EP0511270A1 - New thiazole derivatives - Google Patents

New thiazole derivatives

Info

Publication number
EP0511270A1
EP0511270A1 EP91902804A EP91902804A EP0511270A1 EP 0511270 A1 EP0511270 A1 EP 0511270A1 EP 91902804 A EP91902804 A EP 91902804A EP 91902804 A EP91902804 A EP 91902804A EP 0511270 A1 EP0511270 A1 EP 0511270A1
Authority
EP
European Patent Office
Prior art keywords
ppm
substituted
multiplet
singlet
bromo
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.)
Withdrawn
Application number
EP91902804A
Other languages
German (de)
English (en)
French (fr)
Inventor
John Charles Eriks
Geert Jan Sterk
Henderikus Van Der Goot
Hendrik Timmerman
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.)
Cedona Pharmaceuticals BV
Original Assignee
Cedona Pharmaceuticals BV
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
Application filed by Cedona Pharmaceuticals BV filed Critical Cedona Pharmaceuticals BV
Publication of EP0511270A1 publication Critical patent/EP0511270A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07D277/32—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 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
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to new thiazole derivatives which are: a. a N-[ ⁇ -(thiazol-4 or 5-yl)alkyl]isourea, isothiourea or a guanidine derivative with formula 2 , wherein X represents a sulphur atom and Y represents a nitrogen atom or alternatively X represents a nitrogen atom and Y represents a sulphur atom, n is 1-6, R 1 represents a hydrogen atom or a straight or branched alkyl group with 1-4 carbon atoms and R 2 represents a hydrogen atom, a straight or branched alkyl group with 1-4 carbon atoms or an amino group, Z represents a sulphur atom, an oxygen atom or a NH-group respectively, R 3 represents a hydrogen atom, a phenyl or an alkyl group with 1-4 carbon atoms respectively and R 4 represents a hydrogen atom, a cyano or a benzoyl group respectively;
  • R-substituted ( ⁇ -)phenyl(alkyl) groups or Q represents a R-substituted ( ⁇ -)phenyl(alkyl) group or Q represents a whether or not symmetrical mono-or disubstituted methylidene fragment, wherein R 1 represents a R-substituted (10,11-dihy- dro) optionally aza 5H-dibenzo-[a,d]-cyclohepten-5-yl group or R' represents two whether or not symmetrically with R substituted phenyl groups, wherein R represents hydro
  • R-substituted phenyl rings may be replaced by a (heterocyclic) (aromatic) ring whether or not R-substituted or by a combination of a (condensed) (aromatic) (heterocyclic) R-substituted ring with one or more (condensed) (aromatic) (heterocyclic) rings whether or not symmetrically R-substituted.
  • R-substituted (condensed) (heterocyclic) (aromatic) rings are for example: 2-, 3-, 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, 2-, 3-, 4-[dihydro]pyridyl, 4- or 5-imidazolyl, 2-, 4- or 5-thiazolyl, 2- or 3-furyl, 2- or 3-thienyl, dihydropyridazinon-2 or 6-yl, 2-benzoimidazolyl, etc.
  • the invention also relates to the acid addition salts of the compounds with the formulas 2 and 3.
  • Histamine receptors are classified according to the present knowledge into three categories which are described, mainly for historical reasons, with the qualifications of H 1 - , H 2 - and H 3 -receptor.
  • Each of these classes of receptors presumably has its own and biologically specific function, in as far as they are present and dependent on the location of such a receptor type in the organism involved.
  • a treatment with endogenous or exogenous compounds may be necessary which may stimulate (agonistic activity) or inhibit (antagonistic activity) the receptor system. From the above follows the great importance of compounds capable to agonize or to antagonize in a selective way the different classes of histamine receptors.
  • histamine H 2 -receptor active, compounds It is important to be able to dispose of selective histamine receptor active compounds in order to discriminate between the different receptor types not only from a scientific (pharma-cological) point of view, but also on therapeutic respect notably the stimulation of the histamine H 2 -receptor offers wide perspectives for the treatment of congestive heart diseases, accompanied by heart failure, and certain allergic disorders so that there exists a large interest from within the pharmaceutical industry for the development and application of selective, histamine H 2 -receptor active, compounds.
  • Impromidine (5) described by G.J. Durant et al. in Nature 276, p.403-405 (1978) and Dimaprint (6), described by C.R. Ganellin in Pharmacology of Histamine Receptors, p.40-44 (1982), publishers Wright.PSG., exhibit a moderately to fairly high affinity for the histamine H 2 -receptor.
  • Impromidine (5) the most active guanidine derivatives of formula 7 and Arpromidine (8) all contain under physiological circumstances a protonated N-[3-(imidazol-4-yl)propyl]- guanidine fragment.
  • the imidazole moiety can be replaced by a (substituted)aminothiazole.
  • the invention also relates to a process for the preparation of a ⁇ -aminoalkylthiazole derivative in which one prepares a histamine H 2 -receptor active compound, whether or not in combination with an additionally wanted biological activity, by preparing from a compound with formula 1 or its acid addition salt a compound with a substituted 4- or 5-( ⁇ - thiazoly1-alkyl) guanidine fragment.
  • Examples of such compounds are the compounds with formulas 2 and 3 and their acid addition salts.
  • Additional substitution at the other nitrogen atom may be applied in order to change the activity for the H 2 -receptor into an antagonistic activity.
  • the 2- amino-5-(2-aminoethyl)-4-methylthiazole (12) can be displaced competitatively by cimetidine, while the intrinsic activity (related to the chronotropic effect) is equal to that of histamine, thus rendering it to be a full agonist for the H 2 - receptor with an activity twice as high as that of histamine.
  • the 2-amino-5-(3-aminopropyl)-4-methylthiazole (26b) is a full H 2 -receptor agonist with an activity 30 times as high as that of the corresponding 4 (5)-3-aminopropyl)-imidazole.
  • the 2-amino-5-(2-aminoethyl)-4-methylthiazole (12) shows however contrary to histamine (13), in the testing systems used not a single activity towards the H 1 and H 3 -receptors.
  • the essence of the invention now relates to the replacement of the N-[3-(imidazol-4-yl)propyl]guanidine fragment (9) from the previously mentioned different classes of H 2 -receptor active compounds with i.a. other combined H 1 -receptor antagonistic, calcium antagonistic, phosphodiesterase inhibitory activity etc, by the more H 2 -receptor specific and more active N-[3-(substituted thiazol-4 or 5-yl)propyl]guanidine fragments.
  • the thiazole derivatives with formulas 2-4 thus obtained show a high to very high activity on the H 2 -receptor.
  • the 4- or 5-( ⁇ -aminoalkyl) thiazole derivatives mentioned in the introduction with formula 1 may be obtained using a process not previously described in the literature in high yields by ring closure of a 2-bromo- ⁇ -phthalimidoalkanal (18), a 3-bromo- ⁇ -phthalimidoalkan-2-one (24) or a 1-bromo- ⁇ - phthalimidoalkan-2-one (27) with thioformamide, an alkylthioamide or thiourea in dimethylformamide under mild conditions, followed by hydrazinolysis or hydrolysis with diluted hydrochloric acid of the resulting phthalimido derivatives (19, 25 or 28) as depicted in reaction schemes A and B.
  • reaction scheme A one uses as starting materials for the preparation of the 2-bromo- ⁇ -phthalimidoalkanals (18) ⁇ -phthalimidoalkanols (16) which may be obtained using processes known from the literature. Conversion of these ⁇ -phthalimidoalkanols (16) into the corresponding aldehydes (17) is being carried out according to a general method using oxalylchloride/dimethylsulphoxyde, followed by proton abstraction with a mild base such as triethylamine followed by hydrolysis with water as described by K.Omura et al. in Tetrahedron 34, p. 1651-1660 (1978).
  • the necessary ⁇ -haloketones (22) which are to be used for the preparation of the 1- and 3-bromo- ⁇ -phthalimidoalkan-2-ones (24 and 27) are either commercially available or may be obtained in good yield according to a process described in the literature such as for example the process described in the Dutch patent application 65 11581.
  • N-[ ⁇ -(thiazol-4 or 5-yl) alkyl] isourea or isothiourea derivatives with formula 2 are obtained by reaction of a 4- or 5-( ⁇ -aminoalkyl)thiazole with formula 1, with a dialkyl-N- cyano-iminodithiocarbonate, a diphenyl-N-cyanocarbonimidate or a diphenyl-N-benzoylcarbonimidate respectively in a suitable solvent according to methods known from the literature and as indicated in reaction scheme C.
  • N-[ ⁇ -(thiazol-4 or 5-yl) alkyl]guanidine derivatives are obtained by reacting a 4- or 5-( ⁇ -aminoalkyl)thiazole with formula 1 together with a S-alkylisothiouronium derivative.
  • the N-[ ⁇ -(thiazol-4 or 5-yl)alkyl]isourea or isothiourea derivatives thus obtained (32) are condensed with a suitable amine (33).
  • N-( ⁇ -substituted alkyl)-N'- subtituted-N"-[ ⁇ -(thiazol-4 or 5-yl)alkyIguanidines with formula 3 (34) thus obtained are purified and subjected to a mild hydrolysis in diluted hydrochloric acid following which the resulting N-( ⁇ -substituted alkyl)-N'-[ ⁇ -(thiazol-4 or 5-yl) alkyl] -guanides with formula 4 (35) can be obtained in good yield eventually after conversion to a suitable acid addition salt.
  • N-( ⁇ -substituted alkyl)-N'substituted-N"-[ ⁇ -(thiazol-4 or 5-yl)alkyl]guanidines with formula 3 may be obtained by reacting a 4- or 5-( ⁇ -aminoalkyl)thiazole with formula 1 together with the corresponding N-( ⁇ -substituted alkyl) isourea or isothiourea derivatives (36) according to methods known from the literature and as indicated in reaction scheme D or by condensation of a 4- or 5-( ⁇ -aminoalkyl)thiazole with formula 1 with a N-( ⁇ -substituted alkyl)-S- alkylthiouronium derivative (41) as indicated in reaction scheme E.
  • the invention also relates to a medicament or a scientific (pharmacological) adjuvant which contains as the active ingredient a compound according to one of the formulas 2-3 or an acid addition salt thereof.
  • a medicament or a scientific (pharmacological) adjuvant which contains as the active ingredient a compound according to one of the formulas 2-3 or an acid addition salt thereof.
  • Melting points were determined by a Mettler FP 5 device for the determination of melting points.
  • Mass spectra are determined on a Varian Mat CH 5 spectrometer or on a Mat 90 (Finnigan Mat, San Jose, U.S.A.).
  • chloroform phase is hjgh-vacuum concentrated.
  • the reaction mixture the inorganic salts are filtered off and the precipitate s rinsed with a little cold methanol, subsequently the filtrate is vacuum concentrated.
  • dichloromethane is dropwise added at such a rate that the temperature is maintained at -50°C. After the addition the stirring is continued for 15 minutes, subsequently a solution of 0.40 mole of an appropriate ⁇ -phthalimido-1-alkanol (16) in circa 400 ml of dry dichloromethane is dropwise added at such a rate that the temperature is maintained at -50°C. After the addition the stirring is continued at -50°C for 30 minutes, subsequently 222 g (2.20 mole) of triethylamine is added thereto. Subsequently the cooling is removed and the reaction mixture is slowly brought with stirring at room temperature, thereafter circa 1250 ml of demineralized water is added.
  • reaction mixture is high vacuum concentrated. Subsequently a little ethanol is added to the residue, it is stirred for 30 minutes, thereafter the crystalline material is filtered off, washed with subsequently ethanol and diethylether, thereafter the precipitate is vacuum dried. If necessary it is recrystallized from an appropriate solvent.
  • the product was crystallized from an ethanol/methanol mixture.
  • 6-Bromo-2-hexanone (22a) is prepared according to a modified process as described in Dutch patent application 6511581 dated March 7,1966, cf. Chem. Abstr. 65, P20151d.
  • a mixture of 552 g (4 mole) of particulated anhydrous potassium carbonate, 404 g (2 mole) of freshly distilled 1,3- dibromopropane, 260g (2 mole) of freshly distilled acetyl acetic ester and 700 ml of absolute ethanol is heated with vigorous stirring until circa 60°C. After the mild exothermal reaction beginning at circa 50°C, the reaction mixture is refluxed for circa 5 hours. After cooling the reaction mixture the inorganic salts are filtered off and the residue is rinsed with absolute ethanol. The combined filtrates are subsequently vacuum concentrated, thereafter to the residue circa 250 ml of demineralized water is added. Subsequently it is extracted with toluene. The collected toluene phases are combined, dried on anhydrous sodium sulfate, filtered and subsequently vacuum concentrated.
  • Boiling point 102-106°C/18 mm Hg Reference: (Chem. Abstr., 65, P 20151d).
  • Mass spectrum M/Z (intensity in %) . 180(0.14): 178(0.11);
  • the 4-phthalimido-2-butanone (23a) was prepared according to a modified process by H. Irai et al., Kogyo Kagaku
  • the 5-phthalimido-2-pentanone ( 23a) is prepared according to Dutch patent app lication 8800998 , April 18 , 1988.
  • the 6-phthalimido-2-hexanone (23b) is prepared as described for the 5-phthalimido-2-pentanone (23a) in Dutch patent application 8800998, April 18,1988.
  • the 1-bromo- ⁇ -phthalimido-2-alkanones (27) are prepared according to Dutch patent application 8800998, April 18,1988.
  • the 4-( ⁇ -phthalimidoalkyl)thiazoles (28) are prepared as described for the 5-( ⁇ -phthalimidoalkyl)thiazoles (25) in example IX.
  • Mass spectrum M/Z (intensity in %): 143 (19.3); 127(3.4); 114 (100).
  • Mass spectrum M/Z (intensity in %): 157.(13.3): 141 (53.6); 127(100); 113 (9.5).
  • Mass spectrum M/Z (intensity in %) : 171(28.9); 154(75.1); 127(100); 115(9.7).
  • Mass spectrum M/Z (intensity in %): 143(4.4); 127(9.9);
  • Mass spectrum M/Z (intensity in %): 143(12.4); 126(6.8);
  • the 5-(2-(aminoethyl)-4-methylthiazoledihydro- chloride (26c) may, if desired, also obtained in the following manner: A solution of 25.0 g (o,175 mole) of 5-(2-hydroxyethyl)- 4-methylthiazole (Fluka A.G., Chem. Fabrik, CH-9470 Buchs) in 150 ml of aqueous-48% hydrogen bromide solution is refluxed for 48 hours. After cooling the reaction mixture is
  • the 1 H-NMR-spectrum is identical to the spectrum as obtained with the preparation of the 5-(2-aminoethyl)-4-methylthiazole- dihydrochloride (26c) as described in example Xllg.
  • the precipitate obtained is subsequently filtered off and washed
  • the viscous oil obtained comprising crude N-[2-(2-amino-4- methylthiazole-5-yl)ethyl]-N'-cyano-N"-(3,3-diphenylpropyl)- guanidine (34a) is subsequently taken up without any purification in 100 ml of 2N aqueous hydrochloric acid, thereafter there is refluxed for 3 hours. After cooling there is vacuum concentrated and the residue dissolved in absolute methanol. After filtration a solution of 0.02 mole of
  • N-[3-(2-amino-4-methylthiazole-5-yl)propyl]- N'-(3,3-diphenylpropyl)guanidine (35b) was prepared in a manner analogous to that of the N-[2-(2-amino-4-methyl- thiazole-5-yl)ethyl]-N'-(3,3-diphenylpropyl)guanidine (35a), as described in example XVIIIa, from N-cyano-N'-(3,3- diphenylpropyl)-0-phenylisoureum (37a) and 2-amino-5-(3- aminopropyl)-4-methylthiazole dihydrochloride (26b) with the proviso that the reaction mixture was refluxed for
  • reaction mixture is decolorised with activated carbon, filtered and vacuum concentrated. The residue is subsequently taken up in 100 ml of 2N aqueous hydrochloric acid
  • the viscous oil obtained comprising N-[3-(2-amino-4-methylthiazole-5-yl)propyl]-N'- cyano-N"-(3,3-diphenylpropyl)guanidine (34b) is hydroly zed after column chromatography (Kieselgel 60-80, eluent
  • a solution of 1.34 g (0.005 mole) of N-[3-(2-amino- 4-methy1thiazole-5-yl)propyl]-N'-cyano-S-methylisothioureum (32c) and 1.41 g (0.005 mole) of 2-[3-amino-1-(3,4-dichlorophenyl)propyl]pyridine* in circa 50 ml of pyridine is
  • demineralized water is added thereto and the precipitate obtained is filtered off, then recrystallized from a methanol/water mixture.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical 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)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
EP91902804A 1990-01-19 1991-01-18 New thiazole derivatives Withdrawn EP0511270A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
NL9000132 1990-01-19
NL9000132A NL9000132A (nl) 1990-01-19 1990-01-19 Nieuwe thiazoolderivaten.

Publications (1)

Publication Number Publication Date
EP0511270A1 true EP0511270A1 (en) 1992-11-04

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EP91902805A Withdrawn EP0511271A1 (en) 1990-01-19 1991-01-18 Thiazole derivatives
EP91902804A Withdrawn EP0511270A1 (en) 1990-01-19 1991-01-18 New thiazole derivatives

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Application Number Title Priority Date Filing Date
EP91902805A Withdrawn EP0511271A1 (en) 1990-01-19 1991-01-18 Thiazole derivatives

Country Status (9)

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EP (2) EP0511271A1 (nl)
JP (2) JPH05503096A (nl)
AU (2) AU7058191A (nl)
CA (2) CA2074180A1 (nl)
IE (2) IE910172A1 (nl)
IL (2) IL96997A0 (nl)
NL (1) NL9000132A (nl)
WO (2) WO1991010657A1 (nl)
ZA (2) ZA91418B (nl)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1713780B1 (en) * 2004-02-05 2012-01-18 Probiodrug AG Novel inhibitors of glutaminyl cyclase

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2636037A (en) * 1947-10-10 1953-04-21 Sharp & Dohme Inc 2-amino-4-piperidinoethyl-thiazole
FR2073427A1 (en) * 1969-11-28 1971-10-01 Sogeras 4-methyl-5-ethyl-n-heterocyclic thiazoles - with antianoxic activity
FR2361111A1 (fr) * 1976-08-11 1978-03-10 Roussel Uclaf Nouveaux derives de 5-thiazole alkylamine, un procede pour leur preparation et leur application comme medicaments
US4166860A (en) * 1977-10-11 1979-09-04 William H. Rorer, Inc. Imidazole amidinoureas for stimulating H2 -receptors
US4474794A (en) * 1982-03-19 1984-10-02 Eli Lilly And Company N-Thiazolylmethylthioalkyl-N1 -alkenyl (or alkynyl)guanidines and related compounds
NL8601585A (nl) * 1986-06-19 1988-01-18 Vereniging Voor Christelijk Wetenschappelijk Onderwijs N-(2-gesubstitueerde alkyl)-n-imidazol-4-yl alkyl guanidine.
NL8800998A (nl) * 1988-04-18 1989-11-16 Cedona Pharm Bv Werkwijze voor het bereiden van een al of niet gesubstitueerd 4(5)-(omega-aminoalkyl) imidazool.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9110657A1 *

Also Published As

Publication number Publication date
ZA91419B (en) 1991-10-30
NL9000132A (nl) 1991-08-16
WO1991010657A1 (en) 1991-07-25
AU7058191A (en) 1991-08-05
JPH05503694A (ja) 1993-06-17
AU7064491A (en) 1991-08-05
CA2074175A1 (en) 1991-07-20
WO1991010656A1 (en) 1991-07-25
IE910172A1 (en) 1991-07-31
IL96998A0 (en) 1992-03-29
IE910171A1 (en) 1991-07-31
EP0511271A1 (en) 1992-11-04
CA2074180A1 (en) 1991-07-20
IL96997A0 (en) 1992-03-29
JPH05503096A (ja) 1993-05-27
ZA91418B (en) 1991-10-30

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