前苏联专利SU1607688A3 Method of producing derivatives of dihydrobenzfuran- or chroman-carboxamides or their additive salts

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专利摘要:
The invention relates to heterocyclic compounds, in particular to the preparation of derivatives of dihydrobenzofuran or chroman-carboxamides in the form @ where R 1 is H or methyl N = 1 or 2 R 2 - ethyl, allyl cyclopropylmethyl or cyclohexenylmethyl X-H or amino group YH or CL, cyclopropylmethylsulfonyl, methylsulfamoyl or ethylsulfonyl, provided that Y can only be cyclopropylmethylsulfonyl, when R 2 is ethyl, and N = 1, or Y can be only H or CL, or cyclopropylmethylsulfonyl, when R 2 is ethyl and N = 2, or when R 2 is allyl, and N = 1 or 2, or their additive salts of pharmacologically compatible acids, which have a neuroleptic effect and can be used in medicine. The goal is to develop a method for producing more active compounds. The preparation is carried out from the compound f-ly HOOC-C = CH-C (Y) = C (X) -C = C OC (R 1 ) - (CH 2 ) N , where X, Y, R 1 and N are indicated above, and ethyl chloroformate in the presence of triethylamine in the medium of an organic solvent (chloroform) at 0 - 5 ° С and dihaloalkylamine with a spontaneous increase in temperature. The compound obtained is treated with the amine of the f-ly N 2 NR 2 , where R 2 is indicated above, at 40-80 ° C. The desired product is isolated in free form or as an additive salt with a pharmacologically compatible acid. 8 tab.
公开号:SU1607688A3
申请号:SU884355973
申请日:1988-06-28
公开日:1990-11-15
发明作者:Франсешини Жаклин；Маргари Жозетт
申请人:Лаборатуар Делагранж (Фирма)；
IPC主号:

专利说明:

04
The invention relates to a process for the preparation of novel dihydro-benzofuran or chroman carboxamide derivatives or their additive salts of pharmacologically compatible acids, which have a neuroleptic effect and can be used in medicine.
The purpose of the invention is to obtain new derivatives. dihydrobeneofuran or chroman with a higher neuroleptic effect.
Example. I- {1-Cyclohexene-methyl-2-pyrrolidinylmethyl) -b-etype sulfonyl-chroman-8-carboxamide.
N- (2 5-Dichloropentyl) -6-ethylsulfonyl-1-chroman-8-carbamide.
75 g of 6-ethylsulfonone-1-chroman-8-carboxylic acid, 280 ml of chloroform and 28 g of triethylamine are introduced into a 1-liter flask. It is cooled to 0 ° C, and 68 g of the product of the snort is dissolved by heating in 136 ml of isopropanol. The boiling solution is filtered with charcoal and then cooled. Those formed with the crystals are precipitated, washed with isopropanol, then with ether and dried in air, then at
The resulting weight is 57 g (t.pcs., yield 49%).
By this method, the following compounds are prepared;
2) N- (1-I.disclox-methyl-methyl-2-pyr-rolidinylmethyl) -5-methylsulfamoyl-210
30 g of ethyl chloroformate are added dropwise, 15 methyl-2,3-dihydrobenzofuran-7-carb supports the temperature. The mixture is then stirred for 30 minutes at.
In a flask with a capacity of 2 liters of DROPPED, 54 g of 2,5-dichloro-pentamine amine hydrochloride, 280 ml of chloroform and 28 g of triethylamine, then the solution prepared above is added dropwise. The temperature rises to 27 ° C. Then the solution obraoxamide, so pl. 155-156 ° C;
3) N- (1-cyclohexenylmethyl-1-2-pyrrolidinylmethyl) -6-methylsulfamoyl-chroman-8-carboxamide, m.p. 144,520 145,
4) N- (1-cyclohexenylmethyl-2-pyrrolidinylmethyl) -5-cyclopropylmethylsulfonyl-2-metsh-2, 3-dihydrobenzene w-7-carboxamide-methanesulfonate.
bathe water. Chloroform layer of 25 so pl. 126 C;
5) N- (l-e 6-cyclopropsh 8-carboxes
canted, dried over sodium sulfate, then chloroform is distilled off, ending the stripping under vacuum, up to constant weight.
The weight obtained was 107 g (yield 94%).
N - (} - Cyclohexenylmethyl-2-pyrrolidinylmethyl) -6-3tilsulphonyl-chroman-8-carboxamide.
107 g are introduced into a 1 liter flask.
thirty
5) N- (l-ethI-2-pyropolydinylmethyl 6-cyclopropylmethylsulfonic 1-chroman-8-carboxamide, mp 106-106.5 C;
6) .Ы- (1-а1ШШ1-2-pyrrolidinylmeth-tsht) -6-cyclopropylmethyl-sulfonyl-hr man-8-carboxamide, m.p. 114 C;
7) N- (1-cyclopropylmethyl-2-pyrro-lidinylmethyl) -6-cyclopropylmethyl-sulfonyl-chroman-8-carboxamide.
finely dispersed K- (2,5-dichloropentyl) - ,, melting point „95 С;
6-ethylsulfonyl-chroman-8-carboxam-8) N- (1-cyclopropylmethyl-2-pyrpid and 203.5 g of 1-cyclohexeniLmeti.pami- heated at for 2 hours.
, on.
then leave the solution in a drying cabinet for 48 hours. After adding water and 30 ml of 30% sodium hydroxide, an excess of amine is distilled off. It is cooled, then extracted with ether. The precipitate formed.
sucked, washed with ether and dried in air. 47 g of product are obtained.
40
J
45
rolidinylmethyl) -6-ethylsulfonesh1-xr man-8-carboxamide-hydrochloride, mp
182-183 ° C;
9) H- (1-cyclopropyl metsh1-2-pyrride lidinylmethyl) -5-amino-6-ethyl-1-sulphyl-chroman-8-carboxamide, m.p. 15 152 С;
10) N-1-cyclopropylmethyl-2-pyr-lidinylmethyl) -5-ethylsulfonyl-2-methyl-2,3-dihydrobenzofuran-7-carbox mid-chloride, m.p. 137-138 ° C;
11) H- (1-ztil-2-pyrrolidinylmetroman chroman-8-carboxamide fumarate, t.p.
On the other hand, the ether extracts are evaporated and the residue is treated with methylene chloride. The solution is dried over potassium carbonate, then the methylene chlorine is distilled off, ending the stripping under vacuum, up to constant weight. The residue is treated with ether, then the crystals formed are sucked off, washed and dried in air. An additional 21 g of product is obtained,
m
-
607688d
68 g of the product is dissolved by heating in 136 ml of isopropanol. The boiling solution is filtered with charcoal, then cooled. The resulting crystals are precipitated, washed with isopropanol, then ether, and dried in air, then at
The resulting weight is 57 g (t.pcs., yield 49%).
By this method, the following compounds are prepared;
2) N- (1-I.disclox-methyl-methyl-2-pyr-rolidinylmethyl) -5-methylsulfamoyl-210
methyl 2,3-dihydrobenzofuran-7-carboxamide, so pl. 155-156 ° C;
3) N- (1-cyclohexenylmethyl-1-2-pyrrolidinylmethyl) -6-methylsulfamoyl-chroman-8-carboxamide, m.p. 144.5145,
4) N- (1-cyclohexenylmethyl-2-pyrrolidinylmethyl) -5-cyclopropylmethylsulfonyl-2-metsh-2, 3-dihydrobenzofuran-7-carboxamide-methanesulfonate.
m.p. 126 C;
5) N- (l-ethI-2-pyropolydinylmethyl) -l 6-cyclopropylmethylsulfone 1-chroman-8-carboxamide, so pl. 106-106.5 C;
6) .Ы- (1-а1ШШ1-2-pyrrolidinylmethyl-pcb) -6-cyclopropylmethyl-1 sulfonyl-hpr-man-8-carboxamide, m.p. 114 C;
7) N- (1-cyclopropylmethyl-2-pyrrolidinylmethyl) -6-cyclopropylmethyl-sulfonyl-chroman-8-carboxamide.
8) N- (1-cyclopropylmethyl-2-pyr-
40
45
rolidinylmethyl) -6-ethylsulfonone 1-chromoman-8-carboxamide-hydrochloride, m.p.
182-183 ° C;
9) H- (1-cyclopropylmethyl-1-2-pyrrolidinylmethyl) -5-amino-6-ethyl-1-sulfonyl-chroman-8-carboxamide, m.p. 151-152 C;
10) N-1-cyclopropylmethyl-2-pyrrolidinylmethyl) -5-ethylsulfonyl-2-methyl-2,3-dihydrobenzofuran-7-carboxamide-chloride, m.p. 137-138 ° C;
11) H- (1-methyl-2-pyrrolidinylmethyl) - chroman-8-carboxamide-fumarate, i.e.
122-123 C;
12) N- (1-ztil-2-pyrrolidinylmethyl) -5-cyclopropylmethyl-1-sulfonyl-2-me-. TSh1-2, Z-dihydrobenzofuran-7-carboxamid, so pl. 1P-I2 ° C;
13) K- (1-cyclohexenylmethyl-2-pyrrolidinylmethyl) -6-chlorochroman-8-carboxamide fumarate, m.p. 166-1b7 C; . „14) K- (1-od1КЛОгексенш1метш1-2-pyrrolidinylmethyl) -5-HLOR-2,3-dihydrob T50
Zofuran-7-carboxamide, so pl.
15) Neutral ethanedisulfonate N- (l-cyclohexene-Imethyl-2-pyrrolidinyl-methyl) -5-chloro-2-methyl-2, 3-dihyd. m.p.
16) N- (l-cyclopropylmethyl-2-pypo-lidinylmeth1) -5-amino-6-metsh1-sulphamoyl-chroman-8-carboxamide-chlorohydrate, m.p. 248-249 ° C;
17) N- (l-ethyl-2-pyropolydinylmethyl) -5-ethylsulfonish1-4-methoxy-2-methyl1-2,3-dihydrobenzofuran-7-carboxamide hydrochloride, m.p. 138-140 s;
18) N- (l-ethyl-2-pyropolydinylmethyl type) -5-methyl-6-ethylsulfonyl-chroman-8-carboxamide, m.p. 149 ° C;
19) N- (1-cyclopropylmethyl-2-pyrro-lidinylmethyl) -5-methyl-6-ethylsulfonyl-chroman-8-carboxamide, m.p. 100 °
The compounds of formula I were subject to toxicological and pharmacological radiation. Their acute toxicity was studied in mice, with the compounds administered intravenously, subcutaneously, intraperitoneally, and orally.
Doses, caused by the death of 50% of animals (LD5d), were determined by the Bliss method, the results are shown in Table. one.
A study of the effects of compounds of the formula I on the central nervous system was carried out using well-known tests. In particular, they studied the effect of inhibition of spontaneous mobility of y, the cataleptigenic ability in rats, antagonisms with respect to some effects of conditions caused by apomorphine and amphetamine.
The inhibitory effect of the compounds on spontaneous mobility in the mouse was observed and recorded using the photoelectric method according to the method of Winter and Flataker AND by activography using the Animex apparatus.
The compounds were administered intraperitoneally or orally, respectively, 15 or 60 minutes before registering the reaction.
Doses of compounds inhibiting 50% mortality () are presented in Table. 2
Apomorphine and amphetamine cause stereotyped movements in rats that are antagonized by antipsychotics. 1.25 mg / kg apomorphine
was administered intravenously, as in the Yanssen test, the compound of formula I was administered subcutaneously 60 minutes before and antagonism was observed later. 20 min after administration of apomor-. Finanza, or 0.50 mg / kg, was administered subcutaneously according to the Puech method, the compound of formula I was administered intraperi-10only 30 minutes before the administration of apomorphine and the effect was observed 20 minutes after the administration of apomorphine.
In a test in which decamphetamine was used, implemented according to the Janssen method, 10 mg / kg of dexamphetamine was administered intravenously, the test product was administered subcutaneously at the same time and the effect was measured 60 minutes after these injections. 20 The ID values are presented in Table 3.
The cataleptigenic function of the compounds of formula I was studied in rats. Each of the compounds was administered subcutaneously in increasing doses to groups of 10 25 rats (one group for each dose). Each group was observed for 7 hours, and the percentage of animals with catalepsy was set at any time, with the immobility as a criterion of the cataleptical state for 30 s, the rat forelimbs were moved apart and placed on wooden cubes 4 cm high.
The dose causing catalepsy in 50% of the animals () was determined graphically with maximum effect. The following values were obtained:
five
0
Connection 2 3 4 10
Compound
No
EDUO mg / kg
6.6 17.6
2 3, J
20.7
I 13
14 15
mg /
kg
Ed, oh.
5 I, 66
1.5
2.7 1.35
In another test using 0 apomorphine, the state of verticalization is observed, which it causes in mice and which is antagonized by neuroleptic agents according to Puech.
5 The compound was administered intraperito-. neapno 30 min before apomorphine (1 mg / kg s.c.) and antagonism was observed 45-50 min after the compound was administered.
Doses inhibiting 50% of this compound () are as follows:
connection to
2 3 6 7 8 10
connection number
one
12 13 14 15
Id-peritoneally,.
. mg / kg
0.55-0.63
1.20-1.24
0,67-0,69
3.2-3.5 to 3.3-4.1 0.40-0.55
intraperitoneally, mg / kg 15 0,105-0,126
3.1-4.5 -0.32-0.35 0.27-0.29 0.28-0.34 20
The neuroleptic activity of the compounds of formula I was revealed by a test of inhibition of spontaneous motor function in mice, a test of inhibition of stereotypes induced by apomorphism in rats, and a test of antagonism of behavior in the vertical position induced by apomorphine in mice.
The same tests were tested with compounds closest to the prototype ZO, and the results were compared with the results obtained with compounds of formula 1
The following prototype connections were obtained: 35
compound A - K- (1-eth1-2-pyrrolidinylmethyl) -2-methyl-5-methylsulfamoyl-2, 3-dihydrobenzofuran-7-carboxyamide (the activity of this compound is compared with the activity of the proposed Q 2, which differs only in the pyrrolidine substituent);
Compound B — K- (1-ethyl-2-pyrrO — Lidishishmethyl) -6-mets1 sulfamo-1; -chro-45 man-8-carboxamide (the activity of this compound is compared with the activity of the proposed compound 3, which differs only in the substituent pyrrolidine, and with the activity of compound 5, which differs only in the substituent in position 6);
Compound C - y - (1-ethyl-2-pyrrolidinyl methyl) -6-sulfamoip-xp oma n-8-yarboxamide (the activity of this compound is compared with the activity of compounds 5 and P, which differs only in the substituent in position o); Compound D-N - (- all-2-pyropolydinylmethyl) -6-methyl sulfamoyl-chromo-8-carboxamide (the activity of this compound is compared with the activity of compound 6, which differs only in the substituent in position 6
Compound E - K- (1-ethyl-2-pyrrolidinylmethyl) -6-ethylsulfonyl chroman-8-carboxamide (the activity of this compound is compared with the activity of compounds 1 and 8, which differ only in the pyrrolidine substituent).
In tab. 4 presents data on the inhibition of spontaneous motor function in the smaller, in table. 5 - data on the antagonism of the effect of apomorphine
in rats.
Antagonism of the verticalization caused by apomorphine in mice gives the following results:
Compound
A E S
D E F Connection
2
3 P
6
one
8 10
Ido, mg / kg, int peritonapno
8-8,6 11,5-14,7 64
1.9-2.2
2-2,2
,eight
, mg / kg, intraperitoneally 0.55-0.63 1.20-1.24 15.3-17.7 0.67-0.69 0.105-0.126 3.3-4.1 0.4-0, 55
The results presented show that replacing only one substituent in the formula of the compounds of the prototype with a substituent according to formula I significantly enhances the activity of the compound.
Replacing two substituents also increases the activity of the compounds obtained, as shown by the results of experiments with the proposed compounds 4, 7, 13, and 15.
The results of the tests carried out prove that the compounds of the formula I can (sometimes in very small doses) inhibit spontaneous mobility in the muscles, cause catalepsy in the rat and antagonize some conditions (stereotypy, verticalization) caused by apomorphine or amphetamine in mice or rats.
Therefore, compounds I possess typical pharmacological characteristics of neuroleptic agents, some of which may be highly potent.
Clinical tests with compounds of formula I confirmed their neuroleptic potential.

权利要求:
Claims (1)
[1]
Invention Formula
The method of producing dihydrobenzofuran or chromancarboxamide derivatives of general formula
, (CH7) p
CCfNH
-sn, -y
h
n R.
X y
R,
de R, is hydrogen or methyl;
an integer of 1 or 2; ethyl, allyl, cyclopropylmethyl or cyclohexenylmethyl group;
hydrogen or amino group; hydrogen or chlorine, cyclopropylmethylsulfonyl, methylsulfonamide or ethylsulfonic, provided that Y can only be cyclopropylmethylsulfonyl when Rj is ethyl, an is an integer equal to 1, or Y can be only hydrogen or chlorine, or cyclopropylmethylsulfoa 2, p 2,
NEED when Rj. ethyl,
n is an integer equal to or when R is allyl, and an integer equal to 1 or
or their additive salts of pharmacologically compatible acids, u and with the fact that the formulas
chesky tea total
ha
rV
, (SNG) and
soon
where X, Y, Kip have the indicated values,
reacting with ethyl chloroformate in the presence of triethylamine in the medium of an organic solvent, such as chloroform, at a temperature and then with dihaloalkylamine of the formula
H2N-CH2-CH- (CHi) 2-CH2
On Hal
where Hal is a halogen atom with a spontaneous increase in temperature and the resulting compound of the general formula
Y
W
.SN,) p
CONH-CH2-CH (CH2) 7-CH, I I
Hal hal
35 where X, Y, R ,, Hal and n are specified
meanings
subjected to interaction with the amine of the General formula
40
R.
It has
Of
specified values.
Where
at 40-80 s and the desired product is isolated in free form or as an additive salt with a pharmacologically compatible 45-compatible acid.
Table 1
Table 3
Stereotype in the presence of apomorphine (1.25 mg / kg) intravenously, UDjg, mg / kg, subcutaneously
3
five
WITH
eleven
D
6
Ё 1
eight
F 10
; 68,422,4-23,6
0.3750.64-0.65
Inhibitory effect of 20% 79.3-87.8
at 200 mg / kg
0.73.2.5-2.7 28
Inactive at 200 mg / kg100
5.47.8-9.3.
. 11.49.4-9.7
2,451,6-1,9
249-12,2
0.1340.18-0.23
9,37,1-8,1
3,432.1-2.3
3.61.2-1.6
Table 5
Stereotype in the presence of apomorphine (0.5 mg / kg) subcutaneously; mg / kg, intraperitoneally

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AU667874B2|1992-02-06|1996-04-18|Smithkline Beecham Plc|Benzopyran, benzothiopyran and benzofuran derivatives as 5-HT4 antagonists|

CA2146930A1|1992-10-13|1994-04-28|Francis David King|Heterocyclic -esters or -amides used as 5-ht4 receptor antagonists|

JP2999669B2|1993-08-24|2000-01-17|株式会社三和化学研究所|Benzo [b] furancarboxamide derivatives, their preparation and use|

法律状态:

优先权:

申请号 | 申请日 | 专利标题

FR8601279A|FR2593504B1|1986-01-30|1986-01-30|NOVEL DIHYDROBENZOFURANNE - AND CHROMANE - CARBOXAMIDE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND THEIR USE AS NEUROLEPTICS|

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