IE47897B1 - 2-methoxybenzamide derivatives - Google Patents
2-methoxybenzamide derivativesInfo
- Publication number
- IE47897B1 IE47897B1 IE558/79A IE55879A IE47897B1 IE 47897 B1 IE47897 B1 IE 47897B1 IE 558/79 A IE558/79 A IE 558/79A IE 55879 A IE55879 A IE 55879A IE 47897 B1 IE47897 B1 IE 47897B1
- Authority
- IE
- Ireland
- Prior art keywords
- mol
- methoxy
- acid
- benzamides
- formula
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyrrole Compounds (AREA)
Abstract
Benzamides, in the form of racemates or enantiomers, corresponding to the formula (I> in which n and m are independently of one another equal to 1, 2, 3 or 4 and R is the radical CF3 or an alkylthio radical in which the alkyl is linear or branched and has from 1 to 6 carbon atoms, and also their addition salts with pharmaceutically acceptable acids. The compounds are useful in treating disorders of the central nervous system, and a process for preparing them and pharmaceutical compositions containing them are also disclosed.
Description
The present invention relates to 2Hnethoxybenzamides in the form of racemates or enantiomers, their addition salts with pharmaceutically acceptable acids, their preparation and their application in therapy.
The compounds of the invention correspond to the formula (I)
<“2>—C»2 in which n and m are independently of one another equal to 1, 2, 3 or 4 and R is the radical CF^ or an alkylthio radical in which the alkyl is linear or branched and has from 1 to 6 carbon atoms.
The compounds of the invention are active in the field of the central nervous system.
According to the invention, the compounds are prepared by the condensation of a 2-methoxy-5-R-benzoic acid (II) or tine of its functional derivatives (halide or ester) with a pyrrolidine, in the form of the racemate or an enantiomer, of the formula (III)
7 8 9 7
(ΙΠ)
2-Methoxy-trifluoromethylbenzoic acid has already been described in the literature.
The 2-methoxy-5-alkylthiobenzoic acids (II) and their chlorides are obtained in accordance with the following reaction scheme: .
HOOC
CH
(II)
The (cycloalkyl)-alkylpyrrolidines (III) are obtained, for example, in accordance with the processes their French described by the Applicant Company in / Patents 74/41,718 and 77/19,391.
The condensation is carried out at a temperature of to 30°C, in a solvent such as acetone.
The following examples illustrate the present invention. The analyses and the IR and NMR spectra confirm the structure of the compounds.
Example 1 N-[(l-Cyclopropylmethylpyrrolidin-2-yl)-methyl]2-methoxy-5-methylthiobenzamide and its hydrochloride.
1. 2-Methoxy-5-chlorosulphonylbenzoic acid.
ml (0.506 mol) of chlorosulphonic acid are introduced into a three-necked flask equipped with a stirrer and. a condenser, and the system is cooled to 5°. 20 g of 2methoxybenzoic acid are then added in small portions at a rate which is such that the temperature can be kept between 10 and 15°. Once the addition is complete, the medium is allowed to return to ambient temperature and then to remain at this temperature for 1 hour. The temperature is then gradually increased to 60-70° and. kept at this value for 1 hour, this corresponding to the end of the evolution of gas. The medium is then allowed to cool and this brown liquid is poured inte a mixture of 60 ml of water and 250 g of ice.
A solid appears which is filtered off and washed several times with ice-cooled water. It is then dried in vacuo at 80°C(
Melting point = 145-5°C,
2. Dlthio-bis-(9-methoxybenzoic-3) acid.
100 g (0.4 mol) of 2-methoxy-5-chlorosulphonylben2oic acid, 750 ml of ethanol and 500 ml of 12 N concentrated hydrochloric acid are introduced into a reactor equipped with a mechanical stirrer.
130.8 g (2 mols) of zinc powder are added in portions to the vigorously stirred suspension in the course of about 2 hours, in such a way as to keep the temperature at 15-2O°C, whilst cooling, if necessary, with a bath of ice-cooled water.
At the end of the operation, the medium is filtered.
litre of water and, whilst stirring, 70 g of ferric chloride are added to the filtrate. The mixture is stirred for 1 hour and the product which has precipitated is then filtered off and washed 3 times with water. It is purified by dissolving it in a solution of sodium bicarbonate in the presence of charcoal. The insoluble material is filtered off. The filtrate is acidified with excess hydrochloric acid and the resulting precipitate is filtered off, washed 3 times with water and then dried.
The compound is obtained after recrystallisation from acetic acid, washing with ether and drying for 8 hours at 80°C in vacuo.
Melting point = 212-212.5°C.
3. 2-Methoxy-5-methylthiobenzoic acid and its chloride.
50 g (0,136 mol) of dithio-bis-(4-methoxybenzoic-3) acid are introduced into a reactor and a solution of 27.3 g (0.682 mol) of NaOH iri 1 litre of water is added.
34.8 g (0.275 mol) of methyl sulphate are added dropwise to the resulting solution. The mixture is stirred for 4 hours and then extracted with ether. The aqueous phase is collected and acidified. The resulting oil is extracted with ether and the extract is dried over magnesium sulphate and evaporated. A solid is collected which is triturated with cyclohexane.
Melting point = 68.5-69°C.
14,4 ml (0.2 mol) of thionyl chloride and 19.8 g
1- (0.1 mol) of the acid are introduced into an Erlenmeyer flask. The mixture is stirred at ambient temperature and heated under reflux for 4 hours.
It is evaporated to dryness and the residual oil is distilled in a bulbed tube.
ii Boiling point (0.1 mm Hg) = 180°C.
4. N-f(l-Cyclopronvlmethvloyrrolidin-2-yl)-methyl]-2methoxy-3-methylthiobenzamide.
.7 g (0.069 mol) of l-cyclopropylmethyl-2-aminomethylpyrrolidine, 9.6 g (0.069 mol) of potassium carbonate
:. and some acetone are introduced into an Erlenmeyer flask.
t (0,069 mol) of 2-methoxy-5-methylthiobenzoic acid chloride are added dropwise, whilst cooling with an ice bath and under a stream of nitrogen. The mixture Is stirred for 2 hours at ambient temperature. It is evaporated to dryness at a temperature it30oC and the residue is taken up in water and chloroform. The organic phase is collected Arid extracted in an acid medium and the aqueous phase is rendered alkaline and extracted with chloroform. The extract is dried over magnesium sulphate and evaporated.
An oil is collected which is passed through a silica column, using acetone as the eluant.
Boiling point (0.05 mm Hg) = 240°C.
. Hydrochloride.
6,68 g (0.02 mol) of N-[(l-cyclopropylmethylpyrrolidin-2-yl)-methyl]-2-methoxy-5-methylthiobenzamide are introduced into 100 ml of ether. An equimolecular amount of a solution of hydrogen chloride in ether is added dropwise and the oil is separated off.
The oil is taken up in 100 ml of ether and the mixture is stirred and then evaporated to dryness.
The residual oil is triturated with 100 ml of ethyl 1 acetate, A white solid appears after one hour. ·' It is filtered off and dried.
Melting point = 111.5-H2°C
Example 2 (S)(-) Isomer of N-[(1-cyclopropylmethylpyrrolidin-2-yl)~methyl]~2-methoxy-5-methylthiobenzamide. .-0 10.7 g (0.069 mol) of (s)-2-aminomethyl-l-cyclopropylmethylpyrrolidine, 9.6 g (0.069 mol) of potassium carbonate and some acetone are introduced into an Erlenmeyer flask.
g (Ο.Ο69 mol) of 2-methoxy-5-methylthiobenzoic acid chloride in acetone solution are added dropwise, whilst 25 cooling with an ice bath and under a stream of nitrogen.
The mixture is allowed to return to ambient temperature dnd stirred for two hours.
It is evaporated to dryness and the residual oil is triturated with water and ether. The organic phase is collected'and extracted in an acid medium and the extract is rendered alkaline with sodium carbonate and extracted with ether. The extract is
- dried over magnesium sulphate and evaporated and an oil is collected which is passed through a silica column, using ethyl acetate and then acetone as the eluants. The oil obtained is distilled.
Bo’iling point (0.03 mm Hg) = 220°C.[a]^° = -83°
1.-. (c = 1, DMF).
The hydrochloride is obtained in a solution of hydrogen chloride in ether.
Melting point = ll6-ll6.5°C.
[
Example 3 N-[(l-Cyclopropylmethylpyrrolidin-2~yl)-methyl]2-methoxy-5-ethylthiobenzamide.
1. 2-Methoxy-5-ethylthiobenzoic acid and its chloride.
The procedure of Example 1 is followed, the methyl sulphate being replaced by ethyl sulphate.
2v· Melting point = 58-9°C for the acid.
Boiling point (0.05 mm Hg) = 16O°C for the acid chloride.
2. N--[ (l-CyclopropyLmethylpyrrolidin-2-yl)-methvH-2me.thoxy-3-ethylthlobpnzamide.
'5 9.4 g (0.0611 mol) of l-cyclopropylmethyl-2-aminomethylpyrrolidine, 8.5 g (0.0611 mol) of potassium carbonate and some acetone are introduced into an Erlenmeyer flask.
14.1 g (0.0611 mol) of 2-methoxy-5-ethylthiobenzoio acid chloride in acetone are added dropwise at a temperature £ 10°C and under a stream of nitrogen. The mixture is stirred for 2 hours at ambient temperature. It is evaporated to dryness and the residue is taken up in water and chloroform; the organic phase is separated off and extracted in an acid medium, the extract is rendered alkaline and extracted with chloroform and the extract is dried over magnesium sulphate and evaporated.
An oil is collected which is passed through a silica column, using acetone as the eluant. An oil is collected which is distilled.
Boiling point (0.05 mm Hg) = 240°C.
Example 4 N-[(l-Cyclopropylmethylpyrrolidin-2-yl)-methyl]~
2-methoxy-5-trifluoromethylbenzamide and.-· its hydrochloride.
6,37 g (0.0413 mol) of 2-aminomethyl-l-cyclopropylmethylpyrrolldine, 5.7 g (0.0413 mol) of potassium carbonate and 125 ml of acetone are introduced into an Erlenmeyer flask, the mixture is then cooled to about 5°C and 9.85 g (0.0413 md) of 2-methoxy-5-trifluoromethylbenzoic acid chloride in 50 ml of acetone are poured dropwise into the mixture, slowly (T < 8°C) and under a stream of nitrogen. After the addition, the mixture is stirred for 2 hours in melting ice and for 1 hour at ambient temperature and then evaporated to dryness.. The residue is taken up in water and ether, the etheh fihase is decanted^ the mother liquors are re-extracted twice and the organic extracts are washed before drying them over magnesium sulphate. They are filtered, the filtrate is evaporated to dryness and a yellow oil is obtained.
The benzamide hydrochloride is prepared by stirring the product in dry ether, using a solution of HC1 in ether.
The solid is filtered off, washed and dried. The solid is recrystallised twice from acetone and a fine white powder is obtained:
Melting point = 149.5-15O°C.
Example 5 (3)(-) Isomer of N-[(1-cyclopropylmethylpyrrolidin2-yl)-methyl]-2-methoxy-5-trifluoromethylbenzamide.
2.15 g (0.0139 mol) of (s)-2-aminomethyl-l-cyclo~ propylmethylpyrrolidine, 1.92 g (0.0139 mol) of potassium carbonate and 100 ml of acetone are introduced into an Erlenmeyer flask. 3.32 g (0.0139 mol) of 2-metftoxy-5trifluoromethylbenzoic acid chloride in acetone ara added dropwise, whilst cooling in an ice hath and under a stream of nitrogen. The mixture is allowed to return to ambient temperature and stirred for two hours.
It is evaporated to dryness and the residue is taken up in water and ether. The organic phase is collected and extracted in an acid medium. The extract is rendered alkaline with sodium carbonate and extracted with ether and the extract is dried over magnesium sulphate and evaporated.
An oil is collected which is distilled.
Boiling point (0.05 mm Hg) = 250°C.
[α]§° =-75.5° [c = 1, DMF].
η
7897
TABLE
Compound R m n Melting point or Boiling point (°C) 1 CH^S 1 1 base Boiling point (0.05 mm Hg) = 240 HC1 Melting point = 111.5-112 (S)2 ch3s 1 1 base Boiling point (0.05 mm Hg) = 220 HC1 Melting point = 116-116.5 3 c2h5s 1 1 base Boiling point (0.05 mm Hg) = 240 4 cf3 1 1 HC1 Melting point = 149.5-150 (s)5 CF3 1 1 base Boiling pqint (0.05 mm Hg) = 250
The compounds of the invention have been subjected to pharmacological tests in the field of the central nervous system.
The toxicity was evaluated in male mice of the Swiss CD1 strain,· having a mean weight of 20 g, using intraperitoneal administration.
Thd LD 50 varies from 75 to 200 mg/kg.
The neuroleptic activity was determined by the antagonism towards the ''climbing induced by apomorphine in mice fc. Gouret (1975) J. Pharmacol. (Paris) 4, 541].
The AD 50 varies from 0.03 to 0.08 mg/kg, administered intraperitbneally.
7 8 9 7
The compounds of the invention can be used in the treatment of various psychosomatic complaints and psychic disorders (depressive states and psychoses).
The invention comprises all pharmaceutical compositions 5 which contain the compounds (I) and their salts as active principles, in association with any excipients which are appropriate to their oral, endorectal or parenteral administration.
All the pharmaceutical forms appropriate to oral, endorectal or parenteral administration are suitable.
The daily dosage can range from 1 to 200 mg.
Claims (8)
1. Benzamides, in the form of racemates or enantiomers, corresponding to the formula (I) in which n and m are independently of one another equal to 1, 2, 3 or 4 and R is the radical CF3 or an alkylthio radical in which the alkyl is linear or branched and has from 1 to 6 carbon atoms, and also their addition salts with pharmaceutically acceptable acids.
2. Benzamides according to claim 1, wherein m and n are equal to 1.
3. Benzamides according to claim 1 or 2, wherein R is CF^, CH^S or C2H5S.
4. Any one of the compounds according to claim 1 hereinbefore specifically disclosed.
5. Process for the preparation of the compounds according to claim 1, which process comprises reacting a 2-methoxy-5-R-benzoic acid (II) or one of its functionally equivalent derivatives with a pyrrolidine, in the form of the racemate or an enantiomer. of the formula (III)
6. Process according to claim 5 substantially as described in any one of the foregoing Examples 1 to 5.
7. A compound of formula (I) when prepared by a process according to claim 5 or 6.
8. A pharmaceutical composition comprising a compound according to any of claims 1 to 4 and 7 together with a pharmaceutically acceptable excipient or diluent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7805580A FR2418226A1 (en) | 1978-02-27 | 1978-02-27 | METHOXY-2 ALKYLTHIO-5 BENZAMIDES AND THEIR THERAPEUTIC APPLICATION |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE790558L IE790558L (en) | 1979-08-27 |
| IE47897B1 true IE47897B1 (en) | 1984-07-11 |
Family
ID=9205110
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE558/79A IE47897B1 (en) | 1978-02-27 | 1979-08-08 | 2-methoxybenzamide derivatives |
Country Status (23)
| Country | Link |
|---|---|
| JP (1) | JPS54122269A (en) |
| AT (1) | AT373581B (en) |
| AU (1) | AU521854B2 (en) |
| BE (1) | BE874490A (en) |
| CA (1) | CA1105937A (en) |
| CH (1) | CH637378A5 (en) |
| DE (1) | DE2907377A1 (en) |
| DK (1) | DK82379A (en) |
| ES (1) | ES478073A1 (en) |
| FI (1) | FI790658A (en) |
| FR (1) | FR2418226A1 (en) |
| GB (1) | GB2014995B (en) |
| GR (1) | GR66973B (en) |
| IE (1) | IE47897B1 (en) |
| IL (1) | IL56747A0 (en) |
| IT (1) | IT1114210B (en) |
| LU (1) | LU80976A1 (en) |
| NL (1) | NL7901472A (en) |
| NO (1) | NO790648L (en) |
| NZ (1) | NZ189771A (en) |
| PT (1) | PT69290A (en) |
| SE (1) | SE430501B (en) |
| ZA (1) | ZA799808B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU609828B2 (en) * | 1987-05-25 | 1991-05-09 | Foreshore Protection Pty Limited | Revetment mattress |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2245628B1 (en) * | 1973-09-28 | 1977-03-11 | Ile De France |
-
1978
- 1978-02-27 FR FR7805580A patent/FR2418226A1/en active Granted
-
1979
- 1979-02-26 DE DE19792907377 patent/DE2907377A1/en not_active Withdrawn
- 1979-02-26 PT PT69290A patent/PT69290A/en unknown
- 1979-02-26 CH CH188379A patent/CH637378A5/en not_active IP Right Cessation
- 1979-02-26 NL NL7901472A patent/NL7901472A/en not_active Application Discontinuation
- 1979-02-26 JP JP2247679A patent/JPS54122269A/en active Pending
- 1979-02-26 AU AU44604/79A patent/AU521854B2/en not_active Ceased
- 1979-02-26 DK DK82379A patent/DK82379A/en not_active Application Discontinuation
- 1979-02-26 ES ES478073A patent/ES478073A1/en not_active Expired
- 1979-02-26 IT IT20542/79A patent/IT1114210B/en active
- 1979-02-26 NO NO790648A patent/NO790648L/en unknown
- 1979-02-26 CA CA322,283A patent/CA1105937A/en not_active Expired
- 1979-02-26 NZ NZ189771A patent/NZ189771A/en unknown
- 1979-02-26 ZA ZA00799808A patent/ZA799808B/en unknown
- 1979-02-26 SE SE7901708A patent/SE430501B/en unknown
- 1979-02-27 BE BE0/193730A patent/BE874490A/en not_active IP Right Cessation
- 1979-02-27 LU LU80976A patent/LU80976A1/en unknown
- 1979-02-27 GB GB7906954A patent/GB2014995B/en not_active Expired
- 1979-02-27 AT AT0149479A patent/AT373581B/en not_active IP Right Cessation
- 1979-02-27 IL IL56747A patent/IL56747A0/en unknown
- 1979-02-27 GR GR58492A patent/GR66973B/el unknown
- 1979-02-27 FI FI790658A patent/FI790658A/en not_active Application Discontinuation
- 1979-08-08 IE IE558/79A patent/IE47897B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PT69290A (en) | 1979-03-01 |
| IT1114210B (en) | 1986-01-27 |
| DK82379A (en) | 1979-08-28 |
| BE874490A (en) | 1979-08-27 |
| NZ189771A (en) | 1980-11-14 |
| FR2418226B1 (en) | 1980-11-07 |
| SE7901708L (en) | 1979-08-28 |
| DE2907377A1 (en) | 1979-09-06 |
| LU80976A1 (en) | 1980-09-24 |
| GB2014995B (en) | 1982-07-28 |
| JPS54122269A (en) | 1979-09-21 |
| NL7901472A (en) | 1979-08-29 |
| AU4460479A (en) | 1979-09-06 |
| CH637378A5 (en) | 1983-07-29 |
| GR66973B (en) | 1981-05-15 |
| SE430501B (en) | 1983-11-21 |
| IL56747A0 (en) | 1979-05-31 |
| AT373581B (en) | 1984-02-10 |
| ES478073A1 (en) | 1979-05-16 |
| IT7920542A0 (en) | 1979-02-26 |
| IE790558L (en) | 1979-08-27 |
| NO790648L (en) | 1979-08-28 |
| ZA799808B (en) | 1980-06-25 |
| FR2418226A1 (en) | 1979-09-21 |
| AU521854B2 (en) | 1982-05-06 |
| FI790658A (en) | 1979-08-28 |
| CA1105937A (en) | 1981-07-28 |
| GB2014995A (en) | 1979-09-05 |
| ATA149479A (en) | 1983-06-15 |
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