GB1598127A

GB1598127A - Benzoxazine carboxamides having lipogenesis-inhibiting properties

Info

Publication number: GB1598127A
Application number: GB31589/78A
Authority: GB
Original assignee: Shell Internationale Research Maatschappij BV
Current assignee: Shell Internationale Research Maatschappij BV
Priority date: 1977-03-17
Filing date: 1978-03-15
Publication date: 1981-09-16
Also published as: BE864918A; DD137714A5; PL205322A1; GB1598126A; PL127781B1; DK117478A; IE780532L; DE2811236A1; GB1598128A; NL7802921A; LU79238A1; FR2424741A1; IE46676B1; JPS53116377A

Description

PATENT SPECIFICATION

( 21) Application No 31589/78 ( 22) Filed 15 Mar, ( 62) Divided out of No 1598126 ( 31) Convention Application No 778816 ( 32) Filed 17 March 1977 in ( 33) United States of America (US) ( 44) Complete Specification published 16 Sept 1981 ( 51) INT CL 3 C 07 D 265/36 C 07 C 79/26 91/44 ch 1978 ( 19) ( 52) Index at acceptance C 2 C 1564 200 213 220 221 225 226 227 22 Y 247 255 25 Y 271 280 29 X 29 Y 305 30 Y 311 313 314 31 Y 321 32 Y 332 337 342 34 Y 364 365 366 368 36 Y 37 X 385 453 45 Y 509 50 Y 511 51 X 531 579 584 610 620 621 623 624 628 62 X 65 X 660 661 662 670 671 672 678 694 802 80 Y AA BE KF KJ KP KT LG LS MK ML SD ( 72) Inventor JOHN BERNARD CARR ( 54) BENZOXAZINE CARBOXAMIDES HAVING LIPOGENESIS-INHIBITING PROPERTIES ( 71) We, SHELL INTERNATIONALE RESEARCH MAATSCHAPPIJ B.V, a company organised under the laws of The Netherlands, of 30 Carel van Bylandtlaan, The Hague, The Netherlands, do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the

following statement:-

The invention relates to benzoxazinme carboxamides having lipogenesis-inhibiting properties.

The invention provides a compound of the general formula I or an acid addition salt, for example a hydrohalide, thereof; wherein N is 0, 1 or 2; R, each of which when N is 2 may be the same or different, is a fluorine, chlorine or bromine atom, a nitro, amino, methylsulphonylamino or trifluoromethyl group, an alkyl or alkoxy group having 1 to 6 carbon atoms, or a cycloalkyl group having 3 to 6 carbon atoms; R 1 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; and R 2 is a hydrogen atom or an alkyl group having I to 4 carbon atoms.

Any alkyl moiety may be straight-chain or branched.

Preferably N is 0, or N is I and R is a chlorine atom or an alkyl or trifluoromethyl group Preferably R' is a hydrogen atom and preferably R 2 is a hydrogen atom or a methyl group If N is 1, R is preferably a substituent in the 6-position.

Those compounds of the invention wherein R 1 represents an alkyl group exist in the form of cis and trans-isomers In addition, optical isomerism exists due to the assymetric carbon atom at the 2-position of the ring and, if R' is an alkyl group, the asymetric carbon atom at the 3-position of the ring The invention should be understood to include all possible optical and geometric isomers individually, and mixtures thereof.

Examples of compounds of the general formula I include those given in the following table.

R' H H H H H H H Me Me H H H H Pr H.

H H H H R 2 H H H H H H H H Me Bu i-Pr Et i-Bu H H H H H H n R 1 6-methoxy 1 6-cyclohexyl 1 6-amino 1 6-bromo 1 7-methyl 1 5-chloro 1 8-chloro 0 0 0 1 6-chloro 1 6-bromo 1 6-methyl 1 6-chloro 2 6,7-dichloro 2 6,8-dichloro 2 6-chloro-8-methyl 2 6-nitro-8-methyl 2 6-nitro-8-chloro The invention also provides a process for the preparation of a compound according to the invention, which comprises reacting a compound of the general formula ( 11) 1 598 127 1,598,127 e O XC-0-r I R 2 wherein R', R 2, N and R have the meanings given for the general formula I, and Y represents an alkyl, preferably a methyl or ethyl, group, with 2-propenamine, in the presence of a solvent, for example ethanol.

The reaction may be carried out at room temperature, but is preferably carried out under reflux Preferably a four-to-six fold molar excess of 2-propenamine is used.

The compounds of the general formula I and physiologically tolerable acid addition salts thereof have been found to inhibit lipogenesis in mammals Pharmaceutical compositions containing compounds according to the present invention are described and claimed in our copending Application No 10303/78 (Serial No.

1598126).

The following Examples illustrate the invention.

Example 1

3,4 dihydro N ( 2 propenyl) 2 H 1,4 benzoxazine 2 carboxamide ( 1) The hydrochloride of 3,4-dihydro 2 H 1,4 benzoxazine 2 carboxylic acid ethyl ester (IA) was prepared as white crystals, m p: 186-1880 C by condensation of o aminophenol and ethyl 2,3dibromopropionate in dry acetone in the presence of potassium carbonate according to the procedure described in British Patent Specification No 1,057,528 IA was treated with sodium bicarbonate to prepare the free base (IB).

A solution of 7 3 g of (IB) and 6 84 g of 2 propenamine in 50 ml of ethanol was stirred at room temperature for 3 days.

Then solvent and excess amine were stripped off and the residue was partitioned between ether and water The ether layer was separated and the aqueous layer was extracted with ether The ether solutions were combined, washed with water, dried (Mg SO 4), and concentrated to give 1, as white crystals, m p: 90-91 C.

Example 2

3,4 dihydro 4 methyl N ( 2propenyl) 2 H 1,4 benzoxazine2 carboxamide To a stirred solution of 2 6 g of(l B) in 50 ml of ethanol, a solution of 3 76 g of thallium ethoxide in 50 ml of ethanol was added dropwise at room temperature The resulting mixture was stirred at room temperature for 24 hours Then a solution of 1.8 g of methyl iodide in 50 ml of dimethylformamide was added and the resulting mixture was stirred at room temperature for 72 hours The mixture then was filtered and the solvent was stripped from the filtrate to leave a gum This product was refluxed overnight in ethanol containing a small amount of sulphuric acid as catalyst The resulting mixture was cooled and neutralised with sodium bicarbonate; the solvent was stripped off and the residue was partitioned between water and methylene chloride The methylene chloride layer was separated and the aqueous layer was extracted with methylene chloride; the methylene chloride solutions were combined, washed with water, dried (Mg SO 4) and the solvent was stripped off to give a liquid residue The residue was dry column chromatographed through silica gel, using Solvent No 3 (a 4:30:66 by volume mixture of tetrahydrofuran, ethyl acetate and hexane) as eluent On work-up, the faster-moving, major component was separated, dissolved in ether and treated with hydrogen chloride gas to form a gum.

The gum was separated and triturated with ethanol and the resulting solution was cooled to give the hydrochloride salt of the ethyl ester of 3,4 dihydro 4 methyl 2 H 1,4 benzoxazine 2 carboxylic acid ( 2 A) as white crystals, m p: 89-93 C.

A solution of 1 1 g of 2 A, and 5 ml of 2 propenamine in 25 ml of ethanol was refluxed for 16 hours The solvent and excess amine were stripped off and the residue was passed through a silica gel column using Solvent No 3 as eluent The solvent was stripped off to give 2, as light yellow liquid, boiling point not determined.

Example 3

6 chloro 3,4 dihydro N ( 2propenyl) 2 H 1,4 benzoxazine 2 carboxamide ( 3) 100 43.0 g of 2 amino 4 chlorophenol were dissolved in 500 ml of anhydrous acetone containing 42 O g of anhydrouspotassium carbonate The mixture was heated to reflux temperature and 105 23.0 g of ethyl 2,3 dibromopropionate were added dropwise In three additional portions each, additional ester and carbonate were added to the refluxing mixture until a total of 124 g of carbonate 110 and 85 8 g of ester had been added The mixture was refluxed for 21 hours Solids were filtered from the mixture and washed with acetone The filtrate was stripped of solvent and the residue was taken up in 115 water The water solution was extracted with ether The ether extract was dried (Mg SO 4) and the solvent was stripped The residue was eluted through a silica gel column using Solvent No 3, the solvent was 120 stripped and the residue was recrystallised 1,598,127 from ethanol, then from ether to give ethyl 6 chloro 3,4 dihydro 2 H 1,4 benzoxazine 2 -carboxylate ( 3 A), as white crystals, m p: 85 5-86 5 C.

3 was prepared as while platelets, m p:

114-114 5 C, by treating 3 A with 2 propenamine by the procedure of Example 1 of our copending Application No.

10303/78 (Serial No 1598126).

Example 4

6 methyl 3,4 dihydro N ( 2propenyl) 2 H 1,4 benzoxazine 2 carboxamide ( 4) 29.3 g of ethyl 2,3 dibromopropionate were added over a ten minute-period to a refluxing mixture of 19 0 g of anhydrous potassium carbonate, 56 6 g of 2 amino p cresol and 500 ml of dry acetone The ethyl 2,3 dibromopropionate and potassium carbonate addition was repeated thrice to give a total of 76 g of potassium carbonate and 118 g of ethyl 2,3 dibromopropionate The mixture then was refluxed for 17 hours, filtered and the filtrate was stripped of solvent under reduced pressure The liquid residue was diluted with 300 ml of IN sodium hydroxide solution at 5-10 C, then extracted four times with 300 ml portions of ether The extracts were combined, dried (Mg SO 4) and treated with hydrogen chloride gas at 5-10 C A solid which formed was filtered and extracted with acetone The residue was recrystallised from ethanol to give the ethyl ester of 6 methyl 3,4 dihydro 2 H 1,4 benzoxazine 2 carboxylic acid hydrochloride ( 4 A), as white crystals, m.p: 158-160 C.

42.4 g of 4 A and 38 g of 2 propenamine were mixed in 165 ml of ethanol and the mixture was stirred at room temperature for hours The solvent was removed under reduced pressure The residue was partitioned between ether and water The ether solution was dried (Mg SO 4), about half the solvent was evaporated and the solid which formed was filtered, then dried under reduced pressure to give 4, m.p: 113-115 C.

Example 5

6 nitro 3,4 dihydro N ( 2 propenyl) 2 H 1,4 benzoxazine 2 carboxamide ( 5) 29.2 g of ethyl 2,3-dibromopropionate were added dropwise to a refluxing mixture of 19 g of anhydrous potassium carbonate, 70.9 g of 4 nitro 2 aminophenol and 500 ml of dry acetone The ethyl 2,3 dibromopropionate and potassium carbonate addition was repeated thrice to give a total of 76 g of potassium carbonate and 118 g of ethyl 2,3 dibromopropionate The reaction mixture was refluxed for 17 hours, then filtered The filtrate was concentrated under reduced pressure The residue was washed with dilute sodium hydroxide solution, then was extracted with ether and with methylene chloride The solvents were evaporated.

Thin layer chromatographic analyses indicated that both products were the same.

They were combined and recrystallised from ether to give the ethyl ester of 6 nitro 3,4 dihydro 2 H 1,4 benzoxazine 2 carboxylic acid (SA), as a solid, m p: 88-90 C.

A mixture of 10 0 g of 5 A 9 1 g of 2 propenamine and 35 ml of ethanol was stirred at room temperature for 3 days The solvent was stripped under reduced pressure The residue was washed with ether, dried, and then recrystallised from ethanol to give 5, as orange crystals, m p:

142-144 C.

Example 6 85

3,4 dihydro 6 ((methylsulphonyl)amino) N ( 2 propenyl) 2 H 1,4 benzoxazine 2 carboxamide ( 6) Two 1 gram portions of 10 % palladium 90 on-carbon catalyst were added to 10 g of 5 A in 700 ml of ethanol The mixture was hydrogenated at 50 psig for 2 hours Fresh catalyst was added and the mixture again was hydrogenated This procedure was 95 repeated four times, when thin layer chromatographic analysis indicated that the nitro moiety had been completely converted to the amino moiety The reaction mixture was filtered and the filtrate 100 was concentrated to give the amino derivative ( 6 A) as a brown liquid.

A mixture of 14 7 g of 6 A and 7 3 g of triethylamine in 200 ml of methylene chloride was treated with 8 3 g of methane 105 sulphonyl chloride at 0-5 C The mixture then was stirred for 2 hours, washed with water, dried, filtered, and the solvent was evaporated The residue was washed with a small amount of ethanol, filtered, and 110 recrystallised from ethanol to give the methylsulphonylamino derivative ( 6 B), as a solid, m p: 149-1516 C.

A mixture of 7 3 g of 6 B, 20 ml of 2 propenamine and 10 ml of ethanol was 115 stirred at room temperature for 20 hours.

The solid product was filtered, dried and recrystallised from ethanol/acetone ( 6/1 v/v) to give 6, as white crystals, m.p: 178-180 C 120 Example 7

6 trifluoromethyl 3,4 dihydro N ( 2 propenyl) 2 H 1 1,4 benzoxazine 2 carboxamide ( 7) 87.6 g of finely powdered sodium 125 hydroxide were added in portions over an 1,598,127 8 hour period to a stirred solution of 164 0 g of 2 nitro 4 (trifluoromethyl)chlorobenzene in 220 ml of dimethyl sulphoxide at room temperature The mixture was allowed to stand overnight, then poured into 1 5 litres of cold water The resulting mixture was acidified to p H 1 with concentrated hydrochloric acid An oil formed; it was separated and dissolved in ether The solution was dried (Mg SO 4) and stripped of solvent under reduced pressure.

The residue was mixed with cold sodium hydroxide solution and the mixture was extracted with petroleum ether The water layer was acidified with concentrated hydrochloric acid The resulting oil was separated and dissolved in ether The solution was dried (Mg SO 4) and stripped of solvent under reduced pressure The residue was mixed with cold sodium hydroxide solution and the mixture was extracted with petroleum ether The water layer was acidified with concentrated hydrochloric acid The resulting oil was separated and dissolved in ether The solution was dried (Mg SO 4) and stripped of solvent to give 2 nitro 4 (trifluoromethyl)phenol ( 7 A).

82.2 g of 7 A were dissolved in 300 ml of ethanol 0 5 g of platinum oxide catalyst were added and the mixture was hydrogenated at 50 psig Fresh portions of catalyst were added periodically The reaction mixture was filtered, and the filtrate was concentrated The residue was crystallised from water to give 2 amino 4 (trifluoromethyl) phenol ( 7 B).

11.4 g of potassium carbonate were added to 48 7 g of 7 B in 320 ml of acetone Then 18 2 g of ethyl 2,3 dibromopropionate were added dropwise to the refluxing mixture The ethyl 2,3 dibromopropionate and potassium carbonate addition was repeated thrice, to give a total of 45 6 g of potassium carbonate and 72 8 g of ethyl 2,3 dibromopropionate The reaction mixture then was refluxed for 17 hours and filtered, and the filtrate was stripped of solvent under reduced pressure.

The residue was dissolved in ether; the solution was washed with dilute sodium hydroxide solution, then dried (Mg SO 4) and stripped of solvent The residue was washed with petroleum ether, dried and dissolved in ether The ether solution was partially concentrated and cooled The resulting crystals were filtered and recrystallised from ether to give the ethyl ester of 6 trifluoromethyl 3,4 dihydro 2 H 1,4 benzoxazine 2 carboxylic acid ( 7 C), m.p: 105-1070 C.

A mixture of 20 6 g of 7 C, 25 7 g of 2 propenamine and 34 ml of ethanol was stirred at room temperature for 36 hours.

The excess amine solvent were evaporated under reduced pressure The solid residue was mixed with 150 ml of ether and the remaining solid material was filtered The filtrate was added to petroleum ether and cooled; the resulting viscous material was filtered The filtrate was stripped and the residue was triturated with petroleum ether to give an off-white powder which was purified by dry-column chromatography (silica gel), using ether as eluent The higher Rf band was collected and extracted with ether, the solvent was stripped and the solid residue was recrystallised from ether/hexane ( 4/5 v/v) Thin-layer chromatography indicated that two components were present The product was purified by wet-column chromatography (silica gel) using petroleum ether/ethyl ether ( 1:4 v/v) as eluent The solvent was stripped and the residue was recrystallised from ether/hexane ( 75: 100 v/v) to give 7, as a solid, m p: 85-97 C.

Example 8

The effect of the compounds prepared in Examples 1-7 in the inhibition of lipogenesis was ascertained by immersing samples of swine adipose tissue in a liquid medium containing radioactive glucose and the test chemical for a period of time, then isolating the lipid from the treated tissue and determining the uptake of the radioactive carbon by means of scintillation counting techniques These tests were conducted in swine adipose tissue because in swine, the primary site of lipogenesisi.e fatty acid synthesis-appears to be adipose tissue.

Described in more detail, the tests were conducted according to the following general procedure:

milligrams of slices of swine adipose tissue were incubated at 37 C for 2 hours with shaking in 3 millimetres of KrebsRinger bicarbonate solution containing onehalf the normal calcium ion concentration, micromoles of glucose, 0 5 micro-Curie of glucose U 14 C, and 300 micro-units of insulin, and 5 % dimethyl sulphoxide (DMSO) The test compounds were added as a solution or suspension in DMSO and were present at a concentration of 100 micrograms per millilitre of the incubation mixture.

The incubation was terminated by addition of 0 25 millilitre of IN sulphuric acid The resulting mixture was extracted with a total of 25 millilitres of chloroform:methanol ( 2: 1, v/v) The extracts were washed according to Folch et al (J.

Biol Chem, 226, 497-509, ( 1957)), air dried, and counted in a liquid scintillation counter with 15 millilitres of counting fluid (two parts toluene containing 0 4 % w/v) New England Nuclear Omniflour: I part Triton X-100 ("Triton" is a registered 11 127 5 Trade Mark)) The tests were conducted in triplicate and were accompanied by control tests in which all ingredients, proportions and conditions were the same except that no test compound was included From the date obtained were calculated the percent inhibition of lipid synthesis by the test compounds in each case The data obtained from the tests are set out in the following Table as the percent inhibition of lipogenesis compared to the results obtained in the control tests wherein only the test compound was omitted.

TABLE

Compound No.

1 2 3 4 6 Percent inhibition of lipogenesis 51 63 57 atoms; and R 2 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

2 A compound as claimed in claim 1, wherein R' represents a hydrogen atom.

3 A compound as claimed in either claim 40 1 or claim 2, wherein R 2 represents a hydrogen atom or a methyl group.

4 A compound as claimed in any one of claims 1 to 3, wherein N is 0, or N is 1 and R is a chlorine atom or an alkyl or 45 trifluoromethyl group.

A compound as claimed in any one of claims 1 to 4, wherein N is 1 and R is a substituent in the 6-position.

6 A compound as claimed in claim I and 50 named in any one of Examples 1 to 7 herein.

7 A process for the preparation of a compound as claimed in claim 1, which comprises reacting a compound of the general formula 55 R 2 II

Claims

WHAT WE CLAIM IS:-

1 A compound of the general formula tl' O Tl NH-CH 2-CH=CH 2 l R 1 I R 2 or an acid addition salt thereof, wherein N is 0, 1 or 2; R, each of which when N is 2 may be the same or different, is a fluorine, chlorine or bromine atom, a nitro, amino, methylsulphonylamino or trifluoromethyl group, an alkyl or alkoxy group having 1 to 6 carbon atoms, or a cycloalkyl group having 3 to 6 carbon atoms; R' is a hydrogen atom or an alkyl group having 1 to 4 carbon wherein R', R' N and R have the meanings given in clairr, and Y represents as alkyl group, with 2-propenamine, in the presence of a solvent.

8 A process as claimed in claim 7, carried out substantially as described in any one of Examples 1 to 7 herein.

9 A compound as claimed in claim 1 wherever prepared by a process as claimed in either claim 7 or claim 8.

R C ROGERS, Chartered Patent Agent, Shell Centre, London SE 1 7 NA, Agent for the Applicants.

Printed for Her Majesty's Stationery Office, by the Courier Press, Leamington Spa, 1981 Published by The Patent Office, 25 Southampton Buildings, London, WC 2 A l AY, from which copies may be obtained.

1.598 127 is 1