CA1068713A - Process for preparing substituted guanidines - Google Patents
Process for preparing substituted guanidinesInfo
- Publication number
- CA1068713A CA1068713A CA322,388A CA322388A CA1068713A CA 1068713 A CA1068713 A CA 1068713A CA 322388 A CA322388 A CA 322388A CA 1068713 A CA1068713 A CA 1068713A
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- CA
- Canada
- Prior art keywords
- histamine
- methyl
- alkyl
- formula
- het
- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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, and R2 is hydrogen or (C1-4) alkyl.
The compound 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, and R2 is hydrogen or (C1-4) alkyl.
The compound 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
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 ~Il-receptors (Ash and Schild, Brit. .J. Pharmac.
Chemother, 27, 427, (1966). However, other biological actions of histamine 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 H~-receptors may be defined as those histamillc receptors which are not blocked by mepyramine but are blocked by burimamide. Compounds which block histamine H2-receptors are referred to as histamine ll2-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 ~0687~3 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 the effects 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:
~S
Rl - S - C~
wherein Rl represents a grouping of the structure shown in Formula 2:
llet - CH2S(CH2)2-wherein ~let is imidazole optionally substituted by (Cl 4) alkyl; and R2 is (Cl_4) alkyl. The (Cl_4) alkyl groups are preferably methyl.
It will be understood that the structure illustrated in ~ormula 1 is only one of several possible representations and that other tautomeric forms are also covered by the present invention.
-~0687:13 Hydrates, pharmaceutically acceptable salts, and hydrated pharmaceutically acceptable salts of compounds of Formula 1 are also covered by the present invention.
Preferably Het is a 4-imidazolyl ring optionally substituted by ~Cl 4) alkyl. Particularly preferably Het is a 5-methyl-4-imidazolyl ring.
An example of a specific compound which can be prepared by the present invention is 2-t5-methyl-a-imidazolylmethyl-thio)ethyl N-methyldithiocarbamate.
Compounds of Formula 1 are prepared in accordance Wit]l the invention by reacting a mercaptan of formula RlSH with an isothiocyanate of formula R2NCS, Rl and R2 being as defined for Formula 1. Preferably this reaction is carried out in a solvent such as pyridine.
The mercaptans of formula RlSH can be prepared by reacting ethanedithiol with a compound of formula Het C112 Y where Het is as defined for formula I and Y is chlorine or bromine.
This reaction is preferably effected 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 this invention have been found to inhibit histamine-stimulated secretion ~3687~3 of gastric acid from the lumen-perfused stomachs of rats anaesthetized with urethane, at doses of from 0.5 to 256 micromoles per kiIogram intravenously. This procedure is referred to in the above mentioned paper of Ash and Schild.
The activity o~ these compounds as histamine 112-antagonists is also demonstrated by their ability to inhibit other actions of histamine WiliCIl, according to the above mentioned paper of Ash and Schilcl, are not mediated by histamine ~Il-receptors.
For example, they inhibit the actions of histamine on the isolated guinea pig atrium and isolated rat uterus.
The compounds prepared by 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-inflammatory activity in conventional tests such as the rat paw oedema test, where the oedema is induced by an irritant, the rat paw volume 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 demonstrated.
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.
1~6B713 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 with 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 trochc 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 gelatin capsule, sterile injectable liquid contained for example in an ampoule, or an aqueous or non-aqueous liquid suspension.
16~68'713 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 l~ill 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 compositions 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
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 ~Il-receptors (Ash and Schild, Brit. .J. Pharmac.
Chemother, 27, 427, (1966). However, other biological actions of histamine 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 H~-receptors may be defined as those histamillc receptors which are not blocked by mepyramine but are blocked by burimamide. Compounds which block histamine H2-receptors are referred to as histamine ll2-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 ~0687~3 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 the effects 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:
~S
Rl - S - C~
wherein Rl represents a grouping of the structure shown in Formula 2:
llet - CH2S(CH2)2-wherein ~let is imidazole optionally substituted by (Cl 4) alkyl; and R2 is (Cl_4) alkyl. The (Cl_4) alkyl groups are preferably methyl.
It will be understood that the structure illustrated in ~ormula 1 is only one of several possible representations and that other tautomeric forms are also covered by the present invention.
-~0687:13 Hydrates, pharmaceutically acceptable salts, and hydrated pharmaceutically acceptable salts of compounds of Formula 1 are also covered by the present invention.
Preferably Het is a 4-imidazolyl ring optionally substituted by ~Cl 4) alkyl. Particularly preferably Het is a 5-methyl-4-imidazolyl ring.
An example of a specific compound which can be prepared by the present invention is 2-t5-methyl-a-imidazolylmethyl-thio)ethyl N-methyldithiocarbamate.
Compounds of Formula 1 are prepared in accordance Wit]l the invention by reacting a mercaptan of formula RlSH with an isothiocyanate of formula R2NCS, Rl and R2 being as defined for Formula 1. Preferably this reaction is carried out in a solvent such as pyridine.
The mercaptans of formula RlSH can be prepared by reacting ethanedithiol with a compound of formula Het C112 Y where Het is as defined for formula I and Y is chlorine or bromine.
This reaction is preferably effected 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 this invention have been found to inhibit histamine-stimulated secretion ~3687~3 of gastric acid from the lumen-perfused stomachs of rats anaesthetized with urethane, at doses of from 0.5 to 256 micromoles per kiIogram intravenously. This procedure is referred to in the above mentioned paper of Ash and Schild.
The activity o~ these compounds as histamine 112-antagonists is also demonstrated by their ability to inhibit other actions of histamine WiliCIl, according to the above mentioned paper of Ash and Schilcl, are not mediated by histamine ~Il-receptors.
For example, they inhibit the actions of histamine on the isolated guinea pig atrium and isolated rat uterus.
The compounds prepared by 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-inflammatory activity in conventional tests such as the rat paw oedema test, where the oedema is induced by an irritant, the rat paw volume 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 demonstrated.
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.
1~6B713 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 with 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 trochc 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 gelatin capsule, sterile injectable liquid contained for example in an ampoule, or an aqueous or non-aqueous liquid suspension.
16~68'713 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 l~ill 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 compositions 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
2-(5-Methy_ -imidazolylmet_lthio)ethyl N-methyl-dithiocarbamate_ hydrochloride.
1~368713 a) Sodium (5.2 g) was added, with stirring under nitrogen, to dry ethanol (150 ml). After the sodium had dissolved ethanedithiol (40 ml) was introduced and to this mixture was added 4-methyl-5-chloromethylimidazole hydrochloride (15 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 a saturated solution of hydrogen chloride in ethanol was added until the mixture was acidic. The temperature was then raised and the ethanol distilled off under nitrogen. The residue was taken up in water and continuously extracted with ether to remove the excess ethanedithiol. The a~ueous fraction was then evaporated to dryness and the residue extracted with hot isopropanol. Reducing the volume of the extract and cooling afforded 2-~5-methyl-4-imidazolyl-methylthio)ethanethiol hydrochloride as a white solid which was not purified further.
b) A solution of sodium carbonate was added to a solution of 2-(5-methyl-4-imidazolylmethylthio) ethanethiol hydrochloride (2.5 g) in water (50 ml) to pl-19 and the mixture extracted with ethyl acetate. After drying (MgS04), the extract was evaporated to dryness and the residue taken up in pyridine (25 ml). To this solution was added methylisothiocyanate (1.1 g) and the mixture stirred at room temperature for 1 hour. After this time the mixture was evaporated to dryness, the residue taken up in ethanol and a saturated solution of hydrogen chloride in ethanol added until the mixture was acidic. Addition of ether to this solution afforded a white solid which after repeated recrystallisation :Erom ethanol/ether gave 2-(5-methyl-4-imidazolylmethylthio)ethyl N-methyldithiocarbamate hydrochloride, m.p. 171-172.
(Found: C, 36.5; H, 5.3; N, 14.1; S, 31.9; Cl, 12.2;
C9H,5N3S3.HCl requires: C, 36.3; H, 5.4; N, 14.1; S, 32.3;
Cl, 11.9~).
1~368713 a) Sodium (5.2 g) was added, with stirring under nitrogen, to dry ethanol (150 ml). After the sodium had dissolved ethanedithiol (40 ml) was introduced and to this mixture was added 4-methyl-5-chloromethylimidazole hydrochloride (15 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 a saturated solution of hydrogen chloride in ethanol was added until the mixture was acidic. The temperature was then raised and the ethanol distilled off under nitrogen. The residue was taken up in water and continuously extracted with ether to remove the excess ethanedithiol. The a~ueous fraction was then evaporated to dryness and the residue extracted with hot isopropanol. Reducing the volume of the extract and cooling afforded 2-~5-methyl-4-imidazolyl-methylthio)ethanethiol hydrochloride as a white solid which was not purified further.
b) A solution of sodium carbonate was added to a solution of 2-(5-methyl-4-imidazolylmethylthio) ethanethiol hydrochloride (2.5 g) in water (50 ml) to pl-19 and the mixture extracted with ethyl acetate. After drying (MgS04), the extract was evaporated to dryness and the residue taken up in pyridine (25 ml). To this solution was added methylisothiocyanate (1.1 g) and the mixture stirred at room temperature for 1 hour. After this time the mixture was evaporated to dryness, the residue taken up in ethanol and a saturated solution of hydrogen chloride in ethanol added until the mixture was acidic. Addition of ether to this solution afforded a white solid which after repeated recrystallisation :Erom ethanol/ether gave 2-(5-methyl-4-imidazolylmethylthio)ethyl N-methyldithiocarbamate hydrochloride, m.p. 171-172.
(Found: C, 36.5; H, 5.3; N, 14.1; S, 31.9; Cl, 12.2;
C9H,5N3S3.HCl requires: C, 36.3; H, 5.4; N, 14.1; S, 32.3;
Cl, 11.9~).
Claims (4)
1. A process for preparing 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; and R2 is (C1-4) alkyl which comprises reacting an isothiocyanate of formula R2 NCS with a mercaptan of fromula R1 SH1 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; and R2 is (C1-4) alkyl which comprises reacting an isothiocyanate of formula R2 NCS with a mercaptan of fromula R1 SH1 and if desired obtaining a hydrate or pharmaceutically acid addition salt or hydrated salt thereof.
2. The process according to claim 1 for preparing 2-(5-methyl-4-imidazolylinethylthio)ethyl-N-methyl-dithiocarbamate which comprises reacting 2-(5-methyl-4-imidazolylinethylthio)ethanethiol with methyl isocyanate.
3. A compound of formula wherein R1 represents a grouping of the structure Het - CH2S(CH2)2-wherein Het is imidazole optionally substituted by (C1-4) alkyl;
and R2 is (C1-4) alkyl when prepared or produced by the process of claim 1 or an obvious chemical equivalent thereof .
and R2 is (C1-4) alkyl when prepared or produced by the process of claim 1 or an obvious chemical equivalent thereof .
4. 2-(5-Methyl-4-imidazolylmethylthio)ethyl N-methyl-dithio-carbamate when 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 |
|---|---|---|---|
| CA322,388A CA1068713A (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 |
| CA322,388A CA1068713A (en) | 1975-02-03 | 1979-02-27 | Process for preparing substituted guanidines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1068713A true CA1068713A (en) | 1979-12-25 |
Family
ID=27164310
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA322,388A Expired CA1068713A (en) | 1975-02-03 | 1979-02-27 | Process for preparing substituted guanidines |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1068713A (en) |
-
1979
- 1979-02-27 CA CA322,388A patent/CA1068713A/en not_active Expired
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