GB1565083A – Pseudomonic acid amides
– Google Patents
GB1565083A – Pseudomonic acid amides
– Google Patents
Pseudomonic acid amides
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Info
Publication number
GB1565083A
GB1565083A
GB6884/76A
GB688476A
GB1565083A
GB 1565083 A
GB1565083 A
GB 1565083A
GB 6884/76 A
GB6884/76 A
GB 6884/76A
GB 688476 A
GB688476 A
GB 688476A
GB 1565083 A
GB1565083 A
GB 1565083A
Authority
GB
United Kingdom
Prior art keywords
pseudomonic acid
amide
compound
acid
pseudomonic
Prior art date
1976-02-20
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
GB6884/76A
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beecham Group PLC
Original Assignee
Beecham Group PLC
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.)
1976-02-20
Filing date
1976-02-20
Publication date
1980-04-16
1976-02-20
Application filed by Beecham Group PLC
filed
Critical
Beecham Group PLC
1976-02-20
Priority to GB6884/76A
priority
Critical
patent/GB1565083A/en
1977-02-10
Priority to ZA770772A
priority
patent/ZA77772B/en
1977-02-14
Priority to BE174922A
priority
patent/BE851410A/en
1977-02-14
Priority to US05/768,057
priority
patent/US4139629A/en
1977-02-16
Priority to SE7701722A
priority
patent/SE431649B/en
1977-02-16
Priority to DE19772706548
priority
patent/DE2706548A1/en
1977-02-16
Priority to FR7704368A
priority
patent/FR2349584A1/en
1977-02-18
Priority to IE348/77A
priority
patent/IE44445B1/en
1977-02-18
Priority to DK73777A
priority
patent/DK145823C/en
1977-02-18
Priority to CH209177A
priority
patent/CH629799A5/en
1977-02-18
Priority to NL7701727A
priority
patent/NL7701727A/en
1977-02-19
Priority to JP1766077A
priority
patent/JPS52102279A/en
1980-04-16
Publication of GB1565083A
publication
Critical
patent/GB1565083A/en
Status
Expired
legal-status
Critical
Current
Links
Espacenet
Global Dossier
Discuss
MINDHVHHQZYEEK-UHFFFAOYSA-N
(E)-(2S,3R,4R,5S)-5-[(2S,3S,4S,5S)-2,3-epoxy-5-hydroxy-4-methylhexyl]tetrahydro-3,4-dihydroxy-(beta)-methyl-2H-pyran-2-crotonic acid ester with 9-hydroxynonanoic acid
Natural products
CC(O)C(C)C1OC1CC1C(O)C(O)C(CC(C)=CC(=O)OCCCCCCCCC(O)=O)OC1
MINDHVHHQZYEEK-UHFFFAOYSA-N
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title
claims
description
18
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mupirocin
Chemical compound
C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC(O)=O)OC1
MINDHVHHQZYEEK-HBBNESRFSA-N
0.000
title
claims
description
18
229960003128
mupirocin
Drugs
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title
claims
description
18
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pseudomonic acid
Natural products
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title
claims
description
18
150000001875
compounds
Chemical class
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claims
description
28
238000000034
method
Methods
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claims
description
15
150000001408
amides
Chemical class
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description
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mixture
Substances
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description
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Homo sapiens
Species
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claims
description
9
125000000217
alkyl group
Chemical group
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claims
description
5
229910052739
hydrogen
Inorganic materials
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claims
description
4
238000002360
preparation method
Methods
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claims
description
4
208000035143
Bacterial infection
Diseases
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claims
description
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Hydrogen
Chemical compound
[H][H]
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description
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bacterial infectious disease
Diseases
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chemical substances by application
Substances
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dimethylazanide
Chemical compound
C[N-]C
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claims
description
3
239000001257
hydrogen
Substances
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claims
description
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methylazanide
Chemical compound
[NH-]C
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0.000
claims
description
3
239000000546
pharmaceutical excipient
Substances
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claims
description
3
239000012050
conventional carrier
Substances
0.000
claims
description
2
-1
Pseudomonic acid primary amide
Chemical class
0.000
claims
1
150000001412
amines
Chemical class
0.000
claims
1
OKKJLVBELUTLKV-UHFFFAOYSA-N
Methanol
Chemical compound
OC
OKKJLVBELUTLKV-UHFFFAOYSA-N
0.000
description
24
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Chloroform
Chemical compound
ClC(Cl)Cl
HEDRZPFGACZZDS-UHFFFAOYSA-N
0.000
description
16
XEKOWRVHYACXOJ-UHFFFAOYSA-N
Ethyl acetate
Chemical compound
CCOC(C)=O
XEKOWRVHYACXOJ-UHFFFAOYSA-N
0.000
description
12
239000000243
solution
Substances
0.000
description
12
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Silicium dioxide
Chemical compound
O=[Si]=O
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0.000
description
10
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water
Substances
O
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description
9
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esters
Chemical class
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description
7
239000003981
vehicle
Substances
0.000
description
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Magnesium sulfate
Chemical compound
[Mg+2].[O-][S+2]([O-])([O-])[O-]
CSNNHWWHGAXBCP-UHFFFAOYSA-L
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description
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Natural products
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Anatomy
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description
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Chemical group
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description
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Penicillin G
Chemical compound
N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1
JGSARLDLIJGVTE-MBNYWOFBSA-N
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oil
Substances
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235000019198
oils
Nutrition
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silicon dioxide
Substances
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description
5
238000004809
thin layer chromatography
Methods
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description
5
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2-methylpropyl carbonochloridate
Chemical compound
CC(C)COC(Cl)=O
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0.000
description
4
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Sodium bicarbonate
Chemical compound
[Na+].OC([O-])=O
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0.000
description
4
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Sodium chloride
Chemical compound
[Na+].[Cl-]
FAPWRFPIFSIZLT-UHFFFAOYSA-M
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description
4
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acid
Substances
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description
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Effects
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Effects
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description
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syrup
Substances
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syrup
Nutrition
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description
4
FBPFZTCFMRRESA-FSIIMWSLSA-N
D-Glucitol
Natural products
OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO
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Ilexoside XXIX
Chemical compound
C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+]
DGAQECJNVWCQMB-PUAWFVPOSA-M
0.000
description
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Mycoplasma
Species
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description
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Penicillinase
Proteins
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description
3
DNIAPMSPPWPWGF-UHFFFAOYSA-N
Propylene glycol
Chemical compound
CC(O)CO
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0.000
description
3
239000003242
anti bacterial agent
Substances
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description
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antibiotic agent
Drugs
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239000003814
drug
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230000000694
effects
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description
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filtrate
Substances
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description
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glucose
Substances
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description
3
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magnesium sulfate
Inorganic materials
0.000
description
3
235000019341
magnesium sulphate
Nutrition
0.000
description
3
125000000325
methylidene group
Chemical group
[H]C([H])=*
0.000
description
3
150000002924
oxiranes
Chemical group
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description
3
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penicillin
Drugs
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penicillinase
Drugs
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penicillins
Chemical class
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sodium
Substances
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description
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sodium
Inorganic materials
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description
3
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sodium;chloride;hydrate
Chemical class
O.[Na+].[Cl-]
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sorbitol
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suspension
Substances
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tablet
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testing method
Methods
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thiophenol
Chemical compound
SC1=CC=CC=C1
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description
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Dichloromethane
Chemical compound
ClCCl
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description
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Diethyl ether
Chemical compound
CCOCC
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description
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Dimethylamine
Chemical compound
CNC
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description
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Ethanol
Chemical compound
CCO
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Proteins
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description
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Glycerine
Chemical compound
OCC(O)CO
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Nutrition
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Leucaena leucocephala
Species
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Methylamine
Chemical compound
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Chemical compound
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Chemical group
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magnesium stearate
Chemical compound
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Chemical group
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Chemical group
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pentachlorophenol
Chemical compound
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Polymers
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Nutrition
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Inorganic materials
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Substances
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Substances
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Chemical compound
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1,3-diisopropylcarbodiimide
Chemical compound
CC(C)N=C=NC(C)C
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description
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1-Hydroxybenzotriazole
Chemical compound
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description
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1-methoxy-2-methylpropane
Chemical compound
COCC(C)C
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description
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1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine
Chemical compound
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2,2-dimethylpropanoyl chloride
Chemical compound
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2,4-dinitrophenol
Chemical compound
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4-nitrophenol
Chemical compound
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8beta-hydroxymarrubiin
Natural products
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Nutrition
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Ammonium hydroxide
Chemical compound
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Ascorbic acid
Chemical compound
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Species
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Polymers
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Natural products
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Polymers
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D-glucitol
Chemical compound
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Decylamine
Chemical compound
CCCCCCCCCCN
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0.000
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Dicylcohexylcarbodiimide
Chemical compound
C1CCCCC1N=C=NC1CCCCC1
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241000408655
Dispar
Species
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EU approved colour
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Proteins
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Human genes
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Ethylene oxide
Chemical compound
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Gallus gallus
Species
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Glycine
Chemical compound
NCC(O)=O
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241000282412
Homo
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239000004354
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Substances
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Polymers
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description
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Lactose
Natural products
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Maize starch
Nutrition
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description
1
FXHOOIRPVKKKFG-UHFFFAOYSA-N
N,N-Dimethylacetamide
Chemical compound
CN(C)C(C)=O
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0.000
description
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N-Hydroxysuccinimide
Chemical compound
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description
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Chemical compound
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description
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Phenolsulfonephthalein
Chemical compound
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Sodium bicarbonate-14C
Chemical compound
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DBMJMQXJHONAFJ-UHFFFAOYSA-M
Sodium laurylsulphate
Chemical compound
[Na+].CCCCCCCCCCCCOS([O-])(=O)=O
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239000004141
Sodium laurylsulphate
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Sulfate
Chemical compound
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Theobroma cacao
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Zea mays subsp mays
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aluminium tristearate
Chemical compound
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Chemical group
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125000002915
carbonyl group
Chemical group
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carbonyldiimidazole
Chemical compound
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diethylamine
Chemical compound
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glycolonitrile
Chemical compound
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n’-hexylmethanediimine
Chemical compound
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n-Hexane
Chemical group
CCCCCC
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n-butyl group
Chemical group
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n-propyl group
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p-methoxyphenol
Chemical compound
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penicillin g
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phenolsulfonphthalein
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phosphate buffer
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polyethylene glycol
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potato starch
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propyl p-hydroxybenzoate
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propyl p-hydroxybenzoate
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propylene glycol
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propylparaben
Chemical compound
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reactive intermediate
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serial dilution
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sodium laurylsulphate
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239000007787
solid
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solvent
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sorbic acid
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sorbic acid
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sorbic acid
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sorbitan monooleate
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sorbitan monooleate
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sorbitan monooleate
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tetrahydrofuran
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QORWJWZARLRLPR-UHFFFAOYSA-H
tricalcium bis(phosphate)
Chemical compound
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Classifications
C—CHEMISTRY; METALLURGY
C07—ORGANIC CHEMISTRY
C07D—HETEROCYCLIC COMPOUNDS
C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
A61K31/00—Medicinal preparations containing organic active ingredients
A61K31/33—Heterocyclic compounds
A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
A—HUMAN NECESSITIES
A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
A61P31/04—Antibacterial agents
C—CHEMISTRY; METALLURGY
C07—ORGANIC CHEMISTRY
C07D—HETEROCYCLIC COMPOUNDS
C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
C07D309/10—Oxygen atoms
Description
PATENT SPECIFICATION ( 11) 1565083
C ( 21) Application No 6884/76 ( 22) Filed 20 Feb 1976 ( 23) Complete Specification filed 11 Feb1977 ( 19) ( 44) Complete Specification published 16 April 1980 = ( 51) INT CL 3 C 07 D 407/06; A 61 K 31/35 (C 07 D 407/06, 303/46, 309/10) ( 52) Index at acceptance C 2 C 1300 1672 200 215 246 247 253 25 Y 282 28 X 30 Y 342 34 Y 360 362 366 368 36 Y 574 584 628 62 X 658 65 X 801 802 80 Y AA KM ( 72) Inventor NORMAN HAROLD ROGERS ( 54) PSEUDOMONIC ACID AMIDES ( 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: 5 This invention relates to antibacterial compounds and in particular to a class of amides which have antibacterial activity against certain Gram-positive and Gramnegative organisms, in particular Haemophilis influenzae and Neisseria gonorrhoeae; and also possess good antimycoplasmal activity The compounds are therefore of value in the treatment of veterinary bacterial infections and of particular value in humans 10 in the treatment of bronchitis and venereal disease.
The routine treatment for gonorrhoeae has for many years been the use of penicillin antibiotics However, some strains of gonoccocci are less sensitive to penicillins and the degree of such resistance has gradually increased resulting in larger doses of penicillins being required Furthermore, there have been reports of strains which 15 produce penicillinase, and are thus highly resistant to penicillin therapy The British Medical Journal ( 1976) at page 963 comments: «Now the outlook for the control of gonorrhoeae has been radically changed for the worse by the portentous announcement of the existence of frankly resistant strains owing their resistance to the production of penicillinase, the penicillin-destroying enzyme found by many other bacterial 20 species This is a wholly new development, the consequences of which might well be disastrous «.
We have now found that a class of compounds have high activities against many organisms including N gonorrhoeae, and as the compounds are completely unrelated to the fi-lactam type of antibiotics (including penicillins and cephalosporins), they 25 are completely unaffected by penicillinase.
Pseudomonic acid is the E-isomer of the structure (I):
OH HO 0 +CO 2 (CH 2)8 C 02 H (I OH O and is disclosed as having antibacterial activity in British Patent No 1, 395,907 I has now been found that certain amides of pseudomonic acid have a lower serum 30 binding than the acid itself, and are more active against certain organisms, in particular Neisseria gonorrhoeae.
Accordingly, the present invention provides a carboxylic acid amide of formula (II):
2 1,565,083 2 OH HO C 02 (CH 2)8 C ONR 1 R 2 (II) OH O wherein R’ and R 2 are the same or different and each represents hydrogen or an alkyl group.
Suitable alkyl groups for the groups RI and R 2 include C-, alkyl groups such as methyl, ethyl, n-, and iso-propyl, n-, iso-, and tertbutyl 5 Particular amide groups -CO NRWR 2 include the unsubstituted amide (-CONH 2), the N-methylamide, N,N-dimethylamide, N,N-diethylamide.
The compounds of formula (II) may be prepared from pseudomonic acid of formula (I) by conventional techniques for producing amides of carboxylic acids.
Suitably pseudomonic acid or a reactive derivative thereof is reacted with an amine 10 R’R 2 NH Preferred reactive derivatives include mixed anhydrides formed for example with isobutylchloroformate, ethyl chloroformate, pivaloyl chloride and other reagents for generating mixed anhydrides Alternative N-acylating derivatives of acid (I) are activated esters such as esters with cyanomethanol, p-nitrophenol, 2,4dinitrophenol, thiophenol, halophenol, including pentachlorophenol, monomethoxyphenol or 8-hydroxy 15 quinoline; or amides such as N-acylsacchrins or N-acylphthalimides; or an alkylidene iminoester prepared by -reaction of the acid (I) with an oxime.
Some activated esters, for example the ester formed with 1 hydroxybenztriazole or N-hydroxysuccinimide, may be prepared in situ by the reaction of the acid with the appropriate hydroxy compound in the presence of a carbodiimide, preferably dicyclo 20 hexylcarbodiimide.
Other reactive derivatives of pseudomonic acid include the reactive intermediate formed by reaction in situ with a condensing agent such as a carbodiimide, for example N,N diethyl, dipropyl or diisopropylcarbodiimide, N,N’ di cyclohexylcarbodiimide, or N ethyl N’ dimethylaminopropylcarboiimide; a suitable carbonyl corn 25 pound, for example N,N-carbonyldiimidazole or N,N-carbonylditriazole.
Suitable solvents for the process of this invention include inert aprotic solvents, such as tetrahydrofuran, methylene dichloride, N,N-dimethylacetamide The reaction is generally carried out at low temperature for example -25 C to O C, preferably at about -10 C 30 The antibiotic compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibiotics, and the invention therefore includes within its scope a pharmaceutical or veterinary composition comprising a compound of formula (II) above together with at least one conventional carrier or excipient 35 The compositions may be formulated for administration by any route, although an oral administration is preferred The compositions may be in the form of tablets, capsules, powders, granules, lozenges, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
Tablets and capsules for oral administration may be in unit dose presentation 40 form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate 45 The tablets may be coated according to methods well known in normal pharmaceutical practice Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use Such liquid preparations may contain conventional additives such as suspending agents, for 50 example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; nonaqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, 55 for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
Suppositories will contain conventional suppository bases, e g cocoa, butter or other glyceride.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the 5 vehicle In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing Advantageously adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum The dry lyophilized 10 powder is then sealed in the vial and an accompanying vial of water for injection is supplied to reconstitute the liquid prior to use Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtral 5 tion The compound can be sterilized by exposure to ethylene oxide before suspending 15 in the sterile vehicle Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The compositions may contain from 0 1 % to 99 % by weight, preferably from 10-60 % by weight, of the active material, depending on the method of administration Where the compositions comprise dosage units, each unit will preferably contain 20 from 50-500 mg of the active ingredient The dosage as employed for adult human treatment will preferably range from 100 to 3000 mg per day, for instance 1500 mg.
per day, depending on the route and frequency of administration.
Compositions of this invention may be used as a method for the treatment of veterinary bacterial infections, which method comprises the administration to the non 25 human animal an effective amount of a compound according to the invention.
The following Examples illustrate the present invention.
Example 1.
Pseudomonic acid N-methylamide.
Sodium pseudomonate ( 522 mg; 1 m M) was dissolved in dry, distilled N,Ndimethylacetamide ( 10 ml) and cooled with stirring to -10 C Isobutyl chloroformate ( 0 13 ml); p= 1 04; 1 m M) was added and the solution was maintained at -10 C for 10 minutes A 1 % w/v solution of methylamine in water ( 3 1 ml; 1 rm M) was added quickly and the solution was stirred for 1 hour with the temperature gradually warming to room temperature The mixture was poured into water (ca 50 ml), saturated with sodium chloride and extracted with ethyl acetate ( 4 x 20 ml) The ethyl acetate extract was washed with saturated brine, dried over magnesium sulphate, filtered and the filtrate was evaporated to dryness in vacuo.
( 304 mg) Thin layer chromatography in chloroform/methanol 9:1 showed one major spot Rf= 0 3 with a trace of pseudomonic acid Rf= 0 21 and very small traces at 40 Rf 0 40 and 0 47 This material was chromatographed on a 2 mm thick silica HF 254 20 X 20 cm plate and eluted with 15 % methanol in chloroform The band at Rf= 0 35 (under U V) was removed and eluted from the silica with 20 % methanol in chloroform The resulting oily product was dissolved in ethyl acetate and washed thoroughly with aqueous sodium bicarbonate The organic layer was dred over mag 45 nesium sulphate, filtered and evaporated in vacuo to give the product as an oil ( 127 mg).
Thin layer chromatography revealed 1 component Rf= 0 33 in chloroform/ methanol 9:1 g(C D 13) 0 92 ( 3 H,d,12-Me), 1 20 ( 3 H,d,13-Me), 9 30 (methylene so envelope); 2 18 ( 3 H,s,vinylic C Hs), 2 70 (m, epoxide protons), 2 76 ( 3 H,d,N-Me), 50 5.75 ( 1 H 11, broad s, vinylic H), 6 23 (-NH-); C (CD Cl I) 174 20 (l’-C, s,), 166 95 ( 1-C,s), 156,95 ( 1-C,s), 156 97 ( 3-C,s), 117 71 ( 2-C,d), 75 07 ( 5-C, d), 71 47 ( 13-C,d), 70 60 ( 7-C,d), 69 11 ( 6-C,d), 65,43 ( 16-C,t), 63 83 ( 9 ‘Ct), 61 38 ( 11-C,d), 55 710 ( 10-C,d), 42 94 ( 4-C and 12-C, two d’s), 39 68 ( 8-C, d), 36 74 ( 2 ‘-C,t), 31 72 ( 9-C,d,), 29 139 ( 4 ‘, 5 ‘ and 6 ‘-C), 28 63 ( 8 ‘-CO, 26 35 (N-Me,), 55 26.00 ( 7 ‘-C,d), 25 73 ( 3 ‘-C), 20 84 ( 14-C,q), 19 23 ( 15-C,q) and 12 75 ( 17-C,q); vmax (CH Cls), 3400 (OH str), 3300 (NH str) 1690 (C=O str, ester), 1650 and 1540 (C=O amide I, and C=C), 1510 (amide II) cm-‘ Xmax 222 nm (em 10 700); m/e 513 (M+), 495 (-H O O), 269 ( CH 2 CO,(CH,)8 CONHICH), 227 (Found:
M+ 513 3297200; C,7 H 7,N Osrequires M+ 513 3301422) 60 1,565,083 Example 2.
Pseudomonic Acid Amide.
Sodium pseudomonate ( 522 mg 1 m M) was dissolved in dry, distilled N,Ndimethylacetamide ( 10 ml) and the solution was cooled to -15 C isoButyl chloroformate ( 0 13 ml; p= 1 04; 1 m M) was added and the temperature was maintained 5 at -15 C for 10 minutes A solution of 1 % aqueous ammonia ( 2 0 ml; > 1 m M) was added and the mixture was stirred for 1 hours at room temperature The mixture was diluted with water to approx 75 ml, saturated with sodium chloride and extracted with ethyl acetate ( 4 x 15 ml) The latter was washed with brine, aqueous sodium bicarbonate, dried over magnesium sulphate, filtered and the filtrate was evaporated 10 to a slightly coloured oil ( 269 mg) Thin layer chromatography in chloroform/ methanol 9:1 revealed 1 major component at Rf 0 25 traces of impurities at 0 18 and 0 3 This material was applied to a 20 x 20 cm 2 mm thick preparative silica plate and eluted with 15 % methanol in chloroform.
The band corresponding to the major compound was removed and eluted from 15 the silica with 50 % methanol in chloroform After evaporation the product was obtained as a colourless oil ( 164 mg) Thin layer chromatography revealed 1 component in chloroform/methanol 9:1 at Rf 0 4 81 (CD C 13) 0 90 ( 3 Hd,12Me), 1.19 ( 3 H,d,13-Me), 1 31 (methylene envelope), 2 19 ( 3 H,s,vinylic Me), 2 70 (multiplets, epoxide protons and 4-CH 2), 4 08 ( 2 H,t,9 ‘-CH), 5 76 ( 1 H,s,vinylic H) 20 and 5 83 ( 2 H, broad CONH 2); vmax (CH Cl,) 3450 (OH str), 3350 (NH str), 1700 (C=O ester), 1650-1670 (amide I, and C=C), 1600 (amide II)cmi-; Xmax 222 nm (em 9,230); lalD 2 -5 020 (C,0 6 CHCI 3); m/e 499 (M+, 481 (-H O), 255 (z-CH 2 CO 2 (CH 2)8 CONH 227 (Found: M+ 499 3137700; C 26 H 45 NO 8 requires M+’499 3144930) 25 Example 3.
Pseudomonic acid N,N-dimethylamide.
Sodium pseudomonate ( 2 09 g; 4 m M) was dissolved in dry, distilled N,Ndimethylacetamide ( 20 ml) and cooled with stirring to -10 C iso Butyl chloroformate ( 0 53 mnil; 4 m M) was added maintaining the temperature at -10 C for 10 minutes 30 A solution of dimethylamine in water ( 1 M; 4 2 ml) was added and the solution stirred at O C for half an hour at room temperature for 2 hours The solution was evaporated to dryness in vacuo and the residue dissolved in ethyl acetate, which was washed with sodium bicarbonate solution, brine, dried over magnesium sulphate filtered and evaporated in vacuo to an oil ( 1 197 g) Thin layer chromatography and 35 high pressure liquid chromatography confirmed that the compound was homogeneous.
The oil began to crystallise and on trituration with dry ether affording a white solid ( 776 mg), mp 82-85 a (CDC 13) 5 70 ( 1 H,s,vinylic H), 4 03 ( 2 H,t,9 ‘-CH 2), 2.98 and 2 90 (two 3 H,s,CON(CH,)2), 2 70 (multiplets, epoxide protons Ho and H, 4-CHI), 2 17 ( 3 H,s,vinylic C Hs), 1 31 (methylene envelope), 1 19 ( 3 Hd,13-CH 3) 40 and 0 91 ( 3 H,s,12-CH 3); vmax (CHCI), 3450 (OH str), 2950, 1710 (ester C=O) 1615 (broad, C=C and C=O amide)cm-7; Xmax (Et OH) 219 (em 14,700)nm; lalx 2 -6 88 (c,1 0 CHCG Is); m/e 527 (M+), 509 ( H 20), 465 ( 509N(CH,)2).
(Found: M+ 527 347132; C 28 H 49 NO 8 requires M+ 527,347132).
Biological Data (a) Antibacterial activity against Gram-positive organisms Table 1 shows the MIC values of (,ag/ml) of the compounds of Examples 1 and 2 against six Gram-positive organisms:
1,565,083 :5 1565083 S TABLE 1
M.I C (gg/ml) Compound of Organism Example 1 Example 2 B Subtilis 0 25 0 25 Staph aureus Oxford 0 5 0 5 Staph aureus Russell 1 25 1 0 Staph aureus 1517 1 25 2 5 Strep faecalis 125 100 f 3-Haemolytic StrepCN 10 0 1 (b) Activity against N gonorrhoeae Table 2 shows M I C values (t 1 g/ml) of the compounds of Examples 1 and 2 against twelve strains of N gonorrhoeae compared to benzylpenicillin.
TABLE 2
Compound of Benzyl Strain Penicillin Example 1 Example 2 VDRL 67 0 05 0 002 0 002 69 0 1 0 002 0 002 0 1 A 005 0 005 72 0 2 0 01 0 01 77 0 1 0 005 0 02 82 0 5 0 05 0 05 87 0 01 0 01 0 005 AR 229 1 0 0 05 0 05 2176 0 2 0 02 0 02 H 2057 0 005 0 005 0 005 WHO VII 0 005 0 005 0 002 VD 79 0 2 0 02 0 02 Oxford Staph 0 02 0 05 0 05 Serial dilution in 10 % horse blood agar Incubated in a partial atmosphere of CO 2 for 24 hours at 37 C Inoculated with one drop ( 0 00 lml) of an overnight- cell suspension.
S 1.565 083 0 % (c) Activity against mycoplasma Table 3 shows the antimycoplasmal activities (in terms of M I C) of the compounds of Examples 2 and 3 and demonstrates that both possess good antimycoplasmal activity in vitro against mycoplasmas from human and veterinary sources.
The method used to test for antimycoplasmal activity was as follows: 5 The minimal mhibitory concentration (MIC) of the pseudomonic acid amides was determined in Microtitre plates, by a modification of the metabolicinhibition test (Taylor-Robinson, 1967) The compounds were serially diluted in sterile deionised water to give a range of concentrations from 250-0 5 ug/mrl Mycoplasma broth containing 1 % (w/v) of glucose and 0 005 % (w/v) of phenol red, was added at a 10 strength to compensate for its dilution by the aqueous drug solution Approximately 104 colony forming units of mycoplasma were added to each concentration of drug.
Drug-free infected, non-infected and p H control wells were included on each plate.
Plates were sealed with adhesive tape and incubated at 37 C for seven days The MIC was the lbwest concentration of compound that prevented a colour change in 15 the mycoplasma broth caused by the metabolism of glucose by the mycoplasmas.
Reference Taylor-Robinson, D, 1967 Mycoplasmas of various hosts and their antibiotic o sensitivities Post Grad Med J, 43 Suppl lMarchl, 100.
TABLE 3 to
TABLE 3
MIC /g/ml Source Chicken Mouse Cattle Pig Man t M galli M M agalac M suipneu M M.
septicum synoviae M pulmonis tiae ATCC M dispar moniae pneumoniae fermentans Compound 56 ATCC 25204 ‘JB’ 25025 H 225 (Laber) 429 a MWKL 4 Example 2, O 5 O 5 < 0 5 < O 5 < 0 5 < O 5 250 < O 5 Example 3,0 5 0 5 -X 5 < 0 5 O 5 3 9 250 O 5 (d) Serum Binding The degree of binding to human serum of the compounds of Examples 1 and 2 compared with that of pseudomonic acid was determined by the following procedure:
Test samples were mixed with human serum and placed in visking tubing Serum binding was determined by ultrafiltration, the filtrate obtained being assayed by a 5 hole-in-plate method using Bacillus subtilis ATCC 6633 against standards prepared in 0.05 M p H 7 0 phosphate buffer.
The results are shown in Table 4:
TABLE 4 % unbound in Compound human serum Example 1 20
Example 2 14
Pseudomonic acid sample 1 6 6 sample 2 6 8
Claims (10)
WHAT WE CLAIM IS: 10
1 An amide of pseudomonic acid of formula:OH HO Ho HXCO 2 (CH 2)8 CO NR 1 R 2 2) OH o wherein R, and R 2 are the same or different and each represents hydrogen or an alkyl group.
2 An amide as claimed in claim 1 wherein R' and R 2 represent hydrogen or a 15 C,, alkyl group.
3 Pseudomonic acid N-methylamide.
4 Pseudomonic acid primary amide.
Pseudomonic acid N,N-dimethylamide.
6 A process for the preparation of an amide as claimed in claim 1 which process 20 comprises reacting pseudomonic acid or a reactive derivative thereof with an amine of formula R 1 R 2 NH.
7 A process as claimed in claim 6 substantially as described with reference to any one of Examples 1-3.
8 An amide as claimed in claim 1 whenever produced by a process as claimed in 25 either claim 6 or claim 7.
9 A pharmaceutical or veterinary composition comprising a compound as claimed in any one of claims 1-5 together with at least one conventional carrier or excipient.
10 A method for the treatment of veterinary bacterial infections which method 30 comprises the administration to the non-human animal an effective amount of a compound as claimed in any one of claims 1-55.
DR A HESKETH, Chartered Patent Agent, Agent for the Applicants.
Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1980.
Published by the Patent Office, 25 Southampton Buildings, London, WC 2 A l AY, from which copies may be obtained.
1,565,083
GB6884/76A
1976-02-20
1976-02-20
Pseudomonic acid amides
Expired
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GB6884/76A
GB1565083A
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1976-02-20
1976-02-20
Pseudomonic acid amides
ZA770772A
ZA77772B
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1976-02-20
1977-02-10
Antibacterial compounds
BE174922A
BE851410A
(en)
1976-02-20
1977-02-14
ANTIBACTERIAL COMPOUNDS
US05/768,057
US4139629A
(en)
1976-02-20
1977-02-14
Pseudomonic acid amide antibacterial compounds
SE7701722A
SE431649B
(en)
1976-02-20
1977-02-16
PROCEDURE FOR PREPARING AMIDES OF PSEUDOMONIC ACID WITH ANTIBACTERIAL EFFECT
DE19772706548
DE2706548A1
(en)
1976-02-20
1977-02-16
AMIDE OF PSEUDOMONIC ACID, METHOD FOR MANUFACTURING AND USING IT
FR7704368A
FR2349584A1
(en)
1976-02-20
1977-02-16
PSEUDOMONIC ACID AMIDE WITH ANTIBACTERIAL ACTIVITY
IE348/77A
IE44445B1
(en)
1976-02-20
1977-02-18
Pseudomonic acid amides
DK73777A
DK145823C
(en)
1976-02-20
1977-02-18
ANALOGY PROCEDURE FOR PREPARING AMIDES OF PSEUDOMONIC ACID
CH209177A
CH629799A5
(en)
1976-02-20
1977-02-18
METHOD FOR PRODUCING AMIDES OF PSEUDOMONIC ACID.
NL7701727A
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1976-02-20
1977-02-18
METHOD FOR PREPARING AGAINST BACTERIA ACTIVE COMPOUNDS, AND CONTAINING DOSED PHARMACEUTICAL PREPARATION.
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1994-03-08
Sankyo Company, Limited
Anti-bacterial compound and pharmaceutical compositions thereof
US5380723A
(en)
*
1991-10-07
1995-01-10
Nisshin Flour Milling Co., Ltd.
Indole derivatives
US5399711A
(en)
*
1992-09-18
1995-03-21
Sankyo Company, Limited
Thiomarinol compounds
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1976-06-15
1981-03-25
Beecham Group Ltd
Oxiranylmethyltetrahydropyran derivatives
CA1103264A
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*
1977-09-30
1981-06-16
Norman H. Rogers
Purification of pseudomonic acid
DE2860726D1
(en)
*
1977-11-05
1981-08-27
Beecham Group Plc
Antibacterially active amides, process for their preparation and pharmaceutical compositions containing said amides
US4297365A
(en)
*
1978-08-04
1981-10-27
Ciba-Geigy Corporation
Benzimidazoles and pharmaceutical preparations containing such compounds
EP0026611B1
(en)
*
1979-09-28
1984-02-01
Beecham Group Plc
Antibacterial sulphonamides, processes for their preparation and compositions containing them
IL150907A
(en)
*
2002-07-25
2007-07-04
Stephan Cherkez
Process for the preparation of stable amorphous calcium pseudomonate
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Merck & Co Inc
2,5 - disubstituted - 2 - (carboxyalkoxyaroyl) - 6 - (carboxyalkoxyaryl)-3,4-dihydro-2h-pyrans and their derivatives
US3740437A
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1970-06-25
1973-06-19
Syntex Corp
Naphthyloxyacetic acids and pharmaceutical compositions and methods thereof
US3755603A
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*
1970-07-01
1973-08-28
Syntex Corp
Biphenylyloxyacetic acids in pharmaceutical compositions
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1971-06-12
1975-05-29
Beecham Group Ltd
Antibiotics
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1994-03-08
Sankyo Company, Limited
Anti-bacterial compound and pharmaceutical compositions thereof
US5405762A
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*
1991-05-07
1995-04-11
Sankyo Company, Limited
Culture of alteromonas and process of using the same to produce an antibacterial compound
US5380723A
(en)
*
1991-10-07
1995-01-10
Nisshin Flour Milling Co., Ltd.
Indole derivatives
US5399711A
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*
1992-09-18
1995-03-21
Sankyo Company, Limited
Thiomarinol compounds
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(en)
1977-08-25
BE851410A
(en)
1977-08-16
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(en)
1977-08-20
US4139629A
(en)
1979-02-13
FR2349584A1
(en)
1977-11-25
DK145823C
(en)
1983-08-29
CH629799A5
(en)
1982-05-14
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(en)
1983-03-14
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1977-08-21
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