GB2060620A - 3-Aryl-3-aryloxypropylamines - Google Patents
3-Aryl-3-aryloxypropylamines Download PDFInfo
- Publication number
- GB2060620A GB2060620A GB8028713A GB8028713A GB2060620A GB 2060620 A GB2060620 A GB 2060620A GB 8028713 A GB8028713 A GB 8028713A GB 8028713 A GB8028713 A GB 8028713A GB 2060620 A GB2060620 A GB 2060620A
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- Prior art keywords
- compound
- lower alkyl
- general formula
- substituted
- amino
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/53—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/34—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/32—Oxygen atoms
Abstract
3-Aryl-3-aryloxypropylamines of the general formula (I> <IMAGE> and their pharmaceutically acceptable acid addition salts, wherein R<1> and R<2> are hydrogen or lower alkyl, R<3> is hydrogen, lower alkyl or benzyl, R<4> is hydrogen or lower alkyl, Ar is a phenyl group substituted by at least one trifluoromethyl, lower alkyl, lower alkoxy, nitro or amino group and Ar<1> is a phenyl radical optionally substituted by one or more trifluoromethyl, lower alkyl, lower alkenyl, halogen, nitro, amino or acylamino groups exhibit activity on the central nervous system, e.g. as antidepressants.
Description
SPECIFICATION 3-Aryl-3-aryloxypropylamines
This invention relates to 3-aryl-3-arylpropylamines, to a process for preparing them, to their use and to pharmaceutical preparations containing them.
The present invention provides 3-aryl-3-aryloxypropylamines of the general formula (I)
and their pharmaceutically acceptable acid addition salts, wherein R1 and R2 are hydrogen or lower alkyl,
R3 is hydrogen, lower alkyl or benzyl, R4 is hydrogen or lower alkyl, Ar is a phenyl group substituted by at least one trifluoromethyl, lower alkyl, lower alkoxy, nitro or amino group and Ar' is a phenyl radical optionally substituted by one or more trifluoromethyl, lower alkyl, lower alkenyl, halogen, nitro, amino or acylamino groups.
The invention also provides a process for preparing a compound of general formula (I) or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting an anion of an alcohol of general formula (II)
(where Ar, R1, R2, R3 and R4 are as defined above) with a halo compound of general formula (Ill) XAr' (Ill) where X is fluorine and Ar' is an optionally substituted phenyl radical as defined above other than an amino or acylamino substituted phenyl. The reaction may be carried out in a dipolar aprotic solvent.
Examples of dipolar aprotic solvents include dimethylsulphoxide, dimethylformamide, hexamethylphosphoric triamide and sulpholane. Preferably the solvent is dimethylsulphoxide. The anion of the alcohol of general formula (II) is preferably formed by reacting the alcohol with potassium or sodium hydride or an alkyl or phenyl lithium (e.g. butyl lithium) in a compatible dipolar aprotic solvent.
Preferably the alcohol is reacted with sodium hydride.
The process of the invention can be carried out at convenient temperatures e.g. 0 to 1 000C (for example room temperature); there is generally no need to use reflux temperatures. Good yields of products are generally obtained in relatively short reaction times (e.g. within two to three hours).
If in the process described above the compound of the general formula (I) is obtained as an acid addition salt, such as pharmaceutically acceptable acid addition salt or an acid addition salt such as an oxalate, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base a pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with the conventional procedures for preparing acid addition salts from base compounds.
Examples of acid addition salts are those formed from inorganic and organic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesuiphonic and p-toluenesulphonic acids.
Once a compound of general formula (I) is obtained, if desired it can be converted into another compound of general formula (I) by known methods. For example, a 3-aryl-3-aryloxypropylamine of formula (I) in which both R3 and R4 are methyl can be converted to the compound in which one group is methyl and the other hydrogen by treatment with cyanogen bromide or ethyl or phenyl chloroformate followed by basic hydrolysis. Further a compound of formula (I) in which Ar' is a nitrophenyl group can be reduced to a compound in which Ar' is an aminophenyl. The aminophenyl substituent can be acylated to an acylaminophenyl substituent or may be diazotised and converted to standard procedures to a halophenyl, alkoxyphenyl or unsubstituted phenyl substituent.
The compounds of general formula (I) possess one or more asymmetric carbon atoms, depending upon the particular substituents. The compounds can therefore exist in various stereochemical forms. It will be realised that if the starting material of formula (II) is a mixture of isomers the product of formula (I) will also be a mixture of isomers which may be separated, if required, by standard procedures. If the starting material is a single isomer then the product will also be a single isomer.
The term "lower" as used herein means that the radical referred to contains 1 to 6 carbon atoms.
The radical preferably contains 1 to 4 carbon atoms. Examples of lower alkyl radicals include methyl, ethyl, propyl and butyl. Examples of lower alkoxy radicals include methoxy, ethoxy, propoxy and butoxy.
Examples of lower alkenyl radicals include allyl and methallyl. When R', R2 and/or R3 represent lower
alkyl, the lower alkyl group is preferably a straight chain radical such as methyl, ethyl, n-propyl or n-butyl although R3 may also be, for example, a branched chain lower alkyl group such as isopropyl. When Ar' is substituted by halogen, the halogen may be fluoro, chloro, bromo or iodo. When Ar' is substituted by acylamino the substitutent can be, for example, acetamido.
The compounds of general formula (I) and their pharmaceutically acceptable acid addition salts, including the novel compounds of the invention, generally possess pharmacological activity. In particular the compounds exhibit activity on the central nervous system, e.g. as antidepressants, as indicated by one or more of the standard pharmacological test procedures such as the reserpine hypothermia procedure based upon B. M. Askew, Life Sciences (1963), 1 725-730, the inhibition of noradrenaline or 5-hydroxytryptamine uptake in rat brain slices, the potentiation and prolongation of the effects of amphetamine and the modification of the effects of p-chloroamphetamine.For example, N,N dimethyl-3-(4-methylphenyl)-3-(4-nitrophenoxy)propylamine, a representative compound of the invention, produced potentiation of amphetamine-induced stereotypy in rats (Quinton et al, Nature, 1963,200, 178-179) at 50 mg/kg per os.
The invention further provides a method of treating depression which comprises administering to a warm blooded mammal particularly a human, a therapeutically effective amount of-a compound of the invention. The invention also provides a pharmaceutical composition comprising a novel compound of the invention in association with a pharmaceutically acceptable carrier. Any suitable carrier known in the art can be used to prepare the pharmaceutical compositions. In such a composition, the carrier may be a solid, liquid or mixture of a solid and a liquid. Solid form compositions include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, binders or tablet-disintegrating agents; it can also be an encapsulating material.In powders the carrier is a finely divided solid which is in admixture. with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 to 99, preferably 1080% of the active ingredient.
Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, and cocoa butter. The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (wich or without other carriers) is with it. Similarly cachets are included.
Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs. The active ingredients can be dissolved or suspended in a pharmaceutically acceptable sterile liquid carrier, such as sterile water, sterile organic solvent or a mixture of both. Preferably a liquid carrier is one suitable for parenteral injection. Where the active ingredient is sufficiently soluble it can be dissolved in normal saline as a carrier; if it is too insoluble for this it can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol or polyethylene glycol solutions. Aqueous propylene glycol containing from 10 to 75% of the glycol by weight is generally suitable.In other instances other compositions can be made by dispersing the finely-divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution, or in a suitable oil, for instance arachis oil. Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilised by intramuscular, intraperitoneal or subcutaneous injection. In many instances a compound is orally active and can be administered orally either in liquid or solid composition form.
Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit doses containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders or vials or ampoules. The unit dosage form can be a capsule, cachet or tablet itself, or it can be the appropriate number of any of these in package form. The quantity of the active ingredient in a unit dose of composition may be varied or adjusted from 5 mg. or less to 500 mg. or more, according to the particular need and the activity of the active ingredient. The invention also includes the compounds in the absence of the carrier where the compounds are in unit dosage form.
EXAMPLE 1 N,N-Dimethyl-3-(4-methylphenyl)-3-(4-nitrophenoxy)propylamine A mixture of N,N-dimethyl-3-hydroxy-3-(4-methylphenyl) propylamine (3.86 g, 20 mM), 50% sodium hydride dispersion (1 g) and DMSO (50 ml) was heated at 80 until homogenous, cooled to room temperature and treated dropwise with a solution of 4-fluoronitrobenzene (2.82 g, 20 mM) in
DMSO (20 ml) with cooling (exothermic). After 1 h the reaction mixture was poured on to water (200 ml) and extracted with ether (2 x 200 ml). The ether layer was extracted with 1 N hydrochloric acid (2 x 50 mi), the acid layer basified and extracted with ether (2 x 200 ml). The organic layer was dried and the solvent removed under reducedpressure. The residue was dissolved in ethyl acetate and treated with an excess of a solution of oxalic acid dihydrate in ethyl acetate. The resulting precipitate was removed by filtration, washed well with acetone and dried in vacuo to give the title compound as the oxalate hydrate (4 g). m.p. 188--1900 (d).
Found: C 58.5; H 6.0; 6.7% C18H22N203.C2H204.-41H2O requires: C 58.7; H 6.0; N 6.9%.
EXAMPLES 2-4
The stated products are prepared, following the procedure of Example 1, by reacting the alcohol with sodium hydride and treating the resulting anion with the halo compound.
Example Alcohol Halo Compound Product
2 N-methyl-3-hydroxy-3- 4-fluorobenzo- N-methyl-3
(4-methylphenyl) trifluoride (4-methylphenyl)-3
propylamine (4-trifluoromethylphenoxy)
propylamine
3 N,N-dimethyl-3-hydroxy-3- 4-fluorotoluene N,N-dimethyl-3
(4-trifluoromethylphenyl)- (4-trifluoromethylphenyl)
propylamine 3-(4-methylphenoxy)
propylamine
4 N ,N-dimethyl-3-hydroxy-3- 4-fluoronitrobenzene N ,N-dimethyl-3- (4-methoxyphenyl)- (4-methoxyphenyl)-3
propylamine (4-nitrophenoxy)
propylamine
Claims (10)
1. A 3-aryl-3-aryloxypropylamine of the general formula (I)
or a pharmaceutically acceptable acid addition salt therof wherein R' and R2 are hydrogen or lower alkyl,
R3 is hydrogen, lower alkyl or benzyl, R4 is hydrogen or lower alkyl, Ar is a phenyl group substituted by at least one trifluoromethyl, lower alkyl, lower alkoxy, nitro or amino group and Arl is a phenyl radical optionally substituted by one or more trifluoromethyl, lower alkyl, lower alkenyl, halogen, nitro, amino or acylamino groups.
2. A compound as claimed in claim 1 wherein Ar' is a phenyl radical substituted by a nitro or trifluoromethyl group.
3. A compound as claimed in claim 1 or 2 wherein Ar is a phenyl radical substituted by a lower alkyl group.
4. N,N-Dimethyl-3-(4-methylphenyl)-3-(4-nitrophynoxy)-propylamine or a pharmaceutically acceptable acid addition salt thereof.
5. A process for preparing a compound claimed in claim 1 which comprises reacting an anion of an alcohol of general formula (II)
(wherein Ar, R', R2, R3 and R4 are as defined in claim 1) with a halo compound of general formula (III) XAr' (III) where X is fluorine and Ar' is an optionally substituted phenyl radical as defined in claim 1 other than an amino or acylamino substituted phenyl, if required reducing a product in which Ar' is a phenyl group substituted by nitro to a compound in which Ar1 is substituted by amino and if required acylating the amino substituent to an acylamino substituent, and, if desired, converting a free base of general formula (I) into a pharmaceutically acceptable acid addition salt thereof.
6. A process as claimed in claim 5 where the anion of the alcohol of general formula (ill is formed by reacting the alcohol with potassium or sodium hydride or with an alkyl or phenyl lithium.
7. A process for preparing a compound claimed in claim 1 substantially as hereinbefore described with reference to any one of the Examples.
8. A compound as claimed in claim 1 whenever prepared by the process claimed in any one of claims 5 to 7.
9. A pharmaceutical composition comprising a compound claimed in any one of claims 1 to 4 and 8 in association with a pharmaceutically acceptable carrier.
10. A compound claimed in any one of claims 1 to 4 and 8 for use as an antidepressant.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8028713A GB2060620B (en) | 1979-09-14 | 1980-09-05 | 3-aryl-3-aryloxypropylamines |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7932046 | 1979-09-14 | ||
| GB8028713A GB2060620B (en) | 1979-09-14 | 1980-09-05 | 3-aryl-3-aryloxypropylamines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2060620A true GB2060620A (en) | 1981-05-07 |
| GB2060620B GB2060620B (en) | 1983-05-25 |
Family
ID=26272893
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8028713A Expired GB2060620B (en) | 1979-09-14 | 1980-09-05 | 3-aryl-3-aryloxypropylamines |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2060620B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990003965A1 (en) * | 1988-10-05 | 1990-04-19 | Farmitalia Carlo Erba S.R.L. | Aryloxy-, arylthio-, heteroaryloxy-, heteroarylthio-alkenylene derivatives of amines |
| EP0576766A1 (en) * | 1992-06-29 | 1994-01-05 | Novo Nordisk A/S | Propanolamine derivatives, their preparation and use |
| WO2001062704A1 (en) * | 2000-02-23 | 2001-08-30 | Astrazeneca Ab | Novel use of phenylheteroalkylamine derivatives |
| US6900243B2 (en) | 2000-02-23 | 2005-05-31 | Astrazeneca Ab | Phenylheteroalkylamine derivatives |
| US6953797B2 (en) | 2000-02-23 | 2005-10-11 | Astrazeneca Ab | Use of phenylheteroalkylamine derivatives |
| US7223794B2 (en) | 2001-07-31 | 2007-05-29 | Astrazeneca Ab | Arylheteroalkylamine derivatives and their use as inhibitors of nitric oxide synthase |
-
1980
- 1980-09-05 GB GB8028713A patent/GB2060620B/en not_active Expired
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990003965A1 (en) * | 1988-10-05 | 1990-04-19 | Farmitalia Carlo Erba S.R.L. | Aryloxy-, arylthio-, heteroaryloxy-, heteroarylthio-alkenylene derivatives of amines |
| EP0576766A1 (en) * | 1992-06-29 | 1994-01-05 | Novo Nordisk A/S | Propanolamine derivatives, their preparation and use |
| WO2001062704A1 (en) * | 2000-02-23 | 2001-08-30 | Astrazeneca Ab | Novel use of phenylheteroalkylamine derivatives |
| US6887871B2 (en) | 2000-02-23 | 2005-05-03 | Astrazeneca Ab | Use of phenylheteroakylamine derivatives |
| US6900243B2 (en) | 2000-02-23 | 2005-05-31 | Astrazeneca Ab | Phenylheteroalkylamine derivatives |
| US6953797B2 (en) | 2000-02-23 | 2005-10-11 | Astrazeneca Ab | Use of phenylheteroalkylamine derivatives |
| US7223794B2 (en) | 2001-07-31 | 2007-05-29 | Astrazeneca Ab | Arylheteroalkylamine derivatives and their use as inhibitors of nitric oxide synthase |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2060620B (en) | 1983-05-25 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PE20 | Patent expired after termination of 20 years |
Effective date: 20000904 |