US3876647A - Certain n-cyanoguanidines - Google Patents

Certain n-cyanoguanidines Download PDF

Info

Publication number
US3876647A
US3876647A US384993A US38499373A US3876647A US 3876647 A US3876647 A US 3876647A US 384993 A US384993 A US 384993A US 38499373 A US38499373 A US 38499373A US 3876647 A US3876647 A US 3876647A
Authority
US
United States
Prior art keywords
formula
cyano
pyridyl
compounds
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US384993A
Other languages
English (en)
Inventor
Graham John Durant
John Colin Emmett
Charon Robin Ganellin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Smith Kline and French Laboratories Ltd
Original Assignee
Smith Kline and French Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26240478&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US3876647(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Smith Kline and French Laboratories Ltd filed Critical Smith Kline and French Laboratories Ltd
Priority to US523593A priority Critical patent/US3920822A/en
Application granted granted Critical
Publication of US3876647A publication Critical patent/US3876647A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/32—Sulfur atoms
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • 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
    • 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
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms

Definitions

  • ABSTRACT Primary E. ⁇ aminerAlan L. Rotman Allurney. Agent. or Firm-Joan S. Keps; Richard D. Foggio; William H. Edg'erton [57] ABSTRACT
  • the compounds are cyanoguanidines, for example N- cyano-N'-methyl-N"-[2-((3-hydroxy-2-pyridyl)methylthio-ethyll-guanidine. which are inhibitors of histamine activity.
  • This invention relates to pharmacologically active compounds, in particular to pharmacologically active cyanoguanidines, to processes of preparing these compounds and methods of inhibiting H2 histamine receptors with these compounds.
  • the compounds of the invention can exist as the addition salts but. for convenience, reference will be made throughout this specification to the parent compounds.
  • Histamine is a compound which is believed to act in such a 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.
  • antihistamines drugs commonly called antihistamines" (of which mepyramine is a typical example) is believed to involve a receptor which has been designated as H-l.
  • a further group of substances has recently been described by Black et al. (Nature 1972, 236.
  • H-2 receptors which are distinguished by the fact that they act at his tamine receptors other than the H-l receptor and these other receptors have been designated as H-2 receptors.
  • H-2 receptors his tamine receptors other than the H-l receptor and these other receptors have been designated as H-2 receptors.
  • This latter group of substances, to certain of which the present invention relates. are thus of utility in inhibiting certain actions of histamine which are not inhibited by the above-mentioned antihistamines".
  • the substances of this invention may also be of utility as inhibitors of certain actions of gastrin. 1
  • lower alkyl we mean an alkyl group containing from l to 4 carbon atoms.
  • the cyanoguanidines with which the present invention is concerned may be represented by the following general formula:
  • R is hydrogen or lower alkyl such as methyl
  • X is hydrogen, lower alkyl, trifluoromethyl, hydroxyl, halogen or amino
  • Z is sulphur or oxygen
  • In is 0, l or 2 and n is 2 or 3, the sum of m and n being 3 or 4; or pharmaceutically acceptable acid addition salts thereof.
  • R is methyl or ethyl.
  • m is l and n is 2.
  • Particularly useful specific compounds are N-cyano-N'-methyl-N"-[2-((3-hydroxy-2- pyridyl)methylthio)ethyl]guanidine, N-cyano-N'- methyl-N"-[2-((3-bromo-2-pyridyl)methylthio)ethyl]- guanidine and N-cyano-N '-ethyl-N 2-( 3-bromo-2 pyridyl )methylthio )ethyl ]guanidine.
  • the compounds of the present invention may be produced from an amine of the Formula II:
  • R, Z, X, m and n have the same significance as in Formula I
  • a heavy metal salt of cyanamide such as the lead, mercury or cadmium salt.
  • This process may be conveniently carried out in a solvent such as acetonitrile or oimethylformamide.
  • a desulphurising agent such as a heavy metal salt or oxide and then treated cyanamide.
  • the amine of Formula [I may be reacted with a metal salt of dicyanamide of formula MN (CN): wherein M is a metal eg an alkali metal such as sodium in an appropriate solvent and in the presence of an equivalent amount of a strong acid.
  • M is a metal eg an alkali metal such as sodium in an appropriate solvent and in the presence of an equivalent amount of a strong acid.
  • the compounds represented by Formula l have been found to have pharmacological activity in the animal body as antagonists to certain actions of histamine which are not blocked by antihistamines such as mepyramine. For example, they have been found to inhibit selectively the histaminestimulated secretion of gastric acid from the perfused stomachs of rats anaesthetised with urethane, at doses of from 0.5 to 256 micromoles per kilogram intravenously. Similarly, the action of these compounds may, in many cases, be demonstrated by their antagonism to the effects of histamine on other tissueswhich, according to the above-mentioned paper of Black et., al., are H-2 receptors.
  • tissues are perfused isolated guinea-pig heart, isolated guinea-pig right atrium and isolated rat uterus.
  • the compounds of the invention have been found to inhibit the secretion of gastric acid stimulated by pentagastrin or by food. In addition to the above the compounds of the invention also show some anti-inflammatory activity in conventional tests.
  • 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, given intravenously. Many ofthe compounds of the present invention produce a 50% inhibition in this test at a dose of from 2 to micromoles per kilogram.
  • 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 to an animal 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.
  • solid carriers are lactose. terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozcnge.
  • the amount of solid carrier will vary widely but preferably will be from about 25 mg. to about l gm.
  • the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
  • 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 composition in an effective amount to inhibit histamine activity.
  • the route of administration may be orally or parenterally.
  • each dosage unit will contain the active ingredient in an amount of from about 50 mg. to about 250 mg., most preferably from about mg. to about 200 mg.
  • the active ingredient will preferably be administered in equal doses one to three times per day.
  • the daily dosage regimen will preferably be from about mg. to about 750 mg., most preferably from about 300 mg. to about 600 mg.
  • 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.
  • addition salts include those with hydrochloric, hydrobromic, hydriodic, sulphuric, picric and maleic acids.
  • compositions will be made up in a dosage unit form appropriate to the desired mode of administration, for example as a tablet, capsule, injectable solution or as a cream for topical administration.
  • Example 1 N-Cyano-N-[ 2-( 3-hydroxy-2-pyridyl )methylthio )ethyl]-N"-methyl guanidine i.
  • a solution of 2-((Z-aminoethyl)thiomethyl)-3- hydroxypyridine (7.5 g) in ethanol was added slowly to a solution of dimethylcyanodithioimidocarbonate (6.0 g) in ethanol, with stirring at room temperature. The mixture was set aside overnight at room temperature. Filtration afforded N-cyano-N-[2-((3-hydroxy-2- pyridyl)methylthio)ethylI-S-methylisothiourea (4.85 g), m.p.
  • EXAMPLE 6 Ingredients Amounts Z-pyridyl )methylthio )ethyl Iguanidine. 150 mg. Sucrose mg. Starch 25 mg. Tale 5 mg. Stearic acid 2 mg.
  • the ingredients are screened, mixed and filled into a hard gelatin capsule.
  • the ingredients are screened, mixed and filled into a hard gelatin capsule.
  • a compound of claim 1 such that m is l and n is N CN (GI-I Z(CI-I NB C I 4.
  • a compound of claim 1 said compound being N- whereln R IS hydrogen or lower alkyl; X is hydrogen. cyan0 N,-methyl N,, [2 ((3 bmm0 2 lower alkyl. trifluoromethyl, hydroxyL halogen or amino; Z is sulphur or oxygen; m is O. l or 2 and n is pyndyl)methyhhlo)ethyuguamdme 2 or 3 the sum of m and n being 3 or 4. or a pharma- A C(ImPOUndHOf claim 1, Said comPound being N ceutically acceptable acid addition salt thereof. W 4( 'py y y 2. A compound of claim 1 such that R is methyl or m thyllguilmdlfieethyl.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
US384993A 1972-09-05 1973-08-02 Certain n-cyanoguanidines Expired - Lifetime US3876647A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US523593A US3920822A (en) 1972-09-05 1974-11-14 Inhibition of histamine activity with cyanoguanidines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB4116072A GB1397436A (en) 1972-09-05 1972-09-05 Heterocyclic n-cyanoguinidines
GB615473 1973-02-08

Publications (1)

Publication Number Publication Date
US3876647A true US3876647A (en) 1975-04-08

Family

ID=26240478

Family Applications (2)

Application Number Title Priority Date Filing Date
US385027A Expired - Lifetime US3897444A (en) 1972-09-05 1973-08-02 Pharmacologically active compounds
US384993A Expired - Lifetime US3876647A (en) 1972-09-05 1973-08-02 Certain n-cyanoguanidines

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US385027A Expired - Lifetime US3897444A (en) 1972-09-05 1973-08-02 Pharmacologically active compounds

Country Status (14)

Country Link
US (2) US3897444A (hu)
JP (1) JPS561309B2 (hu)
AU (1) AU472456B2 (hu)
CA (1) CA1045142A (hu)
CY (1) CY855A (hu)
DE (1) DE2344779C3 (hu)
FR (1) FR2199467B2 (hu)
GB (1) GB1397436A (hu)
HK (1) HK55276A (hu)
IE (1) IE38353B1 (hu)
KE (1) KE2626A (hu)
MY (1) MY7600229A (hu)
NL (1) NL187240C (hu)
SG (1) SG28676G (hu)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3953460A (en) * 1973-05-17 1976-04-27 Smith Kline & French Laboratories Limited Ethylene derivatives
US3979398A (en) * 1973-02-08 1976-09-07 Smith Kline & French Laboratories Limited Sulphoxides
US4002759A (en) * 1973-05-17 1977-01-11 Smith Kline & French Laboratories Limited Pyridylbutylamino ethylene compounds
US4024260A (en) * 1973-05-17 1977-05-17 Smith Kline & French Laboratories Limited Ethylene derivatives
US4028379A (en) * 1975-05-15 1977-06-07 Smith Kline & French Laboratories Limited Process for preparing 2-amino-2-alkylthio-1-nitroethylene compounds
US4049671A (en) * 1974-09-02 1977-09-20 Smith Kline & French Laboratories Limited Process for preparing N-cyanoguanidines
US4067984A (en) * 1975-11-05 1978-01-10 Smith Kline & French Laboratories Limited Pyridylbutylamino ethylene compounds
US4083983A (en) * 1975-07-31 1978-04-11 Smith Kline & French Laboratories Limited Alkoxy pyridine compounds
US4104382A (en) * 1972-04-20 1978-08-01 Smith Kline & French Laboratories Limited Pharmaceutical compositions and methods of inhibiting H-1 and H-2 histamine receptors
US4156727A (en) * 1975-07-31 1979-05-29 Smith Kline & French Laboratories Limited Alkoxy pyridine compounds
US4165377A (en) * 1977-04-20 1979-08-21 Ici Americas Inc. Guanidino imidazoles and thiazoles
US4165378A (en) * 1977-04-20 1979-08-21 Ici Americas Inc. Guanidine derivatives of imidazoles and thiazoles
DE2928857A1 (de) * 1978-07-19 1980-02-07 Pliva Pharm & Chem Works Verfahren zur herstellung von n-cyano- n'-methyl-n''- grosse eckige klammer auf 2- geschweifte klammer auf eckige klammer auf (5-methylimidazol-4-yl)-methyl eckige klammer zu -thio geschweifte klammer zu -aethyl grosse eckige klammer zu -guanidin
US4200761A (en) * 1978-04-26 1980-04-29 Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, N.Sol.O. Process for preparing N-cyano-N'methyl-N"-{2-[(4-methyl-5-imidazolyl)-methylthio]-ethyl} guanidine
US4250316A (en) * 1978-11-24 1981-02-10 Bristol-Myers Company Pyridyl guanidine anti-ulcer agents
US4256752A (en) * 1978-02-17 1981-03-17 Deutsche Gold- Und Silber-Scheideanstalt Vormals Roessler Treatment of ulcers with acylated aminoalkyl cyanoguanidines containing a heterocyclic residue
US4287198A (en) * 1971-03-09 1981-09-01 Smith Kline & French Laboratories Limited Pharmacologically active guanidine compounds
US4293699A (en) * 1972-02-03 1981-10-06 Smith Kline & French Laboratories Limited Pharmacologically active guanidine compounds
US4342765A (en) * 1979-01-18 1982-08-03 Imperial Chemical Industries Limited Guanidine derivatives and pharmaceutical compositions containing them
US4514413A (en) * 1982-04-10 1985-04-30 Basf Aktiengesellschaft Gastric acid secretion inhibiting N-(imidazol-1-ylalkyl)thiourea derivatives
US20120259094A1 (en) * 2009-10-15 2012-10-11 Monash University Affinity ligands and methods for protein purification
WO2022034121A1 (en) 2020-08-11 2022-02-17 Université De Strasbourg H2 blockers targeting liver macrophages for the prevention and treatment of liver disease and cancer

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4024271A (en) * 1971-03-09 1977-05-17 Smith Kline & French Laboratories Limited Pharmacologically active guanidine compounds
US4000302A (en) * 1972-04-20 1976-12-28 Smith Kline & French Laboratories Limited Pharmaceutical compositions and methods of inhibiting H-1 and H-2 histamine receptors
GB1421999A (en) * 1973-02-08 1976-01-21 Smith Kline French Lab Heterocyclic containing sulphoxides
GB1489879A (en) * 1974-12-20 1977-10-26 Leo Pharm Prod Ltd N'-cyano-n'-3-pyridylguanidines
IN146736B (hu) * 1975-10-02 1979-08-25 Smith Kline French Lab
GB1565966A (en) 1976-08-04 1980-04-23 Allen & Hanburys Ltd Aminoalkyl furan derivatives
NZ184893A (en) * 1976-09-21 1980-11-28 Smith Kline French Lab Pure crystalline form of cimetidine a(n-methyl-n-cyano-n-(-2-(5-methyl-4imidazolyl) methylthio) ethyl)-guanidine andpharmaceutical compositions containing it
DD129906A5 (de) * 1976-09-21 1978-02-15 Smith Kline French Lab Verfahren zur herstellung einer kristallographisch reinen polymorphen form von cimetidin(cimetidin a)
DE2817078C2 (de) * 1977-04-20 1995-06-14 Zeneca Ltd Guanidinderivate
GB1601459A (en) 1977-05-17 1981-10-28 Allen & Hanburys Ltd Aminoalkyl thiophene derivatives
NZ187376A (en) * 1977-06-03 1981-05-29 Bristol Myers Co N-cyano-n-(2-(4-methyl-5-imidazolyl)methylthio)ethyl)-n-alkynyl guanidines intermediates pharmaceutical compositions
DE2800148A1 (de) 1978-01-03 1979-07-12 Basf Ag Verfahren zur herstellung von 4-methyl-5-chlormethyl-imidazol
DE2963363D1 (en) 1978-05-24 1982-09-09 Ici Plc Antisecretory thiadiazole derivatives, processes for their manufacture and pharmaceutical compositions containing them
JPS5914460B2 (ja) * 1978-12-27 1984-04-04 相互薬工株式会社 Ｈ↓２受容体「きつ」抗剤シメチジンの製造法
NL8000869A (nl) * 1979-02-16 1980-08-19 Eisai Co Ltd Cyanoguanidine-derivaten en werkwijze voor de bereiding daarvan.
US4220654A (en) * 1979-06-04 1980-09-02 Merck & Co., Inc. Cyclic imidazole cyanoguanidines
DE3107599C2 (de) * 1981-02-27 1982-12-16 Ludwig Heumann & Co GmbH, 8500 Nürnberg N-Cyan-N'-methyl-N"-{2-[(5-methylthio-imidazol-4-yl)-methylthio]-äthyl}-guanidin, Verfahren zu seiner Herstellung und diese Verbindung enthaltende Arzneimittel
JPS5933267A (ja) * 1982-08-19 1984-02-23 Fujimoto Seiyaku Kk グアニジン誘導体およびその製造法
NL8303965A (nl) * 1982-12-08 1984-07-02 Degussa Nieuwe etheendiamine- en guanidine-derivaten; werkwijze voor het bereiden daarvan; geneesmiddelen die ze bevatten; werkwijze voor het bereiden van dergelijke geneesmiddelen; toepassing van de verbindingen voor het bereiden van geneesmiddelen en in de geneeskunde.
US4565815A (en) * 1982-12-30 1986-01-21 Biomeasure, Inc. Pyrazolo[1,5-a]-1,3,5-triazines
US4495193A (en) * 1982-12-30 1985-01-22 Biomeasure, Inc. Imidazole compounds which reduce gastric acid secretion
US4617311A (en) * 1985-05-17 1986-10-14 Eli Lilly And Company Antiasthmatic method
DE3531504A1 (de) * 1985-09-04 1987-03-12 Basf Ag 3-aminomethylpyrrol-1-yl-alkylamine und diese verbindungen enthaltende therapeutische mittel
IE58373B1 (en) * 1986-06-18 1993-09-08 Bloomfield Frederick Jacob 5-Lipoxygenase pathway inhibitors
JPH085859B2 (ja) * 1986-07-01 1996-01-24 日本バイエルアグロケム株式会社 新規アルキレンジアミン類
IE71183B1 (en) * 1988-12-27 1997-01-29 Takeda Chemical Industries Ltd Guanidine derivatives their production and insecticides
US5160549A (en) * 1990-10-31 1992-11-03 Foster Wheeler Energy Corporation Tube fin trimming machine and method for use
IT1299198B1 (it) * 1998-03-05 2000-02-29 Nicox Sa Sali nitrati di farmaci antiulcera

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3734924A (en) * 1970-10-14 1973-05-22 Smith Kline French Lab Carboxamidines
US3759944A (en) * 1970-10-14 1973-09-18 Smith Kline French Lab Isothioureas and their derivatives
US3806511A (en) * 1971-04-30 1974-04-23 Sumitomo Chemical Co 1-(3-pyridyl)-2-benzylthio-3-loweralkyl-isothio ureas and derivatives thereof

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3036083A (en) * 1959-05-15 1962-05-22 Ciba Geigy Corp Certain 2-pyridyl lower alkyl guanidines
US3074955A (en) * 1960-11-30 1963-01-22 Us Vitamin Pharm Corp Pyridylalkyl dicyandiamides and guanylureas
BE758145A (fr) * 1969-10-29 1971-04-28 Smith Kline French Lab Iso-thio-urees et derives
BE758146A (fr) * 1969-10-29 1971-04-28 Smith Kline French Lab Derives de l'amidine
GB1338169A (en) * 1971-03-09 1973-11-21 Smith Kline French Lab Ureas thioureas and guanidines
IE36050B1 (en) * 1971-03-09 1976-08-04 Smith Kline French Lab Ureas thioureas and guanidines

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3734924A (en) * 1970-10-14 1973-05-22 Smith Kline French Lab Carboxamidines
US3759944A (en) * 1970-10-14 1973-09-18 Smith Kline French Lab Isothioureas and their derivatives
US3806511A (en) * 1971-04-30 1974-04-23 Sumitomo Chemical Co 1-(3-pyridyl)-2-benzylthio-3-loweralkyl-isothio ureas and derivatives thereof

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4287198A (en) * 1971-03-09 1981-09-01 Smith Kline & French Laboratories Limited Pharmacologically active guanidine compounds
US4293699A (en) * 1972-02-03 1981-10-06 Smith Kline & French Laboratories Limited Pharmacologically active guanidine compounds
US4104382A (en) * 1972-04-20 1978-08-01 Smith Kline & French Laboratories Limited Pharmaceutical compositions and methods of inhibiting H-1 and H-2 histamine receptors
US3979398A (en) * 1973-02-08 1976-09-07 Smith Kline & French Laboratories Limited Sulphoxides
US4002759A (en) * 1973-05-17 1977-01-11 Smith Kline & French Laboratories Limited Pyridylbutylamino ethylene compounds
US4024260A (en) * 1973-05-17 1977-05-17 Smith Kline & French Laboratories Limited Ethylene derivatives
US3953460A (en) * 1973-05-17 1976-04-27 Smith Kline & French Laboratories Limited Ethylene derivatives
US4049671A (en) * 1974-09-02 1977-09-20 Smith Kline & French Laboratories Limited Process for preparing N-cyanoguanidines
US4028379A (en) * 1975-05-15 1977-06-07 Smith Kline & French Laboratories Limited Process for preparing 2-amino-2-alkylthio-1-nitroethylene compounds
US4083983A (en) * 1975-07-31 1978-04-11 Smith Kline & French Laboratories Limited Alkoxy pyridine compounds
US4264608A (en) * 1975-07-31 1981-04-28 Smith Kline & French Laboratories Limited Pharmacologically active compounds
US4426526A (en) 1975-07-31 1984-01-17 Smith Kline & French Laboratories Limited Alkoxypyridyl alkylamines
US4156727A (en) * 1975-07-31 1979-05-29 Smith Kline & French Laboratories Limited Alkoxy pyridine compounds
US4067984A (en) * 1975-11-05 1978-01-10 Smith Kline & French Laboratories Limited Pyridylbutylamino ethylene compounds
US4234735A (en) * 1977-04-20 1980-11-18 Imperial Chemical Industries Limited Guanidino imidazoles and thiazoles
US4262126A (en) * 1977-04-20 1981-04-14 Imperial Chemical Industries Limited Guanidine derivatives of imidazoles and thiazoles
US4165377A (en) * 1977-04-20 1979-08-21 Ici Americas Inc. Guanidino imidazoles and thiazoles
US4165378A (en) * 1977-04-20 1979-08-21 Ici Americas Inc. Guanidine derivatives of imidazoles and thiazoles
US4256752A (en) * 1978-02-17 1981-03-17 Deutsche Gold- Und Silber-Scheideanstalt Vormals Roessler Treatment of ulcers with acylated aminoalkyl cyanoguanidines containing a heterocyclic residue
US4200761A (en) * 1978-04-26 1980-04-29 Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, N.Sol.O. Process for preparing N-cyano-N'methyl-N"-{2-[(4-methyl-5-imidazolyl)-methylthio]-ethyl} guanidine
DE2928857A1 (de) * 1978-07-19 1980-02-07 Pliva Pharm & Chem Works Verfahren zur herstellung von n-cyano- n'-methyl-n''- grosse eckige klammer auf 2- geschweifte klammer auf eckige klammer auf (5-methylimidazol-4-yl)-methyl eckige klammer zu -thio geschweifte klammer zu -aethyl grosse eckige klammer zu -guanidin
DE2928857B2 (de) 1978-07-19 1981-07-23 Pliva pharmazeutische und chemische Fabrik, Zagreb Verfahren zur Herstellung von N-Cyano-N'-methyl-N''-[2-{[(5-methylimidazol-4-yl)-methyl]-thio}-ethyl]-guanidin
US4250316A (en) * 1978-11-24 1981-02-10 Bristol-Myers Company Pyridyl guanidine anti-ulcer agents
US4342765A (en) * 1979-01-18 1982-08-03 Imperial Chemical Industries Limited Guanidine derivatives and pharmaceutical compositions containing them
US4514413A (en) * 1982-04-10 1985-04-30 Basf Aktiengesellschaft Gastric acid secretion inhibiting N-(imidazol-1-ylalkyl)thiourea derivatives
US20120259094A1 (en) * 2009-10-15 2012-10-11 Monash University Affinity ligands and methods for protein purification
US8748582B2 (en) * 2009-10-15 2014-06-10 Monash University Affinity ligands and methods for protein purification
WO2022034121A1 (en) 2020-08-11 2022-02-17 Université De Strasbourg H2 blockers targeting liver macrophages for the prevention and treatment of liver disease and cancer

Also Published As

Publication number Publication date
GB1397436A (en) 1975-06-11
JPS4975574A (hu) 1974-07-20
FR2199467A2 (hu) 1974-04-12
NL7312198A (hu) 1974-03-07
AU472456B2 (en) 1976-05-27
IE38353B1 (en) 1978-03-01
US3897444A (en) 1975-07-29
DE2344779B2 (de) 1979-04-26
HK55276A (en) 1976-09-17
MY7600229A (en) 1976-12-31
NL187240C (nl) 1991-07-16
SG28676G (en) 1987-04-03
DE2344779A1 (de) 1974-03-14
JPS561309B2 (hu) 1981-01-13
CY855A (en) 1976-09-10
CA1045142A (en) 1978-12-26
IE38353L (en) 1974-03-05
AU5890373A (en) 1975-02-06
DE2344779C3 (de) 1981-05-27
KE2626A (en) 1976-05-28
FR2199467B2 (hu) 1977-01-28

Similar Documents

Publication Publication Date Title
US3876647A (en) Certain n-cyanoguanidines
US3881015A (en) Pharmaceutical compositions and methods of inhibiting histamine activity with isothiourea compounds
US4385058A (en) Pyrimidone derivatives
US4112104A (en) Pharmacologically active compounds
US4499101A (en) Pharmacologically active isoxazole and triazole compounds
US3920822A (en) Inhibition of histamine activity with cyanoguanidines
US3905984A (en) Pyridyl substituted thioalkyl-and oxyalkyl-thioureas and ureas
US4301165A (en) Pharmacologically active compounds
US4426526A (en) Alkoxypyridyl alkylamines
US3975530A (en) N-cyano-N'-heterocyclic-alkyl quanidine inhibitors of H2 histamine receptors
US4265896A (en) Amidinosulphonic acid derivatives
US4013659A (en) Certain n,n'-disubstituted guanidine compounds and their use
US4070472A (en) Guanidino, thioureido, isothioureido and nitrovinylamino derivatives of pyridine
US3971786A (en) Pyridyl alkylguanidine compounds, composition therewith, and methods of inhibiting H-2 histamine receptors
US4285952A (en) Pyridyl, thiazolyl and isothiazolyl alkyl bisamidines
US4060621A (en) Pyridyl alkylguanidine compounds
CS196352B2 (en) Process for preparing derivatives of amidinformic acid
US4156727A (en) Alkoxy pyridine compounds
US3932427A (en) Pyridyl substituted aminoalkyl-thioureas and ureas
GB1565205A (en) Heterocyclic sulphoxides
US4133886A (en) Guanidino, thioureido, isothioureido and nitrovinylamino derivatives of pyridine
US4018928A (en) Pyridyl substituted aminoalkyl-thioureas and ureas
NO772669L (no) Fremgangsm}te for fremstilling av farmakologisk aktive forbindelser
US4152443A (en) Imidazolyl thioureas, ureas and guanidines
US4215125A (en) Pyridyl ureas, thioureas and guanidines