CA1070315A - Process for the preparation of bis(heteroarylmethylthioethylguanidino) alkanes and the bis(heteroarylmethylthioethylguanidino) alkanes so formed - Google Patents
Process for the preparation of bis(heteroarylmethylthioethylguanidino) alkanes and the bis(heteroarylmethylthioethylguanidino) alkanes so formedInfo
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- CA1070315A CA1070315A CA283,619A CA283619A CA1070315A CA 1070315 A CA1070315 A CA 1070315A CA 283619 A CA283619 A CA 283619A CA 1070315 A CA1070315 A CA 1070315A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/26—Radicals substituted by sulfur atoms
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pyridine Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A compound of the formula wherein X3 and X4, which may be the same or different, are NY wherein Y is hydrogen, lower alkyl, or cyano; R3 and R4 which may be the same or different, each represent a grouping of the structure Het-(CH2)mZ(CH2)n-where Het is 4-imidazolyl, or a 4-imidazolyl ring substituted by lower alkyl, or is 2-thiaszolyl; Z is sulphur; m is 1 and n is 2; W is NH, and when X3 and X4 are both NH, W may also be sulphur; and p is an integer from 9 to 12; or a pharmaceutically acceptable acid addition salt thereof is provided herein by means of an addition reaction and optionally a further hydrolysis reaction.
These compounds are useful as histamine H2-antagonist, which are useful as inhibitors of gastric acid secretion, as antiinflammatory agents, and as agents, and as agents which act on the cardiovascular system.
A compound of the formula wherein X3 and X4, which may be the same or different, are NY wherein Y is hydrogen, lower alkyl, or cyano; R3 and R4 which may be the same or different, each represent a grouping of the structure Het-(CH2)mZ(CH2)n-where Het is 4-imidazolyl, or a 4-imidazolyl ring substituted by lower alkyl, or is 2-thiaszolyl; Z is sulphur; m is 1 and n is 2; W is NH, and when X3 and X4 are both NH, W may also be sulphur; and p is an integer from 9 to 12; or a pharmaceutically acceptable acid addition salt thereof is provided herein by means of an addition reaction and optionally a further hydrolysis reaction.
These compounds are useful as histamine H2-antagonist, which are useful as inhibitors of gastric acid secretion, as antiinflammatory agents, and as agents, and as agents which act on the cardiovascular system.
Description
~07(~3~5 This invention relates to pharmacologically active compounds, and to processes for preparing these compounds. The compounds of aspects of the invention can exist as acid addition salts, but, for convenience, reference will be made throughout this specification to the present compounds.
Many physiologically active substances elicit their biological actions by interaction with specific sites known as receptors. Histamine is such a substance and has a number of biological actions. Those biological actions of histamine which are inhibited by drugs commonly called "antihistamines", of which mepyramine, diphenhydramine and chlorpheniramine are typical examples, are mediated throu~gh histamine Hl-receptors (Ash and Schild, Brit. J. Pharmac. Chemother, _ , 427J
(1966)). However, other of the 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 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, ~070315 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.
In German Offenlegungschrift 2504794 is described and claimed inter alia histamine H2-antagonists of Formula 1:
xl X2 R ~ -C-W-(CH2) -W-l-NHR
Formula 1 wherein Xl and x2 are sulphur, CHN02 or NY wherein Y is hydrogen, hydroxy, lower alkyl, cyano or CONH2; W is NH or, when Xl and x2 are both NH, sulphur; Rl and R2 are heterocyclicalkyl or heterocyclicalkyl-thioalkyl groups and q:is an integer from 2 to 8.
Surprisingly, it has been found that certain related compounds wherein q is greater than 8 are also useful as histamlne H2-antagonists, and it is to these compounds that the present application relates in one of its broad aspects.
Accordingly, by one aspect of this invention, compounds of Formula 2 are provided which are histamine H2-antagonists:
R NH-C-W-(CH2) W-~-NHR
Formula 2 wherein X3 and X4, which may be the same or different, are NY wherein Y
is hydrogen, lower alkyl, or cyano; R3 and R4, which may be the same or tifferent, each represents a grouping of the structure shown in Formula 3:
( 2)m (CH2)n Formula 3 wherein Het is 4-imidazolyl, or a 4-imidazolyl substituted by lower alkyl (preferably methyl), or is 2-thiazolyl; Z is sulphur; m is 1 and n is 2;
W is NH and when X3 and X4 are both NH, W may also be sulphur; p i5 an 1~7031S
integer fr~m 9 to 12; or pharmaceutically acceptable acid addition salts thereof.
It will be understood that the structure illustrated in Formula
Many physiologically active substances elicit their biological actions by interaction with specific sites known as receptors. Histamine is such a substance and has a number of biological actions. Those biological actions of histamine which are inhibited by drugs commonly called "antihistamines", of which mepyramine, diphenhydramine and chlorpheniramine are typical examples, are mediated throu~gh histamine Hl-receptors (Ash and Schild, Brit. J. Pharmac. Chemother, _ , 427J
(1966)). However, other of the 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 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, ~070315 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.
In German Offenlegungschrift 2504794 is described and claimed inter alia histamine H2-antagonists of Formula 1:
xl X2 R ~ -C-W-(CH2) -W-l-NHR
Formula 1 wherein Xl and x2 are sulphur, CHN02 or NY wherein Y is hydrogen, hydroxy, lower alkyl, cyano or CONH2; W is NH or, when Xl and x2 are both NH, sulphur; Rl and R2 are heterocyclicalkyl or heterocyclicalkyl-thioalkyl groups and q:is an integer from 2 to 8.
Surprisingly, it has been found that certain related compounds wherein q is greater than 8 are also useful as histamlne H2-antagonists, and it is to these compounds that the present application relates in one of its broad aspects.
Accordingly, by one aspect of this invention, compounds of Formula 2 are provided which are histamine H2-antagonists:
R NH-C-W-(CH2) W-~-NHR
Formula 2 wherein X3 and X4, which may be the same or different, are NY wherein Y
is hydrogen, lower alkyl, or cyano; R3 and R4, which may be the same or tifferent, each represents a grouping of the structure shown in Formula 3:
( 2)m (CH2)n Formula 3 wherein Het is 4-imidazolyl, or a 4-imidazolyl substituted by lower alkyl (preferably methyl), or is 2-thiazolyl; Z is sulphur; m is 1 and n is 2;
W is NH and when X3 and X4 are both NH, W may also be sulphur; p i5 an 1~7031S
integer fr~m 9 to 12; or pharmaceutically acceptable acid addition salts thereof.
It will be understood that the structure illustrated in Formula
2 is only one of several representations and that other taut~meric forms are also covered by other aspects of the present invention. It will also be understood that because of the symmetry of the molecular structure, the meanings of R3 and R4 and X3 and X4 may be interchanged~ Hydrates, pharmaceutically acceptable salts, and hydrated pharmaceutically accep-table salts of compounds of Formula 2 are also covered by other aspects of the present invention.
Throughout the present specification and claims the term "lower alkyl~ is intended to mean an alkyl group containing from 1 to 4 carbon atoms and the term "lower alkoxy" is intended to mean an al~oxy group containing from 1 to 4 carbon atoms.
In a preferred group of compounds R3 and R are the same. R3 and/or R are preferably Het-CH2S(CH2)2- and it is particularly prefer-ably that Het is 4-imidazolyl, or is a 4-imidazolyl ring substituted by methyl~ or is 2-thiazolyl.
Preferably X3 or X4 is NH, and most preferably X3 and X4 are both NH. Preferably p is 9 or 10. Examples of specific compounds falling within the scope of aspects o the present invention are:
1~9-bis-[N~-(2-(5-methyl-4-imidazolylmethylthio)ethyl-guanidlno~nonane;
1,lO~bis-lN~-(2-(5-methyl-4-imidazolylmethylthio)ethyl-guanidino]decane;
1,12-bis-~N~-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino~dodecane; and 1,10-bis-~N'-(2-(2-thiazolylmethylthio)ethyl)guanidinoJ-decane.
By another aspect of this invention, a process is provided for - 10~70315 the production of a compound of Formula 1 R NH-C-W(CH2)pW-C-NHR
Formula 1 wherein X3 and X4 which may be the same or different, are NY wherein Y
is hydrogen, lower alkyl or cyano; R3 and R4, which may be the same or different, each represents a grouping of the structure:
( 2)m ( 2)n wherein Het is 4-imidazolyl, or a 4-imidazolyl ring substituted by lower alkyl or is 2-thiazolyl; Z is sulphur; m is 1 and n is 2; W is NH, and when X3 and X4 are both NH, W may also be sulphur and p is an integer from 9 to 12 or a pharmaceutically acceptable acid addition salt thereof, which comprises the step of: treating a compound of the formula R3NHE
where E is hydrogeD or ~ , (where A is lower alkyl, X5 is X3 or -NY' where Y' is a guanidine protecting group, e.g. benzoyl, benzyloxycarbonyl or ethoxycarbonyl) with a compound of the formula GNHR4j where G is AS-CNH(CH2)pNHC- l~6 when E is hydrogen, and G is NH2(CH2) NHC-X
when E is -NHlSA , ~where A and X5 are as defined above and x6 is X4 or NY' where Y' is as defined above) to eliminate a mercaptan of formula ASH
and when X5 or x6 is NY', removing the guanidine protecting group to give the compounds where X3 or X4 is NH; and where X3 and/or X4 are NCN, sub-~ecting the compound to acid hydrolysis to give compounds where X3 and/or X is NH.
By a variant thereof, the compound where X is NH is prepared by the acid hydrolysis of a compound of Formula 1 wherein X3 is NCN.
By another variant, the compound where X4 is NH is prepared by the acid hydrolysis of a compound of Formula wherein X4 is NCN.
b _ 5 _ ~070315 ` By still another variant, the compound where W i8 sulphur and --~ X3 and X4 are both NH, is prepared by treating a compounf of the for~ula Hal-(CH2) -Hal, where Hal is chlorine, bromine or iodine, with a thio-urea of formula R3NHCSNH2 or, when R3 is not the same as R4, successively treaeing with thioureas of formulas R3NHCSNH2 and R4NHCSNH2.
By a further variant, the compound where W is NH and X3 and X4 are both =NY (where Y is hydroxy or lower alkyl) is prepared by treating an isothiourea of formula SA SA
Throughout the present specification and claims the term "lower alkyl~ is intended to mean an alkyl group containing from 1 to 4 carbon atoms and the term "lower alkoxy" is intended to mean an al~oxy group containing from 1 to 4 carbon atoms.
In a preferred group of compounds R3 and R are the same. R3 and/or R are preferably Het-CH2S(CH2)2- and it is particularly prefer-ably that Het is 4-imidazolyl, or is a 4-imidazolyl ring substituted by methyl~ or is 2-thiazolyl.
Preferably X3 or X4 is NH, and most preferably X3 and X4 are both NH. Preferably p is 9 or 10. Examples of specific compounds falling within the scope of aspects o the present invention are:
1~9-bis-[N~-(2-(5-methyl-4-imidazolylmethylthio)ethyl-guanidlno~nonane;
1,lO~bis-lN~-(2-(5-methyl-4-imidazolylmethylthio)ethyl-guanidino]decane;
1,12-bis-~N~-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino~dodecane; and 1,10-bis-~N'-(2-(2-thiazolylmethylthio)ethyl)guanidinoJ-decane.
By another aspect of this invention, a process is provided for - 10~70315 the production of a compound of Formula 1 R NH-C-W(CH2)pW-C-NHR
Formula 1 wherein X3 and X4 which may be the same or different, are NY wherein Y
is hydrogen, lower alkyl or cyano; R3 and R4, which may be the same or different, each represents a grouping of the structure:
( 2)m ( 2)n wherein Het is 4-imidazolyl, or a 4-imidazolyl ring substituted by lower alkyl or is 2-thiazolyl; Z is sulphur; m is 1 and n is 2; W is NH, and when X3 and X4 are both NH, W may also be sulphur and p is an integer from 9 to 12 or a pharmaceutically acceptable acid addition salt thereof, which comprises the step of: treating a compound of the formula R3NHE
where E is hydrogeD or ~ , (where A is lower alkyl, X5 is X3 or -NY' where Y' is a guanidine protecting group, e.g. benzoyl, benzyloxycarbonyl or ethoxycarbonyl) with a compound of the formula GNHR4j where G is AS-CNH(CH2)pNHC- l~6 when E is hydrogen, and G is NH2(CH2) NHC-X
when E is -NHlSA , ~where A and X5 are as defined above and x6 is X4 or NY' where Y' is as defined above) to eliminate a mercaptan of formula ASH
and when X5 or x6 is NY', removing the guanidine protecting group to give the compounds where X3 or X4 is NH; and where X3 and/or X4 are NCN, sub-~ecting the compound to acid hydrolysis to give compounds where X3 and/or X is NH.
By a variant thereof, the compound where X is NH is prepared by the acid hydrolysis of a compound of Formula 1 wherein X3 is NCN.
By another variant, the compound where X4 is NH is prepared by the acid hydrolysis of a compound of Formula wherein X4 is NCN.
b _ 5 _ ~070315 ` By still another variant, the compound where W i8 sulphur and --~ X3 and X4 are both NH, is prepared by treating a compounf of the for~ula Hal-(CH2) -Hal, where Hal is chlorine, bromine or iodine, with a thio-urea of formula R3NHCSNH2 or, when R3 is not the same as R4, successively treaeing with thioureas of formulas R3NHCSNH2 and R4NHCSNH2.
By a further variant, the compound where W is NH and X3 and X4 are both =NY (where Y is hydroxy or lower alkyl) is prepared by treating an isothiourea of formula SA SA
3 li 11 4 R NH-C=N(CH2) N=C-NHR
(where A is lower alkyl) with a compound of formula YNH2, where Y is hydroxy or lower alkyl.
Compounds of Formula 2 wherein W is NH, and X3 and X4 are NH, or N (lower alkyl), may be prepared by a process outlined above.
. .
- 5a -... . .
~7~)31S
lS:
X =
Z
V
_, .
f~ I N
= V N X
$ 1:~ ~
r_ ~
~; ~\ Gq '~1 ' \
/ \
X=C~ / \
N Z /
~/ ' / ¢
~ I
X--~
Z;
r-l / N ~ :
N ~ --I
~3 ~ ~ O
~ ~C ~ = O
X u~
CQX--c~ O
~l ~ .
C
C~ $z ~ ~ ~ a~
5~ U~
~ ~ ¢
V ~ X =C) X u~
N ~1 X
C) ~
O
X= C~ Z
X ~ C ~
O V~
~ ¢
¢
~ -- 6 ---107~)315 1 In Scheme 1, A is lo~er a:Lkyl, ~3 a~d R4, which may be the same or different, are as defined in Formula 2, and X~ and X6, which may be the same or different are sulphur, CHN02, NH, N-(lower alkyl), NCN or NY' where Y' is a guanidine protecting group e.g. benzoyl, benzyloxy-carbonyl or ethoxycarbonyl. In Scheme 1 preferably X5 is not NH or N-(lower alkyl) unless R
is the same as R4. Compounds of ~ormula 2 wherein X3 and X4 are both NH and R3 is not the same as R4 may be prepared by the acid hydrolysis of compounds of Formula 6 wherein X5 and x6 are NCN or N-benzoyl. Compounds of Formula 2 wherein X3 and/or X4 are CONH2 may be prepared by the hydrolysis under mild acid conditions of the corresponding cyanoguanidine of Formula 6 wherein X and/or x6 is NCN.
Step 1 of Route A may be carried out in the presence of, or in the absence of, a solvent. Preferably this reaction is carried out using an excess of the amine NH2(CH2)pNH2 as solvent. Preferably Step 2 of Route A is carried out in the absence of a solvent or in the presence of a polar solvent e.g. a lower alcohol or pyridine. Preferably this reaction is carried out at an elevated temperature, e.g. 100C. When R3 and R4 are the same and X5 and x6 are the same Step 1 and Step 2 of Route A may be carried out simultaneously, without isolating the intermediate of Formula 5.
Preferably both steps of Route B are carried out in a polar solvent, e.g. a lower alcohol or pyridine, and at an elevated temperature, e.g. 100C. When R3 is not the same as R4 preferably one equivalent of the amine R NH2 is used in the first step of Route B and an excess of the amine R ~H2 is used in the second step.
Compounds of formula R NH2 may be prepared by processes 3_ described in British Patent specifications Nos. 1305547, 1338169 and 1421999 and German Offenlegungschrift 2634433.
-1~'7~31S
1` Compounds of Formula 4 wherein X5 is sulphur may be prepared from an amine of folmula R NH2 by successive reaction thereof with carbon disulphide and an alkylating agent, e.g. methyl iodide.
Compounds of Formula 4 wherein X5 is CHN02, N~benzoyl or NCN may be prepared by treating a compound of Formula 9 (AS)2C=X5 wherein X is CHN02, N-benzoyl or NCN, and A is alkyl, with an equivalent amount of an amine of Formula R NH2.
This reaction is conveniently carried out in a solvent e.g. ethanol. The compounds of Formula 4 wherein X
is CHN02 may alternatively be prepared by treating l-methylsulphinyl-l-methylthio-2-nitroethylene (described in German Offenlegungschrift 2634430) with an equivalent amount of an amine of Formula R NH2.
The compounds of ~ormula 4 wherein X5 is NH are conveniently prepared by alkylating a thiourea of formula R NHCSNH2.
These thioureas may be prepared by treating an amine of formula R NH2 with benzoyl isothiocyanate, and hydrolysing the product under alkaline conditions.
The compounds of Formula 7 may be prepared by pr~cesses analogous to those described for the preparation of compounds of Formula 4.
The compounds of Formula 2 wherein X3 and/or X are NY and Y is hydroxy or lower alkyl may be prepared from the corresponding thioureas of Formula 2 wherein X3, and/or X4 are sulphur, and neither X3 nor X4 are NH by alkylating the thiourea, e.g., by treatment with hydrogen chloride in methanol or with methyl iodide, and then treating the resulting isothiourea with hydroxylamine or a lower alkylamine, respectively.
The compounds of Formula 2 wherein X3 and/or X4 are NCN may ` ` lC~70315 alternatively be prepared from the corresponding thioureas of Formula 2 wherein X and/or X4 are sulphur, and neither X3 nor X4 are NH, by alkylation and treatment of the product with cyanamide and a strong base e-g- potassium t-butoxide.
The compounds of Formula 2 wherein X3 or X4 are NCN may also be prepared from the corresponding compounds of ~ormula 2 wherein X3 or X4 are sulphur by reaction of the latter with a heavy metal salt of cya~amide e.gO lead, mercury or cadmium cyanamide in a solvent e.g. acetonitrile and/or dimethylformamide.
The compounds of ~ormula 2 whereir~ W is sulphur and X3`and X4 are both NH may be prepared by alkylating a thiourea of formula R3NHCSNH2 wherein ~3 is as defined in Formula 2 with a dihaloalkane of formula Hal-(CH2)p-Hal, wherein Hal represents chlorine, bromine~ or iodine. Preferably the reaction is carried out on an acid addition salt of the thiourea. Preferably Hal is bromine and the reaction is carried out in a solvent e.g. ethanol. When R3 is not the same as R4 this reaction will be carried out in two s',ages. Preferably there will be an excess of the compound of formula Hal-(CH2)p-Hal in the first stage of the reactlon.
The compounds of aspects of this invention of Formula 2 block histamine H2-receptors, that is they inhibit the biological actions of histamine which are not inhibited by "antihistamines" e.g.
mepyramine but are inhibited by burimamide. For example, the compounds of aspects of this invention have been found to inhibit histamine-stimulated secretion of gastric acid from the lumen-perfused stomachs of rats anaesthetized with urethane, at doses of from 0.5 to 256 micromoles per kilo~ram intra-venously. 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 , . :: ., . , -, .," ., , - -, . : . . :: .: - . :-: . :- . -: . .
1.070315 Schild, are not mediated by histamine Hl-receptors. For example, they inhibit the actions of histamine on the isolated gu nea pig atrium and isolated rat uterus.
The compounds of aspects of this invention inhibit the basal secretion of gastric acid and also that stimulated by pentagastrin or by food.
In addition, in a conventional test, e.g. the measure-ment of blood pressure in the anaesthetized rat, the action of the compounds of aspects o~ this invention in inhibiting the vaso-dilator action of histamine can~also be demonstrated. The level of activity of the compounds of aspects of this invention is illustrated by the effective dose producing 50% inhibition of gastric acid secretion in the ana-esthetized rat and the dose producing 50% inhibition of histamine-induced tachy-cardia in the isolated guine~a pig atrium.
For therapeutic use, the pharmacologically active compounds of aspects of the present invention will normally be administered as a pharmaceutical composition comprising as the or an essential active ingredient at least one such compound in the basic form or in the form of an addition salt with a pharmaceuti-cally acceptable acid and in association with a pharmaceutical carrier therefor. Such addition salts include those with hydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids and may conveniently be formed from the corresponding bases of Formula 2 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.
Pharmaceu~ical compositions comprising a pharmaceutical carrier and a compound of Formula 2 or a pharmaceutically acceptable acid addition salt thereof and methods of blocking histamine H2-receptors which comprise administering ~ ()315 l to an animal ~ compound of Formula 2 or a pharmaceutically acceptable acid addition salt thereof are also provided by the present teaching9. The pharmaceu'lcal carrier employed may be, for example, either a solid or li~uid. Exemplary of solid carriers are lactose, maize or potato or modified starches, dicalcium phosphate, terra alba, sucrose, celluloses, talc, gelatin, microfine silica, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
Exemplary of liquid carriers are syrup, peanut oil, olive oil, alcohol, propylene glycol, polyethylene glycols, water and the like.
A wide variety of pharmaceutical forms can be employed.
Thus, if a solid carrier is used, the preparation 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 will~ vary widely but preferably will be from 25 mg to 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid or an aqueous or nonaqueous liquid suspension. Other additives e.g. preservatives e.g. antioxidants or antibacterials and/or flavourilng or colouring agents may also be included. The liquidiforms may also be prepared in soft gelatin capsules or micracapsules. The sterile solution may be prepared in ampoules, multidose vials or unit dose disposable syringes. The preparation may also be in a semi-solid form e.g. a cream, p~ste, ointment or gel or a liquid or aerosol form for topical administration.
The pharmaceutical compositions are prepared by conventional techniques involving proce~ures e.g. mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
-3~ The active ingredient will be present in the compositions 10~0315 _ in an effective amount to block histamine H2-receptors.
The route of administration may be oral or parenteral.
Preferably, each dosage unit will contain the active ingredient in an amount of from 50 mg to 250 mg.
The active ingredient will preferably be administered one to six times per day. The daily dosage regimen will preferably be from 150 mg to 1500 mg.
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 applicatibn.
This invention in its various aspects is illustrated but in no way limited by the following examples, wherein all temperatures are in degrees Centigrade:-1,10-bis-~N'-(2-(5-Methyl-4-imidazolylmethylthio)ethyl)-guanidino~decane (a) A solution of N-L2-(5-methyl-4-imidazolylmethylthio)-ethyl~thiourea (2.29 g) and methyl iodide (1.56 g) in methanol (5 ml) was kept at room temperature for 18 hours affording S-methyl-N- ~2-(5-methyl-4-imidazolyl-methylthio)ethyl~ isothiouronium iodide (2.3 g) m.p.
128-131.
(b) l,10-Diaminodecane (1.72 g) was added to a solution of S-methyl-~-[2-(5-methyl-4-imidazolylmethylthio)-ethyl]isothiouronium iodide (7.44 g) in water (25 ml) and the mixture was heated under reflux for 2 hours.
Following concentration the residue was converted into the dipicrate with an aqueous solution of sodium picrate. Recrystallisation from ethanol afforded the title compound as the dipicrate (4.79 g) m.p. 104-105.
: :; , .
. , , . , ~ . . . . .. . .
1 (Found: C, 43.65; H, 5.4; N~ 21.1~ S~ 6.0;
C26H48NloS2(C6H3N307)2.H20 requires: C, 43.8; H, ~.4; N, 21.5; S, 6. 2~o) The dipicrate was dissolved in aqueous methanol and treated with ion-exchange resin IRA 400 (Cl ) to afford the dihydrochloride of the title compound.
EXA~IPLE 2 1,12-bis-~N'-(2-(5-Methyl-4-imidazolylmethylthio)ethyl)-guanidinoldodecane Substitution of 1,12-diaminododecane for l,10-diaminodecane in the procedure of Example 1 (b) resulted in the preparation of the dipicrate of the title compound m.p. 68-70.
(Found: C, 45.75; H, 5.6; N, 20.i5; S, 6.0 C28H52HloS2 (C6H3N307)2 requires: C, 45.7; H, 5.6, N, 21.3; S, 6.1%) The dipicrate was dissolved in aqueous methanol and treated with ion-exchange resin IRA 400 (Cl ) to afford the dihydrochloride of the title compound.
l,9-bis-rN' - (2-(5-Methyl-4-imidazolylmethylthio)ethyl)-guanidinol nonane Substitution of 1,9-nonane for l,10-diaminodecane in the procedure of Example l(b) resulted in the preparation of the dipicrate of the title compound m.p. 90-93.
This dipicrate was dissolved in aqueous methanol and treated with ion-exchange resin IRA 400 (Cl ) to afford the dihydrochloride of the title compound.
~ . , :. ... .
1~70315 1,10-bis-~N'-(2-(2-thiazolylmethylthio)ethyl)-guanidino]-decane _ a) A mixture of S-methyl-N-cyano-N'-(2-(2-thiazolyl-methylthio)ethyl)-isothiourea (2.72 g), l,10-diamino-decane (0.9 g) and ethanol (5 ml) was heated on a steam-bath for 20 hours and the mixture was chroma-tographed on silica gel, eluting with ethyl acetate/
isopropanol (5:1). The crude product was re-crystallised from aqueous ethanol to give l,10-bis-N'-cyano-N"-(2-(2-thiazolylmethylthio)ethyl)-guanidino~-decane (0.49 g) m.p. 74-75 .
Found: C, 50.15; H, 6.6; N, 22.7; S, 20.7;
requires: C, 50.3; H, 6.5; N, 22.6; S, 20.7%
b) l,10-bis ~N'-Cyano-N"-(2-(2-thiazolylmethylthio)ethyl)-guanidino3decane (2.0 g) was refluxed with concentrated hydrochloric acid (25 ml) for 24 hours and the mixture was evaporated to dryness. The residue was triturated with ice-cold ethanol, ammonium chloride was filtered off and the filtrate was evaporated to give the title compound, which was converted into the dipicrate by treatment with an excess of sodium picrate solution.
The dip-crate was recrystallised from nitromethane and had m.p. 155-157.
Found: C, 41.55; H, 4.8; N, 19.1; S, 11.8;
C24H42N8S4- (C6H3N307)2 requires: C, 42.0; H, 4.7; N, 19.1; S, 12.5%
Thedipicrate was converted into the tetrahydrochloride of the title compound by treatment with IRA 400 (Cl ) and acidification to pH 2 with concentrated hydro-chloric acid.
3~
- . . ..
. - .
i EXAMPLE 5 1,9-bis-rN-(2-(5-Methyl-~-imidazolylmethylthio)ethyl)-thioureido~nonane A mixture of S-methyl-N-[2-(5-methyl-4-imidazolylmethyl-thio)ethyl~dithiocarbamate, l,9-diaminononane and iso-propanol is boi;ed under reflux for 24 hours and the mixture is evaporated to dryness and the residue purified by chromatography on silica gel to give the title product.
l,9-bis- ~-~2-((5-Methyl-4-imidazolyl)methylthio)ethylamino~-2-nitrovinyl-1-amino~nonane A solution of l-nitro-2-methylthio-2-l2-('5-methyl-4-imidazolyl)methylthio)ethylamino~ethylene (1.15 g) and l,9-diaminononane (0.31 ~3 in ethanol (15 ml) is heated under reflux for 2 hours. The product is purified on an ion-exchange resin (CG 50(H+)) and then on silica gel to yield the title compound.
EXA~PLE 7 a) l,9-Diaminononane is treated with two moles of dimethyl N-cyanodithiocarbamate in ,ethanol at room temperature to give l,9-bis(N'-cyano-S-methyl-thioureido)nonane.
b) l,9-bis-(N'-Cyano-S-methylthioureido)nonane is treated with one equivalent of 2-(5-methyl-4-imidazolyl-methylthio)ethylamine and the mixture is refluxed in pyridine for 12 hours. The pyridine is removed by evaporation and the residue is purified by chroma-tography on silica gel to give l-(N'-cyano-S-methyl-thioureido)-9{N'-cyano-N"-(2-(5-methyl-4-imidazolyl-methylthio)ethyl)guanidino]nonane.
..
1~70315 ,1 ,~
_ c) l-(N'-Cyano-S-methylthioureido)-9-[N!cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino~-nonane is treated with two mcles of 2-(2-thiazolyl-methylthio)ethylamine and the mixture is refluxed in pyridine for 12 hours. The pyridine is removed by evaporation and the residue is purified by chroma-tography on silica gel to give l-[N'-cyano-N"-(2-(2-thiazolylmethylthio)ethyl)guanidino~-9-~N'-cyano-, N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidin~ -1~ nonane, This guanidine is refluxed with concentrated hydro-chloric acid for 24 hours to give 1-[N'-(2-(2-- thiazolylmethylthio)ethyl~guanidino~ -9-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidin~ nonane tetrahydrochloride.
d) Substitution o~ (a) 2-(2-imidazolylmethylthio)ethylamine (b) 2-(4-imidazolylmethylthio)ethylamine (c) 2-(5-bromo-4-imidazolylmethylthio)-ethylamine (d) 2-(5-trifluoromethyl-4-imidazolylmethyl-thio)ethylamine (e) 2-(5-hydroxymethyl-4-imidazolylmethyl-thio)ethylamine (f) 2-(2-pyridylmethylthio)ethylamine (g) 2-(3-methyl-2-pyridylmethylthio)ethylamine (h) 2-(3-methoxy-2-pyridylmethyIthio)ethylamine (i) 2-(3-chloro-2-pyridylmethylthio)ethylamine (j) 2-(3~amino-2-pyridylmethylthio)ethylamine (k) 2-(3-hydroxy-2-pyridylmethylthio)ethylamine (1) 2-(3-isothiazolylmethylthio)ethylamine (m) 2-(4-bromo-3-isothiazolylmethylthio)-ethylamine (n) 2-(3-(1,2,5)-thiadiazolylmethylthio)-ethylamine ,, . . , , ~ .
3L07~)315 (o) 2- (4-chloro-3- (1, 2, 5) -thiadiazolylmethyl-thio)ethylamine (p) 2-(5-amino-2-(1,3,4)-thiadiazolylmethyl-thio)ethylamine for 2-(2-thiazolylmethylthio)ethylamine in procedure (c) above gives:-(a) l-[N'-cyano-N"- ~2-(2-imidazolylmethylthio)ethyl)guanidino~-9-[N' -cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino~ nonane (b) 1- lN'-cyano-N"- (2-- (4-imidazolylmethylthio)ethyl)-guanidinoJ ~9~ LN ' -cyano-N" - (2- (5-methyl-4-imidazolylmethyl-. thio)ethyl)guanidino~nonane (c) l~CN'-cyano-N''- (2--(5-bromo-4-imidazolylmethylthio)ethyl)-guanidin~9-~N ' -cyano-N" - (2- (5-methyl-4-imidazolylmethyl-thio)ethyl)guanidino~nonane (d) l-¦N'-cyano-N"-(2 (5-triIluoromethyl-4-imidazolyl-methylthio)ethyl)guanidino~ -9-LN' -cyano-N"-(2-(5-methyl-
(where A is lower alkyl) with a compound of formula YNH2, where Y is hydroxy or lower alkyl.
Compounds of Formula 2 wherein W is NH, and X3 and X4 are NH, or N (lower alkyl), may be prepared by a process outlined above.
. .
- 5a -... . .
~7~)31S
lS:
X =
Z
V
_, .
f~ I N
= V N X
$ 1:~ ~
r_ ~
~; ~\ Gq '~1 ' \
/ \
X=C~ / \
N Z /
~/ ' / ¢
~ I
X--~
Z;
r-l / N ~ :
N ~ --I
~3 ~ ~ O
~ ~C ~ = O
X u~
CQX--c~ O
~l ~ .
C
C~ $z ~ ~ ~ a~
5~ U~
~ ~ ¢
V ~ X =C) X u~
N ~1 X
C) ~
O
X= C~ Z
X ~ C ~
O V~
~ ¢
¢
~ -- 6 ---107~)315 1 In Scheme 1, A is lo~er a:Lkyl, ~3 a~d R4, which may be the same or different, are as defined in Formula 2, and X~ and X6, which may be the same or different are sulphur, CHN02, NH, N-(lower alkyl), NCN or NY' where Y' is a guanidine protecting group e.g. benzoyl, benzyloxy-carbonyl or ethoxycarbonyl. In Scheme 1 preferably X5 is not NH or N-(lower alkyl) unless R
is the same as R4. Compounds of ~ormula 2 wherein X3 and X4 are both NH and R3 is not the same as R4 may be prepared by the acid hydrolysis of compounds of Formula 6 wherein X5 and x6 are NCN or N-benzoyl. Compounds of Formula 2 wherein X3 and/or X4 are CONH2 may be prepared by the hydrolysis under mild acid conditions of the corresponding cyanoguanidine of Formula 6 wherein X and/or x6 is NCN.
Step 1 of Route A may be carried out in the presence of, or in the absence of, a solvent. Preferably this reaction is carried out using an excess of the amine NH2(CH2)pNH2 as solvent. Preferably Step 2 of Route A is carried out in the absence of a solvent or in the presence of a polar solvent e.g. a lower alcohol or pyridine. Preferably this reaction is carried out at an elevated temperature, e.g. 100C. When R3 and R4 are the same and X5 and x6 are the same Step 1 and Step 2 of Route A may be carried out simultaneously, without isolating the intermediate of Formula 5.
Preferably both steps of Route B are carried out in a polar solvent, e.g. a lower alcohol or pyridine, and at an elevated temperature, e.g. 100C. When R3 is not the same as R4 preferably one equivalent of the amine R NH2 is used in the first step of Route B and an excess of the amine R ~H2 is used in the second step.
Compounds of formula R NH2 may be prepared by processes 3_ described in British Patent specifications Nos. 1305547, 1338169 and 1421999 and German Offenlegungschrift 2634433.
-1~'7~31S
1` Compounds of Formula 4 wherein X5 is sulphur may be prepared from an amine of folmula R NH2 by successive reaction thereof with carbon disulphide and an alkylating agent, e.g. methyl iodide.
Compounds of Formula 4 wherein X5 is CHN02, N~benzoyl or NCN may be prepared by treating a compound of Formula 9 (AS)2C=X5 wherein X is CHN02, N-benzoyl or NCN, and A is alkyl, with an equivalent amount of an amine of Formula R NH2.
This reaction is conveniently carried out in a solvent e.g. ethanol. The compounds of Formula 4 wherein X
is CHN02 may alternatively be prepared by treating l-methylsulphinyl-l-methylthio-2-nitroethylene (described in German Offenlegungschrift 2634430) with an equivalent amount of an amine of Formula R NH2.
The compounds of ~ormula 4 wherein X5 is NH are conveniently prepared by alkylating a thiourea of formula R NHCSNH2.
These thioureas may be prepared by treating an amine of formula R NH2 with benzoyl isothiocyanate, and hydrolysing the product under alkaline conditions.
The compounds of Formula 7 may be prepared by pr~cesses analogous to those described for the preparation of compounds of Formula 4.
The compounds of Formula 2 wherein X3 and/or X are NY and Y is hydroxy or lower alkyl may be prepared from the corresponding thioureas of Formula 2 wherein X3, and/or X4 are sulphur, and neither X3 nor X4 are NH by alkylating the thiourea, e.g., by treatment with hydrogen chloride in methanol or with methyl iodide, and then treating the resulting isothiourea with hydroxylamine or a lower alkylamine, respectively.
The compounds of Formula 2 wherein X3 and/or X4 are NCN may ` ` lC~70315 alternatively be prepared from the corresponding thioureas of Formula 2 wherein X and/or X4 are sulphur, and neither X3 nor X4 are NH, by alkylation and treatment of the product with cyanamide and a strong base e-g- potassium t-butoxide.
The compounds of Formula 2 wherein X3 or X4 are NCN may also be prepared from the corresponding compounds of ~ormula 2 wherein X3 or X4 are sulphur by reaction of the latter with a heavy metal salt of cya~amide e.gO lead, mercury or cadmium cyanamide in a solvent e.g. acetonitrile and/or dimethylformamide.
The compounds of ~ormula 2 whereir~ W is sulphur and X3`and X4 are both NH may be prepared by alkylating a thiourea of formula R3NHCSNH2 wherein ~3 is as defined in Formula 2 with a dihaloalkane of formula Hal-(CH2)p-Hal, wherein Hal represents chlorine, bromine~ or iodine. Preferably the reaction is carried out on an acid addition salt of the thiourea. Preferably Hal is bromine and the reaction is carried out in a solvent e.g. ethanol. When R3 is not the same as R4 this reaction will be carried out in two s',ages. Preferably there will be an excess of the compound of formula Hal-(CH2)p-Hal in the first stage of the reactlon.
The compounds of aspects of this invention of Formula 2 block histamine H2-receptors, that is they inhibit the biological actions of histamine which are not inhibited by "antihistamines" e.g.
mepyramine but are inhibited by burimamide. For example, the compounds of aspects of this invention have been found to inhibit histamine-stimulated secretion of gastric acid from the lumen-perfused stomachs of rats anaesthetized with urethane, at doses of from 0.5 to 256 micromoles per kilo~ram intra-venously. 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 , . :: ., . , -, .," ., , - -, . : . . :: .: - . :-: . :- . -: . .
1.070315 Schild, are not mediated by histamine Hl-receptors. For example, they inhibit the actions of histamine on the isolated gu nea pig atrium and isolated rat uterus.
The compounds of aspects of this invention inhibit the basal secretion of gastric acid and also that stimulated by pentagastrin or by food.
In addition, in a conventional test, e.g. the measure-ment of blood pressure in the anaesthetized rat, the action of the compounds of aspects o~ this invention in inhibiting the vaso-dilator action of histamine can~also be demonstrated. The level of activity of the compounds of aspects of this invention is illustrated by the effective dose producing 50% inhibition of gastric acid secretion in the ana-esthetized rat and the dose producing 50% inhibition of histamine-induced tachy-cardia in the isolated guine~a pig atrium.
For therapeutic use, the pharmacologically active compounds of aspects of the present invention will normally be administered as a pharmaceutical composition comprising as the or an essential active ingredient at least one such compound in the basic form or in the form of an addition salt with a pharmaceuti-cally acceptable acid and in association with a pharmaceutical carrier therefor. Such addition salts include those with hydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids and may conveniently be formed from the corresponding bases of Formula 2 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.
Pharmaceu~ical compositions comprising a pharmaceutical carrier and a compound of Formula 2 or a pharmaceutically acceptable acid addition salt thereof and methods of blocking histamine H2-receptors which comprise administering ~ ()315 l to an animal ~ compound of Formula 2 or a pharmaceutically acceptable acid addition salt thereof are also provided by the present teaching9. The pharmaceu'lcal carrier employed may be, for example, either a solid or li~uid. Exemplary of solid carriers are lactose, maize or potato or modified starches, dicalcium phosphate, terra alba, sucrose, celluloses, talc, gelatin, microfine silica, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
Exemplary of liquid carriers are syrup, peanut oil, olive oil, alcohol, propylene glycol, polyethylene glycols, water and the like.
A wide variety of pharmaceutical forms can be employed.
Thus, if a solid carrier is used, the preparation 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 will~ vary widely but preferably will be from 25 mg to 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid or an aqueous or nonaqueous liquid suspension. Other additives e.g. preservatives e.g. antioxidants or antibacterials and/or flavourilng or colouring agents may also be included. The liquidiforms may also be prepared in soft gelatin capsules or micracapsules. The sterile solution may be prepared in ampoules, multidose vials or unit dose disposable syringes. The preparation may also be in a semi-solid form e.g. a cream, p~ste, ointment or gel or a liquid or aerosol form for topical administration.
The pharmaceutical compositions are prepared by conventional techniques involving proce~ures e.g. mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
-3~ The active ingredient will be present in the compositions 10~0315 _ in an effective amount to block histamine H2-receptors.
The route of administration may be oral or parenteral.
Preferably, each dosage unit will contain the active ingredient in an amount of from 50 mg to 250 mg.
The active ingredient will preferably be administered one to six times per day. The daily dosage regimen will preferably be from 150 mg to 1500 mg.
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 applicatibn.
This invention in its various aspects is illustrated but in no way limited by the following examples, wherein all temperatures are in degrees Centigrade:-1,10-bis-~N'-(2-(5-Methyl-4-imidazolylmethylthio)ethyl)-guanidino~decane (a) A solution of N-L2-(5-methyl-4-imidazolylmethylthio)-ethyl~thiourea (2.29 g) and methyl iodide (1.56 g) in methanol (5 ml) was kept at room temperature for 18 hours affording S-methyl-N- ~2-(5-methyl-4-imidazolyl-methylthio)ethyl~ isothiouronium iodide (2.3 g) m.p.
128-131.
(b) l,10-Diaminodecane (1.72 g) was added to a solution of S-methyl-~-[2-(5-methyl-4-imidazolylmethylthio)-ethyl]isothiouronium iodide (7.44 g) in water (25 ml) and the mixture was heated under reflux for 2 hours.
Following concentration the residue was converted into the dipicrate with an aqueous solution of sodium picrate. Recrystallisation from ethanol afforded the title compound as the dipicrate (4.79 g) m.p. 104-105.
: :; , .
. , , . , ~ . . . . .. . .
1 (Found: C, 43.65; H, 5.4; N~ 21.1~ S~ 6.0;
C26H48NloS2(C6H3N307)2.H20 requires: C, 43.8; H, ~.4; N, 21.5; S, 6. 2~o) The dipicrate was dissolved in aqueous methanol and treated with ion-exchange resin IRA 400 (Cl ) to afford the dihydrochloride of the title compound.
EXA~IPLE 2 1,12-bis-~N'-(2-(5-Methyl-4-imidazolylmethylthio)ethyl)-guanidinoldodecane Substitution of 1,12-diaminododecane for l,10-diaminodecane in the procedure of Example 1 (b) resulted in the preparation of the dipicrate of the title compound m.p. 68-70.
(Found: C, 45.75; H, 5.6; N, 20.i5; S, 6.0 C28H52HloS2 (C6H3N307)2 requires: C, 45.7; H, 5.6, N, 21.3; S, 6.1%) The dipicrate was dissolved in aqueous methanol and treated with ion-exchange resin IRA 400 (Cl ) to afford the dihydrochloride of the title compound.
l,9-bis-rN' - (2-(5-Methyl-4-imidazolylmethylthio)ethyl)-guanidinol nonane Substitution of 1,9-nonane for l,10-diaminodecane in the procedure of Example l(b) resulted in the preparation of the dipicrate of the title compound m.p. 90-93.
This dipicrate was dissolved in aqueous methanol and treated with ion-exchange resin IRA 400 (Cl ) to afford the dihydrochloride of the title compound.
~ . , :. ... .
1~70315 1,10-bis-~N'-(2-(2-thiazolylmethylthio)ethyl)-guanidino]-decane _ a) A mixture of S-methyl-N-cyano-N'-(2-(2-thiazolyl-methylthio)ethyl)-isothiourea (2.72 g), l,10-diamino-decane (0.9 g) and ethanol (5 ml) was heated on a steam-bath for 20 hours and the mixture was chroma-tographed on silica gel, eluting with ethyl acetate/
isopropanol (5:1). The crude product was re-crystallised from aqueous ethanol to give l,10-bis-N'-cyano-N"-(2-(2-thiazolylmethylthio)ethyl)-guanidino~-decane (0.49 g) m.p. 74-75 .
Found: C, 50.15; H, 6.6; N, 22.7; S, 20.7;
requires: C, 50.3; H, 6.5; N, 22.6; S, 20.7%
b) l,10-bis ~N'-Cyano-N"-(2-(2-thiazolylmethylthio)ethyl)-guanidino3decane (2.0 g) was refluxed with concentrated hydrochloric acid (25 ml) for 24 hours and the mixture was evaporated to dryness. The residue was triturated with ice-cold ethanol, ammonium chloride was filtered off and the filtrate was evaporated to give the title compound, which was converted into the dipicrate by treatment with an excess of sodium picrate solution.
The dip-crate was recrystallised from nitromethane and had m.p. 155-157.
Found: C, 41.55; H, 4.8; N, 19.1; S, 11.8;
C24H42N8S4- (C6H3N307)2 requires: C, 42.0; H, 4.7; N, 19.1; S, 12.5%
Thedipicrate was converted into the tetrahydrochloride of the title compound by treatment with IRA 400 (Cl ) and acidification to pH 2 with concentrated hydro-chloric acid.
3~
- . . ..
. - .
i EXAMPLE 5 1,9-bis-rN-(2-(5-Methyl-~-imidazolylmethylthio)ethyl)-thioureido~nonane A mixture of S-methyl-N-[2-(5-methyl-4-imidazolylmethyl-thio)ethyl~dithiocarbamate, l,9-diaminononane and iso-propanol is boi;ed under reflux for 24 hours and the mixture is evaporated to dryness and the residue purified by chromatography on silica gel to give the title product.
l,9-bis- ~-~2-((5-Methyl-4-imidazolyl)methylthio)ethylamino~-2-nitrovinyl-1-amino~nonane A solution of l-nitro-2-methylthio-2-l2-('5-methyl-4-imidazolyl)methylthio)ethylamino~ethylene (1.15 g) and l,9-diaminononane (0.31 ~3 in ethanol (15 ml) is heated under reflux for 2 hours. The product is purified on an ion-exchange resin (CG 50(H+)) and then on silica gel to yield the title compound.
EXA~PLE 7 a) l,9-Diaminononane is treated with two moles of dimethyl N-cyanodithiocarbamate in ,ethanol at room temperature to give l,9-bis(N'-cyano-S-methyl-thioureido)nonane.
b) l,9-bis-(N'-Cyano-S-methylthioureido)nonane is treated with one equivalent of 2-(5-methyl-4-imidazolyl-methylthio)ethylamine and the mixture is refluxed in pyridine for 12 hours. The pyridine is removed by evaporation and the residue is purified by chroma-tography on silica gel to give l-(N'-cyano-S-methyl-thioureido)-9{N'-cyano-N"-(2-(5-methyl-4-imidazolyl-methylthio)ethyl)guanidino]nonane.
..
1~70315 ,1 ,~
_ c) l-(N'-Cyano-S-methylthioureido)-9-[N!cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino~-nonane is treated with two mcles of 2-(2-thiazolyl-methylthio)ethylamine and the mixture is refluxed in pyridine for 12 hours. The pyridine is removed by evaporation and the residue is purified by chroma-tography on silica gel to give l-[N'-cyano-N"-(2-(2-thiazolylmethylthio)ethyl)guanidino~-9-~N'-cyano-, N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidin~ -1~ nonane, This guanidine is refluxed with concentrated hydro-chloric acid for 24 hours to give 1-[N'-(2-(2-- thiazolylmethylthio)ethyl~guanidino~ -9-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidin~ nonane tetrahydrochloride.
d) Substitution o~ (a) 2-(2-imidazolylmethylthio)ethylamine (b) 2-(4-imidazolylmethylthio)ethylamine (c) 2-(5-bromo-4-imidazolylmethylthio)-ethylamine (d) 2-(5-trifluoromethyl-4-imidazolylmethyl-thio)ethylamine (e) 2-(5-hydroxymethyl-4-imidazolylmethyl-thio)ethylamine (f) 2-(2-pyridylmethylthio)ethylamine (g) 2-(3-methyl-2-pyridylmethylthio)ethylamine (h) 2-(3-methoxy-2-pyridylmethyIthio)ethylamine (i) 2-(3-chloro-2-pyridylmethylthio)ethylamine (j) 2-(3~amino-2-pyridylmethylthio)ethylamine (k) 2-(3-hydroxy-2-pyridylmethylthio)ethylamine (1) 2-(3-isothiazolylmethylthio)ethylamine (m) 2-(4-bromo-3-isothiazolylmethylthio)-ethylamine (n) 2-(3-(1,2,5)-thiadiazolylmethylthio)-ethylamine ,, . . , , ~ .
3L07~)315 (o) 2- (4-chloro-3- (1, 2, 5) -thiadiazolylmethyl-thio)ethylamine (p) 2-(5-amino-2-(1,3,4)-thiadiazolylmethyl-thio)ethylamine for 2-(2-thiazolylmethylthio)ethylamine in procedure (c) above gives:-(a) l-[N'-cyano-N"- ~2-(2-imidazolylmethylthio)ethyl)guanidino~-9-[N' -cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino~ nonane (b) 1- lN'-cyano-N"- (2-- (4-imidazolylmethylthio)ethyl)-guanidinoJ ~9~ LN ' -cyano-N" - (2- (5-methyl-4-imidazolylmethyl-. thio)ethyl)guanidino~nonane (c) l~CN'-cyano-N''- (2--(5-bromo-4-imidazolylmethylthio)ethyl)-guanidin~9-~N ' -cyano-N" - (2- (5-methyl-4-imidazolylmethyl-thio)ethyl)guanidino~nonane (d) l-¦N'-cyano-N"-(2 (5-triIluoromethyl-4-imidazolyl-methylthio)ethyl)guanidino~ -9-LN' -cyano-N"-(2-(5-methyl-
4-imidazolylmethylthio)ethyl)guanidin~ nonane (e) l-LN'-cyano-N"-(2 ---- (5-hydroxymethyl-4-imidazolylmethyl-thio)ethyl)guanidino~¦-9-LN'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidinolnonane (f ) I- ~N' -cyano-N"- ~2--(2-pyridylmethylthio)ethyl)guanidin~
9-LN' -cyano-N"`-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino~ nonane (g) l-~N' -cyano-N"- (2--(3-methyl-2-pyridylmethylthio)ethyl)-guanidino~-9-~N' -cyano-N"-(2-(5-methyl-4-imidazolylmethyl-thio)ethyl)guanidino.~ nonane (h) 1- LN' -cyano-N"- ~2 (3-methoxy-2-pyridylmethylthio~ethyl-guanidino~ -9-L~' -cyano-N"-(2-(5-methyl-4-imidazolylmethyl-3 thio)ethyl)guanidino~nonane (i) 1- ~N' -cyano-N"- l2 (3-~ ro-2-pyridylmethylthio)ethyl)-guanidino~l -9- ~' -cyano-N"~-(2-(5-methyl-4-imidazolylmethyl-thio)ethyl)guanidino~ nonane (j ) l-l;N' -cyano-N"-(2 (3-amino-2- pyridylmethylthio)ethyl)-guanidino~-9- rN' -cyano-N"-(2-(5-methyl-4-imidazolylmethyl-thio)ethyl)guanidino~nonane :.
i (k) l-LN'-cyano-N"-(2 (3-hydroxy-2-pyridylmethylthio)ethyl)-guanidino~-9- LN'-cyano-N"-(2-(5-methyl-4-imidazolylmethyl-thio)ethyl)guanidino~nonane (1) 1-~N'-cyano-N"-(2 (3-isothiazolylmethylthio)ethyl)-guanidino~-9-~N'-cyano-N"-(2-(5-methyl-4-imidazolylmethyl-thio)ethyl)guanidino~nonane (m) 1- ~N'-cyano-N"-~2 - (4-bromo-3-isothiazolylmethylthio)-ethyl)guanidino~-9-~N'-cyano-N"-(2-(5-methyl-4-imidazolyl-methylthio)ethyl)guanidinoJnonane (n) 1-~N'-cyano-N"-(2 - (3-(1,2,5)-thiadiazolylmethylthio)-ethyl)guanidino]-9- ~'-cyano-N"-(2-(5-methyl-4-imidazolyl-methylthio)ethyl)guanidino~nonane (o) l-~N'-cyano-N"-(2 (4-chloro-3-(1,2,5)-thiadiazolyl-methylthio)ethyl)guanidino]-9-LN'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino~nonane (p) l-~N'-cyano-N"-~2 (5-amino-2-(1,3,4)-thiadiazolyl-methylthio)ethyl)guanidino~-9-G~'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino~nonane and acid hydrolysis gives the corresponding N,N'-substituted guanidine derivatives~
Treatment of the above amines with benzoyl isothiocyanate and hydrolysis of the products gives the corresponding thioureas, which, when substituted for N-~2-(5-methyl-4-imidazolylmethylthio)ethy~ thiourea in the procedure of Example 1, can be converted into bis-guanidinodecanes.
(i) Reaction of 2-chloro-3-nitropyridine with 2-(2~
cyanoethyl)malonic acid diethyl ester and sodium hydride in tetrahydrofuran gives l-(3-nitro-2-pyridyl)-l,l-bis-(carbethoxy)butyronitrile, m.p.
93 5-94.5, which after alkaline hydrolysis and acidificatiQn gives 2-(3-cyanopropyl)-3-nltropyridine hydrochloride 142-145.5. Reduction with hydrogen .
, .:, . .: .
: .. : : - -, ; .
.. , . . ~ . " .
1(~703~S
_ and palladium on charcoal gives 3-amino-2-(3-cyanopropyl)pyridine, and treatment of this with sodium nitrite and sulphuric acid and subsequent warming gives 2-(3-cyanopropyl)-3-hydroxypyridine.
Methylation with methyl iodide and sodium ethoxide in dimethylsulphoxide and subsequent reduction with lithium aluminium hydride gives 4-(3-methoxy-2-pyridyl)butylamine! Reduction o~ 3-amino-2-(3-cyanopropyl)-3-hydroxypyridine with lithium aluminium hydride gives 4-(3-amino-2-pyridyl~-butylamine. Diazotisation of 4-(3-amino-2-pyridyl) butylamine at pH 1 and treatment with cuprous chloride or cuprous bromide gives 4-(3-chloro-2-pyridyl)butylamine and 4-(3-bromo-2-pyridyl)-butylamine, respectively.
(ii) Substitution of (a) 4-~4-imidazolyl)butylamine (b) 4-(3-methoxy-2-pyridyl)-butylamine (c) 4-(3-chloro-2-pyridyl)-2~ bu,tylamine (d) 4-(3-bromo-2-pyridyl)butylamine (e) 4-(3-amino-2-pyridyl)butylamine for 2-(2-thiazolylmethylthio)ethylamine in the procedure of Example 7 (c) gives:-(a) 1-¦N'-cyano-N"-(4-(4-imidazolyl)butyl)guanidino~-9-LN'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)-ethyl)guanidino~nonane.
(b) 1- CN -cyano-N~-(4-(3-methoxy-2-pyridyl)bUtY1)-guanidino~-9-¦N'-cyano-N"-(2-(5-methyl-4-imidazolyl-methylthio)ethyl)gu~nidino~nonane, -(c) l-~N'-cy~no-N"-(4-(3-chloro-2-pyridyl)butyl)-guanidino~-9-~N'-cyano-N"-(2-(5-methyl-4-imidazolyl-methylthio)ethyl)guanidino~nonane.
(d) 1- ~N' -cyano-N"-(4-(3-bromo-2-pyridyl)butyl)-guanidino~-9-LN'-cyano-N"-(2-(5-methyl-4-imidazolyl-methylthio)ethyl)guanidinolnonane.
(d) l-LN'-cyano-N"-(4-(3-amino-2-pyridyl)butyl)-guanidino]-9-~N'-cyano-N"-(2-C5-methyl-4-imidazolylmethylthio)ethyl)guanidino~nonane.
and acid hydrolysis gives the corresponding N,N'- .*
substituted guanidine derivatives.
Treatment of the above amines with benzoyl iso-thiocyanate and hydrolysis of the products gives the corresponding thioureas, which, when substituted ~or N-~2-(5-methyl-4 imidazolylmethylthio)ethyll-thiourea in the procedure of Example 1, can be converted into bis-guanldinodecanes.
Substitution of (a) 2-(2-(4-imidazolyl)ethylthio)-ethylamine (b) 3-(4-imidazolylmethylthio)-propylamine (c) 3-(2-thiazolyl)propylamine ~or 2-(2-thiazolylmethylthio)ethylamine in the procedure o~ Example 7(c) gives:-(a) l-LN'-cyano-N"-(2-(2-(4-imidazolyl)ethylthio)ethyl)-guanidino~-9-tN'-cyano-N"-(2-(5-methy1-4-imidazolyl-methylthio)ethyl)guanidino3nonane (b) 1-[N'-cyano-N"-(3-(4-imidazolylmethylthio)propyl)-guanidino~ -9-[N'-cyano-N"-(2-(5-methyl-4-imidazolyl-methylthio)ethyl)guanidino~nonane.
(c) l-[N'-cyano-N"-(3-(2-thiazolyl)propyl)guanidino~- 9 N'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)-ethyl)guanidin~ nonane and acid hydrolysis o~ the ~ormer two Products gives the corresponding N,N'-substituted guanidine derivatives.
- 10703~5 N-L2-(5-Methyl-4-imidazolylmethylthio)ethyl~thiourea hydrobromide is refluxed with l,9-dibromononane in ethanol to give l,9-bis-C~(N-(2-(5-methyl-4-imidazolylmethylthio)ethyl))isothioureido] nonane tetrahydrobromide.
EXA~PLE 11 Treatment of l,9-bis LN -cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino~nonane with dilute hydrochloric acid at 40 gives l,9-bis-~N'-carbamPyl-N"-(2-(5-methyl-4-imidazolylmethylthio)-ethyl)guanidino~nonane.
1-) Dry hydrogen chlorid~e is bubbled through a solu~i on of l,9-bis-LN'-(2-(5-methyl-4-imidazolylmethylthio)-ethyl)thioureido~nonane in methanol at 80 for 12 hours and the solvent is removed to gi~e l,9-bis Ls-methyl-N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)- .
isothioureido]nonane tetrahydrochloride.
2) This product is treated with (a) hydroxylamine hydro-chloride and potassium bicar~onate in dry dimethyl-formamide or (b) methylamine in ethanol, to give (a)-l,9-bis-~N'-hydroxy-N"-(2-(5-methyl-4-imidazolyl-methylthio)ethyl)guanidinolnonane, or (b) 1,9-bis[N'-methyl-N"-(2-(5-methyl-4-imidazolyl-methylthio)ethyl)guanidino~nonane N-Cyano-N'-L2-((5-methyl-4-imidazolylmethylthio)ethyl~-S-methylisothiourea is added to an excess of l,9-diamino-nonane, and the mixture was stirred at room te~erature for 15 hours, and extracted with ether. The residue is purified by chromatOgraphy on silica gel, eluting with 3~
. - 21 -.- lC~7~315 1 isopropanol to glve N-cyano-N'-(9-amlnononyl)-N"-~2-(5-methyl-4-lmldazolylmethylthio)ethyl~guanidine.
This aminoncnyl guanidine is re~luxed in isopropanol with (a) S-methyl-N'-~2-(5-methyl-4-lmldazolylmethylthlo)-ethyl~-thiourea hydroiodide .`
(b) S-methyl-N'- ~2-(2-thiazolylmethylthio)ethyll- :
thiourea hydroiodide (c) l-nitro-2-methylthio-2-L2-((5~methyl-4~imidazolyl)-methylthio)ethylamino~ethylene 0 (d) S-methyl-N-L2-((5-methyl-4-imidazolyl)methylthio)-ethyl~dithiocarbamate to give (a) l-~N'-cyano-N"-(2-(5-methyl-4-imidazolylmethyl-thio)ethyl)guanidino~-9-LN'-~2-(5-methyl-4-imidazolylmethylthio)ethyl~-guanidino~nonane.
(b) l-~N'-cyano-N"-(2-~5-methyl-4-imidazolylmethyl-thio)ethyl)guanidino~- 9-LN'-~2-(2-thiazolyl-methylthio)ethy~ guanidinolnonane (c) l-¦N'-cyano-N"-L2-(5-methyl-4-imidazolylmethylthio)-ethyl3guanidino]-9-~1-(2-(5-methyl-4-imidazolyl-methylthio)ethylamino.)-2-nitrovinyl-1-amino~nonane (d) l-~N'-cyano-N"-[2-(5-methyl-4-imidazolylmethylthio)-ethyl~ guanidinol-9-LN'-(2-(.5-methyl-4-imidazolyl-methylthio)ethyl)thioureido~nonane and hydrolysis of these products gives (a) 1,9-bis- LN (2-(5-methyl-4-imidazolylmethylthio)-ethyl)guanidino~nonane (b) l-~N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino~-9-[N'-(2-(2-thiazolylmethylthio)ethyl)-guanidino~nonane (c) 1-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino~-9-~1-(2-(5-methyl-4-imidazolylmethylthio)-. ethylamino)-2-nitrovinyl-1-amino]nonane (d) 1- LN -(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino~-9-~N'-(2-(5-methyl-4-imidazolylmethylthio)-3S ethyl)thioureidolnonane ;,, " ,,,. ~.,. , " " ",, . "... .. ................. ....... . . ..... ...
' 107~3~5 . - EXAMPLE 14 Ingredients Amounts l"9-bis- CN (2-(5-methY1-4-imidaZO1Y1 methylthio)ethyl)guanidino~nonane dihydrochloride 150 mg Sucrose 75 mg Starch 25 mg Talc 5 mg Stearic Acid 2 mg The ingredients are screened, mixed and filled into a hard gelatin capsule.
EXA~PLE 15 By dissolving 50 mg of l,9-bis- LN ( 2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino~ nonane di-hydrochloride in 2 ml Qf sterile water, normal saline or buffered saline, a pharmaceutical composition suitable for parenteral administration is prepared.
Similarly, the other compounds of Formula 1 may be formulated into pharmace.utical compositions by the procedures of Examples 14 and 15. These pharmaceutical compositions are administered to a subject within the dose ranges given hereabove to block histamine H2-receptors.
-.
9-LN' -cyano-N"`-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino~ nonane (g) l-~N' -cyano-N"- (2--(3-methyl-2-pyridylmethylthio)ethyl)-guanidino~-9-~N' -cyano-N"-(2-(5-methyl-4-imidazolylmethyl-thio)ethyl)guanidino.~ nonane (h) 1- LN' -cyano-N"- ~2 (3-methoxy-2-pyridylmethylthio~ethyl-guanidino~ -9-L~' -cyano-N"-(2-(5-methyl-4-imidazolylmethyl-3 thio)ethyl)guanidino~nonane (i) 1- ~N' -cyano-N"- l2 (3-~ ro-2-pyridylmethylthio)ethyl)-guanidino~l -9- ~' -cyano-N"~-(2-(5-methyl-4-imidazolylmethyl-thio)ethyl)guanidino~ nonane (j ) l-l;N' -cyano-N"-(2 (3-amino-2- pyridylmethylthio)ethyl)-guanidino~-9- rN' -cyano-N"-(2-(5-methyl-4-imidazolylmethyl-thio)ethyl)guanidino~nonane :.
i (k) l-LN'-cyano-N"-(2 (3-hydroxy-2-pyridylmethylthio)ethyl)-guanidino~-9- LN'-cyano-N"-(2-(5-methyl-4-imidazolylmethyl-thio)ethyl)guanidino~nonane (1) 1-~N'-cyano-N"-(2 (3-isothiazolylmethylthio)ethyl)-guanidino~-9-~N'-cyano-N"-(2-(5-methyl-4-imidazolylmethyl-thio)ethyl)guanidino~nonane (m) 1- ~N'-cyano-N"-~2 - (4-bromo-3-isothiazolylmethylthio)-ethyl)guanidino~-9-~N'-cyano-N"-(2-(5-methyl-4-imidazolyl-methylthio)ethyl)guanidinoJnonane (n) 1-~N'-cyano-N"-(2 - (3-(1,2,5)-thiadiazolylmethylthio)-ethyl)guanidino]-9- ~'-cyano-N"-(2-(5-methyl-4-imidazolyl-methylthio)ethyl)guanidino~nonane (o) l-~N'-cyano-N"-(2 (4-chloro-3-(1,2,5)-thiadiazolyl-methylthio)ethyl)guanidino]-9-LN'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino~nonane (p) l-~N'-cyano-N"-~2 (5-amino-2-(1,3,4)-thiadiazolyl-methylthio)ethyl)guanidino~-9-G~'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino~nonane and acid hydrolysis gives the corresponding N,N'-substituted guanidine derivatives~
Treatment of the above amines with benzoyl isothiocyanate and hydrolysis of the products gives the corresponding thioureas, which, when substituted for N-~2-(5-methyl-4-imidazolylmethylthio)ethy~ thiourea in the procedure of Example 1, can be converted into bis-guanidinodecanes.
(i) Reaction of 2-chloro-3-nitropyridine with 2-(2~
cyanoethyl)malonic acid diethyl ester and sodium hydride in tetrahydrofuran gives l-(3-nitro-2-pyridyl)-l,l-bis-(carbethoxy)butyronitrile, m.p.
93 5-94.5, which after alkaline hydrolysis and acidificatiQn gives 2-(3-cyanopropyl)-3-nltropyridine hydrochloride 142-145.5. Reduction with hydrogen .
, .:, . .: .
: .. : : - -, ; .
.. , . . ~ . " .
1(~703~S
_ and palladium on charcoal gives 3-amino-2-(3-cyanopropyl)pyridine, and treatment of this with sodium nitrite and sulphuric acid and subsequent warming gives 2-(3-cyanopropyl)-3-hydroxypyridine.
Methylation with methyl iodide and sodium ethoxide in dimethylsulphoxide and subsequent reduction with lithium aluminium hydride gives 4-(3-methoxy-2-pyridyl)butylamine! Reduction o~ 3-amino-2-(3-cyanopropyl)-3-hydroxypyridine with lithium aluminium hydride gives 4-(3-amino-2-pyridyl~-butylamine. Diazotisation of 4-(3-amino-2-pyridyl) butylamine at pH 1 and treatment with cuprous chloride or cuprous bromide gives 4-(3-chloro-2-pyridyl)butylamine and 4-(3-bromo-2-pyridyl)-butylamine, respectively.
(ii) Substitution of (a) 4-~4-imidazolyl)butylamine (b) 4-(3-methoxy-2-pyridyl)-butylamine (c) 4-(3-chloro-2-pyridyl)-2~ bu,tylamine (d) 4-(3-bromo-2-pyridyl)butylamine (e) 4-(3-amino-2-pyridyl)butylamine for 2-(2-thiazolylmethylthio)ethylamine in the procedure of Example 7 (c) gives:-(a) 1-¦N'-cyano-N"-(4-(4-imidazolyl)butyl)guanidino~-9-LN'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)-ethyl)guanidino~nonane.
(b) 1- CN -cyano-N~-(4-(3-methoxy-2-pyridyl)bUtY1)-guanidino~-9-¦N'-cyano-N"-(2-(5-methyl-4-imidazolyl-methylthio)ethyl)gu~nidino~nonane, -(c) l-~N'-cy~no-N"-(4-(3-chloro-2-pyridyl)butyl)-guanidino~-9-~N'-cyano-N"-(2-(5-methyl-4-imidazolyl-methylthio)ethyl)guanidino~nonane.
(d) 1- ~N' -cyano-N"-(4-(3-bromo-2-pyridyl)butyl)-guanidino~-9-LN'-cyano-N"-(2-(5-methyl-4-imidazolyl-methylthio)ethyl)guanidinolnonane.
(d) l-LN'-cyano-N"-(4-(3-amino-2-pyridyl)butyl)-guanidino]-9-~N'-cyano-N"-(2-C5-methyl-4-imidazolylmethylthio)ethyl)guanidino~nonane.
and acid hydrolysis gives the corresponding N,N'- .*
substituted guanidine derivatives.
Treatment of the above amines with benzoyl iso-thiocyanate and hydrolysis of the products gives the corresponding thioureas, which, when substituted ~or N-~2-(5-methyl-4 imidazolylmethylthio)ethyll-thiourea in the procedure of Example 1, can be converted into bis-guanldinodecanes.
Substitution of (a) 2-(2-(4-imidazolyl)ethylthio)-ethylamine (b) 3-(4-imidazolylmethylthio)-propylamine (c) 3-(2-thiazolyl)propylamine ~or 2-(2-thiazolylmethylthio)ethylamine in the procedure o~ Example 7(c) gives:-(a) l-LN'-cyano-N"-(2-(2-(4-imidazolyl)ethylthio)ethyl)-guanidino~-9-tN'-cyano-N"-(2-(5-methy1-4-imidazolyl-methylthio)ethyl)guanidino3nonane (b) 1-[N'-cyano-N"-(3-(4-imidazolylmethylthio)propyl)-guanidino~ -9-[N'-cyano-N"-(2-(5-methyl-4-imidazolyl-methylthio)ethyl)guanidino~nonane.
(c) l-[N'-cyano-N"-(3-(2-thiazolyl)propyl)guanidino~- 9 N'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)-ethyl)guanidin~ nonane and acid hydrolysis o~ the ~ormer two Products gives the corresponding N,N'-substituted guanidine derivatives.
- 10703~5 N-L2-(5-Methyl-4-imidazolylmethylthio)ethyl~thiourea hydrobromide is refluxed with l,9-dibromononane in ethanol to give l,9-bis-C~(N-(2-(5-methyl-4-imidazolylmethylthio)ethyl))isothioureido] nonane tetrahydrobromide.
EXA~PLE 11 Treatment of l,9-bis LN -cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino~nonane with dilute hydrochloric acid at 40 gives l,9-bis-~N'-carbamPyl-N"-(2-(5-methyl-4-imidazolylmethylthio)-ethyl)guanidino~nonane.
1-) Dry hydrogen chlorid~e is bubbled through a solu~i on of l,9-bis-LN'-(2-(5-methyl-4-imidazolylmethylthio)-ethyl)thioureido~nonane in methanol at 80 for 12 hours and the solvent is removed to gi~e l,9-bis Ls-methyl-N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)- .
isothioureido]nonane tetrahydrochloride.
2) This product is treated with (a) hydroxylamine hydro-chloride and potassium bicar~onate in dry dimethyl-formamide or (b) methylamine in ethanol, to give (a)-l,9-bis-~N'-hydroxy-N"-(2-(5-methyl-4-imidazolyl-methylthio)ethyl)guanidinolnonane, or (b) 1,9-bis[N'-methyl-N"-(2-(5-methyl-4-imidazolyl-methylthio)ethyl)guanidino~nonane N-Cyano-N'-L2-((5-methyl-4-imidazolylmethylthio)ethyl~-S-methylisothiourea is added to an excess of l,9-diamino-nonane, and the mixture was stirred at room te~erature for 15 hours, and extracted with ether. The residue is purified by chromatOgraphy on silica gel, eluting with 3~
. - 21 -.- lC~7~315 1 isopropanol to glve N-cyano-N'-(9-amlnononyl)-N"-~2-(5-methyl-4-lmldazolylmethylthio)ethyl~guanidine.
This aminoncnyl guanidine is re~luxed in isopropanol with (a) S-methyl-N'-~2-(5-methyl-4-lmldazolylmethylthlo)-ethyl~-thiourea hydroiodide .`
(b) S-methyl-N'- ~2-(2-thiazolylmethylthio)ethyll- :
thiourea hydroiodide (c) l-nitro-2-methylthio-2-L2-((5~methyl-4~imidazolyl)-methylthio)ethylamino~ethylene 0 (d) S-methyl-N-L2-((5-methyl-4-imidazolyl)methylthio)-ethyl~dithiocarbamate to give (a) l-~N'-cyano-N"-(2-(5-methyl-4-imidazolylmethyl-thio)ethyl)guanidino~-9-LN'-~2-(5-methyl-4-imidazolylmethylthio)ethyl~-guanidino~nonane.
(b) l-~N'-cyano-N"-(2-~5-methyl-4-imidazolylmethyl-thio)ethyl)guanidino~- 9-LN'-~2-(2-thiazolyl-methylthio)ethy~ guanidinolnonane (c) l-¦N'-cyano-N"-L2-(5-methyl-4-imidazolylmethylthio)-ethyl3guanidino]-9-~1-(2-(5-methyl-4-imidazolyl-methylthio)ethylamino.)-2-nitrovinyl-1-amino~nonane (d) l-~N'-cyano-N"-[2-(5-methyl-4-imidazolylmethylthio)-ethyl~ guanidinol-9-LN'-(2-(.5-methyl-4-imidazolyl-methylthio)ethyl)thioureido~nonane and hydrolysis of these products gives (a) 1,9-bis- LN (2-(5-methyl-4-imidazolylmethylthio)-ethyl)guanidino~nonane (b) l-~N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino~-9-[N'-(2-(2-thiazolylmethylthio)ethyl)-guanidino~nonane (c) 1-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino~-9-~1-(2-(5-methyl-4-imidazolylmethylthio)-. ethylamino)-2-nitrovinyl-1-amino]nonane (d) 1- LN -(2-(5-methyl-4-imidazolylmethylthio)ethyl)-guanidino~-9-~N'-(2-(5-methyl-4-imidazolylmethylthio)-3S ethyl)thioureidolnonane ;,, " ,,,. ~.,. , " " ",, . "... .. ................. ....... . . ..... ...
' 107~3~5 . - EXAMPLE 14 Ingredients Amounts l"9-bis- CN (2-(5-methY1-4-imidaZO1Y1 methylthio)ethyl)guanidino~nonane dihydrochloride 150 mg Sucrose 75 mg Starch 25 mg Talc 5 mg Stearic Acid 2 mg The ingredients are screened, mixed and filled into a hard gelatin capsule.
EXA~PLE 15 By dissolving 50 mg of l,9-bis- LN ( 2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino~ nonane di-hydrochloride in 2 ml Qf sterile water, normal saline or buffered saline, a pharmaceutical composition suitable for parenteral administration is prepared.
Similarly, the other compounds of Formula 1 may be formulated into pharmace.utical compositions by the procedures of Examples 14 and 15. These pharmaceutical compositions are administered to a subject within the dose ranges given hereabove to block histamine H2-receptors.
-.
Claims (30)
1. A process for the production of a compound of the Formula 1 Formula 1 wherein X3 and X4 which may be the same or different, are NY wherein Y
is hydrogen, lower alkyl or cyano; R3 and R4, which may be the same or different, each represents a grouping of the structure:
Het-(CH2)mZ(CH2)n-wherein Het is 4-imidazolyl, or a 4-imidazolyl ring substituted by lower alkyl, or is 2-thiazolyl; Z is sulphur; m is 1 and n is 2; and W is NH, and when X3 and X4 are both NH, W may also be sulphur and p is an integer from 9 to 12 or a pharmaceutically acceptable acid addition salt thereof, which comprises the step of:
(a) treating a compound of the formula R3NHE, where E is hydro-gen or , (where A is lower alkyl, X5 is X3 or -NY' where Y' is a guanidine protecting group selected from benzoyl, benzyloxycarbonyl and ethoxycarbonyl) with a compound of the formula GNHR4, where G is when E is hydrogen, and G is when E
is , (where A and X5 are as defined above and X6 is X4 or NY' where Y' is as defined above) to eliminate a mercaptan of formula ASH, and when X5 or X6 is NY', removing the guanidine protecting group to give the compounds where X3 or X4 is NH;
and where at least one of X3 and X4 is NCN, subjecting the com-pound so formed to acid hydrolysis, thereby to provide a compound in which at least one of X3 and X4 is NH.
is hydrogen, lower alkyl or cyano; R3 and R4, which may be the same or different, each represents a grouping of the structure:
Het-(CH2)mZ(CH2)n-wherein Het is 4-imidazolyl, or a 4-imidazolyl ring substituted by lower alkyl, or is 2-thiazolyl; Z is sulphur; m is 1 and n is 2; and W is NH, and when X3 and X4 are both NH, W may also be sulphur and p is an integer from 9 to 12 or a pharmaceutically acceptable acid addition salt thereof, which comprises the step of:
(a) treating a compound of the formula R3NHE, where E is hydro-gen or , (where A is lower alkyl, X5 is X3 or -NY' where Y' is a guanidine protecting group selected from benzoyl, benzyloxycarbonyl and ethoxycarbonyl) with a compound of the formula GNHR4, where G is when E is hydrogen, and G is when E
is , (where A and X5 are as defined above and X6 is X4 or NY' where Y' is as defined above) to eliminate a mercaptan of formula ASH, and when X5 or X6 is NY', removing the guanidine protecting group to give the compounds where X3 or X4 is NH;
and where at least one of X3 and X4 is NCN, subjecting the com-pound so formed to acid hydrolysis, thereby to provide a compound in which at least one of X3 and X4 is NH.
2. A process according to claim 1 wherein a compound of Formula 1, wherein X3 is NH, is prepared by the acid hydrolysis of a compound of Formula 1 wherein X3 is NCN.
3. A process according to claim 1 wherein a compound of For-mula 1 wherein X4 is NH is prepared by the acid hydrolysis of a compound of Formula 1 wherein X4 is NCN.
4. A process according to claim 1 wherein W is sulphur and X3 and X4 are both NH, which comprises treating a compound of the formula Hal-(CH2)p-Hal, where Hal is chlorine, bromine or iodine, with a thio-urea of formula R3NHCSNH2 or, when R3 is not the same as R4, successively treating with thioureas of formulas R3NHCSNH2 and R4NHCSNH2.
5. A process according to claim 1 wherein W is NH and X3 and X4 are both =NH (where Y is hydroxy or lower alkyl), which comprises treat-ing an isothiourea of formula SA SA
R3NH-C=N(CH2)pN=C-NHR4 (where A is lower alkyl) with a compound of formula YNH2 where Y is hydroxy or lower alkyl.
R3NH-C=N(CH2)pN=C-NHR4 (where A is lower alkyl) with a compound of formula YNH2 where Y is hydroxy or lower alkyl.
6. A process of claim 1 wherein R3 and R4 are the same.
7. A process according to claim 1 wherein R3 is Het-Ch2S(CH2)2-.
8. A process according to claim 1 wherein Het is a 4-imidozolyl ring substituted by methyl.
9. A process according to claim 1 wherein X3 or X4 is NH.
10. A process according to claim 1 wherein X3 and X4 are both NH.
11. A process according to claim 1 wherein p is 9 or 10.
12. A process according to calim 1 which comprises treating 1,9-nonane with 5-methyl-N-[2-(5-methyl-4-imidazolylmethylthio)-ethyl]-isothiouronium iodide, thereby to form 1,9-bis-[N'(]-(5-methyl-4-imidaz-olylmethylthio)ethyl)guanidino]nonane.
13. A process according to claim 1 which comprises treating 1,10-diaminodecane with S-methyl-N-[2-(5-methyl-4-imidozolylmethylthio)-ethyl]isothiouronium iodide, thereby to form 1,10-bis-[N'-)])5-methyl-4-imidazolylmethylthio)ethyl)guanidino decane.
14. A process according to claim 1 which comprises treating 1,12-diaminododecane with S-methyl-N-[2-(5-methyl-4-imidazolylmethyl-thio)ethyl]isothiouronium iodide, thereby to form 1,12-bis-[N'-(2(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]dodecane.
15. A process according to claim 1 which comprises treating 1,10-diaminodecane with S-methyl-N-cyano-N'-(2-thiazolylmethylthio)-ethyl-isothiourea and refluxing the so-formed product with hydrochloric acid, thereby to form 1,10-bis-[N'-(2-(2-thiazolymethylthio)ethyl)-guanidino]decane.
16. A compound of the formula wherein X3 and X4, which may be the same or different, are NY wherein Y
is hydrogen, lower alkyl or cyano; R3 and R4, which may be the same or different, each represents a grouping of the structure Het-(CH2)mZ(CH2)n-wherein Het is 4-imidazolyl, or a 4-imidazolyl ring substituted by lower alkyl or is 2-thiazolyl; Z is sulphur; m is 1 and n is 2; W is NH, and when X3 and X4 are both NH, W may also be sulphur; and p is an integer from 9 to 12; or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process of claim 1 or by its obvious chemical equivalent.
is hydrogen, lower alkyl or cyano; R3 and R4, which may be the same or different, each represents a grouping of the structure Het-(CH2)mZ(CH2)n-wherein Het is 4-imidazolyl, or a 4-imidazolyl ring substituted by lower alkyl or is 2-thiazolyl; Z is sulphur; m is 1 and n is 2; W is NH, and when X3 and X4 are both NH, W may also be sulphur; and p is an integer from 9 to 12; or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process of claim 1 or by its obvious chemical equivalent.
17. A compound of claim 16 wherein X3 is NH,whenever prepared by the process of claim 2 or by its obvious chemical equivalent.
18. A compound of claim 16 wherein X4 is NH, whenever prepared by the process of claim 3 or by its obvious chemical equivalent.
19. A compound of claim 16 wherein W is sulphur and X3 and X4 are both NH, whenever prepared by the process of claim 4 or by its obvious chemical equivalent.
20. A compound of claim 16 wherein W is NH and X3 and X4 are both =NY (where Y is hydroxy or lower alkyl), whenever prepared by the process of claim 5 or by its obvious chemical equivalent.
21. A compound of claim 16 wherein R3 and R4 are the same, whenever prepared by the process of claim 6 or by its obvious chemical equivalent.
22. A compound according to claim 16 wherein R3 is Het-CH2S(CH2)2-, whenever prepared by the process of claim 7 or by its obvious chemical equivalent.
23. A compound according to claim 16 wherein Het is a 4-imidazolyl ring substituted by methyl, whenever prepared by the pro-cess of claim 8 or by its obvious chemical equivalent.
24. A compound according to claim 16 wherein X3 or X4 is NH, whenever prepared by the process of claim 9 or by its obvious chemical equivalent.
25. A compound according to claim 16 wherein X3 and X4 are both NH, whenever prepared by the process of claim 10 or by its obvious chemical equivalent.
26. A compound according to claim 16 wherein p is 9 or 10, when-ever prepared by the process of claim 11 or by its obvious chemical equivalent.
27. A compound of claim 16, 1,9-bis-[N'(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]nonane, whenever prepared by the process of claim 12 or by its obvious chemical equivalent.
28. A compound of claim 16, 1,10-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]decane, whenever prepared by the process of claim 13 or by its obvious chemical equivalent.
29. A compound of claim 16, 1,12-bis-[N'-2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]dodecane, whenever prepared by the process of claim 14 or by its obvious chemical equivalent.
30. A compound of claim 16, 1,10-bis-[N'-(2-(2-thiazolylmethyl-thio)ethyl-guanidino]decane, whenever prepared by the process of claim 15 or by its obvious chemical equivalent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB3139176 | 1976-07-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1070315A true CA1070315A (en) | 1980-01-22 |
Family
ID=10322405
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA283,619A Expired CA1070315A (en) | 1976-07-28 | 1977-07-27 | Process for the preparation of bis(heteroarylmethylthioethylguanidino) alkanes and the bis(heteroarylmethylthioethylguanidino) alkanes so formed |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS5315370A (en) |
| AU (1) | AU2734677A (en) |
| BE (1) | BE857218A (en) |
| CA (1) | CA1070315A (en) |
| DE (1) | DE2733953A1 (en) |
| DK (1) | DK331877A (en) |
| ES (1) | ES461100A2 (en) |
| FI (1) | FI772293A (en) |
| FR (1) | FR2359840A1 (en) |
| IL (1) | IL52544A0 (en) |
| LU (1) | LU77845A1 (en) |
| NL (1) | NL7708375A (en) |
| NO (1) | NO772668L (en) |
| PL (1) | PL107847B1 (en) |
| ZA (1) | ZA774552B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4309435A (en) | 1978-10-16 | 1982-01-05 | Imperial Chemical Industries Ltd. | Antisecretory guanidine derivatives and pharmaceutical compositions containing them |
| FR2446829A1 (en) | 1978-11-16 | 1980-08-14 | Glaxo Group Ltd | POLYMETHYLENE DERIVATIVES DISUBSTITUTED IN ALPHA, OMEGA, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| JPS57102852A (en) * | 1980-12-19 | 1982-06-26 | Shionogi & Co Ltd | Dicarboxylic acid diamide |
| EP4196793A1 (en) | 2020-08-11 | 2023-06-21 | Université de Strasbourg | H2 blockers targeting liver macrophages for the prevention and treatment of liver disease and cancer |
-
1977
- 1977-07-18 IL IL52544A patent/IL52544A0/en unknown
- 1977-07-22 DK DK331877A patent/DK331877A/en not_active Application Discontinuation
- 1977-07-26 AU AU27346/77A patent/AU2734677A/en active Pending
- 1977-07-26 LU LU77845A patent/LU77845A1/xx unknown
- 1977-07-27 FR FR7723079A patent/FR2359840A1/en not_active Withdrawn
- 1977-07-27 BE BE179687A patent/BE857218A/en unknown
- 1977-07-27 ZA ZA00774552A patent/ZA774552B/en unknown
- 1977-07-27 NO NO772668A patent/NO772668L/en unknown
- 1977-07-27 CA CA283,619A patent/CA1070315A/en not_active Expired
- 1977-07-27 FI FI772293A patent/FI772293A/fi not_active Application Discontinuation
- 1977-07-27 DE DE19772733953 patent/DE2733953A1/en not_active Withdrawn
- 1977-07-28 PL PL1977199908A patent/PL107847B1/en unknown
- 1977-07-28 NL NL7708375A patent/NL7708375A/en not_active Application Discontinuation
- 1977-07-28 ES ES461100A patent/ES461100A2/en not_active Expired
- 1977-07-28 JP JP9132477A patent/JPS5315370A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| LU77845A1 (en) | 1977-10-25 |
| JPS5315370A (en) | 1978-02-13 |
| DK331877A (en) | 1978-01-29 |
| PL199908A1 (en) | 1978-11-20 |
| NO772668L (en) | 1978-01-31 |
| FR2359840A1 (en) | 1978-02-24 |
| NL7708375A (en) | 1978-01-31 |
| IL52544A0 (en) | 1977-10-31 |
| ZA774552B (en) | 1978-06-28 |
| DE2733953A1 (en) | 1978-02-02 |
| ES461100A2 (en) | 1978-12-01 |
| PL107847B1 (en) | 1980-03-31 |
| BE857218A (en) | 1978-01-27 |
| AU2734677A (en) | 1979-02-01 |
| FI772293A (en) | 1978-01-29 |
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