IL40627A - Alpha-imidazolinonylcarbonylamino derivatives of benzyl-and thienyl-2-methyl-penicillins,their preparation and pharmaceutical compositions or feed additives containing them - Google Patents

Abstract

1392850 Penicillins and intermediates therefor BAYER AG 23 Oct 1972 [23 Oct 1971 25 March 1972] 48700/71 Heading C2C Penicillins of the general formula or their salts in which C* is a carbon atom constituting a centre of chirality; A is a radical of one of the general formulµ (in which general formulµ X is Y is Q 1 is or a radical of formula and Q 2 is a radical of formula wherein R is a straight-chain or branched alkyl radical with up to 5 carbon atoms; R 1 is a hydrogen atom or an alkyl, cycloalkyl, alkenyl or cycloalkenyl radical with up to 10 carbon atoms, or a vinyl, arylvinyl, mono-, di- or trihalo C 1-6 alkyl radical, or an H 2 N-, R-NH-, (R) 2 =N-, aryl -NH-, or aryl C 1-6 alkylamino radical or an alkoxy*, or aralkoxy* radical with up to 8 carbon atoms, or a cycloalkoxy* radical with up to 7 carbon atoms, or an aryloxy*, R-O-V-, R-S-V-, (R) 2 =N-CO-V- or a radical of formulµ V is a divalent organic radical with 1 to 3 carbon atoms; n is 0, 1, or 2; R 2 and R 3 which may be the same or different are each a hydrogen atom or an alkyl or alkenyl radical having up to 8 carbon atoms or a vinyl, allyl or propenyl radical, or a cycloalkyl or cycloalkenyl radical having up to 6 carbon atoms, or a mono-, di-, or tri-halogeno C 1-6 alkyl or aryl radical; R 4 , R 5 and R 6 which may be the same or different are each a hydrogen, nitro, nitrile, (R) 2 =N-, (R) 2 = N-CO-, R-CO-NH-, R-O-CO-, R-CO-O-, R, R-O, H 2 N-SO 2 -, chlorine, bromine, iodine, fluorine or trifluoromethyl radical; and G is a hydrogen atom. or a radical R; with the proviso that the meanings marked* are only available if X is not an -SO 2 - radical); Z is a - CO- or -SO- radical; and B is a radical of the general formula in which R 7 , Rs and R 9 are identical or different radicals selected from hydrogen, halogen, R-, R-O-, R-S-, R-SO-, R-SO 2 -, nitro(R 2 )=N-, R-CO-NH-, HO, and radicals and R is as above defined; and in which above general formulµ the arrow in the divalent linkage member ##Q2 means that the linkage of two atoms by the two free valencies of this linking member is not free to take place in either direction but only in the manner indicated by the arrow are prepared by (i) producing a reactive intermediate by reacting a carboxylic acid, a carboxylic acid salt, or a carboxylic acid silyl or hemisilyl ester of the general formulµ in an aqueous or anhydrous organic solvent when a compound of general formula a or b is reacted, or in an anhydrous inert organic solvent free of hydroxyl groups when a compound of general formula c or d is reacted, at - 70‹ to + 30‹ C., with either (a) a compound of one of the following general formulµ or (b) with a reaction product produced by the reaction of a compound of the general formula with about 1 mol. equivalent of thionyl chloride in an inert anhydrous organic solvent in the presence of at least one mol. equivalent of an organic base acting as an acid-acceptor at a temperature within the range - 40‹ to + 25‹ C.; the reaction product being reacted without prior isolation in the presence of a further mol. equivalent of a base, with about 1 mol. equivalent of the acid of formula (a), or in the presence of 0-1 mol. equivalent of a base, with about 1 mol. equivalent of a compound of formula b, c or d, at a temperature of - 40‹ to + 30‹ C., whereby the reactive intermediate produced is of the general formula (c) (only available for carboxylic acids of formula a) with about 1 mol. equivalent of a carbodiimide in a diluent and in the presence of about 1 mol. equivalent of a compound of Formula XIX whereby the reactive intermediate produced is of the general Formula XX the diluent being anhydrous and free of hydroxyl groups if a compound of the general formula is to be used in step (ii); and (ii) reacting the reactive intermediate with 6-aminopenicillanic acid of the general formula or silyl or disilyl-6-aminopenicillanic acid of Formula XXI and XXII in a solvent in the presence of a base when 6-aminopenicillanic acid is used, or in an anhydrous solvent free of hydroxyl groups when a compound of the Formula XXI or XXII is used, at a temperature in the range of - 70‹ to 50‹ C., to produce the desired penicillin compound, wherein Me<SP>n(+)</SP> is a cation of an n-valent alkali metal or alkaline earth metal or an aluminium cation; R 10 , R 11 and R 12 are the same or different C 1-6 alkyl radicals, R 13 can have any of the meanings given for R and can also be a phenyl radical; R 14 is a -(CH 2 ) 4 -, -(CH 2 ) 5 - or -(CH 2 ) 2 -O-(CH 2 ) 2 , radical; the groups U which can be the same or different are -C # N or -CO-O-C 1-6 alkyl radicals; and W is a halogen atom). Penicillins of the above general formula wherein B is as above defined except that it is not cyclohexadienyl and in which R 7 , R 8 and R 9 which may be the same or different, are each a hydrogen, halogen, R-, R-O-, R-S-, R-SO-, R-SO 2 -, nitro, (R) 2 =N, R-CO-NH, HO or R-CO-O- radical, R being as above defined, provided that when two of R 7 , R 8 and R 9 are hydrogen the other cannot be hydroxyl, and that all three of R 7 , R 8 and R 9 cannot at once be hydrogen, are stated to be novel. The carboxylic acids of formula (a) can be obtained from the amino acids of the general formula by reaction with compounds of the general formula A-Z-W(e), (in which A, B, Q 1 , Q 2 , R 1 , R 2 , X, Y, Z, C* and W are as defined above). Compounds of formulµ (e), (f), (g), (h) and (i) are prepared by conventional methods. Pharmaceutical compositions having antibacterial activity useful in human and veterinary medicine comprise the above penicillins and a carrier. The compositions may be administered orally, parenterally, rectally or topically in conventional pharmaceutical forms. The following starting materials are prepared; α[(3 - methyl - sulphonyl - imidazolidin - 2 - on- 1 - yl)carbonylamino] - phenylacetic acid, -4 - chloro - phenyl acetic acid, and -α- thienyl - (2) - acetic acid and 2,6 - dichlorophenyl acetic acids; α[(3-acetyl-imidazolidin- 2 - on - 1 - yl)carbonylamino] - phenyl acetic acid, -4 - chloro - phenylacetic acid, 4 - mothylphenyl acetic acid, -α - thienyl - (2) - acetic acid, 2,6 - dichloro - phenyl acetic acids, α - [(3 - ethylsulphonyl - imidazolidin - 2 - on- 1 - yl) carbonylamino] - phenyl acetic acid and -p - chlorophenyl acetic acid; and α[(3- methoxy carbonyl - imidazolidin - 2 - on - 1- yl) carbonylamino] - 4 - chlorophenylacetic and α-thienyl (2)-acetic acids. [GB1392850A]

Claims (9)

1. CLAIMS 1. Oompounds which are penicillins of the following general formula or their salts :- in which • 0* is a carbon atom constituting a centre of chirality; A is a radical of the general formula in which is lower alkyl; lower alkylamino'; furyl; lower alkoxy (when X- is CO); X is CO or S02; Z is CO and . B is thienyl, or phenyl substituted "by halogen or lower alkyl.

2. Oompounds according to Claim 1 in which A is

3. Compounds according to Claim 1 in which A is - 78 - 40627/2 Compounds according to Claim 1 in which A is 0 CH5C0-^^i- Compounds according to claim 1 in which A is Compounds according to Claim 1 in which A is Compounds according to Claim 1 in which A is Compounds according to Claim 1 in which A is 9. Compounds according to any of Claims 1 to 8 in which B is halo or alk l-substituted phenyl. 10» Compounds according to any of Claims 1 to|8 in which B is £-methylphenyl . 11. Compounds according to any of Claims 1 toj 8 in which B is jg-chlorophenyl. -.79 - 40627/2 12. Compounds according to any of Claims 1 to ιβ in which B is thienyl-(2). i 13^ Compounds according to any preceding claim, in which C* is in the R-configuration. 1

4. ' <*rl (3-Methylsulphonyl-imidazolidin-2-on-l-yl)-carbonyl-amino] -4-chloro-benzylpenicillin of the formula:- 1

5. ct-[ (3-Methylsulphohyl-imidazolidin-2-on-l-yl)-carbonyl-amino]-a-thienyl (2)-methylpenicillin of the formula:- { (3-Me hylsulphonyl-imidazolidin-2-on-l-yl)-carbonyl amino]-2,.6-dichloro-benzylpenicillin of the formula :- - 80 - 40627/2 17. ; α-[ (3-Acetyl-imidazolidin-2-on-l-yl)-carbonylamino]-4-chloro-benzylpenicillin of the formula:- CH, 18. ct-L(3-Acetyl-imidazolidin-2-on-l-yl)-carbonylamino]-4-meth l-benzylpenicillin of the formula:- "~ 19 · a-[ (3-Acetyl-imidazolidin-2-on-l-yl)-carbonylamino]-a-thienyl (2)-methylpenicillin of the · formulat¬ 2°· j a-[(3-Acetyl-imidazolidin-2-on-l-yl)-carbonylamino]-2,6-dichloro-benzylpenicillin of the formula:- - 81 - 40627/2 21. ct- [(3-Ethylsulphonyl-imidazolidin-2-on-l-yl)-carbonyl amino ]-4-chloro-benzylpenicillin of the formula:- - 82 - ' 40627/2 2· I a- [(3- ethylsulphonyl-imidazolidin-2-on-l-yl)-carbonyl-amino ]-4-methyl-benzylpenicillin of the forraula:- ,23. t-LiJ-Methoxycarbonyl-imidazolidin^-on-l-ylJ-carhonyl-amino ]-4-chloro-benzylpenicillin of the formula:- 24. o-[(3-Methoxycarbonyl-imidazolidin-2-on-l-yl)-carbonyl-amino]-a- hienyl (2)-methylpenicillin of the formula:- 25. Compounds according to any preceding claim which are salts of the acid carboxyl group of a compound of the general formula I with sodium, potassium, magnesium, calcium, alumium, - 83 - 40627/3 - or unsubstituted or substituted ammonium. 2

6. Compounds according to Glaim 1 which are hereinbefo specifically mentioned other than those according to one of Claims 13 to 24. 2

7. A process for the production of compounds according to Claim 1 wherein A has the same meaning as in Claim 1 and B is thienyl or phenyl substituted by halogen or lower alkyl, and also the compounds claimed in copending Application No. 40628 in which B is phenyl, hydroxyphenyl or 1 ,4-cyclo-hexadien-1 -yl, comprising the steps of:- (i) producing a reactive intermediate by reacting a carboxyl acid of the following general formula (V) , a carboxylic acid salt of the following general formula Va, or a carboxylic acid silyl or hemisilyl ester of the general formula Tb or Vc A-Z-NH-CH-COOH V B * A-Z-NH-CH-C0-0 /R10 * / A-Z-NH-CH-CO-O 11 B - 84 - 40627/2 in an aqueous or anhydrous organic solvent when a compound of the general formula V or Va is reacted, or in an anhydrous inert organic solvent free of hydroxyl groups when a compound of general formula Vh or Vc is reacted, at -70°0 to +30°C, with either: (a) a compound of one of the following general formulae VI to or (b) with a reaction product produced by the reaction of a compound of the general formula:- with about 1 mol equivalent of thionyl chloride in an inert anhydrous organic solvent in the presence of at least one mol equivalent of an organic base acting as an acid-acceptor at a temperature within the range -40°0 to +25°C; the said reaction product being reacted without prior isolation in the presence of a further mol equivalent of a base, with about 1 mol equivalent of the carboxylic acid of general formula V, or in the presence of 0-1 mol equivalent of a base, with about 1 mol equivalent of a compound of the general formula Va, Vb or Vc, at a temperature of -40°C to +30°C, whereby the reactive intermediate produced is of the general formula:- 0 A-Z-NH-CH-C U 0-N=C xi; (c) [only available for carboxylic acids of general formula V] with about 1 mol equivalent of a carbodiimide in a diluent and in the presence of about 1 mol equivalent of a compound of the general formula X, whereby the reactive intermediate produced is of the general formula:- the said diluent being anhydrous and free of hydroxy1 groups if a compound of the general formula III or IV is to be used in step (ii) ; and (ii) reacting the reactive intermediate with 6-aminopenicillanic acid of the following general formula II or silyl- or di-silyl-6-aminopenicillanic acid of the general formula III or IV:- II - - 87 - 40627/2 in a solvent in the presence of a ase when 6-aminopenicillanic acid is used, or in an anhydrous solvent free of hydroxyl groups when a compound of the general formulae III or IV is used, at a temperature in the range of -70°C to +50°C, to produce the desired penicillin compound of any preceding claim; [in which general formulae II to Xlla: A, B; C*, tand are ,as, def.ined above; R is a straight or branched alkyl mdical with up to 5 carbon atoms; n(+) Me - is a' cation of an n-valent alkali metal or alkaline earth metal or an aluminium cation; R10» Rll a d R12 are *ηθ same or diff,eren-fc lower alkyl radicals ; can have any of the meanings given for R and can also be a phenyl radical; R14 is a -(CH2)4-, -(CH2)5-, or -(CH2)2-0-(CH2)2- ' radical; the groups U which can be same or different are -CaN or - - 88 - 40627/2 W is a halogen atom ]. 2

8. A process according to claim^' in which the reaction in step (i)(a) is carried out in the presence of about 1 mol equivalent of an N-hydroxy compound of the formula in which U is as defined in claim 26. 2,

9. A process according to claim in which an optical activity present at the chirality centre C* is protected against possible racemization by carrying out the reaction in step (i)(a) or (b) either in the absence of any organic base or in the presence of a weak organic base. 30. The process of claim 27 in which the reaction in step (i)(a) is carried out in the presence of N-methyl-morpholine, N-ethylmorpholine , N,N-dimeth lalanine, pyridine, a weak inorganic base, or a buffer. 31. A process according to any of claims^ 27 to 30 in which the reaction in step (i)(a) is carried out at -70°C to 0°C. 32.' A process according to any of claims, 27 " to ' 31 in which the reaction in step (ii) is carried out at - 0°C to 0°G. 33. A process according to any of claims! 27 to! 31 in which j . 40627/2 the reaction in step (ii) is "carried out at a pH within the range 2 to 9. 34. A process according to claim 33 in which the reactio in step (ii) is carried out at a pH within the range 2 to 3. 35 j A process according to claim 33 in which the said pH is within the range 6.5 to 8.5 . 36. A process for the preparation of the compounds of any of claims 1 to 26 substantially as hereinbefore described or specifically exemplified. 37. Compounds according to claim 1 whenever produced by the process of any of claims 27 to 36 . 38. A pharmaceutical composition containing as an active ingredient a compound according to any of claims 1 to; 26 or 37 in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent of molecu lar weight less than 200 except in the presence of a surface-active agent. 39. A pharmaceutical composition containing as an active ingredient a compound according to any of claims 1 to126' and 37, in the form of. a sterile or isotonic aqueous solution. 40. A composition according to claia;38 or 39 containing from ,0.5 to 95$ of active ingredient, by weight. 41. A pharmaceutical composition according to claim38 or 38 substantially as hereinbefore described or specifically exemplified. 42* A medicament in dosage unit form comprising a compound according to any of claims 1 to!' 26 or! 37 either alone or in admixture with a diluent. 43. A medicament in the form of tablets, pills, dragees, capsules, ampoules or suppositories comprising a compound according to any of claims 1 to 26 or- 37, either alone or in admixture with a diluent-. . 0627/2 , 4. . A. medicament according to claim 2 or 43 , substantially as hereinbefore described or specifically exemplified. 45. A method of combating bacterial infectio inj non-human animals which comprises administering to the animals •an active compound according to any of claims 1 to' 26 ori f! either alone or in admixture with a diluent or in the form of a medicament according to claim 42 , ; 43 or 44 . 46. A method according to claim 45..in which the active compound is administered orally or parenterally at' 25 ,000 to 1, 000,000 U/kg of body weight per day. ■ 47. A method according to claim 46 -substantially as hereinbefore described or specifically exemplified. 48. An animal feedstuff comprising a nutritious material 31 and a compound of any of claims 1 to j 26 and'-5 T