GB1570146A - 7-amino - 3 - heterocyclicthiomethyl-cephem derivatives - Google Patents

7-amino - 3 - heterocyclicthiomethyl-cephem derivatives Download PDF

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GB1570146A
GB1570146A GB3802977A GB3802977A GB1570146A GB 1570146 A GB1570146 A GB 1570146A GB 3802977 A GB3802977 A GB 3802977A GB 3802977 A GB3802977 A GB 3802977A GB 1570146 A GB1570146 A GB 1570146A
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amino
ylthio
carboxylic acid
carbamoylmethyl
methylceph
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GB3802977A
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Beecham Group PLC
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Beecham Group PLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Description

(54) 7-AMIN0-3-HETEROCYCLICTHIOMETHYL-CEPHEM DERIVATIVES (71) We, BEECHAM GROUP LIMITED, a British Company, of Beecham House, Great West Road, Brentford, Middlesex, England, 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:- This invention relates to compounds which are useful as reagents in the preparation of cephalosporins.
In our cognate applications, number 48719/75 (Serial No. 1,570,582) and 14952/76, referred to herein as the parent specification, there are disclosed and claimed cephalosporins of formula (I) and pharmaceutically acceptable salts and esters thereof:
wherein R represents an organic acylamino group; Y represents a 5-membered nitrogen-containing ring; n is zero or 1; and R1 and R2 are the same or different and each is hydrogen or a Ct ,3 alkyl group.
Compounds of formula (I) may be prepared by reacting a compound of formula (II) or an N-protected derivative thereof:
wherein RX is hydrogen or a carboxyl blocking group, m is zero or 1, the dotted line represents a bond in the 2- or 3-position and Y, n, R1 and R2 are as defined in formula (I), with an N-acylating derivative of an acid of formula RqOH, wherein R9 is an organic acyl group such that R in formula (I) represents RNH- and where any reactive groups (such as amino, carboxy and hydroxy groups) may be blocked and thereafter, if necessary, carrying out one or more of the following steps: (i) converting a A2 isomer into the desired A3 isomer; (ii) removing any N-protecting groups; (iii) reducing a sulphoxide compound to form the desired sulphide compound; (iv) removal of any blocking groups from the group RX or the acyl side chain; (v) converting the product to a salt or ester thereof.
Intermediate compounds of formula (II) are novel. Accordingly, the present invention provides a compound of formula (II) as defined above or an N-protected derivative thereof.
Examples of "N-protected derivatives" of compound (II) include N-silyl and N-phosphorylated derivatives.
By the term "N-silyl derivative" of compound (II), we mean the product of reaction of the 7-amino group of compound (II) with a silylating agent such as a halosilane or a silazane of the formula: L3SiU; L2SiU2; L3SiNL2; L,SiNHSiL,; LaSi . NH. COL; L,Si . NH. CO . NH. Silts; LNH . CO . NH . SiL3; L . C. OSiL3 NSiL, wherein U is a halogen and the various groups L which may be the same or different, each represents hydrogen or alkyl, alkoxy, aryl, or aralkyl. Preferred silylating agents are silyl chlorides, particularly trimetahylchlorosilane, and dimethyldichlorosilane.
The term "N-phosphorylated" derivative of compound (II) is intended to include compounds wherein the 7-amino group of formula (II) is substituted with a group of formula: -P.R,Rb wherein Ra is an alkyl, haloalkyl, aryl, aralkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy or dialkylamino group, R, is the same as Ra or is a halogen or Ra and Rb together form a ring.
Suitable carboxyl blocking derivatives for the group --COR" in formula (II) include salts, ester and anhydride derivatives of the carbozylic acid. Examples of such groups are given in the parent specification.
Examples of the group Y in formula (II) include diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl. thiatriazolyl, oxazolyl and oxadiazolyl groups.
Suitable groups Y include oxadiazolyl, thiadiazolyl and thiazolyl.
A preferred group Y is tetrazolyl The integer n is preferably equal to 1.
Suitable groups R1 and R2 include hydrogen, methyl, ethyl, n- and iso-propyl, n-, iso, sec- and t-butyl. Preferably both R' and R are both hydrogen.
Thus, examples of the moiety Y-(CHa) -CONR1R' include: 2-carbamoylmethyl- 1,3,4-oxadiazol-3 -yl; 2-carbamoyl-1,3 ,4-oxad iazol-S -yl; l-carbamoylmethyl-lH-tetrazol-5-yl: 1 - (N-methylcarbamoylmethyl) -iH-tetrazol-5-yl; 1 -(N,N-dimethylcarbamoylmethyl) -lH-tetrazol-5-yl; 2-carbamoylmethyl-l,3,4-thiadiazol-5-yl; 2-carbamoylmethyl- 1 ,3,4-triazol-5-yl; 3 -carbamoylmethyl- 1 ,2,4-triazol-5-yl.
Compounds of formula (II) may be prepared by reaction of a compound of formula III):
wherein R', m and the dotted line are as hereinbefore defined; with a thiol of formula (IV):
wherein Y, n, R1 and R2 are as defined with respect to formula (I). The compounds of formula (IV) are described in our co-pending Application No. 38031/77 (Serial No. 1,570,147) of even date.
The following Examples illustrate the preparation of some of the compounds of this invention.
Example 1.
7-Amino-3 - (1 -carbamoylmethyl-1H-tetrazol-5 -ylthio) methylceph- 3-em-4-carboxylic acid 7-Aminocephalosporanic acid (5.44g., 20mmole) and 5-Mercapto-lH-tetrazol-1- ylacetamide (3.50g., 2.2mmole) were suspended in 50% aqueous acetone (200ml) and solid sodium bicarbonate added until a clear solution was obtained, spH 7.0. The solution was heated at 60 C for 6 hours, uncovered for the final hour which allowed most of the acetone to evaporate, then acidified to pH 4.0 and stirred in an ice bath for one hour. The solid product was collected, washed with a little cold water and dried in vacuo. 3.22g (43.4%), X(CF3CO2H) 4.00 (2H,bs, C2 methylene), 4.69 (2H bs, -CH2S-), 5.56 (4H,s, -CH2CO2NH, and ss-lactam protons), 7.47.8 (2H,m, ONH2).
Example 2.
7-Amino-3- (2-carbamoyl-1,3,4-oxadiazol-5-ylthio) methylceph-3 -em-4-carboxylic acid 71Aminocephalosporanic acid (10.88g, 40mmole) and 5-mercapto-1,3,4-oxadiazol-2-ylcarboxamide (6.40g, 44mmole) in 50% aqueous acetone (500ml) were treated with solid sodium bicarbonate to pH 7 then heated at 600C for 5 hours. The solution was acidified to pH 4.0 with 5N hydrochloric acid, cooled in an ice bath for one hour and the precipitated solid collected, washed with water (100ml) ethanol (200ml) and ether (200ml) and dried in vacuo, 5.87g (41.1%), #(CF3CO2H) 3.5 4.1 (2H,m, C, methylene), 4.44.9 (2H,m, -CH2S-), 5.42 (2H,s, ,8-lactam protons), 7.89 (2H, d, J 28Hz, -CONH2).
Example 3.
7-Amino-3- (1-N-methylcarbamoylmethyl-lH-tetrazol-5-ylthio) methylceph-3-em-4-carboxylic acid 7-ACA and N - methyl - 5 - mercapto - 1H - tetrazol - 1 - ylacetamide were reacted as in example 2 to give the title compound, 44.0 O yield; #(FC3CO2H), 3.05 (3H,d, JSHz, -CONHCH3), 3.92 (2H,s, C, methylene), 4.63 (2H,bs, -CH2S-), 5.47 (4H,s, -CH2CO- and ,8-lactam protons), 7.5-7.8 (1H,m, ONH-).
Example 4.
7-Amino-3-(1-N,N-dimethylcarbamoylmethyl-lH-tetrazol-5-ylthio) - methylceph-3-em-4-carboxylic acid 7-ACA and N,N - dimethyl - 5 - mercapto - 1H - tetrazol - 1 - ylactamide were reacted as described in example 2 to give the title compound in 40.6% yield; 3(CF3CO2H) 3.17 and 3.32 (6H, 2 X s, -CON(CH2), 3.90 (2H, bs, C2 methylene), 4.63 (2H,bs, CH2S-), 5.45 and 5.58 (2H, each, s and bs, -CH2CO- and ss- lactam protons).
Example 5.
7-Amino-3-(2-carbamoylmethyl-1;3,4-thiadiazol-5-ylthio) methylceph-3 -em-4-carboxylic acid 7-ACA and 5 - mercapto - 1,3,4 - thiadiazol - 2 - ylacetamide were reacted as described in example 2 to give the title compound in 69.8% yield; s (CF3CO2H) 3.93 (2H,s, C, methylene), 4.63 (2H,s, -CH2CO-), 4.82 (2H,bs, -CH2S-), 5.47 (2H,s, -lactam protons), 7.27.8 (2H,CONH2).
Example 6.
7-Amino-3-(3-carbamoylmethyl-1,2,4-thiazol-5-ylthio) methylceph-3-em-4-carboxylic acid 7-ACA and 5 - mercapto - 1,2,4 - triazol - 3 - ylacetamide were reacted as in example 2 to give the title compound, 58.4% yield); 16 18 (CF2CO2H) 3.87 (2H, bs, C, methylene), 4.38 (2H,s, -CH2CONH2), 4.55 (2H,bs, CH,S-), 5.40 (2H,s, P- lactam protons), 7.1-7.8 (2H,m, -CONH2).
WHAT WE CLAIM IS: 1. A compound of formula (II)
or an N-protected derivative thereof; wherein RX is hydrogen or a carboxyl-blocking group, m represents zero or 1, the dotted line represents a bond in the 2- or 3-position, Y reDresents a 5-membered nitrogen containing ring, n is zero or 1, and R1 and R2 are the same or different and each is hydrogen or a C,-.6 alkyl group.
2. An intermediate as claimed in claim 1 wherein m is zero, Rx is hydrogen and the dotted line represents a double bond in the 3-position.
3. An intermediate as claimed in either claim 1 or 2 wherein R1 and R2 are both hydrogen.
4. An intermediate as claimed in any one of claims 1 to 3 wherein n is 1.
5. An intermediate as claimed in any one of claims 1 to 4 wherein Y is tetrazolyl.
6. 7 - Amino - 3 - (1 - carbamoylmethyl - 1H - tetrazol - 5 - ylthio) methylceph - 3 - em - 4 - carboxylic acid.
7. 7 - Amino - 3 - (2 - carbamoyl - 1,3,4 - oxadiazol - 5 - ylthio) methylceph3 - em - 4 - carboxylic acid.
8. 7 - Amino - 3 - (1 - N - methylcarbamoylmethyl - 1H - tetrazol - 5 - ylthio)- methylceph - 3 - em - 4 - carboxylic acid.
9. 7 - Amino - 3 - (1 - N,N - dimethylcarbamoylmethyl - 1H - tetrazol - 5- ylthio)methylceph - 3 - em - 4 - carboxylic acid.
10. 7 - Amino - 3 - (2 - carbamoylmethyl - 1,3,4 - thiadiazol - 5 - ylthio)methylceph - 3 - em - 4 - carboxylic acid.
11. 7 - Amino - 3 - (3 - carbamoylmethyl - 1,2,4 - triazol - 5 - ylthio)methyl- ceph - 3 - em - 4 - carboxylic acid.
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (14)

  1. **WARNING** start of CLMS field may overlap end of DESC **.
    Example 4.
    7-Amino-3-(1-N,N-dimethylcarbamoylmethyl-lH-tetrazol-5-ylthio) - methylceph-3-em-4-carboxylic acid 7-ACA and N,N - dimethyl - 5 - mercapto - 1H - tetrazol - 1 - ylactamide were reacted as described in example 2 to give the title compound in 40.6% yield; 3(CF3CO2H) 3.17 and 3.32 (6H, 2 X s, -CON(CH2), 3.90 (2H, bs, C2 methylene), 4.63 (2H,bs, CH2S-), 5.45 and 5.58 (2H, each, s and bs, -CH2CO- and ss- lactam protons).
    Example 5.
    7-Amino-3-(2-carbamoylmethyl-1;3,4-thiadiazol-5-ylthio) methylceph-3 -em-4-carboxylic acid 7-ACA and 5 - mercapto - 1,3,4 - thiadiazol - 2 - ylacetamide were reacted as described in example 2 to give the title compound in 69.8% yield; s (CF3CO2H) 3.93 (2H,s, C, methylene), 4.63 (2H,s, -CH2CO-), 4.82 (2H,bs, -CH2S-), 5.47 (2H,s, -lactam protons), 7.27.8 (2H,CONH2).
    Example 6.
    7-Amino-3-(3-carbamoylmethyl-1,2,4-thiazol-5-ylthio) methylceph-3-em-4-carboxylic acid 7-ACA and 5 - mercapto - 1,2,4 - triazol - 3 - ylacetamide were reacted as in example 2 to give the title compound, 58.4% yield); 16 18 (CF2CO2H) 3.87 (2H, bs, C, methylene), 4.38 (2H,s, -CH2CONH2), 4.55 (2H,bs, CH,S-), 5.40 (2H,s, P- lactam protons), 7.1-7.8 (2H,m, -CONH2).
    WHAT WE CLAIM IS: 1. A compound of formula (II)
    or an N-protected derivative thereof; wherein RX is hydrogen or a carboxyl-blocking group, m represents zero or 1, the dotted line represents a bond in the 2- or 3-position, Y reDresents a 5-membered nitrogen containing ring, n is zero or 1, and R1 and R2 are the same or different and each is hydrogen or a C,-.6 alkyl group.
  2. 2. An intermediate as claimed in claim 1 wherein m is zero, Rx is hydrogen and the dotted line represents a double bond in the 3-position.
  3. 3. An intermediate as claimed in either claim 1 or 2 wherein R1 and R2 are both hydrogen.
  4. 4. An intermediate as claimed in any one of claims 1 to 3 wherein n is 1.
  5. 5. An intermediate as claimed in any one of claims 1 to 4 wherein Y is tetrazolyl.
  6. 6. 7 - Amino - 3 - (1 - carbamoylmethyl - 1H - tetrazol - 5 - ylthio) methylceph - 3 - em - 4 - carboxylic acid.
  7. 7. 7 - Amino - 3 - (2 - carbamoyl - 1,3,4 - oxadiazol - 5 - ylthio) methylceph3 - em - 4 - carboxylic acid.
  8. 8. 7 - Amino - 3 - (1 - N - methylcarbamoylmethyl - 1H - tetrazol - 5 - ylthio)- methylceph - 3 - em - 4 - carboxylic acid.
  9. 9. 7 - Amino - 3 - (1 - N,N - dimethylcarbamoylmethyl - 1H - tetrazol - 5- ylthio)methylceph - 3 - em - 4 - carboxylic acid.
  10. 10. 7 - Amino - 3 - (2 - carbamoylmethyl - 1,3,4 - thiadiazol - 5 - ylthio)methylceph - 3 - em - 4 - carboxylic acid.
  11. 11. 7 - Amino - 3 - (3 - carbamoylmethyl - 1,2,4 - triazol - 5 - ylthio)methyl- ceph - 3 - em - 4 - carboxylic acid.
  12. 12. 7 - Amino - 3 - (2 - carbamoylmethyl - 1,3,4 - oxadiazol - 5 - ylthio)methyl
    ceph - 3 - em - 4 - carboxylic acid.
  13. 13. 7 - Amino - 3 - (2 - carbamoylmethyl - 1,3,4 - triazol - 5 - ylthio)methyl- ceph - 3 - em - 4 - carboxylic acid.
  14. 14. A process for the preparation of a compound as claimed in claim 1 which process comprises reacting a compound of formula (III):
    with a thiol of formula (IV):
    wherein RX m the dotted line Y. n. R1 and R2 are as defined in claim 1.
GB3802977A 1976-11-16 1976-11-16 7-amino - 3 - heterocyclicthiomethyl-cephem derivatives Expired GB1570146A (en)

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