contain one or more optical isomers due to asymmetric carbon atoms in the molecule, and all such isomers and mixtures thereof are included within the scope of the present invention.

The object compound [I] of this invention and its salts can be mixed with conventional organic or inorganic carriers or excipients suitable for oral, parenteral or topical application to form a solid, semi-solid or liquid conventional pharmaceutical preparation. It can be used in the form of The active ingredients are combined with conventional non-toxic, pharmaceutically acceptable carriers, such as tablets, pellets, capsules, batches, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers to be used are not particularly limited, and may include conventional water, glucose, lactose, gum arabic, gelatin, mannitol, starch, etc.
Carriers suitable for the production of pastes, magnesium trisilicate, talc, cornstarch, keratin, colloidal silica, potato starch, urea and other solid, semisolid or liquid preparations can be used, as well as auxiliaries, stabilizers, Thickening and coloring agents and fragrances may also be added.

The dosage or therapeutically effective amount of the object compound [11] of the present invention varies depending on the age and symptoms of each individual patient to be treated, but is generally 0.1 to 100 mg of the active ingredient.
/ kg, more preferably 0.1 to 10 mg/kg.
Administered for treatment of patients as a daily dose.

[Effects of the Invention] The object compound [I] of the present invention and its salts are useful as antiallergic agents for the treatment and prevention of allergic diseases in animals and animals.

In order to demonstrate the usefulness of the target compound [I], the results of pharmacological tests will be explained below.

Test compound Compound A: 2-acetylamino-5-hydroxymethyl-4-[4-(3-indolyl)piperidinomethyl]thiazole Compound B: 5-propionylamino-3-[4-(3-
Indolyl) piperidinomethelco 1.2.4-thiadiazole hydrochloride test 1 Antagonist for anaphylactic asthma in guinea pigs ff Using male Hartley guinea pigs weighing 1305 to 400 g, these animals were tested against ovalbumin in rabbits. Serum (PCA antibody titer 4000) 0.5m! /Animals were sensitized by intravenous injection. 24 hours later, 5.3 animals! They were placed individually in plastic chambers. Using a commercially available sprayer, an aerosol of 5% ovalbumin solution was sprayed into the room for 2 minutes at a rate of 0.16111 Q/min. Test compounds were orally administered at various concentrations 30 minutes before injection of ovalbumin solution. Three animals were used in each administration group. The preventive effect against anaphylaxis is 2 days after antigen spraying.
It was expressed by the number of guinea pigs that survived for more than an hour.

Test Results Test 2 Anti-5R5-A acting peritoneal exudate cells were obtained from glycogen-injected SD rats,
It was adjusted to 1 x 107 pieces/person with Tyrode's solution. 1 ml of cell suspension was incubated for 10 minutes with 1'domethacin (lk/mQ) and various concentrations of the test compound, and then for an additional 10 minutes with C-ionophore (A23187, 1</mQ).
> was cultured. The supernatant was collected by centrifugation, and 5R5-A (
anaphylaxis (slow reactant) activity, mevilamine,
It was measured as the contractile activity of isolated guinea pig ileum in the presence of atropin and methysergide.

Results were expressed as 50% inhibitory concentration of 5R5-A synthesis or release from peritoneal exudate cells.

Test Results As is clear from the above test results, the indolylpiperazine derivative [I] of the present invention has an antiallergic effect,
It is useful for the treatment and prevention of various allergic diseases, such as allergic asthma, allergic rhinitis, allergic tuberculosis, and chronic hives.

[Example code] Hereinafter, this invention will be explained in more detail with reference to Examples.

Example 1 5-Amino-3-chloromethyl-1,2,4-thiadiazole (1,0 g), 3-(4-piperidyl)indole (1,34 g) and sodium hydrogen suboxide (0,67
g) of dry N,N-dimethylformamide (1 ama
) 50-60°C while blowing nitrogen gas into the medium-temperature mixture.
Pour the reaction mixture into water (1 aomn) and stir for 1 hour at room temperature. The generated precipitate is collected by filtration,
Washed with water, recrystallized from ethanol and 5-amino-3-[
4-(3-indolyl)piperidinomethyl]-1,2,
4-thiadiazole (1.24 g) is obtained.

h point: 196-199°C IR (streak seal): 3430. 3280.
1627. 1527°740 cm-' NMR < DMSO-ds, 8), '1, 4
-3.3 (9H1m), 3.50 (2) 1. s>,
6.6-7.7 (5)1. m), 7.87 (2
H,s).

10.72 (IH,s) Elemental analysis Calculated value as 16'19N5S: C61,32,H6,11,N 22.34
Actual value: C61,34, H5,99, N 22.36
In the same manner as in Example 1, the following compounds (Examples 2 to 4) are obtained.

Example 2 5-acetylamino-3-[4-(3-indolyl)biperidinomethylco 1.2.4-thiacyazole LR (sudi-3-l): 3430. 1664.
1100. 740 am-1HMR (DMSO-
ds-8): 1.4 to 3-6 (9H1m>, 2-
25 (3H, s), 3.72 (2H, s),
6.8-7.8 (5H, m).

10.78 (LH, br s) Example 3 5-Propionylamino-3-[4-(3-indolyl)piperidinomethyl]-1,2,4-thiadiazole and its hydrochloride The following physical property values are those of the hydrochloride. It is.

8 points: 231-238°C (isopropyl alcohol-
Recrystallized from n-hexane) IR (Stripe Seal) '3250. 1690.
1378. 740 cn+-'NMR (DMSO
-ds, 8)' 1.14 (3H1t,
J=7.5Hz>, 1.9~4.2 <9H, m>
, 2.62 (2H, q, J=7.5Hz), 4.
53 (2H, s), 6.8-7.8 (5H, m),
10.91 (LH,s).

11.10 (1)1. br), 13.20 (IH
,s) Mass: 369 (M”) Elemental analysis: C19H23N50S-HCl・215H2
Calculated value as 0: C55,24,H6,05,N 1
6.95 Actual value: C55,34,H6,06,N 1
6.33 Example 4 Ethyl 2-acetylamino-4-[4-(3-indolyl)biperidinomethyl-5-thiazolecarboxylate and its hydrochloride The following physical property values are for the hydrochloride.

Melting point = 237-239°C (recrystallized from ethanol) IR
(Stripe 3-le): 3410. 2475. 1
695 am-1HMR (DMSO-d6.δ
): 1.34 (3H, t, J=8.0Hz
>.

2.16 (3H, m), 2.25 (31,
s), 2.8-3.8 (7H.

m), 4.32 (2H, q, J=8.0Hz),
4.66 (2H, brs), 6.8=7.7 (5
H, m), 10.9 (2H, m>, 12.79 (
IH, s) Mass (m/e) i 426 (M”) Elemental analysis:
Calculated value as C22H26N403S-HCl: C5
7.07, H5.8g, N 12.10 Actual value: C
57,10,H5,93,N 12.12 Example 5 A warm mixture of 2-acetylamino-4-[4-(3-indolyl)biperinnomethyl-5-thiazolecarbonate in ethanol (2.5 mQ) Heat at 80°C for 5 hours. The reaction mixture was diluted with 18% sodium hydroxide solution.
Pour into the solution, collect the resulting precipitate by filtration, wash with water, and dry. The obtained crude product is subjected to silica gel column chromatography and eluted with a mixed solvent of chloroform and methanol (5: lv/v). The fractions containing the target product are combined and washed with a 3 solution of IN sodium hydroxide solution. The solvent is distilled off and the residue is recrystallized from ethanol and water to obtain 2-amino-4-[4-(3-indolyl)biperidinometelco-5-thiazolecarvone g).

Melting point: 215-221°C (decomposition) IR (streak 1-l)' 34g0. 33
60. 1680. 1450 am-INMR
(DMSO-d6.S): 1.25 (3)
1. t. , J=8, OHz), 1.4-3.1 (9
H. m), 3.75 (2)1.5), 4.17
(2H.q.

J4. OHz), 6.8-7.6 (5)1. m)
, 7.68 (2)1. s).

10, 66 (IH.br s) Mass (m/e): 384 (M”) 355
, 266, 240, 226.

Elemental analysis" Calculated value as 20'24N402S: C
62.48. H 6.29. N 14.57 Actual value: C 61.99. H 6.18. N14,
39 Example 6 5-amino-3-[4-(3-indolyl)piperidinomethyl]-1.2.4-thiadiazole (L.Og)
and methanesulfonic anhydride (5.563) is heated at 77-78° C. for 10 hours. The reaction mixture was mixed with chloroform (5011111) and methanol (5
Dilute with a mixed solvent of mQ) and pour into water (100 mQ). The mixture is made lidomat neutral with an aqueous sodium hydroxide solution, and the organic layer is separated, washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography and eluted with a mixed solvent of chloroform and methanol to give 5-mesylamino-3-[4-(3-indolyl)piperidinomethyl].
-1.

2,4-thiadiazole (0.11 g) is obtained.

Melting point: 120°C (recrystallized from ethanol) NMR (D
MSO d6,l; )' 1. 5-3.6 (9
H, m), 3. 40<3H. s), 3.68 (2
H,s), 7.1-8.0 (5)1. m)Mass
: 391 (M”) 7: Elementary analysis: C17H2
, N502S22/3C2H50H-l/2H20 Calculated value i C 51.06. H 6.08, N 1
6.24 Actual value: C 50.96. H 5.96.
N 16,19 Noxious,*(M7 To a suspension of lithium aluminum hydride (0.09 g) in dry tetrahydrofuran (2 mQ), with stirring,
While cooling with water, a solution of ethyl 2-acedelamino-4-[4-(3-indolyl)piperidinomethyl]-5-thiazolecarboxylate (1 g) in dry tetrahydrofuran (3 mQ) was added dropwise. After stirring the PM at room temperature for 1 hour, lithium aluminum hydride (0.09 g) is further added. 45% of the mixture
After heating for 1 h at °C, ethyl acetate and water were added,
The organic layer is washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, the residue was subjected to silica gel column chromatography, and chloroform and methanol (1
Purify by eluting with a mixed solvent of 0:1 v/v). f
The resulting residue was subjected to an alumina column chromatograph 1-1, and chloroform and methanol C50: 1 v
/v) for purification by elution with a mixed solvent.

The obtained residue was recrystallized from ethanol to give 2-avitylamino-5-hydroxymethyl-4-[4-(3-
indolyl)piperinzmethyl]theasol (0,07
5g).

Melting point: 223°C IR (Sujoor): 3400. 3200.
1590. 1450 am”NMR (DMSO-
da, S)' 1.35~3.1 (9H1m>,
2.11 (3H, s), 3.50 (2H, s),
4.63 (2H, s), 5.50 (IH, br s
), 6.8-7.6 (5H, m),' 10.68
(LH.

Claims (1)

[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is an amino group or an acylamino group, A is a lower alkylene group, Q is =N- or =C- (In the formula, R^2 means a carboxy group, an esterified carboxy group, or a hydroxy (lower) alkyl group, respectively] An indolylpiperidine derivative and a salt thereof.