US3696110A - Certain hyoscyaminium compounds - Google Patents

Certain hyoscyaminium compounds Download PDF

Info

Publication number: US3696110A
Authority: US; United States
Prior art keywords: hyoscyaminium; bromide; compounds; gastric; quaternary ammonium
Prior art date: 1969-02-18
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Expired - Lifetime

Application number

US82813A

Other languages

English (en)

Inventor

Satoru Tanaka

Kazunori Hasimoto

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

GISAI KK

Original Assignee

GISAI KK

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1969-02-18

Filing date

1970-10-21

Publication date

1972-10-03

1970-10-21 Application filed by GISAI KK filed Critical GISAI KK

1972-10-03 Application granted granted Critical

1972-10-03 Publication of US3696110A publication Critical patent/US3696110A/en

1989-10-03 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

Links

150000001875 compounds Chemical class 0.000 title claims description 12
-1 benzyl halide Chemical class 0.000 claims abstract description 15
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 6
JABDOYKGZCPHPX-XSCYYCMVSA-M butropium bromide Chemical compound [Br-].CCCCOc1ccc(C[N+]2(C)[C@H]3CC[C@@H]2C[C@@H](C3)OC(=O)[C@H](CO)c2ccccc2)cc1 JABDOYKGZCPHPX-XSCYYCMVSA-M 0.000 claims description 5
RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 abstract description 14
150000003839 salts Chemical class 0.000 abstract description 10
RKUNBYITZUJHSG-FXUDXRNXSA-N (S)-atropine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@H]3CC[C@@H](C2)N3C)=CC=CC=C1 RKUNBYITZUJHSG-FXUDXRNXSA-N 0.000 abstract description 8
229930005342 hyoscyamine Natural products 0.000 abstract description 8
229960003210 hyoscyamine Drugs 0.000 abstract description 8
229930003347 Atropine Natural products 0.000 abstract description 6
229960000396 atropine Drugs 0.000 abstract description 6
RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 abstract description 6
230000000903 blocking effect Effects 0.000 abstract description 6
239000007864 aqueous solution Substances 0.000 abstract description 4
230000003287 optical effect Effects 0.000 abstract description 4
230000001734 parasympathetic effect Effects 0.000 abstract description 4
150000003242 quaternary ammonium salts Chemical class 0.000 abstract description 4
208000007101 Muscle Cramp Diseases 0.000 abstract description 3
208000007107 Stomach Ulcer Diseases 0.000 abstract description 3
201000010099 disease Diseases 0.000 abstract description 3
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
208000000718 duodenal ulcer Diseases 0.000 abstract description 3
230000002496 gastric effect Effects 0.000 abstract description 3
201000005917 gastric ulcer Diseases 0.000 abstract description 3
238000010254 subcutaneous injection Methods 0.000 abstract description 3
239000007929 subcutaneous injection Substances 0.000 abstract description 3
230000000973 chemotherapeutic effect Effects 0.000 abstract description 2
231100000053 low toxicity Toxicity 0.000 abstract description 2
230000008602 contraction Effects 0.000 description 9
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
230000000694 effects Effects 0.000 description 7
239000000243 solution Substances 0.000 description 7
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
239000013078 crystal Substances 0.000 description 6
238000003756 stirring Methods 0.000 description 6
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
210000003169 central nervous system Anatomy 0.000 description 4
239000000047 product Substances 0.000 description 4
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
238000001914 filtration Methods 0.000 description 3
238000002844 melting Methods 0.000 description 3
230000008018 melting Effects 0.000 description 3
238000000034 method Methods 0.000 description 3
238000002360 preparation method Methods 0.000 description 3
238000011160 research Methods 0.000 description 3
239000000126 substance Substances 0.000 description 3
OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 2
229960004373 acetylcholine Drugs 0.000 description 2
230000007059 acute toxicity Effects 0.000 description 2
231100000403 acute toxicity Toxicity 0.000 description 2
230000001004 anti-acetylcholinic effect Effects 0.000 description 2
WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 description 2
229910001626 barium chloride Inorganic materials 0.000 description 2
238000001816 cooling Methods 0.000 description 2
238000002474 experimental method Methods 0.000 description 2
230000010287 polarization Effects 0.000 description 2
239000011541 reaction mixture Substances 0.000 description 2
238000000926 separation method Methods 0.000 description 2
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
BDFZQEDEJPQJNB-UHFFFAOYSA-N 1-(bromomethyl)-4-butoxybenzene Chemical compound CCCCOC1=CC=C(CBr)C=C1 BDFZQEDEJPQJNB-UHFFFAOYSA-N 0.000 description 1
QAYLIWBLUTYRTC-UHFFFAOYSA-N 1-(bromomethyl)-4-ethoxybenzene Chemical compound CCOC1=CC=C(CBr)C=C1 QAYLIWBLUTYRTC-UHFFFAOYSA-N 0.000 description 1
GIGRWGTZFONRKA-UHFFFAOYSA-N 1-(bromomethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CBr)C=C1 GIGRWGTZFONRKA-UHFFFAOYSA-N 0.000 description 1
241001106067 Atropa Species 0.000 description 1
241000242873 Scopolia Species 0.000 description 1
206010046555 Urinary retention Diseases 0.000 description 1
RKUNBYITZUJHSG-PJPHBNEVSA-O [(1r,5s)-8-methyl-8-azoniabicyclo[3.2.1]octan-3-yl] 3-hydroxy-2-phenylpropanoate Chemical compound C([C@H]1CC[C@@H](C2)[NH+]1C)C2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-PJPHBNEVSA-O 0.000 description 1
229930013930 alkaloid Natural products 0.000 description 1
125000003342 alkenyl group Chemical group 0.000 description 1
125000000217 alkyl group Chemical group 0.000 description 1
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
229940088506 buscopan Drugs 0.000 description 1
HOZOZZFCZRXYEK-GSWUYBTGSA-M butylscopolamine bromide Chemical compound [Br-].C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)CCCC)=CC=CC=C1 HOZOZZFCZRXYEK-GSWUYBTGSA-M 0.000 description 1
XMLNCADGRIEXPK-KUMOIWDRSA-M chembl2146143 Chemical compound [Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N+]2(C)C)C(=O)C(CO)C1=CC=CC=C1 XMLNCADGRIEXPK-KUMOIWDRSA-M 0.000 description 1
230000000052 comparative effect Effects 0.000 description 1
238000004821 distillation Methods 0.000 description 1
150000004820 halides Chemical class 0.000 description 1
125000005843 halogen group Chemical group 0.000 description 1
230000000266 injurious effect Effects 0.000 description 1
238000010253 intravenous injection Methods 0.000 description 1
238000004519 manufacturing process Methods 0.000 description 1
239000000463 material Substances 0.000 description 1
230000004899 motility Effects 0.000 description 1
239000000825 pharmaceutical preparation Substances 0.000 description 1
230000000144 pharmacologic effect Effects 0.000 description 1
238000000746 purification Methods 0.000 description 1
239000012264 purified product Substances 0.000 description 1
230000033764 rhythmic process Effects 0.000 description 1
239000002904 solvent Substances 0.000 description 1
230000002269 spontaneous effect Effects 0.000 description 1
230000002194 synthesizing effect Effects 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
231100000419 toxicity Toxicity 0.000 description 1
230000001988 toxicity Effects 0.000 description 1
238000005303 weighing Methods 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
- B—PERFORMING OPERATIONS; TRANSPORTING
- B42—BOOKBINDING; ALBUMS; FILES; SPECIAL PRINTED MATTER
- B42D—BOOKS; BOOK COVERS; LOOSE LEAVES; PRINTED MATTER CHARACTERISED BY IDENTIFICATION OR SECURITY FEATURES; PRINTED MATTER OF SPECIAL FORMAT OR STYLE NOT OTHERWISE PROVIDED FOR; DEVICES FOR USE THEREWITH AND NOT OTHERWISE PROVIDED FOR; MOVABLE-STRIP WRITING OR READING APPARATUS
- B42D17/00—Hanging or securing devices for books, newspapers or the like

Definitions

the new quaternary ammonium salts according to the present invention exhibit a strong parasympathetic blocking activity with low toxicity. They therefore are advantageously utilizable for chemotherapeutical treatment of patients suffering from diseases such as, for example, gastric cramp, gastric ulcer, duodenal ulcer and the like.
Aqueous solutions of these salts are stable and are administrated to patients through venous and subcutaneous injections as well as oral administration.
This invention relates to a process for synthesizing new quaternary salts of atropine or its optical isomer called hyoscyamine base and represented by the formula wherein R is lower alkyl or alkenyl group and X is 3. Anti-acetylcholine effect against the contraction halogen atom.
Atropine and its optical isomer called hyoscyamine base are the essential components of the main alkaloids contained in belladonna and scopolia. These compounds exhibit a strong parasympathetic blocking activity and they therefore are utilized for the purpose of therapeutical treatment of diseases such as gastric cramp, gastric ulcer, duodenal ulcer and the like. Unfortunately it was found that they show undesirable side effects such as dryness of mouth, retention of urine, disturbance of heart rhythm and an injurious effect on central nervous system.
Typical solvents which have been found preferable to carry out the above reaction include lower alcohol, acetone, ether and the like.
the reaction takes place readily at room temperature. In order to prevent from racemisation of the reacting materials, it is advisable to carry out the reaction at low temperature.
reaction mixture had a turbid appearance followed by separation of white crystals.

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)

US82813A 1969-02-18 1970-10-21 Certain hyoscyaminium compounds Expired - Lifetime US3696110A (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
JP1153169		1969-02-18

Publications (1)

Publication Number	Publication Date
US3696110A true US3696110A (en)	1972-10-03

Family

ID=11780535

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
US82813A Expired - Lifetime US3696110A (en)	1969-02-18	1970-10-21	Certain hyoscyaminium compounds

Country Status (7)

Country	Link
US (1)	US3696110A (de)
CH (1)	CH510030A (de)
DE (1)	DE1950378C2 (de)
FR (1)	FR2034553B1 (de)
GB (1)	GB1235957A (de)
NL (1)	NL142674B (de)
SE (1)	SE351848B (de)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP0002051A1 (de) *	1977-11-16	1979-05-30	Eisai Co., Ltd.	Anwendung von Butoxybenzylhyoscyaminbromid in pharmazeutischen Zusammensetzungen gegen Taubheit und Tinnitus
US20050226920A1 (en) *	2004-04-13	2005-10-13	Kirk Voelker	Method of decreasing nicotine withdrawal symptoms during smoking cessation.

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
DE1062704B (de) *	1956-08-07	1959-08-06	Licencia Talalmanyokat	Verfahren zur Herstellung von quaternaeren Atropinen
DE1163845B (de) *	1960-10-18	1964-02-27	Egyesult G>ogyszer es Tapszer g>ar Budipest λ ertr Dr C W I otter hos und Dr Ing FI W Lotterhos Pat Anwalte Frankfurt"^	Verfahren zur Herstellung von p-Alkylbenzyl-tropiniumderivaten.
AT246339B (de) *	1960-10-18	1966-04-12	Egyt Gyogyszervegyeszeti Gyar	Verfahren zur Herstellung von neuen p-Alkylbenzyltropiniumderivaten
DE1165037B (de) *	1961-11-21	1964-03-12	Dr. Schwarz Arzneimittelfabrik G.m.b.H., Monheim (RhId.)	Verfahren zur Herstellung von Estern quaternärer Atropiniumsalze.
FR1539224A (fr) *	1966-09-02	1968-09-13	Boehringer Sohn Ingelheim	Procédé pour fabriquer des dérivés de l'acide tropique

1969
- 1969-10-06 DE DE1950378A patent/DE1950378C2/de not_active Expired
- 1969-10-07 GB GB49126/69A patent/GB1235957A/en not_active Expired
- 1969-12-09 CH CH1830569A patent/CH510030A/de not_active IP Right Cessation
1970
- 1970-02-06 NL NL707001733A patent/NL142674B/xx not_active IP Right Cessation
- 1970-02-09 FR FR7004493A patent/FR2034553B1/fr not_active Expired
- 1970-02-13 SE SE01874/70A patent/SE351848B/xx unknown
- 1970-10-21 US US82813A patent/US3696110A/en not_active Expired - Lifetime

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Smithuis, Chem. Abstracts, Vol. 66, Item No. 79,545 a, 1967 *
The Merck Index, Eighth Edition, Page 558, 1968 *
The Merck Index, Seventh Edition, Page 547, 1960 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP0002051A1 (de) *	1977-11-16	1979-05-30	Eisai Co., Ltd.	Anwendung von Butoxybenzylhyoscyaminbromid in pharmazeutischen Zusammensetzungen gegen Taubheit und Tinnitus
FR2409263A1 (fr) *	1977-11-16	1979-06-15	Eisai Co Ltd	Medicament a base de bromure de butoxybenzylhyoscyamine utilisable dans le traitement de la surdite et des tintements d'oreille
US20050226920A1 (en) *	2004-04-13	2005-10-13	Kirk Voelker	Method of decreasing nicotine withdrawal symptoms during smoking cessation.

Also Published As

Publication number	Publication date
SE351848B (de)	1972-12-11
NL142674B (nl)	1974-07-15
DE1950378C2 (de)	1985-10-03
GB1235957A (en)	1971-06-16
CH510030A (de)	1971-07-15
DE1950378A1 (de)	1970-08-27
NL7001733A (de)	1970-08-20
FR2034553B1 (de)	1974-02-01
FR2034553A1 (de)	1970-12-11

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KR860001946B1 (ko)	1986-11-01	1, 4-디히드로피리딘 유도체의 제조방법
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EP0148094A2 (de)	1985-07-10	Anti-Tumormittel das O-Benzyliden-L-Ascorbinsäure oder ein Salz davon enthält, sowie Herstellung dieser letzteren Verbindung
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US4432990A (en)	1984-02-21	5-Aminoimidazoles as immunoregulants
EP0009608B1 (de)	1982-04-21	N-Phenyläthylacetamide, Verfahren zu ihrer Herstellung und sie enthaltende therapeutische Zusammensetzungen
US4585589A (en)	1986-04-29	Water-soluble alkanoyloxy and alkoxycarbonyloxy rifampicin derivatives, process for its preparation, intermediates, and its pharmaceutical composition as antibacterials
JPS6045198B2 (ja)	1985-10-08	縮合環キヌクリジン−バレロラクトン系化合物及びその製法
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US2528175A (en)	1950-10-31	Procaine salts of biosynthetic penicillins
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US4820837A (en)	1989-04-11	1-hydroxy-oxo-5H-pyrido(3,2-a)phenoxazine-3-carboxylic acid esters
DE2702518A1 (de)	1977-07-28	Penicillin- und cephalosporinderivate und verfahren zu ihrer herstellung
US2528176A (en)	1950-10-31	Procaine salts of biosynthetic penicillins
US4010265A (en)	1977-03-01	8-Alkylpyrido[3,4-d]pyridazines
KR970004044B1 (ko)	1997-03-24	약물동력학적으로 개선된 세팔로스포린 유도체, 그의 제조방법, 그를 함유하는 약제학적 조성물 및 합성 중간체
IE53425B1 (en)	1988-11-09	Oral absorption enhancement of carboxylic acid pharmaceuticals using(5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl ester group
JPS6145989B2 (de)	1986-10-11
US2374367A (en)	1945-04-24	Process for preparing therapeutically active substances