US3769319A - N-ethyl-n-(1 - (m-trifluoromethylphenyl)-propyl-(2))-carbamic acid ethyl ester - Google Patents

N-ethyl-n-(1 - (m-trifluoromethylphenyl)-propyl-(2))-carbamic acid ethyl ester Download PDF

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US3769319A
US3769319A US3769319DA US3769319A US 3769319 A US3769319 A US 3769319A US 3769319D A US3769319D A US 3769319DA US 3769319 A US3769319 A US 3769319A
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carbamic acid
ethyl
trifluoromethylphenyl
propyl
ethyl ester
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K Boltze
D Lorenz
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Troponwerke Dinklage and Co
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06Esters of carbamic acids
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S514/00Drug, bio-affecting and body treating compositions
    • Y10S514/909Obesity
    • Y10S514/91Anorectic

Abstract

APPETITE-INHIBITING SUBSTITUTED N-(TRIFLUOROMETHYL PHENYLETHYL)-CARBAMIC ACID ESTERS HAVING THE GENERAL FORMULA

CF3-C6H4-CH2-C(-R1)(-CH3)-N(-R2)-COO-R3

WHEREIN R1 AND R2 ARE HYDROGEN OR LOWER ALKYL WITH THE PROVISO THAT WHEN R1 IS HYDROGEN, R2 IS ALKYL AND R3 IS ALKYL.

Description

Patented Oct. 30, 1973 7 3,769,319 N-ETHYL-N-[l (m-TRIFLUOROMETHYLPHENYL)- PROPYL-(2)]-CARBAMIC ACID ETHYL ESTER Karl-Heinz Boltze, Bensberg-Kippekausen, and Dietrich Lorenz, Klein Hurden, Post Immekeppel, near Bensberg, Germany, assignors to TroponwerkeDinklage & Co., Cologne, Germany No Drawing. Filed June 4, 1971, Ser. No. 150,169

. Int. Cl. C07c 125/06 US. Cl. 260-471 C 1 Claim ABSTRACT OF THE DISCLOSURE v Appetite-inhibiting substituted N-(trifluoromethylphenylethyl)-carbamic acid esters having the general formula 1:21.--. INC AEB g wherein R and R are hydrogen or lower alkyl with the proviso that when R isihydrogen, R, is alkyl and R is alkyl.

This invention relates to' new substituted N-(trifluoromethylphenylethyl)-carbamic acid esters of the general formula @oH -h-iI-c-o-R. mo in. ii (I) wherein the trifluoromethyl group may occupy the ortho, meta or para positions on the phenyl ring, R, is hydrogen or a lower alkyl radical with up to 3 carbon atoms, R is hydrogen or a lower alkyl radical with up to 3 carbon atoms with the proviso that if R, is hydrogen, R is an alkyl radical, and R represents an alkyl radical with 1 to 4 carbon atoms.

In the animal test, the compounds according to the invention exhibit a very good appetite-inhibiting effectiveness, which approximately corresponds tothat of compounds presently used for this purpose in human medicine. However, contrary to a number of compounds available on the market, they do not show any stimulating and motility-increasing effect even in sublethal dosage and are characterized in particular by good compatibility and low toxicity. Thus, for instance, N-ethyl-N-[l-(m-trifluoromethylphenyl)-propyl-(2)]-carbamic acid ethyl ester, an LD of 1,000 mg./kg. was determined with a single oral application on a rat, whereas the compound N- The compounds according to the invention of the gen- I eral Formula I can be made by known methods from amines of the general formula @CH:&NBIR| FiC AH: (II) wherein R and R have the above-mentioned meaning, by

(a) Reacting a Formula H amine with chloroformic acid esters of the general formula ClCOOR wherein R; has the above-mentioned meaning, or

(b) Reacting a Formula H amine with carbonic acid dialkyl esters of the general formula R OCOOR wherein R has the above-mentioned meaning, or

(0) Converting a Formula II amine with phosgene into carbamic acid chlorides of the general formula R1 R. Q i

Ha- -N--CCl mo (in. ii an) and reacting Formula 111 compounds with'alcohols of the general formula R OH, wherein R; has the above-mentioned meaning, or,

(d) In the case where R; is hydrogen, converting the carbamic, acid chlorides (III) into the corresponding isocyanates of the general formula with: splitting 011 of hydrogen chloride, and reacting samewith R 011. In the above Formula II, III and IV, R R and R are defined previously.

The invention will be illustrated further by the followmine-(2) is dissolved in glacial acetic acid and mixed with a 25% excess of acetic anhydride while cooling. The reaction mixture was maintained at C. for 30 minutes,

then broken up with ice water and dissolved in ether. The

ethyl l-(m-trifluoromethylphenyl)-propylamine-(2) used in human medicine and which is chemically closest thereto has an LD of 170 mg./kg. (D. Lorenz, Mitt. Arch. Pharmaz, 36, vol. 12 (1966). Cf. also I. C. Le Douarec, H. Schmitt and M. Laubic, Arch. int. Pharmacodyn, 161, p. 211 (1966). I V

N [Z-methyl-1-(p-trifluoromethylphenyl)-propyl-(2) carbamic acid ethyl ester also has an LD of only ap proximately 2,000 mg./kg. Thus the compounds according to the invention are about five to ten times less toxic than N ethyl-l-(m-trifluoromethylphenyl)-propylamine- (2).. Their appetite-inhibiting etfect is, however, only about two to three times less so that their therapeutic range is two to three times larger. They can, therefore, be handled with'considerably greater safety in human medicine than the preparations used thus far for this purpose.

ethereal solution is shaken out with 5 N hydrochloric acid, dried with sodium sulfate, evaporated and the residue is dissolved in warm ligroin. Through strong cooling N [1 (m tn'fluoromethylphenyl) propyl (2)] acetamide having a melting point of 59-62 C. crystallizes out.

Part 2 .ether and .added drop by drop to a suspension of 0.07

lithium aluminum hydride in absolute ether in the absence of oxygen and moisture. After boiling for five hours, the reaction mixture is broken up with water and 20% solution of caustic soda and filtered. The filtrate is mixed with ethereal hydrochloric acid and evaporated. N-ethyl-l-(mtrifluoromethylphenyl) propylamine (2) hydrochloride having a melting point of 166 C. is obtained. By dissolving this product in water and mixing with a solution of caustic soda the base is obtained, which then is separated by absorption in ether and is dried with sodium sulfate. After evaporating the ether and distilling the residue, N ethyl 1 (m trifiuoromethylphenyl) propylamine- (2) having a boiling point of 98 to 100 C./1O mm. Hg and a refractive index of 11 1.4545 is obtained.

Part 3 1.0 mole of N-ethyl-l-(m-trifiuoromethylphenyl)-propylamine-(Z) from Part 2 in 96% alcohol is added drop by drop at approximately 0 C. to a solution of 1.1 moles of chloroformic acid ethyl ester in 96% alcohol while stirring and cooling and then, in the course of 20 minutes, it is mixed with an aqueous saturated potassium hydrogen carbonate solution. After stirring for three hours. the alcohol is distilled off, the residue absorbed in ether, dried with sodium sulfate and freed of the ether. After distilling in high vacuum, N-ethyl-N-[ l-(m-trifiuoromethylphenyl)- propyl-(2)]-carbamic acid ethyl ester having a boiling point of 83-85" C./S'1O-" mm. Hg is obtained.

EXAMPLE 2 6 grams of 2-methyl-l-(p-trifluoromethylphenyll-propylamine-(Z) are dissolved in ethylene chloride and mixed with a solution of 3.1 g. of chloroformic acid ethyl ester in ethylene chloride while stirring. Subsequently an aqueous solution of 2.9 g. of potassium hydrogen carbonate is C. and the reaction mixture added drop by drop at 4-6 C. The separated ethis stirred for several hours at 20 ylene chloride phase is washed with water, filtered and 2.17 g. (0.01 mole) of Z-methyl-l-(m-trifluoromethylphenyl)-propylamine-(2) are dissolved in a small amount of ethanol and heated with 1.18 g. (0.01 mole) of diethyl carbonate for 5 hours on a water bath. After removal of the solvent, the resultant N-[Z-methyl-l-(m-trifiuoromethylphenyl)-pr0pyl-(Z)]-carbamic acid ethyl ester is distilled 7 off under vacuum. The yield is 1.85 g. (66% of the theoretical).

EXAMPLE 4 2.31 g. (0.01 mole) of N-ethyl-l-(m-trifluoromethyl- I phenyl)-propylamlne-(2) are dissolved in benzene. Phos gene is introduced in the presence of some pyridine while pp. 570 and 571 relied on.

slowly increasing the temperature to 80 C. After having separated the resultant precipitate of pyridine hydrochloride and removed the solvent, the formed N-ethyl-N-[l- (m trifluoromethylphenyl) propyl (2)]carbamic acid chloride is first taken up in ether and then mixed with ethanol. After shaking with water, drying over sodium sulfate and removal of the solvent and recrystallization in etroleum ether, 2.45 g. (80.7% of the theoretical yield) of N ethyl-N-[1-(mtrifluoromethylphenyl)propyl-(2)1 carbamic acid ethyl ester which is identical'with thecompound obtained in Example 1 are obtained.

EXAMPLE 5- References Cited UNITED STATES PA'IENIIS 3,308,019 3/1967 Kopfetal. 2 0-4716. 3,663,595 5/1912 Beregiet al. 260- 411 0 OTHER REFERENCES Adams, P. et 211.: Chemical Reviews LORRAINE A. WEINBERGER, Primary Examiner I L. A. THAXTON, Assistant Examiner US. Cl. X.R.

US3769319D 1971-06-04 1971-06-04 N-ethyl-n-(1 - (m-trifluoromethylphenyl)-propyl-(2))-carbamic acid ethyl ester Expired - Lifetime US3769319A (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4215139A (en) * 1978-03-17 1980-07-29 Hoffmann-La Roche Inc. Carbamic acid derivatives
US5587398A (en) * 1994-06-03 1996-12-24 David R. Elmaleh Meta substituted arylalkylamines and therapeutic and diagnostic uses therefor
US5736573A (en) * 1996-07-31 1998-04-07 Galat; Alexander Lipid and water soluble derivatives of drugs
US6004990A (en) * 1994-06-03 1999-12-21 Zebra Pharmaceuticals Meta substituted arylalkylamines and therapeutic and diagnostic uses therefor
EP3170807A1 (en) 2015-11-23 2017-05-24 Frau Pharma S.r.l. New method for synthesis of fenfluramine, of isomers therof and/or of analogs thereof, and new compositions comprising it

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4215139A (en) * 1978-03-17 1980-07-29 Hoffmann-La Roche Inc. Carbamic acid derivatives
US5587398A (en) * 1994-06-03 1996-12-24 David R. Elmaleh Meta substituted arylalkylamines and therapeutic and diagnostic uses therefor
US6004990A (en) * 1994-06-03 1999-12-21 Zebra Pharmaceuticals Meta substituted arylalkylamines and therapeutic and diagnostic uses therefor
US6313175B1 (en) 1994-06-03 2001-11-06 Biostream, Inc. Meta substituted arylalkylamines and therapeutic and diagnostic uses therefor
US5736573A (en) * 1996-07-31 1998-04-07 Galat; Alexander Lipid and water soluble derivatives of drugs
EP3170807A1 (en) 2015-11-23 2017-05-24 Frau Pharma S.r.l. New method for synthesis of fenfluramine, of isomers therof and/or of analogs thereof, and new compositions comprising it

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