GB1566849A

GB1566849A – 6 – (2 – acylamino – 2 – arylacetamido)penicillanic acids
– Google Patents

GB1566849A – 6 – (2 – acylamino – 2 – arylacetamido)penicillanic acids
– Google Patents
6 – (2 – acylamino – 2 – arylacetamido)penicillanic acids

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Publication number
GB1566849A

GB1566849A
GB712578A
GB712578A
GB1566849A
GB 1566849 A
GB1566849 A
GB 1566849A
GB 712578 A
GB712578 A
GB 712578A
GB 712578 A
GB712578 A
GB 712578A
GB 1566849 A
GB1566849 A
GB 1566849A
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GB
United Kingdom
Prior art keywords
compound
carboxamido
hydroxy
penicillanic acid
acetamido
Prior art date
1978-02-22
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Expired

Application number
GB712578A
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Mitsubishi Kasei Corp

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Mitsubishi Kasei Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
1978-02-22
Filing date
1978-02-22
Publication date
1980-05-08

1978-02-22
Application filed by Mitsubishi Kasei Corp
filed
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Mitsubishi Kasei Corp

1978-02-22
Priority to GB712578A
priority
Critical
patent/GB1566849A/en

1980-05-08
Publication of GB1566849A
publication
Critical
patent/GB1566849A/en

Status
Expired
legal-status
Critical
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Classifications

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07D—HETEROCYCLIC COMPOUNDS

C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Description

(54) 6-(2-ACYLAMINO-2-ARYLACETAMIDO) PENICILLANIC
ACIDS
(71) We, MITSUBISHI CHEMICAL INDUSTRIES LIMITED, a .Japanese body corporate of 5-2 Manmouchi 2-chome, Chiyoda-ku, Tokyo, Japan, 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 6-(2-acylamino-2-arylacetamido) penicillanic acids examples of which are shown to be effective against Gram-negative and Gram-positive bacteria.
While many penicillins have been remarkably effective in the treatment of a variety of infections, few penicillins have been found to possess significant activity against Pseudomonas aeruginosa.
There is a continuing need for different and improved penicillins.
The present invention provides compounds of the general formula:
wherein R, is hydrogen or hydroxy; R2 is hydrogen, methyl or ethyl; and Z is CH=, -N= or VX= wherein X is chloro or bromo. Preferably R2 is hydrogen or methyl.
Also encompassed within this invention are non-toxic, pharmaceutically or veterinarily acceptable salts thereof and pharmaceutically or veterinarily acceptable bioX precursors therefor, as well as pharmaceutical or veterinary formulations and compositions e.g. in unit dosage form.
The tenn «bioprecursor» as used herein means a compound other than a compound of formula I which on administration to an animal or human being is converted in the patient’s body to a compound of formula 1.
As summarized above, this invention relates to a group of compounds useful as antibacterial agents, which compounds are represented by Formula I above.
Also included within the scope of this invention are the non-toxic cationic, a.g., the pharmaceutically acceptable salts of the compounds of this invention. Such salts include, for example, sodium, potassium, calcium, magnesium, ammonium and substituted ammonium salts, e.g., procaine, N,N’-dibenzylethylenediamine.
As one skilled in the art can readily appreciate, the compounds of this invention are sufficiently basic, by virtue of the nitrogen-containing heterocyclic ring, to form acid addition salts; said salts, especially the pharmaceutically acceptable acid addition salts, are also considered within the scope of this invention. Such salts include, for example, inorganic salts such as hydrochlorides and sulfates, and organic salts such as fumarates, malates and formates.
The preparation of the compounds of this invention can be performed by coupling of a 6-(2-amino-2-2arylacetamido) penicillanic acid and a carboxylic acid having the formula (II):
wherein R.. ano Z are as defined herein above, by the reaction of the carboxy function of the carboxvlic acid with the amino function of the 6-(2-amino-2-arylacetamido) penicillanic acid to produce an amide linkage.
The compounds of this invention can be prepared by the reaction of the carboxylic acid with the appropriate 6-(2-amino-2-arylacetamido)penicillanic acid in the presence of a condensing agent, e.g., a carbodiimide such as 1,3-dicyclohexylcarbodiimide.
Excess carbodiimide is converted to the corresponding urea by acidification, the pH is adjusted to near neutrality and the urea is removed by filtration. The products may be recovered by acidification or extraction.
In rendering the carboxy function active to the coupling reaction, the carboxy function mav be converted to an acid halide, acid azide, activated ester (e.g., p-nitrophenyl ester) or mixed carbonic anhydride, or imidazolide through the use of N,N’carbonvldiimidazole. These acylating agents need not be isolated. It is frequently more convenient and practical to use them in the form of the solution, in which they are prepared.
The conversion of the carboxylic acid to a mixed carbonic anhydride may be effected by dissolving the carboxylic acid in a ketone solvent containing a tri-(C1 to C1 )alkvlamine and treating the solution with an anhydride forming reagent, e.g., a
C, to C. alkyl chioroformate or an aryl chloroformate at a temperature of from 0 to – 20″C. The compounds of this invention may be obtained by reacting the mixed anhvdride with the 6-(2-amino-2-arylacetamido)penicillanic acid at a temperature of – 500 to +50 C. Recovery of the product may be effected by precipitation (after acidification of the reaction mixture) or by extraction into an organic solvent such
as ethvl acetate, or methyl isobutyl ketone from the acidified reaction mixture.
The particular methods of coupling employed in preparing the compounds of this invention are each now well recognized in the art. The conditions under which a particular coupling reaction would be carried out will be apparent to those skilled in the art.
The 6-(2-acylamino-2-arylacetamido)penicillanic acids of this invention which are exemplified hereafter are remarkablv effective in treating a number of infections caused by Gram-negative bacteria including Esherichia coli, Proteus vulgaris, Pseudo
monas aeruginosa, and Gram-positive bacteria including Staphylococcus aureus. As described above, the exemplified compounds of this invention exhibit antibacterial activity against microorganisms. Their useful activity can be demonstrated by in vitro tests against various organisms.
The compounds of this invention were tested for antibacterial activity according to the following procedure.
Nutrient broth and nutrient agar were prepared according to the conventional procedure. Nutrient agar was used as a vehicle. The stock solution was prepared at 100a g/ml of the test material in the vehicle. Two-fold dilutions were made with the vehicle and then the diluted stock solution was added to a petri dish and solidified by chilling. Test organisms were grown in the nutrient broth for 20 hours at 37″C.
The hardened surface was inoculated with a loopful of the test organism solution containing 1X106 cells per milliliter and incubated for 20 hours at 37″C. At the end of this period, growth of the organism was observed. The minimum inhibitory concentration (MIC) at which growth of the organism failed to occur was observed and recorded. The following Table 1 summarizes the activity of representative compounds as active antibacterial agents, and compares them with the reference drug Sulbeni cillin T A B L E 1
~~ 1o 1 \o 01 (MIC: g/nii) 0 0 S – CH – – C}I – / \ , CH3 fl – C – Nil C – NH CH No. I z ~ ~ .
– N – CH – cO2K aeruinosa aerufrinosa aefllginosa 0 X-12 * M-16* M20u8* R1 n Z E j w R1 H Z H 6.2 6 j»l » 2 OH < 1.5 0.78 3.1 N oo-o to :n 30 CC 6.2 0I nn O ~J O--U X Compornd nimum Inhibitory Concentration (MIC: g/mi) 0 0 S Ii /\ CH3 mJ (jl No. an o - N - CH 9 CO2K V V Ri 0 M-12 * M-16* M-20O8** E ~~ ~ Ri OH I mi W o" n 1 E 6 011 O=o X%X Compound Minimum Inhibitory Concentration u rj 0 0 S II II / \ CH - C - NH - OH - C - NH - OH - OH 1 Pd Pd ~~~~~~~~~~ No. 1CH5 cu seuomonas Pseudonionas - N - OH - 002K aeruginosa aeniginosa aeniginosa R1 0 M-12 * M-16* M-2008** R R1 3 1 P1 I N N OH 01(3 N N))[011 In general, the compounds of this invention may be utilized in a manner similar to ampicillin and other penicillins. For example, they may be used in various animal species in an amount of 0.1 to 100 mg/kg daily, orally or parenterally in two to five divided doses to treat infections of bacterial origin. Having generally described the invention a more complete understanding can be obtained by reference to certain specific examples, which are included for purposes of illustration only and are not intended to be limiting unless otherwise specified. EXAMPLE. To a suspension of 382 mg (2 m moles) of 3-hydroxypyrido [2,3-b]pyrazine-2- carboxylic acid in 12 ml of dry dimethylformamide was added 365 mg (2.2 m moles) of N,N'-carbonyldiimidazole. The mixture was stirred for 1.5 hours in an ice bath. To this mixture was added a solution of 838 mg (2 m moles) of amoxycillin trihydrate in 5 ml of dimethylformamide and 0.278 ml (2 m moles) of triethylamine. The reaction mixture was stirred for 3 hours at room temperature. To the resultant homogenous solution was added 690 mg (2.22 m moles) of 59% potassium 2-ethylhexanoate-n-butanol solution and then the solution was poured into 150 ml of acetone to give a precipitate, which was filtered, dissolved into 100 ml of water, adiusted to pH 2.0 and then extracted twice with ethyl acetate (100 ml, 50 ml). The ethyl acetate layer was washed twice with 40 ml of water, dried over anhydrous magnesium sulfate and then adjusted to pH 7.0 with potassium 2-ethylhexanoate-n-butanol solu tion to yield crystals. This was filtered, washed with ether and then dried to give 443 mg of potassium 6 - [D - 2 - (3 - fiydroxypyrido[2,3 - b] pyrazine - 2 - carbox amido) - 2 - (p - hydroxyphenyl)acetamido] penicillanate, M.P. > 250 C.
Analysis-Calcd. for C24H21O7N6S1K1
(percent): C, 49.99; H, 3.67; N, 14.58; S, 5.56
Found (percent): C, 47.25; H, 4.22; N, 12.48; S, 576 IR (KBr): 3,400, 3,280, 1,760, 1,635, 1,590, 1,510, 1,455, 1,420 and 1,260 cm NMR (D2o), (100 MHz), (ppm):
1.43 (s, 3H), 1.47 (s, 3H), 4.21 (s, 1H), 5.405.72 (m, 3H), 6.80-7.06
(m, 2H), 7.24-7.56 (m, 3H), 8.22 (q, 1H), 8.56 (q, 1H) Various other 6-(2-acylamino-2-arylacetamido)penicillanic acids were synthesized in accordance with the procedure of the above example, and the results are summarized in the following Table 2.
T A B L E 2
c= , cS v – – – – – c? ri (7 c\ u\ 0 cl) 0 h -cU t – L(X) m – cr m -E m ^3 m EU vvl,v , ‘Cv» CP\ O 0 3 V) (r) t CO cV c7 vC O as so z o O vo n rs i LA o 4 S < - O 4 4 r < ~ o H Op, I I rlv -(V 3 - t (V II > / E \ /CH3 -23: nr: 6 R-C-NII-CH-C-N1{-CIl CII cm No. 10H3 Yield m.p. IR (KBr) NMR (100 MHz) e – N va ~n m uz ^r X 07- CH-C02K 0) m (cm1) (ppm) VVrScV UU VV VV VV V 4 co t x sn Ca rs c\t ~ co ox cq ;rQJ \O c? (y cy ri m o\ q ‘U. E4’V. E’4 9E~ ‘V. E~9 utQ) rl -rcD rlua) rl -Ym 1 o»Y;o’ 1505, O UL O U O O O ,-,-a S I e. \ CA t CA n vo or cn o vo x w sr ot rs \0-;tO 1395, 1310′ H 311), 7.32 H 111), o ~ so ~ ~ ~ ~ 511), 1235, 695, o ‘ 8.26 ooo 01.OIsoo \0 0 O\ m \O O u\ \O 0 ci -r O c( » u\C?O\ n C\ L7r? 0\ u\(7 : 1760, 2630, 1.43 H 311), \O – (s, 2 o»Y;o»ln» 1435, 4.22 (a, 111), 5.i4-.S8 0 m0 o O O O O O UE O O O o, as o (m, H co os O O 511), 4 mt Ct ;r m = Cr mt 4 \0 t Ch CN H H H CN H H CN H td o H H t . 1.42 ~ O O 3 011 CQ .
1590, 1505, 1435, (m, 311), 6.87 (ci, 211), N Oil 1405, 1310, 1230 7.38 (d, 2’H , 8.L)7 (d, iii), 8.39 (d, 1H > 4f 2920, 1760, 1.42 a, 311, l.Li8 (a, 311), .4 1630, 1500, 1430, 4.22 a, 111 , 5.46-5.84 O\Oy II 1410, 131(5, 1230, z 311), 7.32-7.72 (rn, 511 U]Xz I ~ .. sJ C,)S U CEN | P: ~ z}3 < 0 O YH b tt C.o U Io an Xs Dx E an ~ uz on ua v s s Ot l I tsl ~l z o rs v o o ~ N C X Irx \ - O n o rs x - - O ;r E . - .... * .. ~ e 0 P, ~i L,~ '1 0 > ? rf %GX S O k S ~ o ~ ~ ~so ~ ~ co0113 ~ < = 0 Mcal ~ Mo - CII C ~ : = ~ ~ . ~ ~ ~ , ~ ~ < ~ ~ . No. CI - N - < rs cq Yield co rs H co NMR 1p0p0?Z) X J % m c=da" m mt m m'-j m m m Ih ,vy NVV VV1 trrt 0 Ir\C? N c?;ra ~ strs Htce 1 ~3rssX Hcv 5 I3r1N 1590, 1500, 1430, o 311), 7.00 u) o lr\ so 4 cq so ~ \ xo -. rf i4o5, H H H H H 211 , H (d, iH), k h m s ooo (d, 111 P rir 000 1 OOu\ 000 000 z: O rl \D O rl \0 0 N 3380, 1760, 1640, 1.44 (a, 311 , 1.56 He 311), w \o 6 r r > 250 .1590, 1500, 1445, 4.24 r r r ~ 0 O rr\ O 0 6 0 0 O r O 0 0 On t0 1315, 1260, Uo 311), > > J (m, 511), 695, 660, 585 9.00 4 1H), La CA XS7 111) CQ H H n H H \0 n H H \0 CQ 3370, 1760, 1640, 1.45 I 311 O 1.48 (a, 311), N 1590, 1500, C\l 2,.23 111 E v a 625, 585 9.12 a, lii , c\ 1640, 1.43 311, 1L48 (a, 311), ~ a~ 1 O O ox :: 0= :r: S 9 T – s – 8 , o t; o 9 zHz zHz zHz ZHZ – < -! b tz aSo An 3=} Cl O uE xD b cO o t H n H N on ~ ~vu0 N (V coo E . . 8 II - E? ray - CH O No. E x = CH3 Yield m.p. IR (KBr) NMR (100 Nllz) Z N CH-C02K rs (0C) (cm1) ~ (ppm) 0n 01 m tn vv rT\ C Y tcVO a3 H Lt~ rs 3400, 1760, 1640, 2.32 a, 311 , 4.20 (a, ii{), t n ~ H H k E 111) O O O 04 e g o n%o I . ~tA U Having now fully described the invention, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the scope of this invention as set forth herein. Claims (20) WHAT WE CLAIM IS:1. A compound having the formula: wherein R1 is hydrogen or hydroxy; R2 is hydrogen, methyl or ethyl; and Z is -CH=, N= or -CX= wherein X is chloro or bromo. 2. 6 - [D - 2 - (3 - hydroxypyrido [2,3 - b] pyrazine - 2 - carboxamido) - 2 phenylacetamido] penicillanic acid. 3. 6 - [D - 2 - (3 - hydroxypyrido [2,3 - b] pyrazine - 2 - carboxamido) - 2 (p - hydroxyphenyl) acetamido] penicillanic acid. 4. 6 - [D - 2 - (3 - hydroxy - 7 - chloropyrido [2,3 - b] pyrazine - 2 - carboxamido) - 2 - phenyl-acetamidolpenicillanic acid. 5. 6 - [D - 2 - (3 - hydroxy - 7 - chloropyrido [2,3 - b]pyrazine - 2 - carboxamido) - 2 - (p - hydroxyphenyl)acetamido] penicillanic acid. 6. 6 - [D - 2 - (3 - hydroxy - 7 - bromopyrido [2,3 - b] pyrazine - 2 - carboxamido) - 2 - phenyl-acetamido] penicillanic acid. 7. 6 - [D - 2 - (3 - hydroxy - 7 - bromopyrido [2,3 - b] pyrazine - 2 - carboxamido) - 2 - (p-hydroxyphenyl)acetamido] penicillanic acid. 8. 6 - [D - 2 - (7 - hydroxy - pteridine - 6 - carboxamido) - 2 - phenylacetamido] penicillanic acid. 9. 6 - [D - 2 - (7 - hydroxy - pteridine - 6 - 6carboxamido) - 2 - (p - hydroxyphenyl) acetamido] penicillanic acid. 10. 6 - D - 2 - (3 - hydroxy - 6 - methyl - 7 - bromopyrido [2,3 - b] pyrazine2 - carboxamido) - 2 - phenylacetamido] penicillanic acid. 11. 6 - [D - 2 - (3 - hydroxy - 6 - methyl - 7 - bromopyrido [2,3 - b] pyrazine2 - carboxamido) - 2-(p- hydroxyphenyl)acetamido] penicillanic acid. 12. A compound as claimed in claim 1 and substantially as hereinbefore described in the Example or as described in the Example modified by any entry in Table 2. 13. A process for the preparation of a compound as claimed in claim 1, which process comprises activating the carboxy function of a compound of the formula and reacting the activated carboxy function with the amino function of a suitable 6-(2-amino-2-aryl acetamido) penicillanic acid to produce an amide linkage. 14. A process as claimed in claim 13 and substantially as hereinbefore described in the Example or as described in the Example modified by any entry in Table 2. 15. A compound as claimed in claim 1 when produced by a process as claimed in claim 13 or claim 14. 16. A pharmaceutically or veterinarily acceptable salt of a compound as claimed in any one of claims 1 to 12 or claim 15. 17. A pharmaceutically or veterinarily acceptable bioprecursor of a compound as claimed in any one of claims 1 to 12 or claim 15. 18. A pharmaceutical or veterinary formulation comprising a compound as claimed in any one of claims 1 to 12, or claim 15. 19. A pharmaceutical or veterinary composition comprising a compound as claimed in any one of claims 1 to 12 or claim 15 and respectively a pharmaceutically or veterinarily acceptable carrier or diluenr therefor. 20. A formulation or composition as claimed in claim 18 or claim 19 in unit dosage form. GB712578A 1978-02-22 1978-02-22 6 - (2 - acylamino - 2 - arylacetamido)penicillanic acids Expired GB1566849A (en) Priority Applications (1) Application Number Priority Date Filing Date Title GB712578A GB1566849A (en) 1978-02-22 1978-02-22 6 - (2 - acylamino - 2 - arylacetamido)penicillanic acids Applications Claiming Priority (1) Application Number Priority Date Filing Date Title GB712578A GB1566849A (en) 1978-02-22 1978-02-22 6 - (2 - acylamino - 2 - arylacetamido)penicillanic acids Publications (1) Publication Number Publication Date GB1566849A true GB1566849A (en) 1980-05-08 Family ID=9827110 Family Applications (1) Application Number Title Priority Date Filing Date GB712578A Expired GB1566849A (en) 1978-02-22 1978-02-22 6 - (2 - acylamino - 2 - arylacetamido)penicillanic acids Country Status (1) Country Link GB (1) GB1566849A (en) 1978 1978-02-22 GB GB712578A patent/GB1566849A/en not_active Expired Similar Documents Publication Publication Date Title DE2462736C2 (en) 1980-09-11 7-Aminothiazolylacetamido-3-cephem-4-carboxylic acids and processes for making the same DE1795292B2 (en) 1974-08-29 Cephalosporin derivatives and processes for their preparation DE2362279C2 (en) 1982-04-01 Penicillin derivatives and their use in combating bacterial infections DE2633193A1 (en) 1977-02-10 NEW ANTIBACTERIALLY EFFECTIVE COMPOUNDS, METHODS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEM CH618175A5 (en) 1980-07-15 Process for the preparation of penicillins DE2155081B2 (en) 1975-05-15 7- (Isoxazol-5-yl-acetamido) cephalosporanic acid derivatives, processes for their preparation and pharmaceutical compositions containing them DE3626509A1 (en) 1987-02-12 7SS- (2- (2-AMINO-THIAZOL-4-YL) -2-ALKENAMIDO) -3- (ALKYL-CARBAMOYLOXYMETHYL) -3-CEPHEM-4-CARBONIC ACID DERIVATIVES EP0000392B1 (en) 1982-04-28 Cephalosporins and penicillins, processes for their preparation and pharmaceutical compositions containing them DE2739448A1 (en) 1978-03-02 7-SUBSTITUTED AMINOACETAMIDO-OXADETHIACEPHALOSPORINE, METHOD FOR THE PRODUCTION AND USE THEREOF IN THE TREATMENT OF BACTERIAL DISEASES DE3037284C2 (en) 1984-04-12 Penicillin compounds and processes for their production, as well as medicaments containing them GB1566849A (en) 1980-05-08 6 - (2 - acylamino - 2 - arylacetamido)penicillanic acids EP0035161B1 (en) 1983-11-23 Cephalosporins, processes for their preparation and pharmaceutical compositions containing these compounds US4311842A (en) 1982-01-19 Cephalosporin compounds US4164577A (en) 1979-08-14 6-(2-Acylamino-2-arylacetamido)penicillanic acids DE2442702C2 (en) 1983-07-14 Cephalosporin compounds, processes for their preparation and antibacterial agents containing these compounds DE2908033C2 (en) 1989-04-13 DE3541095A1 (en) 1987-05-27 NEW CEPHALOSPORINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS US4728733A (en) 1988-03-01 C-3' thiadiazinyl cephalosporin analogs DE2236422C2 (en) 1981-12-10 Cephalosporin compounds and processes for their preparation DE2818985C2 (en) 1995-08-17 Halogenarylmalonamidooxacephalosporins and their use in combating bacterial infections KR0154901B1 (en) 1998-11-16 Novel cephalosporin antibiotics CH661730A5 (en) 1987-08-14 PENEM CARBONIC ACIDS AND METHOD FOR THE PRODUCTION THEREOF. AT309684B (en) 1973-08-27 Process for the production of new penicillins and cephalosporins DE2522997A1 (en) 1975-12-04 NEW CEPHALOSPORINE, THE PROCESS FOR THEIR MANUFACTURING AND THE PRODUCTS CONTAINING IT DE2202274C2 (en) 1982-05-27 3-Triazolylthiomethyl-cephalosporins and process for their preparation Legal Events Date Code Title Description 1980-07-23 PS Patent sealed 1982-09-22 PCNP Patent ceased through non-payment of renewal fee
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