Method for preparing quaternary organic ammonium compounds or their pharmaceutically acceptable salt

专利摘要:
The novel compounds of the formula <IMAGE> (the meaning of the symbols is given in the description) can be prepared in a manner known per se by customary methods; they can be used as pharmaceutical active compounds.
公开号:SU1628854A3
申请号:SU884613149
申请日:1988-12-16
公开日:1991-02-15
发明作者:Шромм Курт；Ментруп Антон；Рент Эрнст-Отто；Муацевиц Гойко；Траунэкер Вернер
申请人:Берингер Ингельгейм Кг (Фирма)；
IPC主号:

专利说明:

The invention relates to a method for producing new nitrogen-containing organic compounds, in particular to a method for producing quaternary organic ammonium compounds that exhibit bronchodilator, antispasmodic and antiallergic
activity and can be used
in medicine.
The aim of the invention is a method for producing new quaternary ammonium compounds having a higher activity.
 G4
BUT-0-CH-CH2-W-C-CNGCH2-) CHZ-HCl
onsn, s1e
1.9 g of 5-oxy-8-monohydrochloride of concentrated hydrochloric acid is G1-hydroxy-2-4- (4-pyridyl) -2-methyl-2-10 and diluted with acetone. The isolated butylamino-ethyug-1 2H-1,4-benzoxazin-3- (4H) -one is dissolved in a mixture of 3 ml of dimethylformamide and 1 ml of water, and 1.27 g of methyl iodide is added to the solution.
After 12 hours, the solution was added with - J5. Mp. 207-209 С; 56% of theoretical. 5 ml of alcohol are added, acidified. Example 2. Q
after 1 h the crystals are sucked off and 1.2 g of the compound are obtained by replanting with water, concentrated hydrochloric acid and alcohol
HNCJO
CH
i
i
OUSN-CH2-MN-CCN
HE
CH-:
Concentrated hydrochloric acid and diluted with acetone. Allotted
after 1 hour the crystals are sucked off and 1.2 g of the compound are obtained by replanting with water, concentrated hydrochloric acid and alcohol.
CH
i
CCCH
CH-:
HC1
To 3.7 g of monohydrochloride with 5-benzyl-25 acid is converted to hydroxy hydroxy-8-L-hydroxy-2- 3- (4-dimethylamine-containing ammonium and chlorine compounds phenyl) -2-methyl-2-propylamino | -ethyl-2H-1,4-benzoxazin-3- (4H) -one in 7.4 ml of dimethylformamide was added 2.1 g of methyl iodide and allowed to react for 12 hours. After diluting the solution with acetone, ammonium iodide hydrochloride is obtained, which is added by adding hydrochloric acid or through a hydro compound (mp 195-197 ° C).
3.7 g of this benzyloxy compound in 50 ml of methanol is de-benzylated under normal conditions in the presence of palladium on carbon as a catalyst. Get 2 grams above
on the compound 187 ° С (ammonium deoxidation and by treatment of salt, 35%); 6.28% of theoretical. EXAMPLE 3.
ABOUT
9nz
CHOX CH-CH2-NH-C-CH242) 0 CH2-CH2-N-CH7-CH2-COO HC1
OH CH3, CH
To 3.2 g of monohydrochloride 5 - ben-i 12 at room temperature give
Zyloxy-8-G1-hydroxy-2- 3- (4-dimethyl-react. After dilution of acetamino-ethoxyphenyl) -2-methyl-2-prog-4 n. -2-yu and get 2.4 g of the above
(4H) -one in 6 ml of acetone was added with yl. 173-175 ° С (94% of
0.41 g of propiolactone and for a theoretical period.).
Example.
CH3
no-f-n-ov w-s-) - -co-sn2- 2 ii
ONSN3
Cl; H
4.4 g of hydrochloride 5 -oxy-8-A-hydroxy-2- 3- (4-hpor-acetaminophenyl) -2 acid is converted into the hydrochloride containing ammonium and chlorine compounds
(mp. 195-197 ° C).
3.7 g of this benzyloxy compound in 50 ml of methanol is de-benzylated under normal conditions in the presence of palladium on carbon as a catalyst. 2 g are obtained above the above Cl; HCi
methyl 2-propylamino2-ethyl -2H-1,4-benzoxazin-3- (4H) -one, 6 ml pyridine5 16288546
pa and 25 ml of methanol for 6 h of the compound, m.p. 190-192 ° C heat exchanger with reverse refrigeration (77.5% of theory.).
by anybody. After distillation of methanol and pyri-Analogously to Examples 1-4, a dyne oily residue is dissolved with the following compounds, in alcohol and 3.8 g of Compound I above are obtained (mp. 197 ° C;
amorphous)
About NmЈ) 0
HO-CH-CH2-NH-C (CH3) 2-CH2- (0) -. NH-CO-CH2-N (CH3) 3 HCl
onet
C1
I
Compound II (So pl. 173-186 ° C; amorphous)
IV
he
0 -CH-CH2-NH-C {CH3) 2-CH2- (0) -NH-CO-CH2-N (CH3 -HC1
he is on
Compound III (So pl. 203-211 ° C; amorphous)
OH CH3 HO-O CH-CH2-CH-C (CH3) 2-CH2XoXy - CO-CH2-S (CH3) o HC1
he-ae Compound IV (T.pl, 209-210 ° C)
about HNw °
BUT) -CH-CH2-YN-S (CH3) 2-XO-Sh-CO-CHO ZhSNz) sS1e
he
Compound V (mp. 235 ° C)
about HNw ° nsFs3
-CH-CH2-NH-9-CH2- (Oyo-CH7-CH2-NCH3Cl.HCl OHCH-J
Compound VI (mp. 240 ° C)
is clear
HN
but
W
Ho -snsn.
sn
.3
€ H2-NH- -CH2- 0 -0-CH2-CH2-mCH2) 3 - s | .HCl
sn
sn,
NSNA
.3
mCH
-C
sn,
71628854
Compound VII (mp. 231-234 ° C) O
sn3sng e
HO-feVcH-CH7-KH-C-CH7-0 -0-CH2-CH7-N- (
 Sn, Sn3
he
Compound VIII (Tpl. 190-201 ° C; amorine)
ABOUT
CH3 l 5
Ho- -CH-CH7-NH-c-CH2-CH2- (o) C10 -on
ONCHV ®N
Compound IX (mp. 175 hp)
° to
HNw ° CH3 CH3
HO- @ CH-CH2-NH-C-CH2- (o) CH7-COO- “HC1 OHCH.JCHN
Compound X (M.P. 191-193 ° C)
L
HN ;; O
 3 3 / -h
HO-CH-CH7-No. -C-CH2-CH7X2X J-CH2-CHrCOO-HCl
| Camp V
onsngsnplicheniyu XI (So pl. 250-255 ° C)
CH3SNg
HCKOVCH - CH2-NH-C-CH7 X5 -NH-CO-CH2- - (CH2) 3SO, -HCfH90
° nsngiH3
Compound XII (MP: 171-174 ° C)
he
CH:
f
0 -SHON-CH2-YN-C-CH2- 0 CHNGSN2-SOO NS1.2N90
onsn, 2
Compound XIII (M.P. 95-100 0
he
PIJ CH-i
  ®
gbCHOH-CH NH-C-CH.-N- ©
 J yl
onns,
f
Compound XIV (mp. 214-216 ° C)
ABOUT
cI
CH3
-CH2-Sh-C CH2n (o) -0 - CH2-CH7-N - CH2-COO HC1 H20
CH3
Compound XV (M.P. 158-162 ° C)
CH3
° СН3 СН3СНg
HO- -CH-CH2-NH-C-CH2-XO -0-CH2-CH2-N® - CH3
he
Compound XVI (mp. 220-223 ° C)
OH CH3 gNzSNe
but cn-cng-c-cn2 o-sn2-cngy% 2) 3-5о® nGsoon
sn3 (1Nz
he
ns-soon
Compound XVII (MP; 263-265 ° C)
CH5
sc
SNON-CH2-YN-C-CH2 0-SNGSNGSN, 1 / 2H250 1 / 250ГН20 onСН3СН3
Compound XVIII (mp. 234-236 ° d
onsn3sna
CHOH-CH2-NH-C-CH2H OCH2-CH2-N (CH2V-SO J / 2H2SOvH20 OHCH .CH-i
Connection XIX (So pl. 231-234 °
he
CH3
N -
|
CH3
nGsoon
ns-soon
CH5
Comparison of the data in the table indicates a higher activity of new compounds in comparison with the known. The novel compounds are classified as low toxic substances.

权利要求:
Claims (1)
[1]
Invention Formula
The method of producing quaternary organic ammonium compounds of the general formula
Have
Q-CH-CH2-NH-C- (CH2V Kg ONK2
where Q is a group of formulas
OR
de R4 is hydrogen or methyl;
R is hydrogen or hydroxyl; Rg is hydroxyl in position 4 or 5;
R
and RZ is the same and is hydrogen or methyl; n is an integer of 1 or 2; R $ group Formulas
U9
0 —NH — CO— (R8) An0.
R9
Ri ®
NH-CO- (R8) M-N No. 10)
RS
O NH-CO - ((0) An
n
-0- (R8) M-N®-R9 ArP, R9
Rg 0- (B8) and-1M®- (i10) p-A110,
P.9 R
© -№ (R1D) p-A®, R9
(R10) P-Ati,
©
B an
N
where Rg is lower alkylene;
Rg is lower alkyl; R 10 is lower alkylene; m 1.2
Av 1 -4An - anion.
or their pharmacologically acceptable salts, characterized in that the compound of the general formula
Q-CH- CH2-NH-C- (CH2) n-R 3 OH
i
R
where Rj and R have the indicated meanings, R., is the radical corresponding to the radical R3, except that it contains a tertiary amino group instead of a quaternary ammonium group; Q has the same meaning as Q, and possibly OH groups as well as the central NH group can be protected,
13162885414
subjected to alkylation with the subsequent and the target product is given in free, if necessary, removal form or in the form of a pharmacologically
protecting groups by treating a water-acceptable salt. originally in the presence of palladium on coal

类似技术:

---

公开号 | 公开日 | 专利标题

---

SU1628854A3|1991-02-15|Method for preparing quaternary organic ammonium compounds or their pharmaceutically acceptable salts

---

HU203325B|1991-07-29|Process for producing substituted quinazoline derivatives and pharmaceutical compositions containing them

---

IE54667B1|1990-01-03|Dihydropyridine anti-ischaemic and antihypertensive agents, processes for their production, and pharmaceutical compositions containing them

---

CA1193264A|1985-09-10|Pharmaceutically active |bibenzylderivatives

---

IE55798B1|1991-01-16|2-substituted 4-amino-6,7-dimethoxyquinolines

---

AU644295B2|1993-12-02|2-aminopyrimidine-4-carboxamide derivatives, their preparation and their use in therapeutics

---

EP0004066A1|1979-09-19|2-|stilbenes and pharmaceutical compositions containing these substances

---

IE55872B1|1991-02-14|Derivatives of omega-amino acids,the preparation and utilisation thereof,and the compositions containing these derivatives

---

AU669462B2|1996-06-06|4-amino-2-ureidopyrimidine-5-carboxamides, a process for the preparation thereof, pharmaceuticals containing these compounds, and the use thereof

---

DK147640B|1984-10-29|METHOD OF PREPARING NITROIMIDAZOLE DERIVATIVES

---

WO2009058051A1|2009-05-07|5-substituted indol-3-carboxylic acid derivatives exhibiting antiviral activity a method for the production and use thereof

---

EP0028698A1|1981-05-20|Quinoline compounds, process for their preparation, and pharmaceutical compositions

---

US4521619A|1985-06-04|Therapeutically useful sulphur-containing benzylidene derivatives

---

US5229392A|1993-07-20|2-aminopyrimidine-4-carboxamide derivatives, their preparaton and their application in therapy

---

SU990761A1|1983-01-23|Hydrochlorides of derivatives of 4-diphenylmethylene-1-hydroxybenzyl piperidine exhibiting blood circulation improvement capacity

---

GB2055808A|1981-03-11|Oxime ethers

---

US2621182A|1952-12-09|Office

---

US3637705A|1972-01-25|N-3 4-dihalo phenyl piperazines

---

CA1071626A|1980-02-12|Imidazolylquinazoline derivatives

---

RU2111963C1|1998-05-27|2-amino-n- [4-|pyrimidin-2-yl] amino-alkyl pyrimidine-4-carboxamide derivatives, and pharmaceutical composition

---

US4507308A|1985-03-26|Analgesically or anti-inflammatory effective 4-quinolyl anthranilic acid derivatives

---

US4582907A|1986-04-15|2-|acetic acid

---

CS209918B2|1981-12-31|Method of preparation of the | bibenzyles

---

US2844585A|1958-07-22|Quaternary ammonium alkylamino-benzoquinones

---

AU645429B2|1994-01-13|2-Aminopyrimidine-4-carboxamide derivatives, their preparation and their use in therapeutics

同族专利:

---

公开号 | 公开日

---

EP0321864A3|1990-12-27|

---

PL276549A1|1989-08-21|

---

FI885811A|1989-06-20|

---

DD280099A5|1990-06-27|

---

PL160685B1|1993-04-30|

---

DK700788D0|1988-12-16|

---

NO885598L|1989-06-20|

---

EP0321864A2|1989-06-28|

---

JPH02239A|1990-01-05|

---

NZ227367A|1990-07-26|

---

DK700788A|1989-06-20|

---

IL88707D0|1989-07-31|

---

KR890009920A|1989-08-04|

---

HUT53866A|1990-12-28|

---

HU207283B|1993-03-29|

---

DE3743265A1|1989-06-29|

---

YU228688A|1990-08-31|

---

AU2702288A|1989-06-22|

---

PT89234B|1993-07-30|

---

FI885811A0|1988-12-16|

---

PH27509A|1993-08-18|

---

CZ843588A3|1996-08-14|

---

MX14253A|1993-09-01|

---

NO885598D0|1988-12-16|

---

PT89234A|1989-12-29|

---

ZA889387B|1990-08-29|

---

AU618302B2|1991-12-19|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

CA1041523A|1974-06-19|1978-10-31|Queen's University|Preparation of 1-oxapenicillins and novel intermediates therefor|

---

DE3134590A1|1981-09-01|1983-03-10|Boehringer Ingelheim KG, 6507 Ingelheim|NEW BENZO HETEROCYCLES|

---

DE3278014D1|1982-10-01|1988-02-25|Merck & Co Inc|Aralkylaminoethanol heterocyclic compounds|

---

GB8426200D0|1984-10-17|1984-11-21|Glaxo Holdings Ltd|Chemical compounds|DE3918834A1|1989-01-26|1990-08-02|Bayer Ag|ARYL- AND HETEROARYLETHANOL-PYRIDYLALKYLAMINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A PERFORMANCE IN ANIMALS AND AS A MEDICINE AGAINST ADIPOSITAS|

---

WO1999020607A1|1997-10-17|1999-04-29|Yamanouchi Pharmaceutical Co., Ltd.|Amide derivatives or salts thereof|

---

KR20020093083A|2000-04-27|2002-12-12|베링거 잉겔하임 파르마 카게|Novel, slow-acting betamimetics, a method for their production and their use as medicaments|

---

US6951888B2|2002-10-04|2005-10-04|Boehringer Ingelheim Pharma Gmbh & Co. Kg|Betamimetics with a prolonged duration of activity, processes for preparing them, and their use as pharmaceutical compositions|

---

DE10246374A1|2002-10-04|2004-04-15|Boehringer Ingelheim Pharma Gmbh & Co. Kg|New 4--3-alkoxy-benzene-1,2-diol derivatives, are beta-mimetics having a long duration of action, useful e.g. for treating asthma, chronic obstructive pulmonary disease or arrhythmia|

---

DE10253282A1|2002-11-15|2004-05-27|Boehringer Ingelheim Pharma Gmbh & Co. Kg|Treatment of chronic obstructive pulmonary disease, using new or known N-substituted 2-amino-1--oxazin-3-on-8-yl)-ethanol derivative beta-mimetic agents, suitable for once-daily administration|

---

US7056916B2|2002-11-15|2006-06-06|Boehringer Ingelheim Pharma Gmbh & Co. Kg|Medicaments for the treatment of chronic obstructive pulmonary disease|

---

KR100696927B1|2003-04-23|2007-03-20|니뽄 다바코 산교 가부시키가이샤|CaSR ANTAGONIST|

---

US7307076B2|2004-05-13|2007-12-11|Boehringer Ingelheim International Gmbh|Beta agonists for the treatment of respiratory diseases|

---

DE102004024454A1|2004-05-14|2005-12-08|Boehringer Ingelheim Pharma Gmbh & Co. Kg|Novel enantiomerically pure beta agonists, process for their preparation and their use as pharmaceuticals|

---

US7220742B2|2004-05-14|2007-05-22|Boehringer Ingelheim International Gmbh|Enantiomerically pure beta agonists, process for the manufacture thereof and use thereof as medicaments|

---

DE102004024453A1|2004-05-14|2006-01-05|Boehringer Ingelheim Pharma Gmbh & Co. Kg|New long-acting bronchodilators for the treatment of respiratory diseases|

---

US7745621B2|2004-05-14|2010-06-29|Boehringer Ingelheim International Gmbh|Long acting bronchodilators for the treatment of respiratory diseases|

---

WO2007020227A1|2005-08-15|2007-02-22|Boehringer Ingelheim International Gmbh|Method for producing betamimetics|

---

EP2057152A1|2006-08-07|2009-05-13|Boehringer Ingelheim International GmbH|Single enantiomer beta-agonists, methods for the production thereof and the use thereof as medication|

法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

DE19873743265|DE3743265A1|1987-12-19|1987-12-19|NEW AMMONIUM COMPOUNDS, THEIR MANUFACTURE AND USE|

---