Author Topic: Fenozolone - a different stimulant  (Read 1417 times)

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foxy2

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Fenozolone - a different stimulant
« on: March 24, 2002, 10:57:00 PM »
Here is a new one, well its an old one but new to the Hive.
Its an analog of pemoline.

Other names: Fenozolone; Phenozolone; LD 3394;
2-Oxazolin-4-one,  Ordinator;
2-(Ethylamino)-4-oxo-5-phenyl-D2-oxazoline; 2-(Ethylamino)-4-oxo-5-phenyl-2-oxazoline; 2-(Ethylamino)-5-phenyl-2-oxazolin-4-one; 5-Phenyl-2-(ethylimino)-4-oxazolidone; 5-Phenyl-2-ethylamino-4-oxazolinone; 


Appetite depressant 2-ethylamino-5-phenyloxazolin-4-one.
(Laboratoires Dausse S. A.).    Ger.  (1969)
DE  1297108  (6-12-1969)

Abstract
The title compd. (I) is prepd. by cyclization of N-ethyl-N'-(a- phenyl-a-chloroacetyl)urea (II) in the presence of NaOEt as an HCl acceptor.  II itself is prepd. from EtNHCONH2 and PhCHClCOCl.  Thus, a stirred suspension of 17.6 g. EtNHCONH2 in 150 cc. dry C6H6 was treated dropwise (20 min.) with a soln. of 18.9 g. PhCHClCOCl in 100 cc. C6H6, the mixt. kept 15 min. at room temp., then refluxed 5 hrs., and the solvent evapd. to yield 19.6 g. II, m. 146° (C6H6).  A suspension of 165.8 g. II in 900 cc. abs. EtOH was treated with a soln. of 15.8 g. Na in 900 cc. EtOH, the mixt. refluxed 2 hrs., kept overnight at room temp., the ppt. sepd., the filtrate evapd., and the residue triturated with ice-H2O to yield 87% I, m. 148° (C6H6).  I is an appetite depressant, and has a higher therapeutic index than the 2-methylamino analog. 


Here is something else interesting.

The stimulating activity of three higher homologs of 5-phenyl-2-amino-4-oxazolinone [on the central nervous system].
Giudicelli, Rene; Najer, Henri; Prouteau, Monique; Sarret, Monique.   
Compt. Rend.  (1962),  254  2862-4. 
Journal  written in Unavailable.   
CAN 57:11186   AN 1962:411186

Abstract
Substitution of a straight-chain C1-3 alkyl group on the 2-amino group of 5-phenyl-2-amino-4-oxazolinone increases its central exciting properties.


So that means these are more centrally exciteing than pemoline!  Worthwhile, who knows... maybee
:)

foxy2

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Fenozolone
« Reply #1 on: March 24, 2002, 11:13:00 PM »
5-phenyl-2-ethylamino-4-oxazolinone and its preparation

Patent GB963375



Abstract
------------------------------------------------------------
The invention comprises 5-phenyl -2- ethylamino -4- oxazolinone, its preparation by heating an N1-ethyl-N11-(a -phenyl -a - haloacetyl) urea in the presence of a hydrogen halide binding agent, and pharmaceutical preparations containing it. The starting materials are prepared by condensing N-ethylurea with an a -phenyl -a - haloacetyl halide. The compound of the invention may be used as a psychotonic, an "anti-fatigue" agent or an anorexigenic, and may be administered in the form of pharmaceutical preparations (e.g. tablets) containing it together with a diluent.

A new prepn. for 5-phenyl-2-methylamino-4-oxazolinone (I) was developed, and 7 new similar compds. were prepd. EtONa, made from 3.75 g. Na in 250 ml. EtOH, was added to a suspension of 37 g. 1-methyl-3-(a-phenyl-a-chloroacetyl)urea in 250 ml. anhyd. EtOH.  The mixt. refluxed 2 hrs. was left overnight at room temp.  The pptd. NaCl was suction-filtered off and washed well with EtOH.  EtOH of the combined filtrates was evapd. on the H2O bath.  The oily residue was triturated in 200 ml. iced H2O, and then kept at 0° several hrs.  It was then suction filtered off, H2O washed, and vacuum dried over P2O5. 1(27 g.), yield 87%, recrystd. from 230 ml. anhyd. C6H6 gave a cryst. powder, m. 123°.  Similarly prepd. were: 5-phenyl-2-ethylamino-4-oxazolinone (II), m. 148°; 5-phenyl-2-propylamino-4-oxazolinone (III), m. 107°, yield 96%; 5-phenyl-2-isopropylamino-4-oxazolinone (IV), m. 170°, yield 70%; 5phenyl-2-butylamino-4-oxazolinone, m. 105°, yield 80%; 5-phenyl-2-benzylamino-4-oxazolinone, m. 186%, yield 69%; 5-phenyl-2-phenylisopropylamino-4-oxazolinone, m. 167-8°, yield 69.5%; and 5-phenyl-2-isoamylamino-4-oxazolinone, m. 109°, yield 64.5%.  The above compds. were stable in alk. but unstable in acidic soln.  The L.D.50 of I, II, and III on white mice, Kaerber and Behrens method, was 0.225-0.175 g./kg., 0.425-0.175 g./kg., and 0.5250.250 g./kg., resp.  They were used as psychotonics and antifatigue drugs. II, III, and IV were used in anorexigenic treatment.  L.D.50 of IV was 0.4-0.575 g./kg.

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foxy2

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cycloalkyl analogs
« Reply #2 on: March 24, 2002, 11:44:00 PM »
Synthesis of some 2-imino-4-oxazolidinones. VI. 5-Phenyl-2-cycloalkylamino-4-oxazolinones.    
Najer, Henry; Giudieelli, Rene; Menin, Jacques.  
Bull. Soc. Chim. France  (1963),   (8-9),  1810-13.

Abstract
cf. CA 59, 589b.  PhCHClCOCl (I) condensed with a cycloalkylurea gave N-cycloalkyl-N°-(a-phenyl-a-chloroacetyl)ureas, which cyclized in the presence of Na alcoholate to 5-phenyl-2-cycloalkylamino-4-oxazolines (II).  The ultraviolet and infrared spectra of the II showed that the amino form predominates in the existing amino-imino tautomer equil. II (n = 1) (III) is a much more active central nervous system stimulant than the most active 5-phenyl-5-alkylamino-4-oxazolinones.  This activity disappears completely as soon as the cycloalkyl group contains more than 3 C atoms; it depends, therefore, partly on the no. of C atoms in the N-substituent and partly on its aliphatic or alicyclic character.  Cyclopropylurea (17.6 g.), m. 124-5°, 21.3 g. Me2NPh, and 310 cc. dry C6H6 treated during 45 min. with stirring with 33.3 g. I in 130 cc. dry C5H6, kept 1 hr. at room temp., refluxed 5 hrs., cooled, and evapd., and the residual oil triturated 3 times with Et2O and then with 250 cc. H2O gave 24.7 g. N-cyclopropyl-N°-(a-phenyl-a-chloroacetyl)urea (IV), m. 134-5° (1:4 EtOH-hexane).  Similarly prepd. were the following analogs of IV (N-substituent, % yield, and m.p., and m.p. of N-substituted urea used as starting material given): cyclobutyl, 55, 130-1, 173-4.degree.; cyclopentyl, 56, 133, 198-200°; cyclohexyl, 55, 160-1°, 200-2°; CH2CN2CH2, -, 84°, 149°; all recrystd. from EtOH.  IV 16.6 g.) and 1.5 g. Na in 330 cc. abs. EtOH refluxed 2 hrs., filtered, and evapd., and the gummy residue triturated with 150 cc. H2O yielded 11.4 g. III, m. 139-40° (1:4 EtOH-hexane).  Similarly prepd. were the following II (n, % yield, and m.p. given): 2, 61, 155-6°; 3, 50, 159-60°; 4, 70, 178 80°; all recrystd. from EtOH.  5-Phenyl-2-allylamino-4-oxazolinone, m. 123-4.degree., 50%, was prepd. in the same manner. 


5-Aryl-2-cycloalkylamino-4-oxazolinones.

Patent NL6613484

  (It has the deatails)

Abstract
The title compds. of the formula I (R = Ph or p-C6H4Cl and R1 = H or Me) were prepd. by treating p-ClC6H4CHClCO2Cl (II) or PhCHClCO2Cl (III) with cyclopropylurea (IV) or N-cyclopropyl-N-methylurea (V) and treating the product (VI) with Na alcoholate.  I are useful in prepg. psychostimulant, anorexigenic, or sedative compns.  Thus, 39 g. II in 130 cc. C6H6 was added through a dropping funnel over 45 min. to a mixt. of 17.6 g. IV, 21.3 g.  PhNMe2, and 310 ml. C6H6, after 1 hr., the mixt. refluxed 5 hrs., the oily residue poured out, the C6H6 distd., the residue washed 3 times in 100 ml. Et2O, and the Et2O evapd. in vacuo to yield 28.6 g. N-cyclopropyl-N'-[a-(p-chlorophenyl)-a-chloroacetyl]urea (VII), m. 132° (H2O).  VII (28.7 g.) was dissolved in a soln. of 2.3 g. Na in 500 ml. EtOH, the soln. refluxed 2 hrs., and NaCl and alc. removed to give 18 g. I (R = p-C6H4Cl, R1 = H), m. 211°.  I (R = Ph, R1 = Me) was also prepd. by treating V with III to yield N-cyclopropyl-N-methyl-N'-(a-phenyl-a-chloroacetyl)urea (VIII), and treating VIII with Na alcoholate.  I had strong stimulant effects on the central nervous system, a strong anorexigenic activity, and negligible cardiovascular activity.


Tautomerism of 5-phenyl-2-alkyl(or aralkyl)imino-4- oxazolidones with 5-phenyl-2-alkyl(or aralkyl)amino-4-oxazolinones.    
Najer, Henry; Giudicelli, Rene; Menin, Jacques; Loiseau, Jacques.   
Compt. Rend.  (1962),  254  2173-5. 

Abstract
cf. CA 55, 27268i.  Refluxing PhClCHCOCl over (MeNH)2CO in C6H6, with Et3N present, gave H.  Heating Me2NH with 2-imino-5-phenyl-4-oxazolidinone in EtOH in a sealed tube at 120° gave III.  Unexpectedly, III proved to be a central nervous system stimulant, as were I but II was not.  Comparison of the ultraviolet and infrared spectra confirmed the suspicion that I exist predominantly in the tautomeric aminooxazolinone (IV) forms.  In alcohol, the l and log e, resp., are: II, 209, 4.24; III, 228, 4.43.  The series IV: (R .dbd. Me), 221, 4.48; (R .dbd. Et), 221, 4.42; (R .dbd. Pr), 222, 4.46; (R .dbd. iso-Pr), 221, 4.44; (R .dbd. Bu), 223, 4.34; (R .dbd. Bz), 225, 4.48; (R .dbd. phenylisopropyl), 225 mm, 4.46.  The infrared comparisons, limited to the bands of valence vibrations of CO and C: N bonds, assign conjugated double bonds to the tautomers for which these frequencies are lowered (Bellamy, The Infrared Spectra of Complex Molecules, 1954 (CA 48, 12562c)).  Found for CO, C:N, resp.: II, 1765, 1700; III, 1730, 1630 cm.-1.  The same decrease (CO, 1720-1745 and C:N, 1645-1680 cm.-1) is noted on comparison of the infrared spectra of IV with that of II.  

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foxy2

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5-Phenyl-2-cycloalkylamino-4-oxazolinones
« Reply #3 on: March 24, 2002, 11:49:00 PM »
5-Phenyl-2-cycloalkylamino-4-oxazolinones

Patent GB1005738



Abstract
Ureas of the general formula PhCHX-CONHCONHR (I), where X is a halogen and R is a C3-6 cycloalkyl group, are cyclized in the presence of a Na alkoxide to give the title compds.  Thus, 33.3 g.  PhCHClCOCl in 130 ml. anhyd. C6H6 is added in 45 min. to a mixt. of 17.6 g. cyclopropylurea and 21.3 g. PhNMe2 in 310 ml. anhyd. C6H6 and the mixt. kept 1 hr. and refluxed 5 hrs. to give 55% N-cyclopropyl-N1-(a-phenyl-a-chloroacetyl)urea (II), m. 134-5° (alc.).  Similarly prepd. are the following I (X = Cl) (R and m.p. given): cyclopentyl, 133°; cyclohexyl, 160-1°. II (16.6 g.) is added to a soln. of 1.5 g. Na in 330 ml. abs. alc. and the soln. is refluxed 2 hrs. to give 11.4 g. 5-phenyl-2-cyclopropylamino-4-oxazolinone (III), m. 139-40° (alc.-hexane).  Similarly prepd. are (m.p. given): 5-phenyl-2-cyclopentylamino-4-oxazolimone, 159-60°; and 5-phenyl-2-cyclohexylamino-4-oxaxolinone, 178-80°.  III can be used as an antifatigue agent.


Pharmacological properties of two derivatives of 5-phenyl-2-cyclopropylamino-4-oxazolinone (LD 3695).
Giudicelli, Rene; Najer, Henry; Menin, Jacques; Prouteau, Monique.       
C. R. Hebd. Seances Acad. Sci., Ser. D  (1967),  265(2),  165-8. 
Journal in French. CAN 67:73543   
Abstract
2-(N-Methyl-N-cyclopropylamino)-5-phenyloxazolin-4-one (I) and 2-cyclopropylimino-3-methyl-5-phenyloxazolidin-4-one (II) are prepd. from the title compd.  I is more effective than II as a central nervous system stimulating agent and as an anorexigenic agent.  Thus, a soln. of 12.5 g. Na in 500 ml. MeOH is treated with 108 g. 2-cyclopropylamino-5-phenyloxazolin-4-one, 69.5 g. Me2SO4 is added, the mixt. is refluxed 2 hrs., the alc. is evapd., and 1 l. 0.5N NaOH is added to the residue.  The mixt. is extd. with CH2Cl2, the CH2Cl2 is evapd., ether is added to the residue, and the mixt. is filtered to give 25.9 g. I, m. 94-5.degree. (EtOAc-hexane); the ether filtrate is evapd. to give 19.3 g. II, m. 106° (iso-PrOH).  Ir and uv data are given.

foxy2

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cyclopropyl analogs
« Reply #4 on: March 25, 2002, 03:04:00 AM »
5-Phenyl-2-cyclopropylamino-4-oxazolinone(I) and 5-phenyl-2-(N-cyclopropyl-N-methylamino)-4-oxazolinone(II)  are both very potent.

I is approximately equal in strength to dl-amphetamine except it has a larger safe therapeutic safety window.

II had equal stimulateing properties to d-amphetamine and is longer lasting.  Its is less toxic orally and has only a very slight cardio-vascular effect in the cat or dog in doses up to 5 mg/kg administered parenterally(thats quite high doses).


Who knows what the other risks are for these compounds, mentally and physically.  They seem like VERY interesting canidates for experimentation.  Several recent patents have mentioned the n-ethyl analog, which leads me to believe that serious toxicity issues have yet to bee found.  Wonder what the substituted analogs are like? ie. methylenedioxy, trimethoxy, 4-Br-2,5-dimethoxy  ect ect

Who's going to bee the Shulgin of oxazolinone's???
:)

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foxy2

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a-Chlorophenylacetyl chloride synthesis
« Reply #5 on: March 25, 2002, 04:45:00 AM »
a-Chlorophenylacetyl chloride.    
Indian Patent  146686  (8-11-1979)

Abstract
a-Chlorophenylacetyl chloride was prepd. in 72% yield by treatment of mandelic acid with SO2Cl2 (see thread

Post 208448

(Osmium: "Re: Making SO2Cl2", Novel Discourse)
for prep of SO2Cl2) in the presence of DMF at room temp for 80 h. 

Other methods

Patent US4639541



Patent GB1374324



The following two patents go together

Patent US3794679


Patent US3812183



Patent GB1425304







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foxy2

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Propargylpemoline
« Reply #6 on: March 25, 2002, 05:17:00 AM »
What do ya know, this made the mice happy!!!
;D
And its easy to make from Pemoline(see Rhodiums for the synth of Pemoline).  The oral LD/50 for mice is mice and huge for this one(250-1000 mg/kg).


Synthesis and antidepressant activity of 5-phenyl-2-(2-propynylamino)-2-oxazolin-4-one and derivatives.
Lee, Cheuk-Man; Horrom, Bruce W.; Michaels, Raymond J.; Rasmussen, Ronald M.; Plotnikoff, Nicholas P.
J. Med. Chem.  (1972),  15(12),  1252-5.
Abstract
Propargylpemoline [5-phenyl-2-(2-propynylamino)-2-oxazolin-4-one] (I) [32962-46-2], the most active in a series of related compds., had much greater and more prolonged antidepressant activity in mice than pemoline or methylphenidate.  I at 2.5 mg/kg orally showed significant activity in the mouse dopa response potentiation test for antidepressant activity.  I was prepd. by refluxing 2-amino-5-phenyl-2-oxazolin-4-one with 2-propynylamine in EtOH.


2-Propargylamino-5-phenyl-2-oxazolin-4-one and its derivatives.

Patent US3578672


Abstract
The title compds. (I, X is, e.g., H, 4-Cl, 2-Me, or 3,4,5-(MeO)3; R is H, Me, or Ph; R1, R2 is H or Me) were prepd. from 2-amino-5-phenyl-2-oxazolin-4-one and propargylamines, or from 1-(chlorophenylacetyl)-3-(1,1-dimethyl-2-propynyl)urea and NaOEt in EtOH.  Oral doses of 0.5-20 mg/kg of I to warm-blooded animals were antidepressant.  Oral LD50 in mice were 250-1000 mg/kg.

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foxy2

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2,2-diethylpemoline
« Reply #7 on: March 25, 2002, 05:37:00 AM »
2-(Diethylamino)-5-phenyl-2-oxazolin-4-one.

Patent DE1237570

(in German)
Abstract
A mixt. of 176.1 g. 2-imino-5-phenyl-2-oxazolin-4-one and 648 g. Ac2O was heated at 100° with stirring to give 87% 2-acetamido-5-phenyl-2-oxazolin-4-one (I), m. 194-6°.  Et2NH (219.3 g.) was added in small portions with stirring at room temp. to 218.1 g. I to give 85% the title compd. (II), m. 74-6°.


Compounds producing central nervous system stimulation and anorexia.

Patent US3313688


Abstract
I, where R1 and R2 are lower alkyl, and their acid addn. salts are prepd.  Thus, a mixt. of 8.8 g. 5-phenyl-2-imino-4-oxazolidinone, 9 g. dimethylamine, and 50 ml. ethanol is heated in an autoclave at 125° for 2 hrs. and cooled, and the ethanol removed to give 2-dimethylamino-5-phenyl-2-oxazolin-4-one (II), m. 137-9° (EtOAc-H2O); hydrochloride (prepd. with alc. HCl), m. 167-71° (decompn.).  Similarly prepd. are 5-phenyl-2-diethylamino-2-oxazolin-4-one, m. 76-7°, hydrochloride, m. 149-54°, 5-phenyl-2-diisobutylamino-2-oxazolin-4-one-HCl, and 2-ethylmethylamino-5-phenyl-2-oxazolin-4-one, m. 104-7°.  Unit dosages of 25-150 mg.  II are used to counteract depression and melancholia and to control appetite in the treatment of obesity.

Dimethyl analog

Patent US3665075



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foxy2

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2-Amino-2-oxazolin-4-ones. I. Synthesis.
« Reply #8 on: March 25, 2002, 05:50:00 AM »
2-Amino-2-oxazolin-4-ones. I. Synthesis.   
Howell, Charles F.; Quinones, Nicanor Q.; Hardy, Robert A., JR.
J. Org. Chem.  (1962),  27  1079-85. 
Abstract
A series of new 5-aryl-2-dialkylamino-2-oxazolin-4-ones has been prepd, by (a) condensation of mandelic acid derivs, with dialkylcyanamides, (b) aminolysis or (c) alkylation of 2-amino-5-aryl-2-oxazolin-4-ones, and (d) aminolysis of 5-aryl-2-thio-2,4-oxazolidinedioneswith secondary amines.  Pharmacol. results indicate that 2-dimethylamino-5-phenyl-2-oxazolin-4-one is particularly interesting as a mild stimulant and anorexic agent.


2-Amino-2-oxazolin-4-ones. II. Tautomerism.    
Howell, Charles F.; Quinones, Nicanor Q.; Hardy, Robert A., JR.    
J. Org. Chem.  (1962),  27  1680-91.
Abstract
Comparison of the phys. and chem. properties of 2-amino-5-phenyl-2-oxazolin-4-one with mono- and dimethyl homologs of known tautomeric structure has shown that the 2-amino-2-oxazolin-4-one structure is indicated rather than the 2-imino-4-oxazolidinone structure previously formulated.  The latter form, however, prevails in the conjugated 5-phenyl-2-phenylimino-4-oxazolidinone.


2-Amino-2-oxazolin-4-ones. III. Spectral studies.   
Howell, Charles F.; Fulmor, William; Quinones, Nicanor Q.; Hardy, Robert A., Jr.
J. Org. Chem.  (1964),  29(2),  370-3.


Central nervous-system stimulant.
The synthesis of 5-phenyl-2-methylimino-4-oxazolidinone.

Patent US3047461




5-Phenyl-2-dialkylamino-2-oxazolin-4-ones

Patent US3037990


Antoncho

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Wow! I'm impressed!
« Reply #9 on: March 25, 2002, 10:15:00 AM »
This is quite a work, Foxy! I hope someone, someday, will make use of this information! Not to mention the possible analogues, as well as purely pharmacological implications this comp'd produces.

Let me too throw a dice - for the visually impaired people like myself, here's how it looks:



Antoncho

foxy2

  • Guest
The real goodies
« Reply #10 on: March 25, 2002, 10:25:00 AM »
Antoncho
The real goodies are the N-cyclopropyl and the N-cyclopropyl-N-methyl.  Those two are right up there with amphetamine in strength.

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