WO1986004935A1 - Amidinourea process and pharmaceutical composition - Google Patents
Amidinourea process and pharmaceutical composition Download PDFInfo
- Publication number
- WO1986004935A1 WO1986004935A1 PCT/US1985/000266 US8500266W WO8604935A1 WO 1986004935 A1 WO1986004935 A1 WO 1986004935A1 US 8500266 W US8500266 W US 8500266W WO 8604935 A1 WO8604935 A1 WO 8604935A1
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- WO
- WIPO (PCT)
- Prior art keywords
- methylamidinourea
- formula
- compound
- hydrogen
- alkyl
- Prior art date
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- 0 CC1(CCCCC1)C(C)(CCC1*)CC(*)C1N(*)C(NC(*)=*)=O Chemical compound CC1(CCCCC1)C(C)(CCC1*)CC(*)C1N(*)C(NC(*)=*)=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/24—Y being a hetero atom
Definitions
- This invention relates to amidinoureas, improved processes for their preparation, and pharmaceutical compositions.
- amidinoureas prepared by the present invention have been reported to be effective anti-diarrheal agents.
- U.S. Patent No. 4,060,635 amidinourea compounds and a method for the treatment of diarrhea by administering these compounds are described. Methods by which these compounds have been prepared include the following general syntheses.
- amidinoureas may also be prepared by degradation of the corresponding biguanide as shown in Scheme II below.
- Scheme II When a 1-substituted phenylbiguanide compound is hydrolyzed in acid at raised temperature, then the resultant product is 1-substituted phenyl-3-amidinourea.
- the starting material When it is desired to have R n substitution, the starting material of course will be an aniline having N-alkyl substitution. Reaction with phosgene results in the carbamoyl chloride which is then reacted with the guanidine to prepare the amidinourea as shown in Scheme III below.
- amidinourea compounds may be formulated into anti-diarrheal compositions.
- liquid compositions including the amidinourea compounds degrade over prolonged periods of time, thereby limiting their use.
- This invention relates to an improved process for the preparation of a compound of Formula I
- X, Y and Z are hydrogen, alkyl, alkoxy, cyano, acyloxy, alkenyl, alkynyl, halo, haloalkyl, haloalkoxy, amino, acyl, carbamoyl, nitro, hydroxy, arylalkoxy or alkylsulfonyl;
- R 1 , R 2 and R 3 are each independently hydrogen, alkyl, cycloalkyl or aralkyl; or R 2 and R 3 together with the nitrogen atom to which they are attached form a 5, 6, or 7 membered ring which may include 0-2 additional heteroatoms of N, O or S; provided that at least one of R 1 , R 2 or R 3 is other than hydrogen; the improvement comprising the use of a ketone as the reaction medium, with a lower alkyl ketone being preferred.
- This invention also relates to a method for the preparation of a liquid pharmaceutical composition comprising a compound of Formula I.
- a liquid pharmaceutical composition comprising a compound of Formula I.
- the process according to this invention comprises the use of a ketone as the reaction medium. It has been found that the use of such reaction medium results in formation of a crystalline precipitate of an amidinourea of Formula I, which can be easily separated and purified for use as a pharmaceutical product.
- the most desired ketone is acetone, although other lower alkyl ketones such as methylethyl ketone and ethylethyl ketone may be utilized in the reaction process.
- loweralkyl refers to an alkyl hydrocarbon group of from 1 to 5 carbon atoms which may be straight chained or branched, while “alkyl” refers to an alkyl hydrocarbon group which may have as many as ten carbon atoms.
- cycloalkyl refers to a cycloalkyl group having 3-7 carbon atoms.
- the "loweralkoxy" radical signifies an alkoxy group containing from 1 to about 5 carbon atoms which may be straight chained or branched.
- the preferred "aryl” group is phenyl
- the preferred "aralkyl” groups are benzyl and phenethyl.
- the preferred "halo loweralkyl” group is trifluoromethyl.
- the preferred "halo loweralkoxy" group is trifluoromethoxy.
- the most preferred process is a process for the preparation of a compound of Formula V
- X and Y are hydrogen, alkyl, halo, alkoxy, haloalkyl or haloalkoxy; and R 2 and R 3 are hydrogen, alkyl, cycloalkyl, aralkyl or alkoxy; provided that at least one of R 2 and R 3 is other than hydrogen.
- the mixture is chilled to 10°C in an ice bath and the solid collected by filtration.
- the filter cake is washed with 2 1 of cold acetone.
- the solid is suspended in 4 1 of water and stirred for 30 minutes.
- the suspension is filtered and the solid washed on the filter with 4 1 of water.
- the solid is suspended in 2.5 1 of water at 60°C. 670 ml of concentrated hydrochloric acid are added to the suspension while stirring. After dissolution is complete 360 g of sodium chloride (USP--crystal) is added in portions. Using a water bath the mixture is cooled to 18°C over a period of 1 hr. The suspension is filtered and the solid washed with 1 1 of a cold 4% solution of sodium chloride in 0.36 molar hydrochloric acid. The material is partially dried on the filter.
- the suspension is filtered and the solid washed with 2 1 of a cold 4% solution of sodium chloride in 0.36 molar hydrochloric acid and then with the 1 1 of cold wash solution prepared above.
- the solid is left on the filter until no additional filtrate can be collected.
- the filter cake is spread on a tray and dried at 50°C in a mechanical convection oven for 24 hrs. This yields 1480.3 g of 1-(2,6-dimethylphenyl)-3-methyl amidinourea hydrochloride, M.P. 200-203°C.
- 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride (1,267 g, greater than 0.1% N,N"-bis (2,6-dimethyIphenylcarbamoyl)-N'-methylguanidine hydrochloride) is suspended in 2,534 ml of methylene chloride at RT and stirred for 2 hrs. The suspension is filtered and the filter cake is washed with 2 1 of methylene chloride. The solid is air dried to obtain 1 ,194 g (94.2%) of 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride, M.P. 200-203°C.
- the isocyanates of Table I may be prepared as described above from the corresponding anilines which are either known, or may be prepared by known techniques.
- chlorination or bromination of an acetanilide or aniline may be carried out in acetic acid, or in the presence of a small amount of iodine dissolved in an inert solvent such as carbon tetrachloride.
- a solution of chlorine or bromine is then added while the temperature is held near 0°C.
- lodination may also be carried out by known methods using iodine monochloride (Cl I).
- Alkylation may be carried out on an acetanilide using an alkyl halide and aluminum chloride under Friedel-Crafts conditions to obtain desired alkyl substitution.
- Nitration may be carried out using fuming nitric acid at about 0°C.
- a nitro compound may be hydrogenated to the corresponding amine which may then be diazotized and heated in an alcohol medium to form the alkoxy compound.
- An amino compound may also be diazotized to the diazonium fluoroborate which is then thermally decomposed to the fluoro compound.
- a chloro, bromo or iodo compound may also be reacted with trifluoromethyliodide and copper powder at about 150°C in dimethylformamide to obtain a trifluoromethyl compound [Tetrahedron Letters: 47,4095 (1959)].
- a halo compound may also be reacted with cuprous methanesulfinate in quinoline at about 150°C to obtain a methylsulfonyl compound.
- the starting aniline may contain the corresponding acyloxy or aralkyloxy groups.
- acyloxy or aralkyloxy groups may be prepared in the usual fashion by acylating the starting hydroxy aniline compound with an acyl halide or anhydride in the presence of a tertiary amine or aralkylating with an aralkyl halide or sulfate. Of course the amine function would be protected in the customary manner.
- Hydrogenation to the desired hydroxy compound may then take place after the formation of the amidinourea. This may be accomplished with a metal catalyst (Pd/C, Pt etc.) in a polar medium (ethanol, THF, etc.), sodium in liquid ammonia, etc.
- the 3,4-dihydroxy amidinourea compound may be prepared from the corresponding 3,4-dibenzyloxyaniline.
- the hydroxy compounds may also be prepared by hydrolysis of the acyl or alkoxy compounds with acid.
- phenylamidinourea may be halogenated or nitrated as above, etc.
- the compounds of Formula I are useful anti-diarrheal agents.
- Various tests can be carried out in animal models to show the ability of the compounds of Formula I to exhibit reactions that can be correlated with anti-diarrheal activity in humans.
- the following tests show the ability of the compounds of this invention to inhibit diarrhea in animals and are known to correlate well with anti-diarrheal activity in humans. These are considered to be standard tests used to determine anti-diarrhea properties. This correlation can be shown by the activities of compounds known to be clinically active.
- the amidinoureas of this invention can be considered to be anti-diarrheal agents.
- the compounds of Formula I may be administered orally, parenterally or rectally. Administration by the oral route is preferred. Orally, these compounds may be administered in tablets, hard or soft capsules, aqueous or oily suspensions, dispersible powders or granules, emulsions, syrups or elixers.
- the optimum dosage will depend on the particular compound being used and the type and severity of the condition being treated. In any specific case the appropriate dosage selected will further depend on factors of the patient which may influence response to the drug; for example, general health, age, weight, etc. of the subject being treated.
- the composition may contain such selected excipients as inert diluents such as calcium carbonate, lactose, etc.;granulating and disintegrating agents such as maize starch, alginic acid, etc.; lubricating agents such as magnesium stearate, etc.; binding agents such as starch gelatin, etc.; suspending agents such as methyl cellulose, vegetable oil, etc.; dispersing agents such as lecithin, etc.; thickening agents such as beewsax, hard paraffin, etc.; emulsifying agents such as naturally-occurring gums, etc.; non-irritating excipients such as cocoa butter, polyethylene glycols, etc.; and the like.
- excipients as inert diluents such as calcium carbonate, lactose, etc.;granulating and disintegrating agents such as maize starch, alginic acid, etc.; lubricating agents such as magnesium stearate, etc.; binding agents such
- the dosage unit form will generally contain between 0.1 mg and about 500 mg of the active ingredients of this invention.
- the preferred unit dose is between 1 mg and about 50 mg.
- the compositions may be taken 1-8 times daily depending on the dosage unit required.
- active amidinourea may be administered alone or in admixture with other agents having the same or different pharmacological properties.
- the debilitating effects of diarrhea result partially from electrolyte imbalance in the patient, so that it is recommended that a solvent or diluent forming the carrier of the liquid pharmaceutical compositions, whether designed for injection or oral administration, should incorporate electrolyte balance.
- the precise composition of the electrolyte replenisher incorporated in the liquid compositions will depend on the age and the general health and condition of the patient, but in many cases it is appropriate to use a commercially available electrolyte replenisher. These generally include sodium chloride alone or in combination with potassium salts, calcium salts, lactates or bicarbonates, and typical examples are Ringer's Solution, Darrow's Solution (for injection), Ringer's Injection and Lactated Ringer's Injection. These and other examples of commercially available electrolyte replenishers may be found in the "Pharmacopeia of the United States".
- a particularly preferred liquid anti-diarrheal composition is one in which the carrier is a solvent or diluent comprising a saline solution of substantially isotonic concentration.
- Liquid compositions for oral use are preferably aqueous, so as to permit the inclusion of an electrolyte.
- Ingredients suitable for incorporation in the carrier of an aqueous liquid suspension are for example suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidine, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally occurring phosphatide, for example lecithin, condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxyethanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, for example polyoxyethylene sorbitol mono-oleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan
- Aqueous suspensions may also in particular contain one or more preservatives, for example ethyl- or n-propyl-p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose.
- preservatives for example ethyl- or n-propyl-p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose.
- Oily suspensions may be formulated .by suspending the amidinourea in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
- Sweetening agents, such as those set forth above, and flavouring agents may here also be added to provide a palatable oral preparation. These compositions may also be preserved by the addition of an anti-oxidant such as ascorbic acid.
- the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these.
- the emulsions may also contain sweetening and flavouring agents.
- Syrups and elixirs in particular may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavouring and colouring agents.
- sweetening agents for example glycerol, sorbitol or sucrose.
- Such formulations may also contain a demulcent, a preservative, and flavouring and colouring agents.
- liquid compositions may be formulated for injection.
- they may take the form of a sterile injectable aqueous suspension formulated according to the known art and containing those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
- An injectable composition is preferably a sterile injectable solution or suspension of the amidinourea in a parenterally acceptable diluent or solvent, for example a sterile aqueous solution buffered to a pH of 4.0 to 7.0 and made isotonic with sodium chloride.
- the present invention relates to a method of providing a stable dosage form for preparation into a liquid form immediately prior to its use. More particularly the present invention is a method for the preparation of a liquid pharmaceutical composition suitable for oral administration or parenteral injection, said composition comprising a pharmaceutically acceptable liquid vehicle and from 1 to 25 mg of a compound of the Formula I
- X, Y and Z are hydrogen, alkyl, alkoxy, cyano, acyloxy, alkenyl, alkynyl, halo, haloalkyl, haloalkoxy, amino, acyl, carbamoyl, nitro, hydroxy, arylalkoxy or alkylsulfonyl;
- R 1 , R 2 and R 3 are each independently hydrogen, alkyl, cycloalkyl or aralkyl; or R 2 and R 3 together with the nitrogen atoms to which they are attached form a 5, 6, or 7 membered ring which may include 0-2 additional heteroatoms of N, O or S; provided that at least one of R 1 , R 2 or R 3 is other than hydrogen; which method comprises combining the compound of Formula I with the vehicle by the steps of:
- step (d) preparing the liquid composition for administration by dissolving the dessicated composition in a dosage volume of liquid vehicle comprising either sterile water or a sterile electrolyte replenisher solution; the said dosage amount and volume being for either single or multiple doses, and in the latter case a preservative being added in step (a) or step (d).
- aqueous solution for parenteral administration is prepared as follows:
- a sterilized aqueous solution for oral administration containing 1-(2,6-dimethylphenyl)-3-amidinourea hydrochloride is made up from the following ingredients: 1-(2,62dimethylphenyl)-3- amidinourea hydrochloride 5 mg
- a sterile solution suitable for interperitoneal injection containing 10 mg of 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride in each 10 ml (1:1 wt/vol), is prepared from the following ingredients: 1-(2,6-dimethylphenyl)-3- methylamidinourea hyrochloride 10 g Benzyl benzoate 100 cm 3
- Tablets of 850 mg are prepared by maximum compression of a mixture of the following ingredients: 1-(2 ,6-dimethylphenyl)-3- methylamidinourea hyrochloride 500 mg Tricalcium phosphate 200 mg
- Protective excipients such as ethylcellulose, dibutylphthalate, propylene glycol, wax (white and/or carnauba), spermaceti, methylene chloride and rectified diethyl ether may optionally be included among the ingredients.
- a lot of tablets, each containing 20 mg of 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride are prepared from the following ingredients: 1-(2,6-dimethylphenyl)-3- methylamidinourea hyrochloride 1 kg Dicalcium phosphate 1 kg
- a lot of two-piece hard gelatin capsules, each containing 25 mg of 1-(2,6-dimethylphenyl)-3-methyl amidinourea hydrochloride, are prepared from the following types and amounts of ingredients: 1-(2,6-dimethylphenyl)-3- methylamidinourea hyrochloride 500 g Dicalcium phosphate 500 g
- the ingredients are mixed thoroughly and filled into capsules for oral administration to animals at the rate of about one every four hours. If desired, slow release or delay release forms can be provided, depending on choice of capsules and formulating ingredients.
- Tablets for oral administration each containing 25 mg of 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride, are prepared from a mixture of the following ingredients:
- Potato starch USP 346 g The mixture is moistened with an alcoholic solution of 20 g of stearic acid and granulated through a sieve. After drying, the following ingredients are added:
- Colloidal silicum dioxide 64 g and the whole is thoroughly mixed and compressed into tablets.
- Capsules are prepared from the following mixture: 1-(2,6-dimethyl ⁇ henyl)-3- methylamidinourea hyrochloride 15 g Magnesium stearate 3 g
- Finely divided silica sold under the trademark CAB-O-SIL by Godfrey L. Cabot, Inc., Boston, MA 2 g
- the mixture is filled into gelatin capsules, each capsule containing 500 mg of the mixture and thus 15 mg of 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride.
- amidinoureas of general Formula I above can be formulated in a similar manner for either oral or parenteral administration as injectable or infusible solutions.
- the solid or liquid formulations can also be dispersed in the food or dissolved in the drinking water or the liquid diet of the patient.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Saccharide Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP19850901245 EP0217787A4 (en) | 1985-02-15 | 1985-02-15 | Amidinourea process and pharmaceutical composition. |
HU851054A HUT43034A (en) | 1985-02-15 | 1985-02-15 | Process for preparing amidino-urea derivatives and pharmaceutical compositions comprising such compounds |
PCT/US1985/000266 WO1986004935A1 (en) | 1985-02-15 | 1985-02-15 | Amidinourea process and pharmaceutical composition |
AU39926/85A AU575132B2 (en) | 1985-02-15 | 1985-02-15 | Preperation of amidinoureas |
JP60500895A JPS62501839A (en) | 1985-02-15 | 1985-02-15 | Method for producing amidinourea and pharmaceutical composition |
NO86863783A NO863783L (en) | 1985-02-15 | 1986-09-23 | AMIDINOUREAPE PROCESS AND PHARMACEUTICAL PREPARATION. |
FI864067A FI864067A (en) | 1985-02-15 | 1986-10-08 | FOERFARANDE FOER FRAMSTAELLNING AV EN AMIDINOUREA OCH PHARMACEUTISK KOMPOSITION. |
DK489186A DK489186A (en) | 1985-02-15 | 1986-10-14 | PROCEDURE FOR MANUFACTURING AMIDINOUR INGREDIENTS AND PHARMACEUTICAL PREPARATIONS |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US1985/000266 WO1986004935A1 (en) | 1985-02-15 | 1985-02-15 | Amidinourea process and pharmaceutical composition |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1986004935A1 true WO1986004935A1 (en) | 1986-08-28 |
Family
ID=22188585
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1985/000266 WO1986004935A1 (en) | 1985-02-15 | 1985-02-15 | Amidinourea process and pharmaceutical composition |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP0217787A4 (en) |
JP (1) | JPS62501839A (en) |
AU (1) | AU575132B2 (en) |
DK (1) | DK489186A (en) |
FI (1) | FI864067A (en) |
HU (1) | HUT43034A (en) |
NO (1) | NO863783L (en) |
WO (1) | WO1986004935A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU605584B2 (en) * | 1987-04-10 | 1991-01-17 | Reanal Finomvegyszergyar | Method for the preparation of amidino-urea derivatives |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3539616A (en) * | 1966-07-07 | 1970-11-10 | Burroughs Wellcome Co | 1-amidino-3-(cyanophenyl) ureas |
US3903084A (en) * | 1974-02-11 | 1975-09-02 | Upjohn Co | Carboximidoyl urea derivatives |
US3984467A (en) * | 1969-03-03 | 1976-10-05 | Sterling Drug Inc. | Anthelmintic 1-(substituted phenyl)-3-alkanimidoyl ureas |
US4110328A (en) * | 1975-10-30 | 1978-08-29 | Cooper Laboratories, Inc. | Bis-carbamylguanidinoazaalkane antimicrobial compounds |
US4404225A (en) * | 1979-07-03 | 1983-09-13 | Ciba-Geigy Corporation | Thiourea derivatives having pesticidal activity |
US4440949A (en) * | 1979-01-08 | 1984-04-03 | William H. Rorer, Inc. | Amidinoureas |
US4487779A (en) * | 1981-07-06 | 1984-12-11 | William H. Rorer, Inc. | Substituted phenyl amidinoureas |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4060635A (en) * | 1975-03-31 | 1977-11-29 | William H. Rorer, Inc. | Amidinoureas for treating diarrhea |
-
1985
- 1985-02-15 HU HU851054A patent/HUT43034A/en unknown
- 1985-02-15 JP JP60500895A patent/JPS62501839A/en active Pending
- 1985-02-15 AU AU39926/85A patent/AU575132B2/en not_active Ceased
- 1985-02-15 WO PCT/US1985/000266 patent/WO1986004935A1/en not_active Application Discontinuation
- 1985-02-15 EP EP19850901245 patent/EP0217787A4/en not_active Withdrawn
-
1986
- 1986-09-23 NO NO86863783A patent/NO863783L/en unknown
- 1986-10-08 FI FI864067A patent/FI864067A/en not_active Application Discontinuation
- 1986-10-14 DK DK489186A patent/DK489186A/en not_active Application Discontinuation
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3539616A (en) * | 1966-07-07 | 1970-11-10 | Burroughs Wellcome Co | 1-amidino-3-(cyanophenyl) ureas |
US3984467A (en) * | 1969-03-03 | 1976-10-05 | Sterling Drug Inc. | Anthelmintic 1-(substituted phenyl)-3-alkanimidoyl ureas |
US3903084A (en) * | 1974-02-11 | 1975-09-02 | Upjohn Co | Carboximidoyl urea derivatives |
US4110328A (en) * | 1975-10-30 | 1978-08-29 | Cooper Laboratories, Inc. | Bis-carbamylguanidinoazaalkane antimicrobial compounds |
US4440949A (en) * | 1979-01-08 | 1984-04-03 | William H. Rorer, Inc. | Amidinoureas |
US4404225A (en) * | 1979-07-03 | 1983-09-13 | Ciba-Geigy Corporation | Thiourea derivatives having pesticidal activity |
US4487779A (en) * | 1981-07-06 | 1984-12-11 | William H. Rorer, Inc. | Substituted phenyl amidinoureas |
Also Published As
Publication number | Publication date |
---|---|
AU3992685A (en) | 1986-09-10 |
FI864067A0 (en) | 1986-10-08 |
FI864067A (en) | 1986-10-08 |
JPS62501839A (en) | 1987-07-23 |
HUT43034A (en) | 1987-09-28 |
NO863783D0 (en) | 1986-09-23 |
EP0217787A4 (en) | 1988-07-21 |
NO863783L (en) | 1986-09-23 |
DK489186D0 (en) | 1986-10-14 |
AU575132B2 (en) | 1988-07-21 |
DK489186A (en) | 1986-10-14 |
EP0217787A1 (en) | 1987-04-15 |
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