GB2184725A - Taurine derivatives - Google Patents
Taurine derivatives Download PDFInfo
- Publication number
- GB2184725A GB2184725A GB08630271A GB8630271A GB2184725A GB 2184725 A GB2184725 A GB 2184725A GB 08630271 A GB08630271 A GB 08630271A GB 8630271 A GB8630271 A GB 8630271A GB 2184725 A GB2184725 A GB 2184725A
- Authority
- GB
- United Kingdom
- Prior art keywords
- process according
- reaction
- cis
- effected
- compounds
- Prior art date
- 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.)
- Granted
Links
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical class NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 9
- 125000005544 phthalimido group Chemical group 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 150000004820 halides Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 2
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 230000003496 anti-amnesic effect Effects 0.000 abstract description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- LRTRXDSAJLSRTG-UHFFFAOYSA-N 4-bromobutanoyl chloride Chemical compound ClC(=O)CCCBr LRTRXDSAJLSRTG-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000002475 cognitive enhancer Substances 0.000 description 2
- 230000001777 nootropic effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229960003080 taurine Drugs 0.000 description 2
- IPLKGJHGWCVSOG-UHFFFAOYSA-N 4-chlorobutanoic acid Chemical compound OC(=O)CCCCl IPLKGJHGWCVSOG-UHFFFAOYSA-N 0.000 description 1
- 206010003497 Asphyxia Diseases 0.000 description 1
- -1 N-[(2-phthalimido)ethylsulfonyl]-2-oxo-pyrrolidine Chemical compound 0.000 description 1
- GMZVRMREEHBGGF-UHFFFAOYSA-N Piracetam Chemical compound NC(=O)CN1CCCC1=O GMZVRMREEHBGGF-UHFFFAOYSA-N 0.000 description 1
- 229910006074 SO2NH2 Inorganic materials 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003109 amnesic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 230000004641 brain development Effects 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000002433 hydrophilic molecules Chemical class 0.000 description 1
- 238000011302 passive avoidance test Methods 0.000 description 1
- 229960004526 piracetam Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Landscapes
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Hospice & Palliative Care (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Psychiatry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pyrrole Compounds (AREA)
Abstract
Compounds of general formula <IMAGE> wherein R represents a phthalimido,cis-1,2-cyclohexanedicarboximido, cis(1,2,3,6)-tetrahydrophthalimido or 1,8-naphtholimido group. The compounds have been found to exhibit anti-amnesic activity. A process for the preparation of the compounds is described and exemplified.
Description
SPECIFICATION
Taurine derivatives
This invention relates two novel taurine derivatives, a processfortheir preparation and pharmaceutical compositions containing them. The compounds have been found to have antiamnesic activity.
Taurine is an amino acid that is present in a large number of living tissues and especially in the brain. Some researchers have associated a deficiency of the compound with inadequate brain development. Taurine is a very hydrophilic compound, however, and does not readily pass through the blood-brain barrier. This characteristic has prompted the synthesis of numerous derivatives of taurine in an attempt to discover compounds of increased lipophilicitywith the ability to pass the blood-brain barrierandthus supplytaurine to the brain.
We have now discovered taurine derivatives having interesting pharmacological properties.
Thus, in one aspect, the invention provides compounds of general formula
wherein R represents a phthalimido, cis-1 ,2-cyclohexane-dicarboximido, cis-( 1 2,3,6)-tetra- hydrophthalimido or 1,8-naphtholimido group, and saltsthereof.
The compounds according to the invention have been found to exhibit an antiamnesic or nootropic activity. They have a remarkable lipophilic nature.
Thus, in accordance with a further aspect of the invention, there are provided pharmaceutical compositions comprising at least one compound of formula (I) or pharmacologically acceptable saltthereof in association with a pharmaceutical carrier or excipient.
The compounds according to the invention may be conveniently prepared by a process which comprises reacting a compound of formula
R-CH2CH2-SO2NH2 (II) with a 4-halobutanoic acid halide, conveniently in the presence of a base, preferably an organic base such as triethylamine or pyridine. The 4-halobutanoic acid halide is preferably selected from 4-chloro- and 4-bromobutanoic acid chloride.
The reaction is advantageously conducted in the presence of a solvent such as an organic aproticsolvent.
Examples of solvents which may be used include dimethylformamide, dioxan and acetonitrile. If desired, it is also possible to employ the organic base as the reaction solvent.
The reaction may conveniently be effected at a temperature offrom 40 to 1 200C.
The starting sulphonamides offormula (Il) are either known or may be prepared by conventional techniques such as those described in R. Winterbottom et al., J.A. Chem. Soc. 69, 1393-1401,1947.
The following non-limiting Examples serve to illustrate the invention.
EXAMPLE 1 N-[2-( 1, 8-Naphthollimido)eth ylsulfon yU-2-p yrrolidone 27.5 g of4-chlorobutanoic acid chloride are added dropwise to 100 ml of pyridine cooled with an ice bath.
After addition is complete, 50 g 2-(1 ,8-naphthoilimido)ethanosulfonamide are added and the mixture is heated for 24 hours at 80. The product is worked up by pouring into 1 1 of 2N hydrochloric acid. The solution formed is collected by filtration, dissolved in 300 ml of refluxing ethanol over 30 min. and decolourised with 5 g of activated charcoal. The mixture is filtered and crystallizes on cooling. 20 g of crystals identified as N-[2-(1 ,8-naphthoilimido)ethylsulfonyl]-2-pyrrolidone are obtained; m.p. 107-109"C.
EXAMPLE 2 N-f2-(cis 1,2- Cycloh exanedicarboximido)eth ylsulfon yI)-2-p yrrolldone To a suspension of 26 g of 2-(cis-1 ,2-cyclohexanedicarboximido)ethanosulfonamide in 100 ml of dimethylformamidewere added 20 g oftriethylamine and 20 g of 4-bromobutanoic acid chloride. The mixture was stirred and heated for 6 hours at 60"C and for 30 min. at 80"C. Then, it was concentrated under reduced pressure until one third of its initial volume. The residual oil was poured into 200 ml of water and extracted several times with diethyl ether.The ethereal phase was first washed with dilute hydrochloride acid and then with a 3% aqueous sodium hydroxide solution; it was dried over anhydrous sodium sulfate and concentrated to afford 13 g of N-[2-(cis-1 ,2-cyclohexanedicarboximido)ethylsulfonyl]-2-pyrrolidone; m.p.
107-109OC Physical data of compounds of the invention
R M.P.( C) IR(cm~1) 1 ,8-naphthoilimido 207-209 1150,1340,1660,1 700,1740 cis-(1 ,2,3,6) tetra- hydrophthalimido 111-113 1150,1355,1700,1730 ci-1 2-cyclohexane- dicarboxymido 107-109 1160,1350,1695,1740 phthalimido 176-178 1160,1340,1710
Pharmacological activity of compounds ofthe invention N-[2-(1 ,8-Naphthoilimido)ethylsulfonyl]-2-oxo-pyrrolidine, N-[2-(1 ,2,3,6-tetrahydrophthalimido)- ethylsu If onyl]-Z-oxo-pyrrolidi ne, N-[2-(cis-1 ,2-cyclohexanedicarboxymido)ethyl-su lfonylj-2-oxo-pyrrolidine, N-[(2-phthalimido)ethylsulfonyl]-2-oxo-pyrrolidine and piracetam were tested for antiamnesic ("nootropic") activity using a one-trial passive avoidance test in the rat. Carbon dioxide asphyxiation was the amnesic treatment and test compounds were administered orally to groups of rats at a dose of 1000 mg/kg one hour before the retrievaltrial. Anti-amnesic activity was demonstrated for all the products, showing to have significantly slower rates of entry, (i.e. longertimesto enterthe chamber)than the vehicle (control).
Claims (9)
1. Compounds of general formula
wherein R represents a phthalimido, cis-1 ,2-cyclohexanedicarboximido, cis-(1 ,2,3,6)-tetrahydrophthalimido or 1 ,8-naphtholimido group
2. A process forthe preparation of a compound as defined in claim 1 which comprises reacting a compound offormula R-CH2CH2-SO2N H2 (II) (wherein R is as defined in claim 1) witha 4-halobutanoic acid halide.
3. A process according to claim 2 wherein the 4-halobutanoic acid halide is 4-chloro- or4-bromobutanoic acid chloride.
4. A process according to either of claims 2 and 3 wherein the reaction is effected in the presence of an organic base.
5. A process according to claim 4 wherein the base is triethylamine or pyridine.
6. A process according to any one of claims 2 to 5 wherein the reaction is effected in the presence of an organic aprotic solvent.
7. A process according to claim 6 wherein the solvent is dimethylformamide, dioxan, acetonitrile oran organic base used forthe reaction.
8. A process according to any one of claims 2 to 7 wherein the reaction is effected at a temperature offrom 40 to 1200C.
9. A pharmaceutical composition comprising as active ingredient at ieast one compound according to claim 1 in association with a pharmaceutical carrier or excipient.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES550311A ES8606271A1 (en) | 1985-12-20 | 1985-12-20 | Taurine derivatives |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8630271D0 GB8630271D0 (en) | 1987-01-28 |
| GB2184725A true GB2184725A (en) | 1987-07-01 |
| GB2184725B GB2184725B (en) | 1989-11-01 |
Family
ID=8490516
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8630271A Expired GB2184725B (en) | 1985-12-20 | 1986-12-18 | Taurine derivatives |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS62148483A (en) |
| BE (1) | BE905919A (en) |
| CH (1) | CH670641A5 (en) |
| DE (1) | DE3643383A1 (en) |
| ES (1) | ES8606271A1 (en) |
| FR (1) | FR2592045A1 (en) |
| GB (1) | GB2184725B (en) |
| IT (1) | IT1213573B (en) |
| PT (1) | PT83668B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9804004D0 (en) | 1998-02-25 | 1998-04-22 | Sca Packaging Ltd | Trays |
-
1985
- 1985-12-20 ES ES550311A patent/ES8606271A1/en not_active Expired
-
1986
- 1986-11-03 PT PT83668A patent/PT83668B/en not_active IP Right Cessation
- 1986-12-15 BE BE0/217529A patent/BE905919A/en not_active IP Right Cessation
- 1986-12-15 JP JP61298584A patent/JPS62148483A/en active Pending
- 1986-12-17 FR FR8617682A patent/FR2592045A1/en not_active Withdrawn
- 1986-12-18 DE DE19863643383 patent/DE3643383A1/en not_active Withdrawn
- 1986-12-18 GB GB8630271A patent/GB2184725B/en not_active Expired
- 1986-12-19 CH CH5113/86A patent/CH670641A5/de not_active IP Right Cessation
- 1986-12-19 IT IT8622798A patent/IT1213573B/en active
Also Published As
| Publication number | Publication date |
|---|---|
| FR2592045A1 (en) | 1987-06-26 |
| BE905919A (en) | 1987-04-01 |
| JPS62148483A (en) | 1987-07-02 |
| ES8606271A1 (en) | 1986-04-01 |
| IT8622798A0 (en) | 1986-12-19 |
| IT1213573B (en) | 1989-12-20 |
| PT83668B (en) | 1988-08-17 |
| GB8630271D0 (en) | 1987-01-28 |
| CH670641A5 (en) | 1989-06-30 |
| DE3643383A1 (en) | 1987-10-01 |
| GB2184725B (en) | 1989-11-01 |
| PT83668A (en) | 1986-12-01 |
| ES550311A0 (en) | 1986-04-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |