CA1068714A - Process for preparing substituted guanidines - Google Patents
Process for preparing substituted guanidinesInfo
- Publication number
- CA1068714A CA1068714A CA322,389A CA322389A CA1068714A CA 1068714 A CA1068714 A CA 1068714A CA 322389 A CA322389 A CA 322389A CA 1068714 A CA1068714 A CA 1068714A
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- histamine
- formula
- het
- compounds
- methyl
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Abstract
ABSTRACT OF THE DISCLOSURE
Pharmacologically active compounds of the formula:
wherein R1 represents Het-CH2S(CH2)2-wherein Het is imidazole, optionally substituted by (C1-4) alkyl.
The compounds can be in the form of a hydrate, a pharmaceutically acceptable acid addition salt or a hydrated salt thereof. The compounds are histamine H2- antagonists and are useful as inhibitors of gastric acid secretion, as anti-inflammatory agents and as agents which act on the cardiovascular system.
Pharmacologically active compounds of the formula:
wherein R1 represents Het-CH2S(CH2)2-wherein Het is imidazole, optionally substituted by (C1-4) alkyl.
The compounds can be in the form of a hydrate, a pharmaceutically acceptable acid addition salt or a hydrated salt thereof. The compounds are histamine H2- antagonists and are useful as inhibitors of gastric acid secretion, as anti-inflammatory agents and as agents which act on the cardiovascular system.
Description
:~068714 This invention relates to a process for preparing pharmacologically active compounds which block histamine H2-receptors. The compounds prepared by the invention can exist as acid addition salts but, for convenience, reference will be made throughout this specification to the free bases.
Many physiologically active substances elicit their biological actions by interaction with specific sites known as receptors.
Histamine is such a substance and it has a number of biological actions. Those biological actions of histamine which are inhibited by drugs commonly called "antihistamines" of which mepyramine is a typical example, and diphenhydramine and chlorpheniramine are other examples, are mediated through histamine Hl-receptors ~Ash and Schild, Brit. J. Pharmac.
Chemother, 27, 427, ~1966). Howe~er, o~her biological actions of his-tamine are not inhibited by "antihistamines" and actions of this type which are inhibited by a compound described by Black et al. ~Nature, 236, 385 ~1972)) and called burimamide are mediated through receptors which are defined by Black et al. as histamine H2-receptors. Thus histamine H2- receptors may be defined as those histamine receptors which are not blocked by mepyramine but are blocked by burimamide. Compounds which block histamine H2-receptors are referred to as histamine H2-antagonists.
Blockade of histamine H2-receptors is of utility in inhibiting the biological actions of histamine which are not inhibited by "antihistamines". Histamine H2-antagonists are therefore useful, for example, as inhibitors of gastric acid secretion, as anti-inflammatory agents and as agents which act on the cardiovascular system, for example as inhibitors of ~he effects ~06871~
of histamine on blood pressure. In the treatment of certain conditions, for example inflammation and in inhibiting the actions of histamine on blood pressure, a combination of histamine Hl- and H2- antagonists is useful.
The compounds prepared by this invention are histamine H2-antagonists. These compounds are represented by the following formula:
Rl - S - C
wherein Rl represents a grouping of the structure shown in formul~ 2:
Het - CH2S~CH2)2-POR~IULA 2 wherein Het is optionally substituted by ~Cl 4) alkyl, preferably methyl. It will be understood that the structure illustrated in Formula 1 is only one of several possible representations and that other tautomeric forms are also covered by the ?resent invention. Hydrates, pharmaceutically acceptable salts, and hydrated pharmaceutically acceptable salts of compounds of Formul~a 1 are z~so covered by the present invention.
Preferably Het is a 4-imidazoly~ ring optionally substituted by ~Cl 4) a'kyl. P.articularly pr~ferably Het is a 5-methyl-4-imidazolyl ring.
An example of a specific compound which can be prepared by the present invention is S-(2-(5-methyl-4-imidazolylmethylthio)ethyl) dithiocarbamate.
The compounds of Formula 1 are prepared in accordance with the invention by reacting a thiocyanate of formula RlSCN, Rl being as defined for Formula 1, with hydrogen sulphide. This reaction is preferably carried out at low temperatures in a solvent such as ethanol. The thiocyanates can conveniently be prepared by rea-Qting a compound of the formula RlY, wherein Rl is as defined for Formula 1 and Y is chlorine or bromine, with potassium thiocyanate.
The compounds of formula RlY can be prepared from the corresponding alcohols of formula RlOH by standard techniques, e.g., the chlorides can be prepared from the corresponding alcohols by reaction with thionyl chloride.
The alcohols of formula RlOH can be prepared by the reaction of mercaptoethanol with a compound of formula HetCH2Y, in which Het has the same significance as in Formula 2 and Y represents chlorine or bromine. Preferably this reaction is carried out in a solvent in the presence of a base, such as with sodium ethoxide in dry ethanol.
The compounds of Formula 1 block histamine H2-receptors, that is they inhibit the biological actions of histamine which are not inhibited by "antihistamines" such as mepyramine but are inhibited by burimamide. For example, the compounds of thi5 invention have been found to inhibit histamine-stimulated Secretion ~pf gastric acid from the lumen-perfused stomachs of rats anaesthetized with urethane, at doses of from 0.5 to 256 micromoles per kilogram intravenously. This procedure is referred to in the above mentioned paper of Ash and Schild.
The activity of these compounds as histamine H2-antagonists is also demonstrated by their ability to inhibit other actions of histamine which, according to the above mentioned paper of Ash and Schild, are not mediated by histamine Hl-receptors.
For example, they inhibit the actions of histamine on the isolated guinea pig atrium and isolated rat uterus.
The compounds prepared by the process of this invention inhibit the basal secretion of gastric acid and also that stimulated by pentagastrin or by food.
In addition, the compounds prepared by this invention show anti-inflammatoTy activity in conventional tests such as the Tat paw oedema test, where the oedema is induced by an irritant, the rat paw Yolume is reduced by subcutaneous injection of doses of a compound of Formula 1. In a conventional test, such as the measurement of blood pressure in the anaesthetised cat, the action of the compounds prepared by this invention in inhibiting the vasodilator action of histamine can also be demonstra~ed. The level of activity of the compounds is illustrated by the effective dose producing 50~ inhibition of gastric acid secretion in the anaesthetized rat and the dose producing 50~ inhibition of histamine-induced tachycardia in the isolated guinea pig atrium.
~068714 For therapeutic use, the pharmacologically active compounds will normally be administered as a pharmaceutical composition comprising as the or an essential active ingredient at least one such compound in basic form or in the form of a pharmaceutically acceptable acid addition salt and associated Wit]l a pharmaceutical carrier therefor~ Such addition salts include those with hydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids and they can conveniently be formed from the corresponding bases of Formula 1 by standard procedures, for example by treating the base with an acid in a lower alkanol or by the use of ion exchange resins to form the required salt, either directly from the base or from a different addition salt.
The pharmaceutical carrier employed can be solid or liquid.
Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water and the like.
A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the compositions can be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier can be varied widely but preferably will be from about 25 mg to about 1 g. If a liquid carrier is used, the compositions can be in the form of a syrup , emulsion, soft gelatine capsule, sterile injectable liquid contained for example in an ampoule, or an aqueous or non aqueous liquid suspension.
106~714 The pharmaceutical compositions can be prepared by conventional techniques involving procedures such as mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
The active ingredient will be present in the composition in an effective amount to block histamine H2-receptors. The route of administration can be oral or parenteral.
Advantageously the composition will be made up in a dosage form appropriate to the desired mode of administration, for example as a tablet, capsule, injectable solution or as a cream or ointment for topical application.
Preferably, each dosage unit will contain the active ingredient in an amount of from about 50 mg to about 250 mg.
The active ingredient will preferably be administered one to six times per day. The daily dosage regimen will preferably be from about 150 mg to about 1500 mg.
The invention is illustrated and in no way limited by the following Example wherein all temperatures are given in degrees Centigrade.
EXAMPLE
S-~2-(5-Methyl-4-imidazolylmethylthio)ethyl]dithiocarbonate hydrochloride.
a) Sodium ~3.0 g ) was added, with stirring under nitrogen, to dry ethanol ~75 ml). After the sodium had dissolved mercaptoethanol ~9.0 ml) was introduced and to this mixture was added 4-methyl-5-chloromethylimidazole hydrochloride (10 g), as a solid, over a period of 1.5 hours at room temperature.
The mixture was then stirred for a further 1 hour at room temperature. After this time the reaction was warmed and the ethanol distilled off at reduced pressure. The residue was taken up in water, acidified with concentrated hydrochloric acid, and continuously extracted with ether to remove the excess mercaptoethanol. The aqueous fraction was then basified using solid sodium carbonate and continuously extracted with ethyl acetate. To the extract was added a further volume of ethyl acetate and the whole warmed to re-dissolve the crude product which had deposited. After drying (MgS04) and reducing the volume crystallisation from this solution below 40 coQling to -15 afforded 2-~5-methyl-4-imidazolylmethylthio)ethanol, m.p. 74-76.
~Found: C, 49.1; H, 6.8; N, 16.2; C7Hl2N20 S
requires; C, 48.8; H, 7.0; N, 16.3%).
b) 2-~5-Methyl-4-imidazolylmethylthio)ethanol ~0.34 g,
Many physiologically active substances elicit their biological actions by interaction with specific sites known as receptors.
Histamine is such a substance and it has a number of biological actions. Those biological actions of histamine which are inhibited by drugs commonly called "antihistamines" of which mepyramine is a typical example, and diphenhydramine and chlorpheniramine are other examples, are mediated through histamine Hl-receptors ~Ash and Schild, Brit. J. Pharmac.
Chemother, 27, 427, ~1966). Howe~er, o~her biological actions of his-tamine are not inhibited by "antihistamines" and actions of this type which are inhibited by a compound described by Black et al. ~Nature, 236, 385 ~1972)) and called burimamide are mediated through receptors which are defined by Black et al. as histamine H2-receptors. Thus histamine H2- receptors may be defined as those histamine receptors which are not blocked by mepyramine but are blocked by burimamide. Compounds which block histamine H2-receptors are referred to as histamine H2-antagonists.
Blockade of histamine H2-receptors is of utility in inhibiting the biological actions of histamine which are not inhibited by "antihistamines". Histamine H2-antagonists are therefore useful, for example, as inhibitors of gastric acid secretion, as anti-inflammatory agents and as agents which act on the cardiovascular system, for example as inhibitors of ~he effects ~06871~
of histamine on blood pressure. In the treatment of certain conditions, for example inflammation and in inhibiting the actions of histamine on blood pressure, a combination of histamine Hl- and H2- antagonists is useful.
The compounds prepared by this invention are histamine H2-antagonists. These compounds are represented by the following formula:
Rl - S - C
wherein Rl represents a grouping of the structure shown in formul~ 2:
Het - CH2S~CH2)2-POR~IULA 2 wherein Het is optionally substituted by ~Cl 4) alkyl, preferably methyl. It will be understood that the structure illustrated in Formula 1 is only one of several possible representations and that other tautomeric forms are also covered by the ?resent invention. Hydrates, pharmaceutically acceptable salts, and hydrated pharmaceutically acceptable salts of compounds of Formul~a 1 are z~so covered by the present invention.
Preferably Het is a 4-imidazoly~ ring optionally substituted by ~Cl 4) a'kyl. P.articularly pr~ferably Het is a 5-methyl-4-imidazolyl ring.
An example of a specific compound which can be prepared by the present invention is S-(2-(5-methyl-4-imidazolylmethylthio)ethyl) dithiocarbamate.
The compounds of Formula 1 are prepared in accordance with the invention by reacting a thiocyanate of formula RlSCN, Rl being as defined for Formula 1, with hydrogen sulphide. This reaction is preferably carried out at low temperatures in a solvent such as ethanol. The thiocyanates can conveniently be prepared by rea-Qting a compound of the formula RlY, wherein Rl is as defined for Formula 1 and Y is chlorine or bromine, with potassium thiocyanate.
The compounds of formula RlY can be prepared from the corresponding alcohols of formula RlOH by standard techniques, e.g., the chlorides can be prepared from the corresponding alcohols by reaction with thionyl chloride.
The alcohols of formula RlOH can be prepared by the reaction of mercaptoethanol with a compound of formula HetCH2Y, in which Het has the same significance as in Formula 2 and Y represents chlorine or bromine. Preferably this reaction is carried out in a solvent in the presence of a base, such as with sodium ethoxide in dry ethanol.
The compounds of Formula 1 block histamine H2-receptors, that is they inhibit the biological actions of histamine which are not inhibited by "antihistamines" such as mepyramine but are inhibited by burimamide. For example, the compounds of thi5 invention have been found to inhibit histamine-stimulated Secretion ~pf gastric acid from the lumen-perfused stomachs of rats anaesthetized with urethane, at doses of from 0.5 to 256 micromoles per kilogram intravenously. This procedure is referred to in the above mentioned paper of Ash and Schild.
The activity of these compounds as histamine H2-antagonists is also demonstrated by their ability to inhibit other actions of histamine which, according to the above mentioned paper of Ash and Schild, are not mediated by histamine Hl-receptors.
For example, they inhibit the actions of histamine on the isolated guinea pig atrium and isolated rat uterus.
The compounds prepared by the process of this invention inhibit the basal secretion of gastric acid and also that stimulated by pentagastrin or by food.
In addition, the compounds prepared by this invention show anti-inflammatoTy activity in conventional tests such as the Tat paw oedema test, where the oedema is induced by an irritant, the rat paw Yolume is reduced by subcutaneous injection of doses of a compound of Formula 1. In a conventional test, such as the measurement of blood pressure in the anaesthetised cat, the action of the compounds prepared by this invention in inhibiting the vasodilator action of histamine can also be demonstra~ed. The level of activity of the compounds is illustrated by the effective dose producing 50~ inhibition of gastric acid secretion in the anaesthetized rat and the dose producing 50~ inhibition of histamine-induced tachycardia in the isolated guinea pig atrium.
~068714 For therapeutic use, the pharmacologically active compounds will normally be administered as a pharmaceutical composition comprising as the or an essential active ingredient at least one such compound in basic form or in the form of a pharmaceutically acceptable acid addition salt and associated Wit]l a pharmaceutical carrier therefor~ Such addition salts include those with hydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids and they can conveniently be formed from the corresponding bases of Formula 1 by standard procedures, for example by treating the base with an acid in a lower alkanol or by the use of ion exchange resins to form the required salt, either directly from the base or from a different addition salt.
The pharmaceutical carrier employed can be solid or liquid.
Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water and the like.
A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the compositions can be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The amount of solid carrier can be varied widely but preferably will be from about 25 mg to about 1 g. If a liquid carrier is used, the compositions can be in the form of a syrup , emulsion, soft gelatine capsule, sterile injectable liquid contained for example in an ampoule, or an aqueous or non aqueous liquid suspension.
106~714 The pharmaceutical compositions can be prepared by conventional techniques involving procedures such as mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
The active ingredient will be present in the composition in an effective amount to block histamine H2-receptors. The route of administration can be oral or parenteral.
Advantageously the composition will be made up in a dosage form appropriate to the desired mode of administration, for example as a tablet, capsule, injectable solution or as a cream or ointment for topical application.
Preferably, each dosage unit will contain the active ingredient in an amount of from about 50 mg to about 250 mg.
The active ingredient will preferably be administered one to six times per day. The daily dosage regimen will preferably be from about 150 mg to about 1500 mg.
The invention is illustrated and in no way limited by the following Example wherein all temperatures are given in degrees Centigrade.
EXAMPLE
S-~2-(5-Methyl-4-imidazolylmethylthio)ethyl]dithiocarbonate hydrochloride.
a) Sodium ~3.0 g ) was added, with stirring under nitrogen, to dry ethanol ~75 ml). After the sodium had dissolved mercaptoethanol ~9.0 ml) was introduced and to this mixture was added 4-methyl-5-chloromethylimidazole hydrochloride (10 g), as a solid, over a period of 1.5 hours at room temperature.
The mixture was then stirred for a further 1 hour at room temperature. After this time the reaction was warmed and the ethanol distilled off at reduced pressure. The residue was taken up in water, acidified with concentrated hydrochloric acid, and continuously extracted with ether to remove the excess mercaptoethanol. The aqueous fraction was then basified using solid sodium carbonate and continuously extracted with ethyl acetate. To the extract was added a further volume of ethyl acetate and the whole warmed to re-dissolve the crude product which had deposited. After drying (MgS04) and reducing the volume crystallisation from this solution below 40 coQling to -15 afforded 2-~5-methyl-4-imidazolylmethylthio)ethanol, m.p. 74-76.
~Found: C, 49.1; H, 6.8; N, 16.2; C7Hl2N20 S
requires; C, 48.8; H, 7.0; N, 16.3%).
b) 2-~5-Methyl-4-imidazolylmethylthio)ethanol ~0.34 g,
2 mmol) and thionyl chloride ~0.238 g, 2 mmol) were heated together, with stirring, at reflux temperature in chloroform (lO ml) for one hour, giving a grey solution and a green oil.
A second equivalent of thionyl chloride (0.238g) was added at reflux temperature and immediately the oil went into solution and a solid started to crystallise. After a further 15 minutes at reflux temperature the mixture was cooled and the solid collected ~0.395 g). Recrystallisation from acetonitrile gave l-chloro-2-~5-methyl-4-imidazolylmethylthio)ethane hydrochloride, m.p. 163-165, (0.2~ g). (Found: C, 37.1; H, 5.2; N, 12.6;
S, 14-1; Cl, 31-2; C7HllCl N2S requires: C, 37.0; H, 5.3;
N, 12.3; S, 14.1; Cl, 31.2%).
1~168714 d) l-Chloro-2-~5-methyl-4-imidazolylmethylthio)ethane hydrochloride (2.1 g) and potassium thiocyanate (0.97 g) were heated together under reflux in ethanol (50 ml) for 3 days. The mixture was evaporated to dryness and the residue was taken up in water, basified with sodium carbonate and extracted with chloroform. The chloroform extracts were dried (MgS04) and evaporated to a residue which was recrystallised from acetonitrile to give 2-(5-methyl-4-imidazolylmethylthio)-ethylthiocyanate m.p. 101-103C.
(Found: C, 45.3; H, 5.3; N, 19.5; S, 29.3; C8HllN3S2 requires: C, 45.0; H, 5.2; N, 19.7; S, 30.1DD).
e) Hydrogen sulphide was passed for 1 hour at a pressure of 15 cm.Hg above atmospheric into a solution of 2-(5-methyl-4-imidazolylmethylthio~ethyl thiocyanate (2.0 g) in ethanol ~20 ml) at -15. Ethanolic hydrogen chloride was added followed by ether. The crude solid was converted into the free base and was purified by column chromatography (silica gel/5 methanol in chloroform). Reconversion to the hydrochloride and crystallisation from ethanol afforded S-[2-(5-methyl-4-imidazolylmethylthio)ethyl]dithiocarbamate hydrochloride, m.p. 191-193.
(Found: C, 34.1; H, 5.0; N, 14.9; S, 32.2; Cl, 12.3;
C3H13N3S3.HCl requires: C, 33.8; H, 5.0; N, 14.8; S, 33.9;
Cl, 12.5~)
A second equivalent of thionyl chloride (0.238g) was added at reflux temperature and immediately the oil went into solution and a solid started to crystallise. After a further 15 minutes at reflux temperature the mixture was cooled and the solid collected ~0.395 g). Recrystallisation from acetonitrile gave l-chloro-2-~5-methyl-4-imidazolylmethylthio)ethane hydrochloride, m.p. 163-165, (0.2~ g). (Found: C, 37.1; H, 5.2; N, 12.6;
S, 14-1; Cl, 31-2; C7HllCl N2S requires: C, 37.0; H, 5.3;
N, 12.3; S, 14.1; Cl, 31.2%).
1~168714 d) l-Chloro-2-~5-methyl-4-imidazolylmethylthio)ethane hydrochloride (2.1 g) and potassium thiocyanate (0.97 g) were heated together under reflux in ethanol (50 ml) for 3 days. The mixture was evaporated to dryness and the residue was taken up in water, basified with sodium carbonate and extracted with chloroform. The chloroform extracts were dried (MgS04) and evaporated to a residue which was recrystallised from acetonitrile to give 2-(5-methyl-4-imidazolylmethylthio)-ethylthiocyanate m.p. 101-103C.
(Found: C, 45.3; H, 5.3; N, 19.5; S, 29.3; C8HllN3S2 requires: C, 45.0; H, 5.2; N, 19.7; S, 30.1DD).
e) Hydrogen sulphide was passed for 1 hour at a pressure of 15 cm.Hg above atmospheric into a solution of 2-(5-methyl-4-imidazolylmethylthio~ethyl thiocyanate (2.0 g) in ethanol ~20 ml) at -15. Ethanolic hydrogen chloride was added followed by ether. The crude solid was converted into the free base and was purified by column chromatography (silica gel/5 methanol in chloroform). Reconversion to the hydrochloride and crystallisation from ethanol afforded S-[2-(5-methyl-4-imidazolylmethylthio)ethyl]dithiocarbamate hydrochloride, m.p. 191-193.
(Found: C, 34.1; H, 5.0; N, 14.9; S, 32.2; Cl, 12.3;
C3H13N3S3.HCl requires: C, 33.8; H, 5.0; N, 14.8; S, 33.9;
Cl, 12.5~)
Claims (4)
1. A process for preparing a compound of the formula:
wherein R1 represents a grouping of the structure Het - CH2S(CH2)2-wherein Het is imidazole optionally substituted by (C1-4) alkyl, which comprises reacting a thiocyanate of formula R1SCN with hydrogen sulphide and if desired obtaining a hydrate or pharmaceutically acid addition salt or hydrated salt thereof.
wherein R1 represents a grouping of the structure Het - CH2S(CH2)2-wherein Het is imidazole optionally substituted by (C1-4) alkyl, which comprises reacting a thiocyanate of formula R1SCN with hydrogen sulphide and if desired obtaining a hydrate or pharmaceutically acid addition salt or hydrated salt thereof.
2. The process according to claim 1 for preparing (S-[2-(5-methyl-4-imidazolylmethylthio)ethyl]-dithiocarbamate which comprises reacting 2-(5-methyl-4-imidazolylmethylthio)ethyl thiocyanate with hydrogen sulphide.
3. A compound of the formula wherein R1 represents a grouping of the structure Het-CH2S(CH2)2-wherein Het is imidazole optionally substituted by (C1-4) a or a hydrate or pharmaceutically acceptable acid addition salt or hydrated salt thereof when prepared or produced by the process of claim 1 or by an obvious chemical equivalent thereof.
4. S-(2-(5-Methyl-4-imidazolylmethylthio)ethyl)dithiocarbamate whenever prepared or produced by the process of claim 2 or an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA322,389A CA1068714A (en) | 1975-02-03 | 1979-02-27 | Process for preparing substituted guanidines |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB4538/75A GB1542840A (en) | 1975-02-03 | 1975-02-03 | Heterocyclic dithiocarbamates and isothioureas |
| CA244,784A CA1067501A (en) | 1975-02-03 | 1976-02-02 | Process for preparing substituted guanidines |
| CA322,389A CA1068714A (en) | 1975-02-03 | 1979-02-27 | Process for preparing substituted guanidines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1068714A true CA1068714A (en) | 1979-12-25 |
Family
ID=27164311
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA322,389A Expired CA1068714A (en) | 1975-02-03 | 1979-02-27 | Process for preparing substituted guanidines |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1068714A (en) |
-
1979
- 1979-02-27 CA CA322,389A patent/CA1068714A/en not_active Expired
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