Oxazolidines and compositions containing the same

• US 4,743,604 A
• Filed: 11/01/1984
• Issued: 05/10/1988
• Est. Priority Date: 11/10/1983
• Status: Expired due to Fees

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Muller, Marcel, Alig, Leo
• Primary Examiner(s): Daus, Donald G.
• Assistant Examiner(s): Shen, Cecilia
• Application Number:
  US06/667,186
• Time in Patent Office: 1,286 Days
• Field of Search: 548/215, 548/226, 548/227, 548/229, 544/369, 514/252, 514/376
• US Class Current: 424/442
• CPC Class Codes: C07D 263/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 263/06 with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 333/38 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 409/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The oxazolidines of the formula ##STR1## wherein n signifies the number 1 or 2,

T signifies lower carbalkoxy,

X signifies phenoxymethyl optionally mono-fluorinated or mono-chlorinated in the ortho-position or phenyl optionally monosubstituted by fluorine, chlorine, trifluoromethyl or lower-alkoxy,

Y signifies hydrogen or methyl, and

Z signifies a phenyl or thienyl residue substituted in a defined manner,

and the physiologically compatible salts thereof have catabolic activity and can be used for the treatment of obesity and diabetes mellitus or for the treatment of conditions which are associated with an increased protein breakdown, or as feed additives for fattening animals. They are manufactured starting from corresponding primary amines.

Claims

1. Oxazolidines of the formula ##STR10## wherein n is the number 1 or 2,

T is lower-carbalkoxy,

X is phenoxymethyl or phenyl optionally monosubstituted by fluorine, chlorine, trifluoromethyl or lower-alkoxy,

Y is hydrogen or methyl,

Z is a group of the formula ##STR11## R¹ is lower-alkyl, optionally N-mono-lower-alkylated or N-di-lower-alkylated aminomethyl or a group --C(O)R², --C(R³)═

CH--(CH₂)_m --C(O)R², --C(H,R³)--(CH₂)_m+1 --C(O)R², --C(H,R³)--(CH₂)_p --OH or --C(R³)═

CH--C(CH₃)═

CH--COOCH₃,

R¹¹ is hydroxy, lower-alkoxy, lower-alkanoyloxy, sulphamoyl, benzyloxy or phenoxy or a group R¹, --O--(CH₂)_q --OH, --O--(CH₂)_q --COOR⁴ --O--(CH₂)_q --O--(CH₂)_t --R⁵ or, ##STR12## R² is hydroxy, lower-alkyl, lower-alkoxy, dimethylaminoethoxy, lower-alkoxycarbonylethyl or optionally mono-lower-alkylated or di-lower-alkylated amino,

R³ is hydrogen or methyl,

R⁴ is lower-alkyl,

R⁵ is hydrogen, lower-alkyl or phenyl optionally para-substituted by chlorine, fluorine, trifluoromethyl, lower-alkyl or lower-alkoxy,

R⁶ is lower-alkyl or phenyl optionally para-substituted by fluorine, chlorine, lower-alkyl or lower-alkoxy,

m and p are whole numbers of 0 to 6,

v is a whole number of 2 to 4,

q and t are whole numbers of 1 to 6,

and physiologically compatible salts thereof.

2. Compounds according to claim 1, wherein the substituent R¹¹ present on a phenyl group Z is hydroxy, lower alkoxy, lower-alkanoyloxy, sulphamoyl or a group R¹, --O--(CH₂)_q --OH or --O--(CH₂)_q --O--(CH₂)_t --R⁵ and R⁵ is hydrogen, lower-alkyl or phenyl, and the remaining symbols have the same significance as in claim 1.

3. Compounds according to claim 1, wherein T is carbomethoxy.

4. Compounds according to claim 1, wherein X is phenyl monosubstituted by chlorine or trifluoromethyl in the meta-position, or phenoxymethyl, especially those in which the C-atom bonded to a phenoxymethyl group X has the S-configuration or the C-atom bonded to a phenyl group X has the R-configuration.

5. Compounds according to claim 1, wherein Y is methyl, especially those in which the C-atom bonded to a methyl group Y has the R-configuration.

6. Compounds according to claim 1, wherein Z is phenyl or thienyl substituted by carbamoyl, methoxycarbonyl or 2-(ethoxy or methoxy)-carbonyl-1-methylvinyl.

7. Compounds according to claim 1, wherein Z is phenyl substituted by hydroxy, 6-hydroxyhexoxy, 2-ethoxyethoxy, 2-phenethoxy-2-ethoxy or (ethoxy or methoxy)-carbonylmethoxy.

8. Compounds according to claim 1, wherein T is carbomethoxy, X is phenyl monosubstituted by chlorine or trifluoromethyl in the meta-position, or phenoxymethyl, Y is methyl and Z is phenyl or thienyl substituted by carbamoyl, methoxycarbonyl or 2-(ethoxy or methoxy)-carbonyl-1-methylvinyl, or phenyl substituted by hydroxy, 6-hydroxyhexoxy, 2-ethoxyethoxy, 2-phenethoxy-2-ethoxy or (ethoxy or methoxy)-carbonylmethoxy.

9. Compounds according to claim 1, wherein the C-atom bonded to a methyl group Y has the R-configuration, the C-atom bonded to a phenoxymethyl group X has the S-configuration and the C-atom bonded to a phenyl group X has the R-configuration.

10. In accordance with claim 1, methyl(E)-p-[(R)-2-[(2RS,5RS)-2-methoxycarbonyl)-5-(α

,α

,.alpha.-trifluoro-m-tolyl)-3-oxazolidinyl]propyl]-β

-methyl-cinnamate.

11. In accordance with claim 1, methyl(2RS,5R)-3-[(R)-3-(p-carbamoylphenyl)-1-methylpropyl]-5-phenoxymethyl-2-oxazolidinecarboxylate.

12. In accordance with claim 1, methyl(2RS,5R)-3-[(RS)-4-(5-carbamoyl-2-thienyl)-2-butyl]-5-phenyl-2-oxazolidinecarboxylate.

13. In accordance with claim 1, methyl(2RS,5R)-3-[(R)-3-(p-carbamoylphenyl)-1-methylpropyl]-5-phenyl-2-oxazolidinecarboxylate.

14. An animal feed composition comprising feed to which there is admixed a suitable quantity of a compound of the formula ##STR13## wherein n is the number 1 or 2,

T is lower-carbalkoxy,

X is phenoxymethyl or phenyl optionally monosubstituted by fluorine, chlorine, trifluoromethyl or lower-alkoxy,

Y is hydrogen or methyl,

Z is a group of the formula ##STR14## R¹ is lower-alkyl, optionally N-mono-lower-alkylated or N-di-lower-alkylated aminomethyl or a group --C(O)R², --C(R³)═

CH--(CH₂)_m --C(O)R², --C(H,R³)--(CH₂)_m+1 --C(O)R², --C(H,R³)--(CH₂)_p --OH or --C(R³)═

CH--C(CH₃)═

CH--COOCH₃,

R¹¹ is hydroxy, lower-alkoxy, lower-alkanoyloxy, sulphamoyl, benzyloxy or phenoxy or a group R¹, --O--(CH₂)_q --OH, --O--(CH₂)_q 13 COOR⁴ --O--(CH₂)_q --O--(CH₂)_t --R⁵ or, ##STR15## R² is hydroxy, lower-alkyl, lower-alkoxy, dimethylaminoethoxy, lower-alkoxycarbonylethyl or optionally mono-lower-alkylated or di-lower-alkylated amino,

R³ is hydrogen or methyl,

R⁴ is lower-alkyl,

R⁵ is hydrogen, lower-alkyl or phenyl optionally para-substituted by chlorine, fluroine, trifluoromethyl, lower-alkyl or lower-alkoxy,

R⁶ is lower-alkyl or phenyl optionally para-substituted by fluorine, chlorine, lower-alkyl or lower-alkoxy,

m and p are whole numbers of 0 to 6,

v is a whole number of 2 to 4,

q and t are whole numbers of 1 to 6, or a physiologically compatible salt thereof.

15. A composition in accordance with claim 14, wherein T is carbomethoxy.

16. A composition in accordance with claim 15, wherein the compound of formula I is methyl(E)-p-[(R)-2-[(2RS,5RS)-2-methoxycarbonyl)-5-(α

,α

,.alpha.-trifluoro-m-tolyl)-3-oxazolidinyl]propyl]-β

-methyl-cinnamate.