GB607720A - Manufacture of biguanide derivatives - Google Patents
Manufacture of biguanide derivativesInfo
- Publication number
- GB607720A GB607720A GB35238/45A GB3523845A GB607720A GB 607720 A GB607720 A GB 607720A GB 35238/45 A GB35238/45 A GB 35238/45A GB 3523845 A GB3523845 A GB 3523845A GB 607720 A GB607720 A GB 607720A
- Authority
- GB
- United Kingdom
- Prior art keywords
- chloro
- methyl
- iodo
- bromo
- phenyl
- Prior art date
- 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
Links
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
- C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Biguanide derivatives of the general formula RR1N-C(: NH) - NH-C(: NH)-NR11R111, wherein R1 and R111 may each represent hydrogen or a hydrocarbon radical and R and R11 may each represent a hydrocarbon radical, provided that of the groups represented by R, R1, R11 and R111 (any or all of which may bear one or more non-acidic substituents) at least one but not more than two must be aryl, are manufactured by interaction of a guanidine derivative RR1N-C(: NH)-NH2 with a cyanamide derivative R11R111NCN. The reaction may be effected by heating the reactants together, optionally in the presence of a solvent or diluent, the guanidine derivative being used in the form of the free base or as a salt, whilst if the cyanamide is monosubstituted it may be used in the form of a salt with a base (in which case the guanidine derivative is also used in the form of a salt). The products are useful as chemotherapeutic agents or intermediates therefor, antimalarial activity being particularly marked in those in which one of the two pairs of substituents (R and R1 or R11 and R111) contains more than one and fewer than eight carbon atoms, whilst of the other pair one is hydrogen and the other a phenyl radical substituted by at least one halogen atom in m- or p-position to the nitrogen atom, e.g. substituted by chlorine, bromine or iodine in the m- or p-position and bearing another substituent, such as an alkyl or alkoxy group, in the p- or m-position respectively, or substituted by halogen in both one m-position and the p-position, or in both m-positions, or in both m-positions and the p-position. Salts of the products with organic and inorganic acids, e.g. acetic, lactic, methanesulphonic, methylenedisalicylic, methylene - bis - 2 : 3 - hydroxynaphthoic or hydrochloric acid, are obtainable by dissolving the biguanides in aqueous solutions of the acids and evaporating off the water, or preferably by mixing the components in an organic solvent, e.g. acetone or an alcohol in which the salts are sparingly soluble. In examples: (1) p - chlorophenylguanidine is heated with dimethylcyanamide to produce N a -p-chlorophenyl-No -dimethylbiguanide; (2) diethylcyanamide and methylisopropylcyanamide similarly yield the No -diethyl and No -methyl-No -isopropyl derivatives respectively; (3) p-chlorophenylguanidine and phenylmethylcyanamide are refluxed in n-butanol to give Na - p - chlorophenyl - No - phenyl - No - methylbiguanide; (4) to (26) from the appropriate intermediates there are similarly prepared Na - p - iodo-, -m - chloro-, -3 : 4 - dichloro-, -3-chloro-4-bromo- and -iodo-, -3 : 5-dichloro-, -3 : 4 : 5 - trichloro-, -3 - chloro - 4 - methyl-, -4-chloro-3-methyl- and -m-bromo-phenyl-N-isopropylbiguanide, Na - p - iodophenyl - No - methyl - No -isopropylbiguanide, Na -p-chloro-phenyl-No -isopropylbiguanide, Na -p-methoxy-phenyl - No - dimethylbiguanide, Na - p - chloro-and -p-methoxy - phenyl - No - cyclohexylbiguanide, Na -p-chlorophenyl-No -p-tolylbiguanide, Na -p-tolyl-No -diethyl- and -No -cyclohexylbiguanide, Na -p-bromophenyl-No -n-propylbiguanide, Na -diphenyl-No -isopropylbiguanide and Na - p - bromophenyl - No - diethyl-, -No -ethyl-No -methyl-No -isopropyl-biguanide; (29) p-chlorophenylguanidine hydrochloride and dimethylcyanamide are refluxed in n-butanol, yielding the product of (1); (28) phenylguanidine carbonate and p-chlorophenylcyanamide similarly yield Na -p-chlorophenyl-No -phenylbiguanide; (29) a mixture of p-chlorophenylguanidine, its hydrochloride, diethylcyanamide and toluene is refluxed to produce Na -p-chlorophenyl-No -diethylbiguanide; (30) the reaction of (29) is carried out in n-butanol and using a smaller proportion of the hydrochloride, and the product is purified by way of its copper complex compound; (31) isopropylcyanamide similarly yields Na -p-chlorophenyl-No -isopropylbiguanide, which is converted into its acetate; (32) isopropylguanidine sulphate is shaken with a solution of sodium in n-butanol, and the resulting solution is refluxed with p-chlorophenylcyanamide to give the product of (31); from the appropriate alkylguanidine salts there are similarly obtained: (33) the product of (1), and (34) Na -p-chlorophenyl-No -methylbiguanide; (35) dimethylguanidine sulphate is refluxed with a solution of sodium in n-butanol, the mixture is cooled and filtered and the solution refluxed with phenylmethylcyanamide to produce Na -phenyl-Na -methyl-No -dimethylbiguanide; (36) to (41) from the appropriate arylcyanamides and alkylguanidine salts there are similarly prepared Na -diphenyl-No -dimethylbiguanide, Na -phenyl-No -methyl-and -No - isopropyl - biguanide, Na - diphenyl - No - isopropylbiguanide, and Na - p - bromophenyl-No -methyl- and -No -cyclohexylbiguanide; (42) N : N-phenylmethylguanidine hydrochloride and phenylmethylcyanamide are similarly reacted to form Na -No -diphenyl-Na -No -dimethylbiguanide; (43) to (47) from the appropriate arylguanidine salts and substituted cyanamides there are similarly prepared Na -p-bromophenyl-No -dimethyl-, -No -phenyl-No -methyl-, -No -isopropyl-, -No -isobutyl- and -No - methyl - No - n - butyl - biguanide; (48) p - bromophenylguanidine hydrate is mixed with pentanol, part of the pentanol is distilled off and the resulting dry solution is refluxed with diethylcyanamide to produce N-a -bromophenyl - No - diethylbiguanide; (49) n -butyl - cyanamide similarly yields Na -p-bromophenyl-No -n-butylbiguanide; (50) sodium p-chloro-phenylcyanamide (obtained by treating p-chlorophenylcyanamide in ether with excess of a solution of sodium methoxide in methanol) is refluxed with cyclohexylguanidine in n-butanol to give Na - p - chlorophenyl - No - cyclohexylbiguanide. Additional starting materials specified are m-iodo-, 3-bromo-4-iodo-, 3 : 4-dibromo-, 3-iodo-4-chloro-, p-nitro-, 3-iodo-4-bromo-, 3 : 4-diiodo-, 3 : 5-dichloro-4-bromo-and -iodo- and 4-chloro-3-bromo-phenylguanidine, ethylguanidine, N : N-diethylguanidine, n-propylguanidine, N : N-methyl-n-propylguanidine, N : N - methylisopropylguanidine, N : N - methyl-n - butylguanidine and n - butylguanidine; methyl - n - propylcyanamide, di - n - butylcyanamide, o- and m-tolylcyanamide, p-anioylcyanamide, p-phenetylcyanamide, a - and b -naphthylcyanamide, 3 : 4- and 3 : 5-dichloro-, 3-iodo-4-bromo-, 3 : 4-diiodo-, 3-chloro-4-methyl-, 3 : 5-dichloro-4-bromo- and -iodo-, p- and m-iodo-, 3-chloro-4-bromo- and -iodo-, 3-bromo-4-chloro-and -iodo-, 3 : 4-dibromo-, 3-iodo-4-chloro-, p-hydroxy-, m-chloro-, 3 : 4 : 5-trichloro-, p-nitro-, 4-chloro-3-methyl- and m-bromo-phenyl-cyanamide. Guanidine derivatives of the kind employed as starting materials are obtainable in the form of their hydrochlorides by condensing the appropriate amine hydrochloride with cyanamide, or (when free from aryl groups) in the form of their sulphates by reaction of the appropriate amine with S-methylisothiourea sulphate. Cyanamides of the general formula given above but containing only alkyl groups are obtainable by the action of bromine on a mixture of the appropriate amine and potassium cyanide, whilst those containing aryl groups may be made by the action of an alkaline lead solution on the corresponding thiourea. Isopropylcyanamide is obtainable by adding cyanogen bromide to a solution of excess of isopropylamine in petroleum ether between -5 DEG and 0 DEG C., the solution obtained after filtering off the isopropylamine hydrobromide formed being suitable for immediate use in example (31).
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB35238/45A GB607720A (en) | 1945-12-31 | 1945-12-31 | Manufacture of biguanide derivatives |
FR954888D FR954888A (en) | 1945-12-31 | 1946-12-31 | |
ES176286A ES176286A1 (en) | 1945-12-31 | 1946-12-31 | A PROCEDURE FOR THE OBTAINING OF BIGUANIDA DERIVATIVES |
FR58093D FR58093E (en) | 1945-12-31 | 1948-03-15 | Manufacturing process for biguanide derivatives |
CY7549A CY75A (en) | 1945-12-31 | 1949-02-04 | Manufacture of biguanide derivatives |
MY12/54A MY5400012A (en) | 1945-12-31 | 1954-12-30 | Manufacture of biguanide derivatives |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB35238/45A GB607720A (en) | 1945-12-31 | 1945-12-31 | Manufacture of biguanide derivatives |
FR58093T | 1948-03-15 |
Publications (1)
Publication Number | Publication Date |
---|---|
GB607720A true GB607720A (en) | 1948-09-03 |
Family
ID=61024212
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB35238/45A Expired GB607720A (en) | 1945-12-31 | 1945-12-31 | Manufacture of biguanide derivatives |
Country Status (4)
Country | Link |
---|---|
CY (1) | CY75A (en) |
FR (2) | FR954888A (en) |
GB (1) | GB607720A (en) |
MY (1) | MY5400012A (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2529992A (en) * | 1948-02-20 | 1950-11-14 | Usines Chimiques Rhone Poulene | Production of n'-p-chlorophenyl-n-isopropyl biguanide |
US2556315A (en) * | 1948-02-20 | 1951-06-12 | Rhone Poulenc Sa | Production of a salt of p-chlorophenyl cyanamide and isopropylguanidine |
US2606923A (en) * | 1950-05-13 | 1952-08-12 | Rohm & Haas | Tertiary alkylcyanamides |
WO2010132982A1 (en) * | 2009-05-18 | 2010-11-25 | Ottawa Hospital Research Institute | Treatment of muscle disease characterized by insulin resistance |
EP2522653A2 (en) * | 2010-01-06 | 2012-11-14 | HanAll Biopharma Co., Ltd. | Biguanide derivative, a preparation method thereof and a pharmaceutical composition containing the biguanide derivative as an active ingredient |
US10626085B2 (en) | 2014-11-20 | 2020-04-21 | Immunomet Therapeutics Inc. | Biguanide compound and use thereof |
-
1945
- 1945-12-31 GB GB35238/45A patent/GB607720A/en not_active Expired
-
1946
- 1946-12-31 FR FR954888D patent/FR954888A/fr not_active Expired
-
1948
- 1948-03-15 FR FR58093D patent/FR58093E/en not_active Expired
-
1949
- 1949-02-04 CY CY7549A patent/CY75A/en unknown
-
1954
- 1954-12-30 MY MY12/54A patent/MY5400012A/en unknown
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2529992A (en) * | 1948-02-20 | 1950-11-14 | Usines Chimiques Rhone Poulene | Production of n'-p-chlorophenyl-n-isopropyl biguanide |
US2556315A (en) * | 1948-02-20 | 1951-06-12 | Rhone Poulenc Sa | Production of a salt of p-chlorophenyl cyanamide and isopropylguanidine |
US2606923A (en) * | 1950-05-13 | 1952-08-12 | Rohm & Haas | Tertiary alkylcyanamides |
WO2010132982A1 (en) * | 2009-05-18 | 2010-11-25 | Ottawa Hospital Research Institute | Treatment of muscle disease characterized by insulin resistance |
US8993633B2 (en) | 2009-05-18 | 2015-03-31 | Fate Therapeutics, (Canada) Inc. | Treatment of muscle disease characterized by insulin resistance |
EP2522653A2 (en) * | 2010-01-06 | 2012-11-14 | HanAll Biopharma Co., Ltd. | Biguanide derivative, a preparation method thereof and a pharmaceutical composition containing the biguanide derivative as an active ingredient |
EP2522653A4 (en) * | 2010-01-06 | 2013-06-12 | Hanall Biopharma Co Ltd | Biguanide derivative, a preparation method thereof and a pharmaceutical composition containing the biguanide derivative as an active ingredient |
US9416098B2 (en) | 2010-01-06 | 2016-08-16 | Immunomet Therapeutics Inc. | Biguanide derivative, a preparation method thereof and a pharmaceutical composition containing the biguanide derivative as an active ingredient |
US9993446B2 (en) | 2010-01-06 | 2018-06-12 | Immunomet Therapeutics Inc. | Biguanide derivative, a preparation method thereof, and a pharmaceutical composition containing the biguanide derivative as an active ingredient |
US10376480B2 (en) | 2010-01-06 | 2019-08-13 | Immunomet Therapeutics Inc. | Biguanide derivative, a preparation method thereof, and a pharmaceutical composition containing the biguanide derivative as an active ingredient |
US10626085B2 (en) | 2014-11-20 | 2020-04-21 | Immunomet Therapeutics Inc. | Biguanide compound and use thereof |
US11572341B2 (en) | 2014-11-20 | 2023-02-07 | Immunomet Therapeutics Inc. | Biguanide compound and use thereof |
Also Published As
Publication number | Publication date |
---|---|
MY5400012A (en) | 1954-12-31 |
FR58093E (en) | 1953-09-21 |
FR954888A (en) | 1950-01-06 |
CY75A (en) | 1949-02-04 |
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