GB1598128A

GB1598128A - Benzopyran carboxamides having lipogenesis-inhibiting properties

Info

Publication number: GB1598128A
Application number: GB31590/78A
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: DD137714A5; DK117478A; FR2424741A1; DE2811236A1; LU79238A1; GB1598126A; NL7802921A; GB1598127A; PL205322A1; BE864918A; PL127781B1; JPS53116377A; IE780532L; IE46676B1

Description

PATENT SPECIFICATION (") 1 598 128

( 21) Application No 31590/78 ( 22) Filed 15 March 1978 ( 62) Divided out of No1598126 ( 19 ( 31) Convention Application No778534 4 ( 32) Filed 17 March 1977 e ( 31) Convention Application No 779648 ( 32) Filed 21 March 1977 in ( 33) United States of America (US) ( 44) Complete Specification published 16 Sept 1981 ( 51) INT CL 3 C 07 D 311/74 ( 52) Index at acceptance C 2 C 1673 200 213 220 221 225 226 22 Y 247 253 25 Y 270 271 280 304 30 Y 313 31 Y 326 337 342 34 Y 360 362 366 368 36 Y 37 X 491 579 584 623 628 62 X 62 Y 65 X 672 676 678 802 Y AA BE KF KP MB ( 72) Inventor JOHN BERNARD CARR ( 54) BENZOPYRAN 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: 5

The invention relates to benzopyran carboxamides having lipogenesisinhibiting properties.

The invention provides a compound of the general formula 0 0 i I CE-NH-CH -CH=CH 2 (I) R X wherein X represents a hydrogen atom or a hydroxyl group and R represents a 10 hydrogen or a halogen atom; a nitro, amino, trifluoromethyl or methylsulphonylamino group; an alkyl or alkoxy group having 1 to 6 carbon atoms; a cycloalkyl group having from 3 to 6 carbon atoms; or a phenyl, phenoxy, benzyl or 2-phenethyl group optionally-substituted on the ring by one or two of the same or different substituents selected from halogen atoms, nitro groups and alkyl 15 groups having from I to 6 carbon atoms; and wherein if X represents ahydroxyl group, this group is cis to the 0 I 1 -C-NH-CH 2 CH=CH 2 group.

Any alkyl moiety present in the group R may be straight-chain or branched 20 Any halogen atom is preferably a bromine or chlorine atom.

The invention should be understood to include the individual optical isomers of compounds of the general formula I and mixtures thereof.

Preferably R represents a hydrogen or chlorine atom or a phenyl or cyclohexyl group, and preferably X represents a hydrogen atom 25 The invention also provides a process for the preparation of a compound of the general formula I, which comprises reacting a compound of the general formula 2 1,598, 1282 0 O IC O ( 11) R X wherein R and X have the meanings given above and Y represents an alkyl, preferably a methyl or ethyl group, with 2-propenamine The reaction is preferably carried out under reflux in a suitable solvent, for example ethanol, using a 4 to 6fold excess of 2-propenamine 5 The invention further provides a process for the preparation of a compound of the general formula I wherein X represents a hydrogen atom, which comprises reacting a compound of the general formula 0 0 1 CC ( 111) L-lt R wherein R has the meaning given above, with 2-propenamine Suitably an excess 10 of 2-propenamine is used, and the reaction is carried out under reflux in a suitable solvent, for example methylene chloride The compounds of the general formulae II and III may be prepared by any suitable method-see for example -Witiak et al, J Med Chem 14 758-66 ( 1971) and 18 934-42 ( 1975) and Taylor et al J Chem Soc.

London 1950, 2724-5 15 The compounds of the general formula I have been found to inhibit lipogenesis in mammals for example, to lower the levels of cholesterol and triglyercides in the blood of mammals Pharmaceutical compositions containing compounds of the general formula I are described and claimed in our copending Application No.

10303/78 (Serial No 1598126) 20 The following Examples illustrate the invention.

Example I

6-chloro-3,4-dihydro-N-( 2-propenyl)-2 H Ibenzopyran-2-carboxamide ( 1) A solution of 3 1 g of 6chloro 3,4 dihydro 2 H I benzopyran 2 25 carboxylic acid (Witiak et al ( 1971) supra) in 15 ml of thionyl chloride was refluxed for 45 minutes The excess thionyl chloride then was stripped off and the residual liquid taken up in 50 ml of methylene chloride To this stirred solution was added dropwise a solution of 2 5 g of 2-propenamine in 10 ml of methylene chloride The resulting mixture was stirred at room temperature overnight, then was washed with 30 water, dried (Mg SO) and stripped of solvent Dry column chromatography of the solid product through silica gel, using solvent No 3 (a 4:30:66 by volume mixture of tetrahydrofuran, ethyl acetate and hexane) as eluent, followed by recrystallization of the product from methylene chloride and hexane gave 1, as a pale yellow solid, m p: 112 5-114 C 35 Example 2

3,4-dihydro-N-( 2-propenyl)-2 H I -benzopyran-3-carboxamide ( 2) A solution of 10 4 g of the methyl ester of 2 H 1 benzopyran 3 carboxylic acid (Taylor et al, supra) in 50 ml of methanol containing 300 mg of 10 % palladium-on-carbon catalyst was hydrogenated in a Parr apparatus for 1 5 hours, 40 at an initial pressure of 44 psig The mixture was then filtered through a Celite (Trade Mark) pad, the filtrate was stripped of solvent, and the product was vacuum distilled to give methyl ester of 3,4 dihydro 2 H I benzopyran carboxylic acid ( 2 A), as a colorless liquid, b p: 86-88 ( 0 01 Torr).

A solution of 5 g of 2 A and 5 7 g of 2-propenamine in 50 ml of ethanol was 45 refluxed for 6 days Stripping of the solvent, followed by charcoal treatment of the product and recrystallization of the treated product from ether-hexane, gave 2, as white crystals, m p: 114 5-115 5 C.

1,598,128 3 1,598,128 3 Example 3

3,4-dihydro-N-( 2-propenyl)-2 H 1-benzopyran-2-carboxamide ( 3) 3 was prepared as white crystals, m p: 76-77 C from the ethyl ester of chroman-2-carboxylic acid (Witiak et al ( 1971)) and 2-propenamine, by the procedure described in the last paragraph of Example 2 5 Example 4

3,4-dihydro-6-phenyl-N-( 2-propenyl)-2 H 1-benzopyran2-carboxamide ( 4) 4 was prepared as a white solid, m p: 123-124 C from the ethyl ester of 3,4 dihydro 6 phenyl 2 H I benzopyran 2 carboxylic acid (Witiak et al 10 ( 1975)) and 2-propenamine by the procedure described in the last paragraph of Example 2.

Example 5

6-cyclohexyl-3,4-dihydro-N-( 2-propenyl)-2 H I benzopyran-2-carboxamide ( 5) 15 was prepared, as white crystals, m p: 93-94 C by the procedure described in the last paragraph of Example 2, from the ethyl ester of 6 cyclohexyl 3,4 dihydro 2 H 1 benzopyran 2 carboxylic acid (Witiak et al ( 1975)) and 2propenamine.

Example 6 20

6-chloro-3,4-dihydro-N-( 2-propenyl)-2 H I -benzopyran3-carboxamide ( 6) To a stirred, refluxing mixture of 50 g of 3 chloro 6 hydroxybenzaldehyde and 62 ml of acrylonitrile in 50 ml of water, a solution of 12 8 g of sodium hydroxide in 120 ml of water, was added dropwise over a three-hour period 25 Then an additional 62 ml of acrylonitrile was added and the stirred mixture was refluxed for 2 hours, then allowed to stand at room temperature overnight The crystals which formed were filtered off, washed with water and dried to give a solid, which was recrystallized from ethanol The solution was filtered and cooled to give 6 chloro 3,4 dihydro 4 hydroxy ( 2 H) 1 benzopyran 3 carbonitrile 30 ( 6 A) as a solid A mixture of 6 A with 250 ml of methanol containing 2 ml of sulphuric acid was refluxed for 4 days and stripped of solvent The resulting residue was dry column chromatographed over silica gel, using solvent No 3 as eluent The product obtained on work-up was rechromatographed and recrystallised from ether to give methyl 6 chloro 2 H 1 benzopyran 3 carboxylate ( 6 B) as 35 light yellow needles, m p: 106-109 C.

700 mg of 6 B were dissolved in 75 ml of ethyl acetate and the solution was treated with hydrogen (initial pressure of 30 psig), in the presence of a 10 % palladium-on-carbon catalyst, for 8 hours The reaction mixture then was filtered and stripped of solvent to give methyl 6 chloro 3,4 dihydro 2 H I 40 benzopyran 3 carboxylate ( 6 C), as a yellow liquid, boiling point not determined.

A mixture of 500 mg of 6 C, 5 ml of 2-propenamine and 25 ml of ethanol was refluxed for 18 hours The solvent was then stripped off and the residue was taken up in methylene chloride, triturated with hexane and cooled to give a solid The solid was redissolved in ethanol, the solution was passed through a short silica gel 45 column and the eluent was stripped of solvent The residue was recrystallized from methylene chloride/hexane to give 6, as white needles, m p: 171-171 5 C.

Example 7

6-chloro-4-hydroxy-N-( 2-propenyl)-2 H 1-benzopyran-2carboxamide (cis isomer) ( 7) 50 A solution of 512 mg of the ethyl ester of 6 chloro 3,4 dihydro 4 hydroxy 2 H I benzopyran 2 carboxylic acid (prepared by treating' the ethyl ester of 6 chloro 3,4 dihydro 4 oxo 2 H I benzopyran 2 carboxylic acid (Witiak et al, supra) with sodium borohydride), 570 mg of 2propenamine and 20 ml of ethanol was stirred at room temperature for 72 hours, 55 then stirred for 3 hours while heated by a steam bath The solvent was stripped off and the residue was crystallized from methylene chloride/hexane to give 7, as white crystals, m p: 129-130 5 C.

Example 8

Tests to determine lipogenesis inhibition of compounds prepared in Examples 60 1 to 7 were conducted according to the following general procedure:

1.598 128 Tissue slices ( 200 milligrams for liver; 150 milligrams for adipose tissue) were incubated, at 37 C for 2 hours with shaking in 3 millilitres of KrebsRinger bicarbonate solution containing one-half the normal calcium ion concentration, 60 micromoles of glucose, 0 5 micro-Curie of glucose-U-14 C, 300 micro-units of insulin, and 5 % dimethyl sulphoxide (DMSO) The test compounds were present at 5 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 incubation 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 10 scintillation counter with 15 millilitres of counting fluid (two parts toluene containing 0 4 % w/v New England Nuclear Omnifluor:l part Triton X-100) ("Triton is a registered Trade Mark) The tests were conducted in triplicate and were accompanised by control tests in which all ingredients, proportions and conditions were the same except that no test compound was included From the 15 data obtained, the percent inhibition of lipid synthesis by the test compound was calculated The results are shown in the following Table.

TABLE I

Percent Inhibition Compound No of Lipid Formation 20 1 59 2 83 3 72 4 76 5 40 25 6 67 7 55 Example 9

The effects of compounds I and 2 on the levels of cholesterol and triglycerides in the blood of a mammal were established as follows: 30 The procedure of Schurr et al, Lipids, 7, 68-74 ( 1972) was followed In this procedure, hyperlipemia was induced in rats by intraperitoneal injection of Triton WR-1339 ("Triton" is a registered Trade Mark) (oxyethylated tertiaryoctylphenol/formaldehyde polymer, Ruger Chemical Co), employing four groups of ten Sprague-Dawley strain male albino rats, each rat weighing 260-280 grams 35 After a 2-week stabilising period, two groups (III and IV) were fasted for 24 hours.

Then each rat was injected with a solution of the polymer in a saline vehicle ( O 15 M sodium chloride solution; ( 62 5 milligrams of polymer per millilitre solution)), to give a dosage of 225 milligrams of polymer per kilogram of rat body weight Two control groups (I and II) were also fasted and each rat received 2 millilitres of the 40 saline vehicle Groups II and IV received the test compounds in the vehicle, while Groups I and III received the vehicle only The concentration of test compound in the vehicle was 8 22 x 10-3 millimoles/millilitre A total dose of 0 124 millimoles/kilogram of body weight was administered to the rats Each rat received two 2-millilitre doses by gastric incubation, the first immediately after the polymer 45 injection, and the other 20 hours later Fasting was continued following injection of the polymer 43 hours after the polymer was injected, the rats were anesthetised and blood was drawn from the abdominal aorta and centrifuged Triglyceride content of the plasma was determined by the method of Eggstein, Wochenschr, 44, 267 ( 1966) Cholesterol content of the plasma was determined by the method of 50 Holub et al, Clin Chem, 18, 239 ( 1972) The results are shown in Tables 2 and 3.

Statistical analysis of the results show that:

(I) Comparison of Groups I and II indicate the effect of the drug on the normal rat Compound I significantly lowered serum cholesterol levels in the normal rate (Table 2) 55 ( 2) Groups III and IV were both hyperlipemic, Group 111 being the control and Group IV receiving the experimental drug Compounds I and 2 both significantly lowered the cholesterol level (Ill vs IV) Both compounds also significantly lowered triglyceride levels in the hyperlipemic group (III vs IV) (Table 3).

A TABLE 2

Effect of Test Compounds on Plasma Cholesterol Drug-Treated Drug-Treated Triton Hyper Triton HyperCompound Control Group (I) Control (II) lipemic (III) lipemic (IV) 1 71 4 + 8 04 62 8 + 8 77 144 9 + 72 88 102 6 + 17 38 5 2 64 9 + 12 04 63 4 12 18 167 1 + 72 76 109 6 + 22 14 TABLE 3

Effect of Test Compounds on Plasma Triglycerides Drug-Treated Drug-Treated Triton Hyper Triton Hyper 10 Compound Control Group (I) Control (II) lipemic (III) lipemic (IV) 1 43 8 + 6 52 44 7 + 10 87 142 5 + 64 52 39 2 + 4 80 2 33 1 + 9 09 39 6 + 8 24 136 8 + 60 8 48 1 16 8

Claims

WHAT WE CLAIM IS:-

1 A compound of the general formula 15 0 0-x II IEC-NH-C Hi-CH=CH 2 (I) R X wherein X represents a hydrogen atom or a hydroxyl group and R represents a hydrogen or a halogen atom; a nitro, amino, trifluoromethyl or methylsulphonylamino group; an alkyl or alkoxy group having 1 to 6 carbon atoms; a cycloalkyl group having from 3 to 6 carbon atoms; or a phenyl, phenoxy, benzyl 20 or 2-phenethyl group optionally-substituted on the ring by one or two of the same or different substituents selected from halogen atoms, nitro groups and alkyl groups having from I to 6 carbon atoms; and wherein if X represents a hydroxyl group, this group is cis to the 0 11 2 _-C-NH-CH 2-CH=CH 2 25 group.

2 A compound as claimed in claim 1, wherein R represents a hydrogen or chlorine atom or a phenyl or cyclohexyl group.

3 A compound as claimed in claim 1, named in any one of Examples I to 7 herein 30 4 A process for the preparation of a compound as claimed in claim 1, which comprises reacting a compound of the general formula 0 0 Il C-0-y (II) R X wherein R and X have the meanings given in claim 1, and Y represents an alkyl group, with 2-propenamine 35 A process for the preparation of a compound as claimed in claim 1 wherein X represents a hydrogen atom, which comprises reacting a compound of the general formula 0 O JX C-Cl (III) R 1.598 128 6 1 598,128 6 wherein R has the meaning given in claim 1, with 2-propenamine.

6 A process as claimed in either claim 5 or claim 6 carried out substantially as described in either Examples 2 to 7 or Example 1, respectively.

7 A compound as claimed in claim 1, whenever prepared by a process as claimed in any one of claims 4 to 6 5 R C ROGERS, Chartered Patent Agent, Shell Centre, London SEI 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 IAY, from which copies may be obtained.