The compounds are C2 -C8 straight chain alkanes terminally substituted, symmetrically or unsymmetrically, by N-(N'-substituted guanidino), N-(N', N"-disubstituted guanidino), N-(N'-substituted thiouredo), N-(nitromethylene amidino) or S-(N-substituted isothioureido) groups. Two compounds of the invention are 1,3-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]propane and 1,3-bis-[S-(N-2-(5-methyl-4-imidazolylmethylthio)ethyl)isothioureido]p ropane. The compounds of this invention are inhibitors of H-2 histamine receptors.
|
1. A compound of the formula: ##STR18## wherein R1 and R2, which may be the same or different, each represent a grouping of the structure:
Het -- (CH2)m Z -- (CH2)n -- wherein Het is imidazole which is attached at a ring carbon and which is optionally substituted by lower alkyl or halogen; Z is sulphur or a methylene group; m is 0, 1 or 2; n is 2 or 3 and the sum of m and n is 3 , or 4 or when the adjoining X1 or X2 is sulphur, 2; X1 and X2, which may be the same or different, are each sulphur or NY wherein Y is hydrogen or lower alkyl; W is NH, and when X1 and X2 are NH, W may also be sulphur; and q is an integer from 2 to 8; or a pharmaceutically acceptable acid addition salt thereof. 3. A compound according to
6. A compound according to
11. A compound according to
12. A compound according to
13. A compound according to
14. A compound according to
15. A compound according to
16. A pharmaceutical composition to inhibit H-2-histamine receptors, said H-2 -histamine receptors, said H-2 histamine receptors being those histamine receptors which are not inhibited by mepyramine but are inhibited by burimamide, comprising, in an effective amount to inhibit H-2 histamine receptors, a compounds of
17. A method of inhibiting H-2 histamine receptors, said H-2 histamine receptors being those histamine receptors which are not inhibited by mepyramine but are inhibited by burimamide, which comprises administering to an animal in need of inhibition of said H-2 histamine receptors in an effective amount to inhibit said H-2 histamine receptors a compound of
18. A compound according to
19. A compound according to
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This invention relates to new compounds having pharmacological activity. These compounds are inhibitors of H-2 histamine receptors. In addition, this invention relates to pharmaceutical compositions comprising these compounds and to methods of inhibiting H-2 histamine receptors by administering these compounds. The compounds of this invention can exist as the addition salts but, for convenience, reference will be made throughout this specification to the parent compounds.
Many of the physiologically active substances within the animal body, in the course of their activity, combine with certain specific sites known as receptors. Histamine is a compound which is believed to act in this way, but since the actions of histamine fall into more than one type, it is believed that there is more than one type of histamine receptor. The receptors involved in the type of action of histamine which is blocked by drugs commonly called "antihistamines", of which mepyramine is a typical example, have been designated as H-1 histamine receptors (Ash and Schild, Brit. J. Pharmac. Chemother. 27. 427. (1966)). The receptors involved in the type of action of histamine which is not blocked by "antihistamines" such as mepyramine have been designated as H-2 histamine receptors and burimamide has been defined as an H-2 histamine receptor inhibitor Black et al. Nature 236, 385 (1972)). Thus, H-2 histamine receptors may be defined as those histamine receptors which are not inhibited by mepyramine but are inhibited by burimamide.
Inhibitors of H-2 histamine receptors are of utility in inhibiting actions of histamine which are not inhibited by "antihistamines". They are useful, for example, as inhibitors of gastric acid secretion.
The compounds of this invention are H-2 histamine receptor inhibitors. These compounds are represented by the following general formula: ##STR1## wherein R1 and R2, which may be the same or different, each represent a grouping of the structure shown in Formula II:
het--(CH2)m Z--(CH2)n --
wherein Het is a nitrogen containing 5 or 6 membered heterocyclic ring such as imidazole, pyridine, thiazole, isothiazole, oxazole, isoxazole, pyrazole, triazole, thiadiazole, pyrimidine, pyrazine or pyridazine which is optionally substituted by lower alkyl, hydroxyl, halogen or amino; Z is sulphur or a methylene group; m is 0, 1 or 2; n is 2 or 3 and the sum of m and n is 3,4, or when Y is other than hydrogen, methyl, or hydroxyl, 2; X1 and X2, which may be the same or different, are each sulphur, CHNO2 or NY wherein Y is hydrogen, hydroxy, lower alkyl, cyano, CONH2 or SO2 R3 ; R3 is lower alkyl, substituted or unsubstituted aryl, preferably phenyl or tolyl, trifluoromethyl or amino; W is NH, and when X1 and X2 are NH W may also be sulphur; and q is an integer from 2 to 8: or a pharmaceutically acceptable acid addition salt thereof.
It will be understood that the structure illustrated in Formula I is only one of several representations and that other tautomeric forms are also covered by the present invention.
Throughout the present specification and claims by the term `lower alkyl` we mean an alkyl group containing from 1 to 4 carbon atoms.
In a preferred group of compounds R1 and R2 are the same. R1 and/or R2 are preferably Het--CH2 S(CH2)2 -- and it is particularly preferable that Het is imidazole, optionally substituted by methyl or halogen; thiazole; or isothiazole or pyridine optionally substituted by methyl, hydroxyl or halogen.
Likewise it is preferred that X1 and X2 be the same. Useful series of compounds are those wherein X1 and X2 are both sulphur, wherein X1 and X2 are both NY and Y is hydrogen or cyano, and wherein X1 and X2 are both CHNO2.
It is preferred that q be from 2 to 4, particularly 3. Examples of specific compounds falling within the scope of the present invention are:
1,2-bis-[N'-(2-(5-methyl-4-imidazolyimethylthio)ethyl)thioureido] -ethane
1,3-bis-[N'-(2-(5-methyl-4-imidazolyimethylthio)ethyl)thioureido] -propane
1,4-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)thioureido] -butane
1,3-bis-[N'-(2-(5-methyl-4-imidazolyimethylthiop)ethyl)guanidino] propane
1,3-bis-[N'-cyano-N"-(2-(5-methyl-4-imidazolyimethylthio)thyl)guanidino] propane
1,3-bis-[S-(N-2-(5-methyl-4-imidazolyimethlthio)ethyl)isothioureido] propane
The compounds of Formula I wherein W is NH, R2 is the same as R1, X1 and X2 are both X3, X3 being sulphur, CHNO2, NH, NCN, or NSO2 R4, R4 being lower alkyl, substituted or unsubstituted aryl, preferably phenyl or tolyl, or trifluoromethyl, may be prepared by treating an excess (preferably two equivalents) of a compound of Formula III:
r1 nhe
wherein E is hydrogen or ##STR2## X3 being as defined above and A being lower alkyl, with a compound of Formula IV:
bnh(ch2)q NHB
wherein both the groups B are hydrogen when E is ##STR3## and are ##STR4## when E is hydrogen, X3 and A being as defined above.
Preferably this reaction is carried out in a solvent, such as ethanol, isopropanol or pyridine. When X3 is NCN or NSO2 R4 the reaction may be modified by first adding a silver salt, such as silver nitrate, to the reactant bearing the ##STR5## function, removing the silver alkyl mercaptide which is formed, and then adding the reacting amine.
Compounds of Formula III wherein E is ##STR6## and X3 is sulphur may be prepared from an amine of formula R1 NH2 by successive reaction thereof with carbon disulphide and an alkylating agent, such as methyl iodide.
Compounds of Formula III wherein E is ##STR7## and X3 is CHNO2, NCN, or, NSO2 R3 may be prepared by treating a compound of Formula V
(as)2 c = x3
wherein X3 is CHNO2, NCN, or NSO2 R4 and A is alkyl, with an equivalent amount of an amine of formula R1 NH2. This reaction is conveniently carried out in a solvent such as ethanol.
The compounds of Formula III wherein E is ##STR8## and X3 is NH are conveniently prepared by alkylating a thiourea of formula R1 NHCSNH2. These thioureas may be prepared by treating an amine of formula R1 NH2 with benzoyl isothiocyanate, and hydrolysing the product under alkaline conditions.
The compounds of Formula IV wherein both the groups are ##STR9## may be prepared from the corresponding diamines by methods similar to those described above for the preparation of compounds of Formula III wherein Y is ##STR10## Mild acid hydrolysis of the compounds of Formula I wherein X1 and X2 are both NCN yields the compounds of Formula I wherein X1 and X2 are both NCONH2. Acid hydrolysis of the compounds of Formula I wherein X1 and X2 are both NCN yields the compounds of Formula I wherein X1 and X2 are both NH.
The compounds of Formula I wherein X1 and X2 are both NHSO2 NH2 may be prepared from the corresponding compounds of Formula I wherein W is NH and X1 and X2 are both NH by reaction of the latter compounds with N-piperidylsulphamide. This reaction is conveniently carried out in boiling ethanol.
The above methods of synthesis may be modified to produce those compounds wherein W = NH and X1 and X2 and/or R1 and R2 are different. In this case the starting material is conveniently the diamine of Formula IV, wherein both the groups B are hydrogen, which is first treated with a suitable reagent to form a mono-protected diamine of Formula VI:
qnh(ch2)q NH2
wherein q has the above significance and Q is a suitable protecting group e.g., an acid labile protecting group such as benzoyl or formyl. Reaction of this compound with one equivalent of a compound of Formula III wherein E is ##STR11## gives the compound of Formula VII: ##STR12##
wherein R1, X3, Q and q have the above significance. Treatment of this compound with acid followed by reaction with a substance of Formula VIII: ##STR13##
wherein A, R2 and X2 have the above significance and R2 and/or X2 are not identical to R1 and/or X1 in Formula VII results in the required compound of Formula I wherein R1 and R2 and/or X1 and X2 are different. Alternatively, the amine of Formula VI may be converted into a compound of Formula IX: ##STR14##
wherein Q, q, X3 and S have the above significance, by the general methods described above for the preparation of compounds of Formula IV wherein E is ##STR15## Treatment of a compound of Formula IX with an amine of formula R1 NH2, R1 being as defined above, gives a compound of Formula VII which may be converted into a compound of Formula I by successive treatment with acid and a compound of Formula VIII as described above.
It will be appreciated that the above processes for the production of compounds of Formula I wherein W is NH involve the reaction between a compound of Formula III and a compound of Formula X
bnh(ch2)q NHG
wherein B is hydrogen when E is ##STR16## and B is ##STR17## when E is hydrogen, A being lower alkyl and X3 being sulphur, CHNO2, NH, NCN or NSO2 R4, R4 being lower alkyl, substituted or unsubstituted aryl or trifluoromethyl, q is as defined in Formula I and G is B or a group --CX2 NHR2 wherein X2 and R2 are as defined in Formula I.
The compounds of Formula I wherein X1 and/or X2 are NY and Y is hydroxy or lower alkyl may be prepared from the corresponding thiourea of Formula I wherein X1, and/or X2 is sulphur, and neither X1 nor X2 are NH by alkylating the thiourea, e.g., by treatment with hydrogen chloride in methanol or methyl iodide, and then treating the resulting compound with hydroxylamine or a lower alkylamine, respectively.
The compounds of Formula I wherein X1 and/or X2 are NCN may alternatively be prepared from the corresponding thiourea of Formula I wherein X1 and/or X2 is sulphur, and neither X1 nor X2 are NH, by alkylation and treatment of the product with cyanamide and a strong base such as potassium t-butoxide.
The compounds of Formula I wherein X1 or X2 are N.CN may also be prepared from the corresponding compounds of Formula I wherein X1 or X2 are sulphur by reaction of the latter with a heavy metal salt of cyanamide such as lead, mercury or cadmium cyanamide in a solvent such as acetonitrile and/or dimethylformamide.
The compounds of Formula I wherein W is sulphur and X1 and X2 are both NH may be prepared by alkylating a thiourea of Formula R1 NHCSNH2 wherein R1 is as defined in Formula I with a dihalo compound of formula Hal--(CH2)q --Hal, wherein Hal represents chlorine, bromine or iodine. Preferably the reaction is carried out on an acid addition salt of the thiourea, Hal is bromine and the reaction is carried out in a suitable solvent such as ethanol.
The compounds of Formula I are inhibitors of H-2 histamine receptors, that is they are inhibitors of the actions of histamine which are not blocked by "antihistamines" such as mepyramine but are blocked by burimamide. For example, the compounds of this invention have been found to inhibit selectively the 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 kilogram intravenously. This procedure is described in the above mentioned paper of Ash and Schild. Also, the activity of these compounds as H-2 histamine receptor inhibitors is demonstrated by their antagonism to other actions of histamine which, according to the above mentioned paper of Ash and Schild, are not mediated by H-1 histamine receptors. For example, the H-2 histamine receptor inhibitory activity of the compounds of this invention is demonstrated by antagonism of the actions of histamine in stimulating isolated guinea pig atrium and inhibiting contractions in the isolated rat uterus.
The compounds of this invention inhibit the secretion of gastric acid stimulated by pentagastrin or by food. The level of activity found for the compounds of the present invention is illustrated by the effective dose range in the anaesthetised rat, as mentioned above of from 0.5 to 256 micromoles per kilogram, intravenously. Many of the compounds of the present invention produce a 50% inhibition in this test at a dose of from 1 to 10 micromoles per kilogram.
For therapeutic use, the pharmacologically active compounds 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 pharmaceutically 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 I 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. Pharmaceutical compositions comprising a pharmaceutical carrier and a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof and methods of inhibiting H-2 histamine receptors which comprise administering a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof are also objects of this invention. The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examplary 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 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 about 25 mg to about 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 such as in an ampoule, or an aqueous or non-aqueous liquid suspension.
The pharmaceutical compositions are prepared by conventional techniques, involving procedures such as mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
The active ingredient will be present in the compositions in an effective amount to inhibit H-2 histamine receptors. The route of administering may be orally or parenterally. 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 in equal doses one to six times per day. The daily dosage regimen will preferably be from about 150 mg to about 1500 mg. Other pharmacologically active compounds may in certain cases be included in the composition. Advantageously the composition will be made up in a dosage unit form appropriate to the desired mode of administration, for example as a tablet, capsule or injectable solution.
The invention is illustrated but in no way limited by the following examples wherein all temperatures are in degrees Centigrade:
PAC 1,2-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)thioureido]ethane.(a) A solution of 4-methyl-5-(2-aminoethyl)thiomethyl)imidazole (10.2 g) in ethanol (75 ml) was added slowly, with stirring, to carbon disulphide (200 ml). The mixture was set aside overnight at room temperature and the solid formed was collected and recrystallised from aqueous isopropyl alcohol to afford N-[2-(5-methyl-4-imidazolyl)methylthio)ethyl]dithiocarbamic acid (9.8 g)., m.p. 127°-129°.
(Found: C, 38.6: H, 5.5: N, 16.7: C8 H13 N3 S3 requires: C, 38.8: H, 5.3: N, 17.0%).
(b) Methyl iodide (4.0 g) was added to a suspension of the dithiocarbamic acid (7.0 g) in methanol (100 ml). After stirring at room temperature for 1.5 hours, a solution was obtained. Concentration followed by recrystallisation of the residue from isopropyl alcohol-ether gave S-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]dithiocarbamate hydriodide (8.6 g), m.p. 167°- 169°.
(Found: C, 27.7: H, 4.0: N, 10.8: I, 32.9: C9 H15 N3 S3 .HI requires: C, 27.8: H, 4.1: N, 10.8: I, 32.6%).
(c) A solution of the above hydriodide (5.5 g) in absolute ethanol (60 ml) was added to a solution of sodium (0.325 g) in ethanol (100 ml). Following filtration, a solution of 1,2-diaminoethane (0.424 g) in ethanol (30 ml) was added to the filtrate which was heated under reflux for 24 hours. Following concentration, the residual oil was purified by repeated repreciptation from isopropanol with water and from isopropanol with ether. Finally chromatographic purification on a column of silica gel with ethyl acetate-ethanol (3:1) as eluant and final precipitation from isopropanol-ether gave the title compound as a colourless low melting solid, containing approximately 4.5% diethyl ether.
The NMR spectrum of a solution in 2 H6 dimethyl sulphoxide, recorded at 60 mHZ showed the following resonances:
| __________________________________________________________________________ |
| --NH-- --CS--NH-- --: |
| multiplet at δ7.7 |
| integral, 6.0 protons: |
| imidazole-2-H:-- |
| singlet at δ7.48 |
| calculated, 6.0 protons. |
| imidazole-CH--2 --: |
| singlet, at δ3.68 |
| integral, 12.4 protons: |
| --CH--2 --NH--CS--NH--CH--2 : |
| multiplet at δ3.5 |
| calculated, 12.0 protons. |
| --CH2 CH--2 S--: |
| multiplet, at δ2.62 |
| integral could not be |
| measured |
| imidazole-CH-- 3 : |
| singlet, at δ2.13: |
| the integral was used as |
| the internal standard, |
| equal to 6.0 protons. |
| __________________________________________________________________________ |
The spectrum also showed the presence of 4.5% w/w diethyl ether.
(Found: C, 45.6: H, 6.7: C18 H30 N8 S4 + 4.5%. C4 H10 O requires: C, 45.3: H, 6.5%)
PAC 1,3-bis-[N'-(2-(5-methyl-4-imidazolyl methylthio)ethyl)thioureido]propaneS-Methyl-N'-[2-(5-methyl-4-imidazolyl)methylthio)ethyl] dithiocarbamate hydriodide (7.8 g) was converted into the free base with sodium (0.46 g) in ethanol. Reaction with 1,3-diaminopropane (0.74 g) and purification by the method described in Example 1 gave the product which was further purified by successive treatment of a solution in methanol-water with cationic and anionic exchange resins. Following precipitation from isopropanol-ether, the title compound was obtained as a colourless low melting solid containing approximately 4.5% diethyl ether.
The NMR spectrum of a solution in 2 H6 dimethyl sulphoxide recorded at 60 mHZ showed the following resonances.
| __________________________________________________________________________ |
| --NH ----CS--NH ----. |
| triplet δ7.62 |
| integral, 7.0 protons: |
| imidazole-2H --: |
| singlet δ7.42 |
| calculated 6.0 protons. |
| imidazole-CH --2 : |
| singlet, δ3.67 |
| integral 13.0 protons (including |
| H2 O in NMR solvent): calculated |
| CH --2 NH--CSNH--CH2 : |
| multiplet, δ3.5 |
| CH2 --CH --2 --S: |
| triplet δ2.60 |
| integral 5.0 protons (including |
| DMSO-d5): calculated 4∅ |
| imidazole-CH3 : |
| singlet δ2.13: |
| The integral was used as the |
| integral standard, equal to |
| 6.0 protons. |
| CH2 CH --2 CH2 : |
| multiplet δ1.7: |
| integral 2.0 protons; |
| calculated 2.0 protons. |
| __________________________________________________________________________ |
The spectrum also showed the presence of 4.5% weight/weight diethyl ether.
(Found: N, 21.7: S, 24.6; C19 H32 N8 S4 + 4.5% C4 H10 O requires: N, 21.4: S, 24.5%)
PAC 1,4-bis-[N'-(2-(5Methyl-4-imidazolylmethylthio)ethyl)thioureido] butaneS-Methyl-N' -[2-(5-methyl-4-imidazolyl)methylthio)ethyl] dithiocarbamate hydriodide (5.5 g) was converted into the free base with sodium in ethanol. Reaction with 1,4-diaminobutane (0.63 g) and subsequent purification by the method described in Example 1 afforded the title compound as a low-melting colourless solid containing approximately 5.9% diethyl ether.
The NMR spectrum of a solution in 2 H6 dimethyl sulphoxide recorded at 60 mHZ showed the following resonances.
| ______________________________________ |
| --NH ----CS--NH ----: |
| multiplet, δ 7.6 |
| integral 5.8 protons: |
| calculated, |
| imidazole-2H --: |
| singlet, δ7.47 |
| 6.0 protons |
| imidazole-CH --2 : |
| singlet, δ3.69 |
| integral 12.6 protons: |
| calculated, |
| CH2 CH --2 N--: |
| multiplet, δ3.5 |
| 12.0 protons. |
| CH2 CH --2 S: |
| triplet, δ2.63 |
| The integral could |
| not be measured. |
| CH --3 -Imidazole: |
| singlet, δ2.15: |
| The integral was |
| used as the internal |
| standard equal - to 6.0 protons. |
| CH2 --(CH --2)2 --CH2 : |
| multiplet, δ1.5 |
| integral 4.2 protons |
| calculated |
| 4.0 protons. |
| ______________________________________ |
The spectrum also showed the presence of 5.9% weight/weight diethyl ether.
(Found: C, 47.6:k H, 7.2; C20 H34 N8 S4 + 5.9% C4 H10 O requires: C, 47.7: H, 7.1%)
PAC 1,5-bis[N'-(2-(5-Methyl-4-imidazolyimethylthio)ethyl)thioureido]thioureido] pentaneThe reaction of S-methyl-N'-[2-(5-methyl-4-imidazolyl)methylthio)ethyl] dithiocarbamate with 1,5-diaminopentane by the method described in Example 1 gave the title compound as an amorphous powder which contained residual ether and water.
(Found: C, 47.5: H, 7.2: N, 19.9: S, 23.3: C21 H36 N8 S4 +2% C4 H10 O + 2% H2 O requires: C, 47.1: H, 7.1: N, 20.3: S, 23.3%).
The NMR spectrum of a solution in 2 H6 dimethyl sulphoxide recorded at 60 mHZ showed the following resonances.
| __________________________________________________________________________ |
| --NH ----CS--NH ----: |
| multiplet, 435-465 Hz |
| integral 5.3 protons |
| imidazole-2H --: |
| singlet, δ7.47 |
| calculated, 6.0 protons |
| imidazole-CH --2 : |
| singlet, δ3.68 |
| integral 12.3 protons |
| CH --2 CH2 S + CH2 CH2 N: |
| multiplet, 185-235 Hz |
| calculated 12.0 protons |
| CH2 --CH --2 --S: |
| multiplet, 140-175 Hz |
| integral 4.5 protons |
| (including DMSO-d5) |
| calculated 4 protons |
| CH --3 -Imidazole: |
| singlet, δ2.15: |
| The integral was used |
| as the internal |
| standard equal to |
| 6 protons. |
| CH --2 (CH --2 --CH2)2 NH |
| multiplet, 70-110 Hz |
| Integral 5.3 protons |
| calculated 6.0 protons |
| __________________________________________________________________________ |
(i) A solution of N-[2-((5-methyl-4-imidazolyl)methylthio)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]thiouronium iodide (2.3 g), m.p. 128°-131°. The iodide was converted into the corresponding sulphate by ion-exchange on an ion-exchange resin (IRA 401) in the sulphate form.
(ii) 1,3-Diaminopropane (0.37 g) was added to a solution of S-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiouronium sulphate (2.93g) in water (10 ml) and the mixture was heated under reflux for 2 hours. Following concentration the residue was converted into the picrate with an aqueous solution of sodium picrate. Recrystallisation from ethanol afforded the title compound as the dipicrate (1.1 g) m.p. 114-6°.
(Found: C, 40.3; H, 4.2; N, 23.7; S, 6.9; C19 H36 N10 S2.2 C6 H3 N3 O7 requires: C, 40.3; H, 4.4; N, 24.2; S, 6.9%).
The dipicrate was dissolved in aqueous methanol and treated with ion-exchange resin IRA 400 (Cl-) to afford the dihydrochloride (Found: Cl, 12.8% C19 H36 N10 S2. 2HCl requires: Cl, 13.1%)
PAC 1,2-bis-[N'-(2-(5-Methyl-4-imidazolylmethylthio)ethyl) guanidino]ethaneThe reaction of 1,2-diaminoethane (0.60 g) with S-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiouronium sulphate (5.86 g) by the method described in Example 5 afforded the title compound which was isolated as the dipicrate (3.5 g), m.p. 201-203°.
(Found: C, 39.5; H, 4.3; N, 24.2; S, 6.9; C18 N34 N10 S2. 2 C6 H3 N3 O7 requires: C, 39.6; H, 4.2; N, 24.6; S, 7.0%).
PAC 1,5-bis-[N'-(2-(5-Methyl-4-imidazolylmethylthio)ethyl) guanidino]pentaneThe reaction of 1,5-diaminopentane (0.43 g) with S-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethylthiouronium sulphate (2.52 g) by the method described in Example 5 afforded the title compound which was isolated as the dipicrate (1.8 g) m.p. 115-120°.
PAC 1,3-bis-[N'-Cyano-N"-(2-(5-methyl-4-imidazolylmethylthio) ethyl)guanidino]propanea) A mixture of 1,3-bis-[N-cyano-S-methyl-isothioureido]propane (1.67 g) and 5-methyl-4-(2-aminoethyl)imidazole (2.36 g) in anhydrous pyridine (40 ml) was heated under reflux for 8 hours. Following concentration and trituration with acetonitrile-water (2:1) the product was chromatographed on a column of silica with elution by a mixture of chloroform (85 parts) and methanolic ammonia (15 parts) to yield the title compound.
The NMR spectrum of a solution in 2 H6 dimethyl sulphoxide showed the following resonances.
| ______________________________________ |
| imidazole-2H -- |
| ; Singlet, δ 7.56 |
| N-H -- ; multiplet, δ 7.22 |
| imidazole-CH --2 |
| ; singlet, δ 3.68 |
| CH2 CH --2 NH |
| ; multiplet, δ 3.25 |
| CH2 CH --2 S |
| ; multiplet, δ 2.65 |
| CH --3 -imidazole |
| ; singlet, δ 2.16 |
| CH2 CH --2 CH2 |
| ; multiplet, δ 1.75 |
| ______________________________________ |
(b) Lead cyanamide (3.0 g) was added to 1,3-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)thioureido] propane (2.5 g) in acetonitrile. Dimethylformamide was added and the mixture was stirred and boiled under reflux for 24 hours. The mixture was filtered, concentrated and purified by chromatography to give the title compound.
(c) A mixture of 1,3-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)thioureido)propane (10.3 g) 55% hydriodic acid (12.2 ml) methyl iodide (5.3 ml) and methanol was boiled under reflux for 4 hours and, evaporated to dryness to give 1,3-bis-[S-methyl-N'-(2-(5-methyl-4-imidazolylmethylthio)-ethyl)isothioure ido)propane tetrahydriodide. This intermediate (2.05 g) was treated with potassium t-butoxide (1.5 g) and cyanamide (0.5 g) in anhydrous t-butanol and the mixture was boiled under reflux overnight, filtered, and purified by chromatography to give the title product.
PAC 1,2-bis-[S-(N-2-(5-Methyl-4-imidazolylmethylthio)ethyl) isothioureido]ethane tetrahydrobromideA solution of N-[2-(5-methyl-4-imidazolyl)methylthio)ethyl] thiourea (3.45 g) in isopropyl alcohol (25 ml) was cooled and 48% aqueous hydrobromic acid (2.54 g) added. The hydrobromide salt was precipitated with excess ether and dissolved in ethanol (25 ml). 1,2-Dibromoethane (1.5 g) was added and the solution obtained was heated under reflux for 24 hours. Concentration and crystallisation from methanol-isopropyl alcohol afforded the title compound (2.2 g) m.p. 215-217°.
(Found: C, 26.7; H, 4.1; N, 13.8; S, 15.8; Br, 39.6; C18 H30 N8 S4. 4 HBr requires: C, 26.7; H, 4.2; N, 13.8; S, 15.8; Br, 39.4%).
PAC 1,3-bis-[5-(N-2-(5-Methyl-4-imidazolyimethylthio)ethyl) isothioureido]propaneThe reaction of N-[2-(5-methyl-4-imidazolyl)methylthio)ethyl] thiourea hydrobromide (from 3.45 g of the thiourea) with 1,3-dibromopropane by the method described in Example 9 afforded the title compound which was isolated as its tetrapicrolonic acid salt (4.75 g), m.p. 165-167° (from nitromethane-ethanol).
(Found: C, 45.2; H, 4.3; N, 21.5; S, 7.8%. C19 H32 N8 S4. 4 C10 H8 N4 O5 requires: C, 45.5; H, 4.1; N, 21.6; S, 8.2%).
The tetrapicrolonate salt was suspended in aqueous methanol and treated with ion-exchange resin IRA 401 (Cl- form) and the suspension stirred for 3 hours. Concentration afforded the tetrahydrochloride (0.9 g), m.p. approx. 110° (Found: C, 35.1; H, 6.0; C19 H32 N8 S4. 4 HCl requires: C, 35.3; H, 5.9%)
PAC 1,4-bis-[S-(N-2-(5-Methyl-4-imidazolylmethylthio)ethyl)isothioureido]butane tetrahydrobromideThe reaction of N-[2-(4-methyl-5-imidazolyl)methylthio) ethyl]thiourea hydrobromide (from 3.45 g of the thiourea) with 1,4-dibromobutane (1.62 g) by the method described in Example 9 afforded the title compound (3.8 g), m.p. 185-187° (from ethanol)
(Found: C, 28.7; H, 4.6; N, 13.4; Br, 38.2; S, 15.1; C20 H34 N8 S4. 4 HBr requires: C, 28.7; H, 4.6; N, 13.4; S, 38.1: S, 15.3%).
When 1,8-diaminooctane is substituted for 1,2-diaminoethane in the procedure of Example 1(c), 1,8-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)thioureido]octane is produced. When 1,8-diaminooctane is substituted for 1,3-diaminopropane in the procedure of Example 5(ii), 1,8-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]octane is produced.
When 1,6-diaminohexane is substituted for 1,2-diaminoethane in the procedure of Example 1(c), 1,6-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)thioureido)hexane is produced. When 1,6-diaminohexane is substituted for 1,3-diaminopropane in the procedure of Example 5(ii), 1,6-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]hexane is produced.
When 1,6-dibromohexane or 1,8-dibromooctane are substituted for 1,2-dibromoethane in the procedure of Example 9 the products are 1,6-bis-[S-(N-2-(5-methyl-4-imidazolylmethylthio) ethyl)isothioureido]hexane and 1,8-bis-[S-(N-2-(5-methyl-4-imidazolylmethylthio)ethyl)isothioureido]octan e, respectively.
Reaction of 4-methyl-5-(2-aminoethyl)thiomethyl)imidazole with
a) N-methanesulphonyliminodithiocarbonic acid dimethyl ester
b) N-p-toluenesulphonyliminodithiocarbonic acid dimethyl ester
c) N-benzenesulphonyliminodithiocarbonic acid dimethyl ester
d) N-trifluoromethanesulphonyliminodithiocarbonic acid dimethyl ester in ethanol at room temperature gave the corresponding
S-methyl-N-[2-(5-methyl-4-imidazolyl)methylthio)ethyl]-N'-sulphonylthiouro nium derivatives which were treated with 1,3-diaminopropane according to the general procedure of Example 5(ii) to give
a) 1,3-bis-[N'-methanesulphonyl-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl) -guanidino]propane
b) 1,3-bis-[N'-toluenesulphonyl-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl) -guanidino]propane
c) 1,3-bis-[N'-benzenesulphonyl-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl) -guanidino]propane
d) 1,3-bis-[N'-trifluoromethanesulphonyl-N"-(2-(5-methyl-4-imidazolylmethylth io)ethyl)-guanidino]propane
PAC 1,3-bis-[N'-Sulphamyl-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidin o]propane1,3-bis-[N'-(2-(5-Methyl-4-imidazolylmethylthio)ethyl)guanidino] propane dihydrochloride (2.7 g) was added to a solution of sodium (0.46 g) in ethanol (50 ml) and the mixture was warmed and stirred for 0.5 hours, cooled and filtered. N-Piperidylsulphamide (1.64 g) was added to the filtrate which was heated under reflux for 24 hours. The mixture was concentrated and purified by chromatography to give the title compound.
PAC 1,3-bis-[N'-Hydroxy-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino] propanea) Dry hydrogen chloride was bubbled through a solution of 1,3-bis-[N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl) thioureido]propane in methanol at 80° for 12 hours, and the solvent was removed to give 1,3-bis[S-methyl-N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl)isothio ureido]propane tetrahydrochloride.
b) The bis-isothiourea prepared above was treated with hydroxylamine hydrochloride and potassium hydrogen carbonate in dry dimethylformamide at 85° under an atmosphere of nitrogen to yield the title product.
PAC 1,3-bis-[N'-Methyl-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]p ropane1,3-bis-[S-Methyl-N'-(2-(5-methyl-4-imidazolylmethylthio)ethyl) isothioureido]propane tetrahydrochloride was heated with methylamine in methanol to give the title product.
Substitution of
a) 4-bromo-5-](2-aminoethyl)thiomethyl]imidazole
b) 4-[(2-aminoethyl)thiomethyl]imidazole
c) 2-[(2-aminoethyl)thiomethyl]thiazole
d) 3-[(2-aminoethyl)thiomethyl]isothiazole
e) 3-chloro-2-[(2-aminoethyl)thiomethyl]pyridine
f) 3-hydroxy-2-[(2-aminoethyl)thiomethyl]pyridine
g) 3-methyl-2-[(2-aminoethyl)thiomethyl]pyridine for 4-methyl-5-(2-aminoethyl)thiomethyl)imidazole in the procedure of Example 1(a) followed by treatment of the product according to the general procedure of Examples 1(b) and 2 gave
a) 1,3-bis[N'-(2-(5-bromo-4-imidazolylmethylthio)ethyl) thioureido]propane
b) 1,3-bis[N'-(2-(4-imidazolylmethylthio)ethyl) thioureido]propane
c) 1,3-bis[N'-(2-(2-thiazolylmethylthio)ethyl)thioureido] propane
d) 1,3-bis[N'-(2-(3-isothiazolylmethylthio)ethyl) thioureido]propane
e) 1,3-bis[N'-(2-(3-chloro-2-pyridylmethylthio)ethyl) thioureido]propane
f) 1,3-bis[N'-(2-(3-hydroxy-2-pyridylmethylthio) ethyl)thioureido]propane
Substitution of the following amines:
a) 2-[2-aminopropylthio]oxazole
b) 3-[(2-aminoethyl)thiomethyl]isoxazole
c) 3-[(2-aminoethyl)thiomethyl]pyrazole
d) 3-[(2-aminoethyl)thiomethyl]-1,2,4-triazole
e) 5-amino-2-[(2-aminoethyl)thiomethyl]-1,3,4-thiadiazole
f) 2-[(2-aminoethyl)thiomethyl]pyrimidine
g) 2-[(2-aminoethyl)thiomethyl]pyrazine
h) 3-[(2-aminoethyl)thiomethyl]pyridazine
i) 1-methyl-2-[(2-aminoethyl)thiomethyl]imidazole
j) 2-[(2-aminoethyl)thiomethyl]imidazole for 4-methyl-5-(2-aminoethyl)thiomethyl)imidazole in the procedure of Example 1(a) followed by treatment of the products according to the general procedure of Examples 1(b) and 2 results in the production of the following products
a) 1,3-bis[N'-(2-(2-oxazolylthio)propyl)thioureido] propane
b) 1,3-bis[N'-(2-(3-isoxazolylmethylthio)ethyl)thioureido] propane
c) 1,3-bis[N-(2-(3-pyrazolylmethylthio)ethyl)thioureido] propane
d) 1,3-bis[N-(b 2(3-(1,2,4-triazolylmethythio)ethyl thioureido]propane
e) 1,3-bis[N-(2-(5-amino-2-(1,3,4-thioadiazolyl)methylthio) ethyl)thioureido]propane
f) 1,3-bis[N-(2-(2-pyrimidylmethylthio)ethyl)thioureido] propane
g) 1,3-bis[N'-(2-(2-pyrazolylmethylthio)ethyl)thioureido] propane
h) 1,3-bis[N'-(2-(3-pyridazolylmethylthio)ethyl)thioureido] propane
i) 1,3-bis[N'-(2-(1-methyl-2-imidazolylmethylthio)ethyl) thioureido]propane
j) 1,3-bis[N'-(2-(2-imidazolylmethylthio)ethyl) thioureido]propane
a) (i) A solution of 4-(2-aminoethyl)thiomethyl)imidazole (6.0 g) and benzoyl isothiocyanate (6.0 g) in chloroform (150 ml) was heated under reflux for one hour. Concentration followed by recrystallisation from ethyl acetate-isopropyl acetate afforded N-benzoyl-N'-(2-(4-imidazolylmethylthio) ethyl)thiourea (7.5 g). An analytically pure sample (from aqueous isopropyl alcohol) had m.p. 126-128°.
(ii) The benzoyl thiourea (6.0 g) was added to a solution of potassium carbonate (1.4 g) in water (80 ml) at 60°. The solution was maintained at this temperature for one hour, concentrated to low bulk and acidified with hydrochloric acid. Benzoic acid was removed by filtration and the filtrate was basified with potassium carbonate and concentrated under reduced pressure. Following extraction with isopropyl alcohol and concentration, the product was crystallised from isopropyl acetate. Recrystallisation from water gave N-(2-(4-imidazolylmethylthio)ethyl)thiourea (2.5 g)m.p. 135-137°.
(Found: C, 38.9; H, 5.5; N, 26.1; S, 29.6; C7 H12 N4 S2 requires: C, 38.9; H, 5.6; N, 25.9; S, 29.6%)
b) Substitution of
a) 4-bromo-5-[(2-aminoethyl)thiomethyl)imidazole
b) 4-[(2-aminoethyl)thiomethyl]imidazole
c) 2-[(2-aminoethyl)thiomethyl]thiazole
d) 3-[(2-aminoethyl)thiomethyl]isothiazole
e) 3-chloro-2-[(2-aminoethyl)thiomethyl]pyridine
f) 3-hydroxy-2-[(2-aminoethyl)thiomethyl]pyridine
g) 3-methyl-2-[(2-aminoethyl)thiomethyl]pyridine
for 4-(2-aminoethyl)thiomethyl)imidazole in the above procedure and treatment of the products according to the general procedure of Example 5 gives
a) 1,3-bis[N'-(2-(5-bromo-4-imidazolylmethylthio)ethyl) guanidino]propane
b) 1,3-bis[N'-(2-(4-imidazolylmethylthio)ethyl) guanidino]propane
c) 1,3-bis[N'-2-(2-thiazolylmethylthio) ethyl)guanidino]propane
d) 1,3-bis[N'-(2-(3-isothiazolylmethylthio) ethyl)guanidino]propane
e) 1,3-[N'-(2-(3-chloro-2-pyridylmethylthio) ethyl)guanidino]propane
f) 1,3-bis[N'-(2-(3-hydroxy-2-pyridylmethylthio) ethyl)guanidino]propane
Treatment of
a) 2-[2-aminopropylthio]oxazole
b) 3-[(2-aminoethyl)thiomethyl]isoxazole
c) 3-[(2-aminoethyl)thiomethyl]pyrazole
d) 3-[(2-aminoethyl)thiomethyl]-1,2,4-triazole
e) 2-[(3-aminopropylthio]pyrimidine
f) 2-[(2-aminoethyl)thiomethyl]pyrazine
g) 3-[(2-aminoethyl)thiomethyl]pyridazine
h) 1-methyl-2-[(2-aminoethyl)thiomethyl]imidazole
i) 2-[(2-aminoethyl)thiomethyl]imidazole
according to the general procedure of Example 20 gives
a) 1,3-bis[N'-(2-(2-oxazolylthio)propyl)guanidino] propane
b) 1,3-bis[N'-(2-(3-isoxazolylmethylthio)ethyl)guanidino] propane
c) 1,3-bis[N'-(2-(3-pyrazolylmethylthio)ethyl)guanidino] propane
d) 1,3-bis[N-(2-(3-(1,2,4-triazolyl)methylthio)ethyl) guanidino]propane
e) 1,3-bis[N-(3-(2-pyrimidylthio)propyl)guanidino]propane
f) 1,3-bis[N'-(2-(3-pyrazolylmethylthio)ethyl)guanidino] propane
g) 1,3-bis[N'-(2-(3-pyridizylmethylthio)ethyl)guanidino] propane
h) 1,3-bis[N'-(2-(1-methyl-2-imidazolylmethylthio)ethyl) guanidino]propane
i) 1,3-bis[N'-(2-(2-imidazolylmethylthio)ethyl)guanidino] propane
Substitution of
a) 4-(4-aminobutyl)imidazole
b) 4-(4-aminobutyl)-5-methylimidazole
c) 4-(4-aminobutyl)-5-bromoimidazole
d) 4-(4-aminobutyl)thiazole
for 4-methyl-5-(2-aminoethyl)thiomethyl)imidazole in the procedure of Example 1(a) followed by treatment of the product according to the general procedure of Examples 1(b) and 2 gave
a) 1,3-bis-[N'-4-(4-imidazolylbutyl)thioureido]propane
b) 1,3-bis-[N'-4-(5-methyl-4-imidazolylbutyl)thioureido] propane
c) 1,3-bis-[N'-4-(5-bromo-4-imidazolylbutyl)thioureido] propane
d) 1,3-bis-[N'-4-(4-thiazolylbutyl)thioureido]propane
Treatment of
a) 4-(4-aminobutyl)imidazole
b) 4-(4-aminobutyl)-5-methylimidazole
c) 4-(4-aminobutyl)-5-bromoimidazole
d) 4-(4-aminobutyl)thiazole
according to the general procedure of Example 20 gives
a) 1,3-bis-[N'-4-(4-imidazolylbutyl)guanidino]propane
b) 1,3-bis-[N'-4-(5-methyl-4-imidazolylbutyl)guanidino] propane
c) 1,3-bis-[N'-4-(5-bromo-4-imidazolylbutyl)guanidino]propane
d) 1,3-bis-[N'-4-(4-thiazolylbutyl)guanidino]propane
PAC 1-[N'-(2-(5-Methyl-4-imidazolylmethylthio)ethyl)guanidino]-3-[N'-(2-(2-thia zolylmethylthio)ethyl)thioureido]propane(a) (i) 3-Benzoylaminopropylamine was treated successively with carbon disulphide and methyl iodide according to the general procedure of Example 1(a)(b) to give S-methyl-N-(3-benzoylaminopropyl)dithiocarbamate hydriodide
(ii) The above hydriodide was treated with one equivalent of sodium ethoxide and 2[(2-aminoethyl)thiomethyl]thiazole, and the product was hydrolysed with acid to give N-(3-amino-propyl)-N'-(2-(2-thiazolylmethylthio)ethyl)thiourea
(iii) The above thiourea was heated under reflux for 2 hours with an aqueous solution of S-methyl-N-[2-(5-methyl-4-imidazolyl)methylthio)ethyl]thiouronium sulphate in water. The mixture was concentrated and purified by chromatography to give the title compound.
(b) (i) 2-[(2-Aminoethyl)thiomethyl]thiazole was successively treated with carbon disulphide and methyl iodide according to the general procedure of Example 1(a)(b) to give S-methyl-N-[2-(2-thiazolylmethylthio)ethyl]dithiocarbamate hydriodide.
(ii) The above hydriodide was treated with one equivalent of sodium ethoxide and 3-benzoylaminopropylamine and the product was hydrolysed with acid, and subjected to the procedure (a)
(iii) above, to give the title compound.
PAC 1,3-bis-[N'-(2-(4-imidazolylethylthio)ethyl)guanidino]propaneWhen 4-[2-(2-aminoethyl)thioethyl]imidazole is subjected to the general procedure of Example 20 the title compound is produced.
PAC 1,3-bis-[N'-Carbamoyl-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidin o]propaneTreatment of 1,3-bis-[N'-cyano-N"-(2-(5-methyl-4-imidazolylmethylthio)ethyl)guanidino]p ropane with dilute hydrochloric acid at 40° yielded the title product.
PAC 1,3-bis-[1-[2-((5-Methyl-4-imidazolyl)methylthio)ethylamino]-2-nitrovinylam ino]propaneA solution of 1-nitro-2-methylthio-2-[2-(5-methyl-4-imidazolyl)methylthio)ethylamino]eth ylene (2.0 g) and 1,3-diaminopropane (0.26 g) in ethanol (10 ml) was heated under reflux for 2 hours. The product was purified on an ion-exchange resin (GC 50 (H+)), by elution with 0.012 N hydrochloric acid and finally chromatographed on a column of silica gel to yield the title compound.
PAC 1-[1-(2-((5-Methyl-4-imidazolyl)methylthio)ethylamino)-2-nitrovinylamino]-3 -[N'-cyano-N"-(2-(2-pyridylmethylthio)ethyl)guanidino]propane1-Nitro-2-methylthio-2-[2-((5-methyl-4-imidazolyl)methylthio) ethylamino]ethylene was reacted with 3-benzoylaminopropylamine and the product was hydrolysed under acidic conditions and reacted with N-cyano-N'-[2-(2-pyridylmethylthio)ethyl]-S-methylisothiourea to give the title compound. EXAMPLE 29
| ______________________________________ |
| Ingredients Amounts |
| ______________________________________ |
| 1,3-bis-[N'-(2-(5-Methyl-4-imidazolyl- |
| methylthio)ethyl)guanidino]propane |
| 150 mg. |
| dihydrochloride |
| 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.
| ______________________________________ |
| Ingredients Amounts |
| ______________________________________ |
| 1,3-bis-[N'-(2-(5-Methyl-4-imidazolyl- |
| methylthio)ethyl)guanidino]propane |
| 200 mg. |
| dihydrochloride |
| Lactose 100 mg. |
| ______________________________________ |
The ingredients are screened, mixed and filled into a hard gelatin capsule.
Ganellin, Charon Robin, Durant, Graham John
| Patent | Priority | Assignee | Title |
| 4814343, | Nov 02 1987 | U C B, S A | Substituted 1H-imidazoles |
| 5021431, | Apr 02 1985 | Heumann Pharma GmbH & co. | Imidazolyl alkyl guanidine derivatives, processes for their preparation and pharmaceutical preparations containing these compounds |
| Patent | Priority | Assignee | Title |
| DE2,215,503, |
| Executed on | Assignor | Assignee | Conveyance | Frame | Reel | Doc |
| Oct 19 1977 | Smith Kline & French Laboratories Limited | (assignment on the face of the patent) | / |
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