JPH03161470A - Indole derivative - Google Patents

Abstract

NEW MATERIAL:Indole derivative expressed by formula I, salt of said derivative, quaternary ammonium salt of said salt and N-oxide derivative [R1 is H or 1-6C alkyl; R2 is 4-morpholinyl, methyl piperazinyl, benzyl piperazinyl, unsaturated heterocyclic group (said heterocyclic group may be condensed with carbonic aromatic ring), saturated heterocyclic group having carbonyl group on a ring or saturated cyclic amine expressed by formula II (R4 is H, lower alkyl or benzyl; p is 1-3); R3 is 1-6C alkyl; m is 0 or 1; n is 0 or 1-5 and at least one H in -(CH2)n- may be substituted with 1-6C alkyl]. USE:Useful for remedy of phrenopathy, etc., or remedy of neuropathy. PREPARATION:A compound expressed by formula II is subjected to condensation reaction with a compound expressed by formula III to afford the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel indole derivative and a method for producing the same.

Furthermore, the present invention relates to novel indole derivatives that are selectively effective antagonists of 5-HT at the s-HT receptor. The indole derivatives of the present invention are useful for 5-HT in the central nervous system. It acts on receptors and is effective in the treatment of mental disorders (e.g. schizophrenia, chronic illness, depression, anxiety, etc.), and is also used in the treatment of dementia, drug dependence, migraines and other neurological diseases. be done. It also acts on peripheral 5-HT3 receptors and is effective in treating gastrointestinal dysfunction symptoms such as delayed gastric emptying, indigestion, flatulence, and esophageal reflux, as well as vomiting, especially vomiting induced during cancer chemotherapy. be.

[Prior art and problems to be solved by the present invention]

Vomiting is a serious problem frequently seen in patients receiving cancer chemotherapeutic agents, and management of emesis is an extremely important adjunctive therapy for adequate anticancer treatment. Since it was reported that large-dose intravenous administration of metoclobramide is effective in suppressing this vomiting (Gvalla, RJ et al.
l, N. Engal. J. Med. 305
, 905-909 (1981)), good, if not perfect, control of emesis was achieved. However, existing antiemetics, especially compounds with a bezamide structure, have dopamine blocking and central nervous system depressing effects, resulting in undesirable side effects such as sedation,
The patient was found to have ataxic reactions, diarrhea, and inability to sit still.

Recently, a specific antagonist of 5-HT3 receptor was reported to suppress emesis induced during cancer chemotherapy (Cun
ningham. D. et al, The La
ncet, 1198. 1461-1463 (198
7)), 5-IT, antagonists are considered to be drugs that suppress vomiting at lower doses than existing antiemetics and have no undesirable side effects.

The previously known 5-HT3 antagonist is disclosed in Japanese Patent Application Laid-open No. 5921.
684, 62-270583, 63-313757
, those having an azabicyclic partial structure as disclosed in JP-A-1-110684, or imidazole ring moieties as disclosed in JP-A-64-22870 and JP-A-1-131178. It had a

Under these circumstances, it is desired to develop a selectively effective antagonist of 5-HT at the 5-HT receptor, which has a chemical structure different from that of known compounds.

[Means to solve the problem]

In order to solve the above-mentioned problems, the present inventors have synthesized a new compound having an indole ring as a result of intensive research, and found that this compound is a selectively effective antagonist of 5-HT at the 5-IT receptor. The present invention was completed based on the discovery that it has an effect.

That is, the present invention relates to the following general formula (I) R, [wherein R1 is a hydrogen atom, C, to C. is alkyl, and R2 is morpholino, methylpiperazino, penzylbiperazino, or an unsaturated heterocyclic group (this heterocyclic group may be fused with a carbon aromatic ring), or a carponyl group on the ring. or a saturated heterocyclic group having the following general formula (I[) R. (In the formula, R is a hydrogen atom, lower alkyl, or benzyl, and p is an integer of 1 to 3), and X is NH or Nl? , and R3 is C
,~C. is alkyl, m is O or l, n is an integer from 01 to 5, and at least one hydrogen atom in -(cH2)n is from 01 to C. The present invention relates to a compound represented by the following formula (optionally substituted with alkyl), its pharmacologically acceptable acid addition salts, and its quaternary ammonium salts and N-oxide derivatives.

The compound of general formula (I) can be produced by various methods, but for example, indole-3 represented by the following general formula (II) (wherein, R1 is defined in general formula (I)) monocanoleponic acid or di-containing reactive derivatives thereof, such as indole-3-carboxylic acid halide, especially indole-3-carboxylic acid chloride;
The following general formula (III) H-(X)m-(CHz)n-
It can be obtained by condensation reaction with a compound represented by Rx (II[ ) (wherein X, R., m and n are defined in general formula (1)).

This reaction can be carried out under various reaction conditions, but for example when using an acid halide such as indole-3-carboxylic acid chloride, an organic solvent such as diethyl ether, diisobutyl ether, tetrahydrofuran, dimethoxyethane , l,4-dioxane,
In DMF at a temperature in the range of -20° to the boiling point of the solvent, optionally an inorganic or organic acid binder such as pyridine, dimethylaniline, tetramethylurea, metallomagnetium, n-butyllithium, lithium diisobutylene is added. The reaction mixture is reacted with a compound of general formula (III) in the presence of pyramide, sodium amide, metal sodium, and the desired biological product is obtained through the steps of washing, extraction, and purification.

In the above reaction, when the compound of general formula (III) is a basic compound, this compound can be used in excess, thus replacing the acid binder.

The acid addition salts of the compound represented by the above general formula (I) are:
General formula (I) having a group capable of forming acid addition salts in its structure
) refers to the acid addition salt of the compound. Among these salts, physiologically acceptable salts are preferred, such as inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate, and oxalic acid. Examples include organic acid salts such as salts, maleates, fumarates, lactates, malates, citrates, tartrates, benzoates, and methanesulfonates. Further, quaternary ammonium salts of the compound of general formula (I) specifically include lower alkyl halogenides such as methyl iodide, methyl bromide, ethyl iodide, and ethyl bromide, methyl methanesulfonate, and ethyl methanesulfonate. Examples include quaternary ammonium salts such as lower alkyl sulfonate and lower alkylaryl sulfonate such as methyl p-+-luenesulfonate. The compounds of general formula (I), their acid addition salts, quaternary ammonium salts and N-oxide derivatives may exist in the form of hydrates or solvates; Also included in the compounds of the invention are compounds.

Since the compound of general formula (1) has at least one asymmetric carbon atom, several types of stereoisomers may exist. These stereoisomers, mixtures and racemates thereof are included in the compounds of the present invention.

Specific examples of the compound of general formula (I) mentioned above include the following compounds.

IH-indole-3-carboxylic acid, N-2-(4-morpholinyl)ethylamide IH-indole-3-carboxylic acid, N-2-(l-pyrrolidinyl)ethylamide IH-indole-3-carboxylic acid, N-3 -(4-morpholinyl)probylamide 1H-indole-3-carboxylic acid, N-2-biridylamide IH-indole-3-carboxylic acid, N-3-biridylamide LH-indole-3-carboxylic acid, N-2- Pyridylmethylamide IH-indole-3-carboxylic acid, N-3-biridylmethylamide LH-indole-3-carboxylic acid, N-4-pyridylmethylamide (hydrochloride) IH-indole-3-carboxylic acid, N One ethyl. N'
-4-pyridylmethylamide IH-indole-3-carboxylic acid, N-2-(2-biridyl)ethylamide 1H-indole-3-carboxylic acid, N-2-(1-piperidinyl)ethylamide II {-indole-3 -carboxylic acid, N-3-(2-
Methyl-1-biperidinyl)propylamide 1-(LH-indol-3-inolecanoleponinole) = 4-penzylpiperazine 1-(l}I-indol-3-ylcarponyl)-4
-penzylpiperidine 1-(IH-indol-3-ylcarponyl)pyrrolidine 1- (1-methylindol-3-ylcarponyl)
Pyrrolidine 1-(LH-indol-3-ylcarbonyl)-4-
Methyl-piperazine l-methylindole-3-carboxylic acid, N-2- (
4-morpholinyl)ethylamide IH-indole-3
-carboxylic acid, N-3-(2-oquine-1-pyrrolidinyl)pyramide IH-indole-3-carboxylic acid N-4morpholinylamide IH-indole-3-carboxylic acid, N-1-piveridiny Ruamide IH-indole-3-carboxylic acid, N-1-homopiperidinylamide IH-indole-3-carboxylic acid, N-1-pyrrolidinylamide II {-indole-3-carboxylic acid, N 3= (1
-imidazolyl)propylamide]H-indole-3-carboxylic acid, N-(2-penzimidazolyl)methylamide 1H-indole-3-monoleponic acid. N-2-(1
-Methyl-2-pyrrolyl)ethylamide IH-indonole-3-canoleponic acid, N-methyl, N-2- (2
-pyridyl)ethylamide IH-indole-3-carboxylic acid N-1-(4-pyridyl)ethylamide IH-indole-3-carboxylic acid, Nl -(3-pyridyl)ethylamide 18-indole-3-carboxylic acid, N -1-(2-Biridyl)ethylamide II {-indole-3-carboxylic acid, N-1-(3-
pyridyl)-2-probylamide IH-indole-3
-carboxylic acid, N-(1,5-dimethyl-2-pyrrolyl)methylamide IH -indole-3-carboxylic acid, N
-2-Oxo-3-Homobiperidylamide The compounds of the present invention may be administered orally or parenterally, usually in the form of a pharmaceutical preparation. Forms of pharmaceutical preparations include tablets, capsules, suppositories, troches, syrups,
There are creams, ointments, patches, tablets, granules, powders, injections, suspensions, etc. It can also be made into double-layer tablets or multi-layer tablets together with other drugs. Furthermore, the tablets can be made into tablets with conventional coatings, such as sugar-coated tablets, enteric-coated tablets, or film-coated tablets, if necessary.

In the case of a solid preparation, solid additives such as lactose, sucrose, crystalline cellulose, corn starch, calcium phosphate, sorbitol, greenin, carboxymethylcellulose, gum arabic, polyvinylpyrrolidone, hydroxyl pyrrolidone, glycerin, polyethylene glycol, Stearic acid, magnonium stearate, talc, etc. are used.

When preparing a semi-solid preparation, vegetable or synthetic wax, fat, etc. are used.

In the case of a liquid preparation, liquid additives such as sodium chloride, sorbitol, glycerin, olive oil, almond oil, propylene glycol, ethyl alcohol, etc. are used.

The effective amount of these preparations is from 0.1 to 100% by weight of the preparation, suitably from i to 50% by weight in the case of preparations for oral administration, and in the case of injectable preparations. 0 for
．． It is 1 to 10% by weight.

There are no particular restrictions on the administration method or dosage of the compound of the present invention, and it may be selected depending on the various formulations, patient's age, sex, degree of disease, etc., but the effective daily dosage is 0.001 or lng-1000mg
It is.

Specific examples of the method for combining the compounds of the present invention and their pharmacological effects will be shown below as examples.

Example l IH-indole-3-carboxylic acid, N-2-(4-morpholinyl)ethylamide H Indole-3-carboxylic acid chloride (1.7 h,
Add a solution of N-(2-aminoethyl)morpholine (1.44 mQ, ?1 mmo4) in anhydrous THF (10 mQ) to 0 °C.
It was added dropwise over 30 minutes. The reaction solution was stirred for 30 minutes and then left at room temperature overnight.

Saturated sodium bicarbonate solution (20,+ff) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (lOOmQ). The organic layer was washed with saturated brine, dried (Nazcos), and concentrated under reduced pressure. The resulting crude product was recrystallized twice from ethyl acetate/isopropyl ether and chloroform/isopropyl ether to give L33g ( 49%) colorless crystals were obtained.

Melting point 151.1-151.6°C': lRν+l,
ax(KBr) 3380(s), 1629(s), 1
555 (vs), 1452 (s), 1217 (s)
, 118 (vs), 1008 (m), 872 (m)
, 751(s) cm-'; H-N)JRδ(CDCi
2+) 2-53-2.58 (4H, m), 2.62
- 2.68 (2H, m), 3.63 (2tL
d, J=5.9 Hz, J'=IO. 8 Hz),
3.74-3.80 (4H, m), 6.84 (IH,
br. s), 7.22-7.32 (2H, m),
7.42-7.49 (18, m), 7.80 (LH,
d, J■2.9 f{z), 7.95-7.99
(LH, m), 9.44 (IH,'or.s)
; MS (m/z) 274 (M"+1. 1), 2
56(6), (70), too(100).

Example 2 1H-indole-3-carboxylic acid N-(1-pyrrolidinyl)ethylamide 2 144 H Prepared according to the method of Example 1.

Melting point 129.1-129.2°O; IRp max
(KBr) 3380(m), 1621(s), 154
2(s), 1452(m), 1205(m), 11
17 (m), 1011 (m), 864 (m), 757 (
m) cm-'; H-NMRδ(CDCI2s) 1
．． 75-1.88 (2H, m), 2.43-2.
55 (6H, m), 3.58-3.66 (6H, m)
, 7-13 (LH.br.s), 7.19-7
．． 28 (2H, m), 7.38-7.47 (2H,
m), 7.70 (IH, d, J=2.9 Hz),
7.97-8.04 (LH, m), 9,52 (IH.
br. s); MS(m/z)289(M”+
2), 245(35), 201(85).

Example 3 IH-indole-3 (4-morpholinyl) Carboxylic acid, propyl amide de N 3 O H Preparation was carried out according to the method of Example 1.

Melting point 125.9-126.0°C: IRνmax(K
Br) 3400(m), 1605(s), 1548(
vs), 1441(m), 1339(m), 1211
(s), 1141 (m), 1048 (W), 739 (m
)c*-'; H-NMRδ(DMSO-da) l-
70 (4H, br.s), 2.50 - 2.65
(5H, m), 3.30-3.45 (3H, m), 7
．． 08-7.14 (2H, m), 7.40-7.44
(IH, m), 7.80-7.91 (IH, m),
8.00 (IH, s), 8. 'll-8.15 (IH
, m), 11.55 (LH, br.s): MS
(m/z) 259(M”+2, l), 188(
3), 154 (+00).

Example 4 1H-i hmm Dole-3-carboxylic acid, N-2-pi Lysylami de H Preparation was carried out according to the method of Example 1.

Melting point 235-240°O (241-243°C: hydrochloride): IR y max (KBr) 3250 (m),
1650(S), 1575(m), 1535(s),
1430(s), 1300(m). 1190 (m
), 750 (s) cm-'; H-NMRδ (DMSO
-di) 7.05-7623 (3H, m), 7.41
-7.49 (IH, m), 7.79 (IH, t),
8.20-8.38 (3H, m), 8.55 (I
H, d), 10.30 (1}1, s), 11.75
~11.85 (IH, b); MS (m/z) 2
38 (M”+ 1.20), 145 (100), 1
06(33), 89(37).

Example 5 IH-indole-3-carboxylic acid, N-3-pyridylamide H Prepared according to the method of Example 1.

Melting point 248-251'O (245-247°C: hydrochloride): IRymax (KBr) 3350 (W), 2
830(w), 1640(s), 1540(m),
1420(s), 1195(m). 750 (m)
cm-';H-N)JRδ(DMSO-d6)7.10
-7.25 (2H, m), 7.35 (11 {del),
7.40-7. ．． 53 (IH, m), 8-15-8.
35 (5H, m), 8.92 (IH, a), 9.8
7-9.98 (LH. b); MS (m/z) 238
(M″″+l, l3), 144(100), 106
(30), 89(30).

Example 6 IH-indole-3-carboxylic acid. N-2-Biridylmethylamide H Prepared according to the method of Example 1.

Melting point 203-206°C (216-220'O: hydrochloride): IRy max (KBr) 3210 (m)
, 1625(s) , 1560(s), 1440(m)
, 1215(s), 740(s) cm-'; H-NM
RδCDMS○-d@) 4.59 (2H, a), 7.
03-7.28 (3H, m), 7.30-7.45 (
2H, m), 7.73 (LH, t), 8.05
- 8.18 (2H, m), 8.45 to 8-60 (2
H, m), 11.50-11.60 (LH, b)
; MS (m/z) 252 (M”+1.20
), 144 (100), 116 (45), 107 (85
), 89(55).

Example 7 IH-indole-3-carboxylic acid, N-3-pyridylmethylamide H Prepared according to the method of Example 1.

Melting point 232-235°C! (143-148°C: the same hydrochloride); IR v max (KBr) 3140 (m)
, 1615(s), 1550(s), 1445(m
), 1315 (m), 1215 (S), 755 (m),
710 (m) cm-'; H-NMRδ (Duso-a
．． ) 4.52 (2H, a), 705 -7.20
(2H, m), 7.26-7.36 (LH, m)
, 7.42 (IH', dd) , 7.75 (IH, a
), 8.03 (IH, d), 8.16 (IH, dd
), 8.37-8.65 (3H, m). 11.4
5-11.55 (IH, m); MS (m/z) 2
52 (M”+ 1.40), 144 (100), 11
6(22), 79(22).

Example 8 IH-indole-3-carboxylic acid, N-4-biridylmethylamide (filled with hydrochloric acid) H Prepared according to the method of Example 1.

Melting point 207-215°C (hydrochloride); IRy m
ax(KBrXfree)3160(m), 1615
(s), 1540(s), 1445(s), 1320
(m), 1210 (s), 760 (m) cm-'; H
-NMRδ (DMSO-da) 4.74 (2H, d)
, 7.03-7.20 (2H, m), 7.45 (I
H, d), 8.00 (2H, d), 8.12 (IH,
d), 8.21 (IH, s), 8.85 (2H,
d) , 8.89 (IH, t) , 11.71 (IH
, s); MS (m/z) 252CM”+ 1, 45
), 144 (100), 116 (20), 108 (18
), 79(20).

Example 9 IH-indo-inole-3-canoleponic acid, N-ethynole, N'-4-biridylmethylamide H Prepared according to the method of Example 1.

Melting point 128-130'o (107-109°C: hydrochloride); IRvmax (KBr) 3180 (m), 16
00(s), 1530(m), 1450(s), 1
310 (m), l 195 (m), 955 (m), 76
0(m)Cll+-'; H-NMRδ(cDccs)
1.21 (3H, t), 3.57 (2Hq), 4.
80 (2H, s), 7.15-7.35 (6H,
m), 3.57 (2H, q), 4.80 (2H
, s), 7.15-7.35 (6I{, m), 7.
80-7.90 (IH, m), 8.55-8.63 (
2H, m), 8.90-9.05 (l}lb);
MS (m/z) 280 (M"+ 1, 40), 1
44 (100), 116 (42), 89 (44).

Example 1O IH-Indole-3-monocanoleponic acid, N-2-(2
-Biridyl)ethylamide H Prepared according to the method of Example 1.

Melting point 184-186°C (165-170'c: hydrochloride): IRνmax (KBr) 3150 (m)
, 1620(s) , 1550(s), 1420(m)
, 1320(m), 1210(m), 750(s)c
m-'; H-NMRδ(DMSO-di) 2-95
~3.10 (2H, m), 3.57-3.62 (
2H, m), 7.00-7.30 (4H, m), 7
．． 30-7.43 (LH, m), 7.57-7.7
2 (IH, m), 7.85 - 7.98 (IH, m
), 8.07-8.18 (LH, m), 8.48-8
．． 57 (IH, m), 11.35-11.50 (LH
, b): MS (m/z) 266 (M” main 1.45
), 161 (15), 144 (100), 121 (70
), 93(62).

Example 11 IH-indole-3-canoleponic acid, N-2-(l-
piperidinyl)ethylamide H? Preparation was carried out according to the method of Example 1.

Melting point 164℃; IRνmax (KBr) 3308 (
s), 1618(S), 1550(s), 1473(
m), 1277(m), 1243(s), 11l6(
s), 1015(m), 871(m), 741(s)
am-'; H-NMRδ(CDCQ+)2-54(2
H, br. d, J・4.9 Hz), 2.57(
2H, or. dJ■4.4 Hz), 2.63
(IH, d, J=5.9 Hz), 2.66 (IH
, d, J=6.4 t{z), 3.58(IH,
d, 5.9 Hz), 3.62 (IH, t, J=
5.4 Hz), 3.76 (2H, d, J=4.
4Hz). 3.78 (2H, d, J=4.9
Hz), 3.83 (3H, s), 6.75 (IH,
br. s), 7.23-7.32 (2H, m), 7
．． 34-7.42 (lH, m), 7.72 (LH,
s), 7.94-7.99 (IHm); MS
(m/z) 288 (M”+ 1, 65), 269 (
100), 175 (40), 101 (60).

Example 12 1H-i Ndor 3 Carponic acid. N 3 (2 Methyl 1 one piperidinyl) propilua de H Preparation was carried out according to the method of Example 1.

lRy fflax (KBr) 2930 (vs), 16
18 (vs), 1540 (vs), 1453 (vs)
, 1321(s), 1215(s), 1134(m)
, 747(s), 739(s) cm-'; H-N
MRδ (cDc!2.) 1.07 (3H, ct, J・
5.9 Hz), 1.14 (IH, d, J・4.
4 Hz), 1.18-1.38 (2H, m), l
-39-1-67 (3H, m), 1.70-1.89
(2H, m), 1.95-2.13 (LH, m),
2. 15-2.40 (2H, m), 2.80~
3. OO(2H, m), 3.35-3.55(2H,
m), 3.56-3-78 (LH, m), 7.11
-7.26 (2H, m), 7.30-7.50 (2H
, m), 7.71 (LH, br. s), 7.95
- 8.10 (IH, m), 9.58 (LH, b
r. s); MS (m/z) 299 (M″″.25
), 284 (40), 201 (55), 144 (too
).

Example 13 1-(IH-indol-3-ylcarponyl)4-penzylbiperazine 0H 1-bediyldi/lzpiperazine (1.54g, 9.5
mmof2) in anhydrous THF (15 m4).
5M nBuLi hexane solution (6.3m+1.9.
5m+++ol2) was added dropwise over 10 minutes under ice cooling. The resulting dark brown transparent solution was stirred for 30 minutes under water cooling, and then the solvent was distilled off under reduced pressure. Anhydrous THF (20 m (1) was added to the residue, and indole-3-carboxylic acid chloride (1) was added under water cooling.
．． oOg, 5.57 mmoC) of anhydrous THF (5
mQ) solution was added dropwise over 10 minutes at room temperature and stirred overnight.

Ice-cooled diluted hydrochloric acid water was added to the reaction mixture, followed by washing with ethyl acetate. The aqueous layer was adjusted to pH>10 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and then the organic layer was washed with water and saturated brine. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a yellowish brown foamy solid. This was purified using silica gel column chromatography 7E (SiO2: 50g: chloroform/methanol-10/1) to obtain 0.43g of the title compound (
24%) was obtained as a yellow foamy solid.

Foamy solid; lRy fflax (KBr) 318
0 (m), 2810 (m), 1600 (s), 144
0(s), 1318(s), 1205(s), l15
0 (m), 1150 (m), 1010 (s), 750 (
s) cm-'; H-NMRδ (CDCL) 2-48
(4H, br. t), 3.54 (2H, s), 3
．． 73 (4H, br. t), 7.15-7.35 (
9H, m), 7.63-7.70 (IH, m);
MS (m/z) 319 (M”, 20), 175 (
14), 144 (90), 116 (24), 91 (10
0).

Example l4 1-(IH-indol-3-ylcarponyl)-4-
Penzylbiperidine H Prepared according to the method of Example 13.

Foamy solid; IR y max (KBr) 322
0(m), 2910(m), 1595(s), 154
0(m), 1455(m), 1310(w), 121
4(v), 1130(v), 748(m), 700(
W) cm-'; H-NMRδ (CDCQs) 1.50
(2H, m), 1.65 (4H, m), 2.55 (
2H, dJ・6.4 Hz), 2.86 (2H, b
r. d), 4.40 (2H, br.), 7.01
-7.35 (9H, m), 7.65 (IH, m
), 10.27 (lH, br. s); MS (m/
z) 318CM"", 36), 227(l2),
174 (24), 144 (100), 116 (20).

Example 15 1-(IH-indol-3-ylcarponyl)pyrrolidine H Prepared according to the method of Example 13.

Foamy solid; lRy IIlax (KBr) 342
0(v), 3130(m), 2980(w), 158
0(m), 1560(m), 1528(m), 144
5(s), 1340(w), 1230(w), 75
5(m)am-'; H-NMRδ(CDCffs)
1-98 (4H, m), 3-70 (IH, m)
, 7.13-7.25 (2H, m) , 7.40-
7.59 (2H, m), 8. OO(LH, m);
) JS (n+/z) 214 (lJ”. 64), 144
(100), 116(l6), 89(14).

Example 16 1-(1-methylindol-3-ylcarponyl)
Virrolidine Me Prepared according to the method of Example 13.

Foamy solid; IR y max (KBr) 296
0 (m), 2860 (m), 1595 (s), 152
5(s), 1472(s), 1435(S), 134
0(z) , 1245(m) , 1112(m) , 1
070 (w), 762 (m) cm-'; H-NMR
δ (CDCQs) 1.90 (4H, m), 3.68 (
4H, m), 3.79 (3H, s), 7.15-
7.36 (4H, m), 8.14 (IH, d, J
=7.6 Hz); MS (m/z)228 (M”,
25) 158 (100).

Example l7 1-(IH-yne dol-3-ylcarponyl) -4-methyl-piperazine H Prepared according to the method of Example 13.

Foamy solid; IRy max (KBr) 3160 (w
), 1590(s), 1438(m), 144
2(m), 1310(w), 1205(W), 101
0(m), 754(m) cm-'; H-NMRδ(C
DC+2s) 2.35 (3H, s), 2.49 (4H
, s) , 3.78 (4H, s) , 4.00 (I
H, s), 7.20 (2H, m), 7.35-7.
70 (3H, m); MS (m/z) 243 (M'''
, 10) , 186 (16) , 144 (100),
116(30), 83(88).

Example 18 l-methylindole-3-carboxylic acid, N2-(4-
Morpholinyl)ethylamide Me? Preparation was carried out according to the method of Example 1.

Melting point 164.2-164.4°C; IRy max
(KBr) 3308(s), 1618(s), 15
55(s), 1473(m), 1277(m), l2
43(S), 1116(s), 1015(m), 871
(m), 741(s) cm-';1{-NMRδ(
CDCQs) 2-54 (2}1, br. 6, J■
C9 Hz), 2.57 (2H, d, J■4.4
Hz), 2.63 (IH, d, J=5.9Hz)
, 2.66 (IH, d, J=6.4 }1z), 3
．． 58 (IH, d, J=5.9 Hz), 3.62
(l}l, L, J=5.4 1{Z), 3.76(
2}1, d, J=4.4 Hz), 3.78 (2H,
d, J=4.9 Hz), 3.83 (3Hs), 6
．． 75 (IH, br. s), 7.23-7.32
(2H, m), 7.34-7.42 (LH, m),
7.72 (LH, s), 7.94 - 7.99 (I
H, II1); MS (m/z) 288 (M”+ 1
．． 65), 269 (100), 175 (40), 10
1 (60).

Example 19 11 { (2 Indole-3-carboxylic acid, N-3 Oxo l-pyrrolidinyl) provirad ? Preparation was carried out according to the method of Example 13.

Melting point: 201.3-204.2°O. IRνmax(KB
r) 3290(w), 1664(s), 1617(
m), 1579(m), 1445(m), 12l9(
w), 778(w) cm-'; H-NMRδ(D
Mso-d6) 1.63 -1.77 (2H, m)
, 1.85-2.00 (2H, m), 2.23 (2
H,t. J=7.8 Hz), 3.15-3.40
(6}T, m), 7.04 to 7-17 (2H,
m), 7.41 (LH, br. d, J=7.3
Hz), 7.85 (IH, br. L, J■5.
6 Hz), 7.96 (IH, d, J=2.4
Hz), 8.13 (IH, br. d, J=7.
8 Hz), 11.5 (IH, br. s,);
MS (m/z) 285 (M”, 50), 174 (60
), 144(100).

Example 20 1H-i hmm de Ru-3-carboxylic acid N-4-mo Ruforinilami de 0 H Preparation was carried out according to the method of Example 13.

Melting point 232.1-237.2°C: IRνmax(K
Br) 3226(S), 1641(S), 1550
(m). 1452 (m), 1214 (m), 110
1 (m), 882 (m), 757 (m) cm-'; H
-NMRδ(DMSO-d@)2.91(3H, s)
．． 3.35 (2H, s), 3.68 (3H,
s), 7.05-7.18 (2H, m), 7.42 (
LH, a, J=7.8 Hz), 8.00 (IH,
br. s), 8.10 (IH, br. s),
8.94 (18, br. s), 11.6 (LH,
br. s); fJs(m/z)245(M”, 1
5), 160 (98), 102 (100).

Example 21 1H-indole-3-carboxylic acid, N-1-biveridinylamide H Prepared according to the method of Example 13.

Melting point 248.8-251. 5℃; IRνmax
(KBr) 3180(m), 1676(s), 15
25(v), 1457(m), 1374(w), 11
9l(m), 750(m)cm-'; H-NMRδ(
ouso-at) 1.57 (2u, br. s), 1.
92 (3H, br. s), 3.58 (5H, br.
．． s), 7.15-7.26 (2H. m), 7.4
9-7.53(IH, m), 8.10=8.14(I
H, m), 8.50 (LH, d, J=2.9 H
z), 11.9 (IH, S), 12.1 (LH, s
) ; MS (m/z) 243 (M", 5), 160
(30), 144 (90), 100 (100).

Example 22 IH-Indole-3-Carboxylic Acid, N-1-Homobiperidinylamide H Prepared according to the method of Example 1.

Melting point 172.7-174.2°c; IRM l, l
ax(KBr) 3242(s), 2932(s),
1612 (s), 1541 (s), 1429 (S),
l327(m), 1242(m), 1201(m)
, 1103 (v), 740 (s) cm"'; H-
NMRδ (DMSO-ds) 1.62 (8H, b
r. s), 3.11 (4H, br. s), 7.0
3-7.17 (2H, m), 7.38-7.42 (L
H, m), 7.95 (IH, br. s),
9.20 (LH, br. s), 11.5 (IH,
br. s) ; MS (m/z) 258 (M”+1.
20), 160 (80), 144 (80), 98 (1
00).

Example 23 IH-indole-3-carboxylic acid, N-1-pyrrolidinylamide H Prepared according to the method of Example 1.

Melting point 174.7-175.4°O; IRy max (
KBr) 3230 (m), 3158 (m), 162
5(s), 1611(s), 1527(s), 145
7(s), 1429(s) 1204(m), 1
104(m), 754(s)c++-'; H-NM
Rδ(DMSO-da) 1.78 (4H, br.
s), 2.95 (4B, br. s), 7.04-
7.17 (2H, m), 7.35-7.45 (IH,
m), 7.97 (LH, br. s), 8.
10 (IH, br. s), 8.78 (IH, br. s).
s), 11.5 (LH, br. s),; MS(
m/z) 229 (M”. 15), 160 (95), 1
44(85), 85(100).

Example 24 IH-indole-3-carboxylic acid, N-3-(1-imidazolyl)probylamide H Prepared according to the method of Example 1.

Melting point 183-186°O; lRy max (KBr
) 3180(m), l605(s), 1555(s
), 1445(m), 1220(s), 750(
s) cm-'; H-NMRδ (DMSO-da)
1. 99 (2H.qui,), 3.20-3.3
3 (2H, m), 4.05 (2H, t), 69
0 (IH, S), 7.00-7.15 (2H, m),
7.18 (IH, s), 7.35-7.45 (IH,
m), 7.65 (IH, s), 7.91 (LH
, t), 7.98 (LH, d), 8.07
8.18 (LH, m), 11.40 -11.55
(IH, b); MS (m/z) 268 (M”. 4
2), 200 (12), 144 (100), 116 (2
3), 95(77).

Example 25 1H-Indole-3-carboxylic acid, N-(2-penzimidazolyl)methylamide H Prepared according to the method of Example 1;

Melting point 178-181'o (decomposition); IR y ma
x (KBr) 3230 (W), 1670 (s), 16
15(s), 1540(s), 1440(s), 12
40 (m), 750 (s) c++! -'; MS(m
/z) 290 (M”, 37), 146 (100),
119(14), 116(14), 89(14).

Example 26 IH-indole-3-monoleponic acid, N-2(l-methyl-2-pyrrolyl)ethylamide H Prepared according to the method of Example 1.

Melting point 206-207°C; IRνIllax (KB
r) 3400(s), 3l70(m), 1620
(s), 1555(s), 1450(s), 1320(
m), 1210(s), 760(a+), 720(
m) cm-'; H-NMRδ(DMSO-dg)2
．． 78 (2H, t), 3.38 ~ 3.55 (2H
, m), 3.56 (3H, S), 5.80 to 5-90 (
2H, m), 6.55-6.62 (IH, m), 7
．． 00-7.20(2I{,m), 7.41(IH,d
), 7.90~8.05 (2H, m), 8.05~
8.17 (IH, m), 11.40-11.55 (
IH, b): MS (m/z) 267 (M”.80)
, 144(93), 116(95), 107(74),
94(100), 89(83).

Example 27 IH-indole-3-carboxylic acid. N-methyl, N-
2-(2-Biridyl)ethylamide H Prepared according to the method of Example 1.

Melting point 112-114°C; IR v ffiax (
KBr) 3130(m), 1595(s), 154
0(s), 1440(S), 1405(S), 1180
(m), 760 (s) am-'; H-NMRδ(C
DCL) 3.09 (3H, s), 3.15 (2H
,t), 3.97(2H,t), 7.04-7.3
0 (5H, m), 7.56 (IH, dt), 7.6
0 to 7.70 (LH.m), 8.50 (IH.d),
9.60-9.70 (IH.b); MS (m/z)
279 (M”, 35), 174 (20), 144 (10
0), 135 (61), 116 (28), 106 (
25), 93(25).

Example 28 IH-indole-3-carboxylic acid, N-1-(4-pyridyl)ethylamide H Prepared according to the method of Example 1.

Melting point 212-216℃. rRyffiax(KB
r) 3180(m), l620(s), 1540(
s), 1450 (m), 1420 (m), 1210 (S
), 755 (m) cm-'; H-NMRδ (CDCI
2s) 1.63 (3H, d), 5.37 (LH,
qui. ), 6.25 (IH, a), 7.2
0-7.37 (4H, m), 7.37-7.46 (
IH. m), 7.77 (IH, d), 7.95 (LH,
dd), 8.53=8.60 (2H, m),
8.90-9.05 (IH, b); MS (m/z)
265 (M”, 40), 144 (100), 123 (3
0), 116(20), 89(17).

Example 29 IH-indole-3-carboxylic acid, N-1-(3-biridyl)ethylamide H Prepared according to the method of Example 1.

Melting point 180-183°O; IRy, Ilax(K
Br) 3180(m), l620(s), 1540
(s), 1460(m), 1210(m), 75
0(m)c+++-'; H-NMRδ (CDC4.)
1.65 (3H, d), 5.42 (IH.qui.
), 6.35 (LH, d), 7.15-7.30 (
3H, m), 7.33-7.45 (LH, m), 7
．． 68-7.80 (2H, m), 7.88-8.00
(IH, m), 8.50 (IH, dd), 8.71
(IH, d), 9.20-9.35 (IH, b);
MS (m/z) 265 (M”, (100), 121 (
20), 107(20), 89(20).

Example 30 1H-indole-3-carboxylic acid, (2-pyridyl)ethylamide 45), N one 1 144 H Preparation was carried out according to the method of Example 1.

Melting point 180-181°C'; I R y max
(KBr) 3350(w), 2970(v), 1610
(s), 1540(s), 1500(s), 14
40(m), 740Cm') crx-': H-NMR
δ (cDcg.) 1.62 (3H, D), 5.44
(IH. qui-), 7.15-7.47 (5H,
m), 7.60 (IH, d), 7.68 (IH,
dt), 7.81 (IH, d), 8. lO~8.20
(IH, m), 8.61 (LH, ad), 9.03
~9.20 (IH, b); MS (m/z) 26
5CM”, 25), 144 (95), 121 (100
), 1 16(24), 89(20).

Example 31 1H-Indole 3 -carboxylic acid, N-1 (3-Viridyl) 2 -Brobirua de H Preparation was carried out according to the method of Example 1.

Melting point 182-185°O; lRy max (KBr
) 3310 (m), 3100 (m), 1620 (S)
, +540 (S), 1455 (m), 1220 (m)
, 740 (m) cm-'; H-NIJRδ (CDC+
2. -CD. OD) 1.29 (3H, d), 2.9
2 (IH, da), 2.98 (IH, dd), 4.
44C2H. q), 7.10-7.24 (2H, m)
, 7.27-7.45 (2H, m), 7.77 (LH
, dd), 7.82 (IH, s), 7.95 −
8.05 (IH, m), 8.35 (IH, dd),
8.44 (IH, d); MS (m/z) 279 (y
+, 7), 187 (12), 144 (100)
, 116(13), 93(22).

Example 32 IH-indole-3-carboxylic acid. N(l,5-dimethyl-2-pyrrolyl)methylamide H 1B-indonole-3-monocanoleponic acid, N- (1
．． 5-dimethyl-2-pyrrolyl)methylamide Example 1
It was prepared according to method 3.

Foamy solid. H-NMRδ(CDCQs-DMSO-
da-MeOH-d-) 2.19 (3H, s), 3.
50 (3H, s), 4.26 (IH, s), 5.72
(IH, d, J → 3.O Hz), 5.95 (I
H, d, J・3.5 Hz), 7.15 (2H,
m), 7.42 (IH, m), 7.97 (18, s
), 8.13 (IH, m); MS (m/z)2
67 (M”, 80), 144 (52), 108 (10
0).

Example 33 IH-indole-3-carboxylic acid, N-2-oxo 3-hexahydroazepinylamide H Prepared according to the method of Example 1.

Melting point 247.1-248.4℃;
x (KBr) 3260 (m), 1677 (m), 1
621(s), 1543(s), 1482(m), 1
457 (m), 1210 (w), 745 (m) cm-'
; H-NMRδ (DMSO-d@) 1.15-2.0
5 (6H, m), 3.05-3.30 (2H, m)
, 4.55-4.70 (IH, m), 7.08-7
．． 19 (2H, m), 7. ．． 39-7.47 (IH
, m), 7.70 (LH, d, J=6.8 Hz
), 7.85-7.96 (LH, m), 8. OO~
8.10 (2H, m), 11.6 (IH.br.s
); MS (m/z) 271 (M”. 33), 144
(too).

Example 34 For each of the compounds produced according to the above examples,
Antagonism to 5-HT at the 5-HT receptor was tested.

That is, when 5-HT (serotonin) is administered into the jugular vein of anesthetized rats, transient bradycardia occurs (van B
ezold Jarisch Reflex) (Pai
ntal, Physiol. Rov. , 53,
159-227 (1973)). Richa said that this reflex due to 5-HT occurs through 5-HT receptors.
It has been proven by Rdson et al. (Nature, 3
16. 126-131 (1985)). Therefore, 5-HT. 5-HT in receptors
An effective and selective antagonism can be evidenced by an inhibitory effect on this reflex. That is, rats were treated with urethane (
1g/J29i. The animals were anesthetized with p), and blood pressure and heart rate were recorded from the left femoral artery. Taking the bradycardia that occurs when 5-HT (30 μg/k9) is administered into the jugular vein as 100, when the compound of the present invention is administered into the jugular vein 5 minutes before 5-HT administration, 5-H
The inhibition rate was calculated from the bradycardia caused by T. The inhibition rates are summarized in the table below.

In addition, in this test, the compounds of Examples 15, 26,
All but 32 were tested in the hydrochloride form.

Therefore, The concentration to be tested is also the concentration of hydrochloride.

5 HT. antagonism 2 80 74 S3 3 l3 4 27 5 29 23 8 77 22 2l 9 34 l1 22 11 12 l9 l5 37 l8 l6 20 23 21 l8 l7 22 l7 23 l0 Inhibition rate (%) 24 73 62 31 16 12 29 26 32 26 Formulation example 1 tablet ( ■ tablet) Milk Sugar 67vr9 crystalline cellulose 1.5mg corn starch 7mg 100+n9 Each component is mixed uniformly to form a powder for direct application.

This was molded into tablets with a diameter of 6 inches and a weight of 100 cm using a rotary tablet press.

Formulation Example 2 Granules (1 sachet) After the components of A are mixed uniformly, the solution of B is added and kneaded, sized by extrusion granulation, and then dried in a dryer at 50°C. The dried granules have a particle size of 297μm-1460μm.
The sieved material is made into granules. 1 sachet amount is 200
Let n+g.

Formulation example 3 Syrup white sugar
30.00h1) - 7 Ruby} - Le 7
0W/V% 25.0009 Ethyl paraoxybenzoate 0.0309 Glopil paraoxybenzoate 0.015g Flavoring agent 0.200g Glycerin 0.15h 96% ethanol 0.500g Total amount 100ml2 White sugar, D-sorbitol, Methyl paraoxybenzoate,
Brovyl paraoxybenzoate and the above active ingredients are dissolved in 60 g of warm water. After cooling, a solution of flavoring dissolved in glycerin and ethanol is added. Next, add water to this mixture to make it 100 degrees α.

Formulation Example 4 Injection Sodium Chloride 10 rng Total amount 1. OmQ Sodium chloride and active ingredients were dissolved in distilled water, and the total amount was brought up to 1. Let it be Qm4.

Formulation example 5 sitting agent polyethylene glycol 4000 20g all amount 100g Griseri Add the ingredients to the active ingredients and dissolve.

Polyethylene glycol 4000 is added thereto, heated and dissolved, poured into suppository molds, cooled and solidified to produce suppositories weighing 1.5 g each.

Claims (1)

[Claims] The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, R_1 is a hydrogen atom, C_1 to C_5 alkyl, and R_2 is morpholino, methylpiperazino, benzylpipe Radino, or an unsaturated heterocyclic group (this heterocyclic group may be fused with a carbon aromatic ring), or a saturated heterocyclic group having a carbonyl group on the ring, or the following general formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) It is a saturated cyclic amine represented by (In the formula, R_4 is a hydrogen atom, lower alkyl, or benzyl, and p is an integer from 1 to 3). , X is NH or NR_3, and R_3
is C_1-C_6 alkyl, m is 0 or 1, n is an integer of 0, 1-5, -(CH_2)_n
- at least one of the hydrogen atoms in may be substituted with C_1 to C_4 alkyl], and its pharmacologically acceptable acid addition salt, and its quaternary ammonium salt. and N-
Oxide derivative.