IE910995A1 - "The use of guanidine derivatives for the preparation of a pharmaceutical product having NPY antagonistic activity" - Google Patents

"The use of guanidine derivatives for the preparation of a pharmaceutical product having NPY antagonistic activity"

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IE910995A1
IE910995A1 IE099591A IE99591A IE910995A1 IE 910995 A1 IE910995 A1 IE 910995A1 IE 099591 A IE099591 A IE 099591A IE 99591 A IE99591 A IE 99591A IE 910995 A1 IE910995 A1 IE 910995A1
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propyl
pyridin
guanidine
ethyl
bromo
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IE099591A
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IE65252B1 (en
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Martin C Michel
Johann Peter Morsdorf
Heidrun Engler
Helmut Schickaneder
Kurt-Henning Ahrens
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Heumann Pharma Gmbh & Co
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/155Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic 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
    • A61K31/4151,2-Diazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives

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  • Organic Chemistry (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pyridine Compounds (AREA)
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  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

The use of guanidine derivatives with the basic framework <IMAGE> for the manufacture of a medicament with NPY-antagonistic activity and, in particular, for the manufacture of a medicament for the treatment of high blood pressure is described.

Description

The use of guanidine derivatives for the preparation of a pharmaceutical product having NPY antagonistic activity Description Neuropeptide Y (NPY) is a peptide of 36 amino acids which was originally isolated from pigs' brains (K. Tatemoto, Proc. Natl. Sci., USA 79. 5485 (1982)) but has also been found in the human central and peripheral nervous system.
NPY controls the vascular sympathetic tone together with noradrenalin. The systemic - ' use of NPY leads to prolonged rise in the vascular resistance. Boublik et al (J.H. Boublik, N.A. Scott, M.R. Brown and J.E. Rivier, J. Med Chem. 32., 597 (1989)) also proved the participation of NPY in the development7 of high blood pressure.
NPY antagonists therefore constitute a potential new method in the treatment of high blood pressure, but no NPY antagonists have hitherto been known.
Guanidine derivatives having the following basic structure (I) la IE 91995 which have histamine-H2 agonistic and histamine-H^ antagonistic activities are known from DE-OS 35 12 084, 28 214, 35 28 215 and 36 31 334 and from EP-OS 0 199 845. According to the information given in the said documents, these compounds are suitable, by virtue of their pharmacological properties, for use as cardiotonic agents, i.e. compounds which increase the force of contraction of the heart. They are therefore proposed for the therapy of acute and chronic cardiac insufficiency.
It has now been found that the compounds described above surprisingly also have neuropeptide-Y antagonistic activities independently of the above mentioned cardiotonic and positive inotropic activity.
The present invention therefore relates to the use of guanidine derivatives corresponding to the general formula II HH (II) in which R denotes the group wherein R1 denotes a phenyl group which may be unsubstituted or mono- or disubstituted with halogen atoms, C1-C3-alkyl groups or C1-C3-alkoxy groups, or a pyridine ring which may be unsubstituted or mono- or disubstituted with halogen atoms, C1-C3-alkyl groups or C1-C3-alkoxy groups, R2 denotes a hydrogen atom, a Cj-C3-alkyl group, a phenyl optionally mono- or disubstituted with halogen atoms, C1-C3-alkyl groups or -alkoxy groups, or a benzyl or hetero aryl methyl group which may be unsubstituted or mono- or disubstituted with halogen atoms, C1-C3-alkyl groups or C1-C3-alkoxy groups, and n has the value 2, 3 or 4, or in which R denotes the group R3d I R4-C-Z-(CH2)p15 L R5 wherein R3 stands for a pyridine ring or phenyl ring which may be unsubstituted or mono- or disubstituted with halogen atoms, C1-C3-alkyl groups or C1-C3-alkoxy groups, R4 denotes a hydrogen atom or a phenyl group optionally mono- or disubstituted with halogen atoms, C3-C3-alkyl groups or C-2_-C3-alkoxy groups, R5 stands for a hydrogen atom or a methyl or hydroxyl group and Z stands for a single bond, an oxygen atom or a sulphur atom, and p has the value 2 or 3, m has the value 2 or 3 and R' denotes a hydrogen atom or a methyl group, and the physiologically acceptable salts thereof, for the preparation of a pharmaceutical product having NPY antagonistic activity.
The substances considered according to the invention are suitable in particular for the treatment of high blood pressure due to their neuropeptide-Yantagonistic activity.
IE 91995 Another object of this invention is therefore the use of the above-defined guanidine derivatives for the preparation of a pharmaceutical product for the treatment of high blood pressure.
In the general formula II indicated above, R may denote the group R N-(CH2)n~ R2 In this group, R1 stands for an unsubstituted or mono- or disubstituted phenyl group. In the case of substitution, the substituents may in particular be 1 or 2 halogen atoms such as fluorine, chlorine or bromine atoms, preferably fluorine or chlorine atoms, 1 or 2 C1-C3-alkyl groups, preferably methyl or ethyl groups, and 1 or 2 C^-Cg-alkoxy groups such as methoxy or ethoxy groups. Monosubstitution is preferably in the 4-position and disubstitution is preferably in the 3- and 4-position or the 3- and 5-position of the phenyl ring.
The substituent R1 may also be an unsubstituted or a mono- or disubstituted pyridine ring. Examples of suitable substituents on the pyridine ring include halogen atoms such as fluorine, chlorine or bromine atoms, preferably bromine or chlorine atoms, most preferably bromine atoms, -alkyl groups such as methyl or ethyl groups and ζ^-Οβ-alkoxy groups such as methoxy, ethoxy or propoxy groups, preferably methoxy groups.
Linkage of the pyridine ring denoted by R1 to the nitrogen atom in the group R may take place in the 2-, 330 or 4-position of the pyridine ring, the 2- or 3-position being preferred. Linkage in the 2-position of the pyridine ring is particularly preferred.
R2 stands for a hydrogen atom, a C^-Cg-alkyl group, in particular a methyl, ethyl or propyl group, a phenyl IE 91995 group, which may.be unsubstituted or mono- or disubstituted, a benzyl group, which may be unsubstituted or mono- or disubstituted, or a hetero aryl methyl group, which may be unsubstituted or mono- or disubstituted. In the case of substitution, the phenyl group denoted by R2 may be substituted in the same manner and with the same substituents as described above in connection with the substitution of the phenyl group denoted by R1.
In the case of substitution, the benzyl group may 10 be substituted with 1 or 2 halogen atoms such as fluorine, chlorine or bromine atoms, preferably chlorine or fluorine atoms, or C1-C3-alkoxy groups, such as methoxy or ethoxy groups, preferably methoxy groups. In the case of monosubstitution of the benzyl group denoted by R2, the substituent is preferably attached in the para position to the methylene group whereas in the case of disubstitution the 3- and 4-positions of the benzyl group are preferred.
When R2 stands for a hetero aryl methyl group, this group is preferably a thiophenylmethyl, a furanylmethy.l or 0 a pyridinylmethyl < group. The heteroarylmethyl group may also be unsubstituted or, preferably, mono- or disubstituted. The substituents may be halogen atoms such as fluorine, chlorine or bromine atoms, C^-Cg-alkyl groups such as methyl or ethyl groups and linear C1-C3-alkoxy groups such as methoxy groups.
The index n has the value 2, 3 or 4, the value 3 being preferred.
R may also stand for the group R30 R4-C-Z-(CH2)pR5 IE 91995 In this group, R3 may denote an unsubstituted or a monoor disubstituted phenyl group or an unsubstituted or monoor disubstituted pyridine ring. In the case of substitution, suitable substituents are in particular one or two halogen atoms such as fluorine, chlorine or bromine atoms, preferably fluorine or chlorine atoms, 1 or 2 C1-C3-alkyl groups, preferably methyl or ethyl groups, and 1 or 2 C-]_C3-alkoxy groups, such as methoxy or ethoxy groups. Monosubstitution and disubstitution are preferred.
Substitution in the 4-position of the phenyl ring is preferred in the case of monosubstitution and substitution in the 3- and 4-position of the phenyl ring is preferred in the case of disubstitution.
The substituent R3 may also be an unsubstituted or a mono15 or disubstituted pyridine ring, preferably an unsubstituted pyridine ring or a monosubstituted pyridine ring. The substituents of the pyridine ring may be, for example, halogen atoms such as fluorine, chlorine or bromine atoms, preferably bromine or chlorine atoms, most preferably bromine atoms, C1-C3-alkyl groups such as methyl or ethyl groups and C]_-C3-alkoxy groups such as methoxy, ethoxy or propoxy groups, preferably methoxy groups.
Linkage of the pyridine ring denoted by R3 to the carbon atom in the group R may take place in the 2-, 3- or 4-position of the pyridine ring, the 2- or 3-position being preferred. Linkage in the 2-position of the pyridine ring is particularly preferred.
R4 denotes a hydrogen atom or an unsubstituted or mono- or disubstituted phenyl group.' In the case of substitution, the phenyl group denoted by R4 is substituted in the same manner as the phenyl group denoted by R3. R5 denotes a hydrogen atom or a methyl or hydroxyl group. Z stands for a single bond, an oxygen atom or a sulphur atom and p has the value 2 or 3.
In the general formula II, m has the value 2 or 3, IE 91995 preferably 3, and R' denotes a hydrogen atom or a methyl group, preferably a hydrogen atom.
According to the invention, it is preferred to use guanidine derivatives corresponding to the above general formula II in which R stands for one of the following groups: 2-(Diphenylmethoxy) ethyl, 2-[bis - ( 4-fluorophenyl) methoxy]ethyl, 2- [bis-(4-chlorophenyl) methoxy]ethyl, 3-(4-fluorophenyl)-3-(pyridin-2-yl)propyl, 3- (3,4-difluorophenyl)-3-(pyridin-2-yl)propyl, 3-(3,5-difluorophenyl)-3-(pyridin-2-yl)propyl, 3-(4-chlorophenyl)-3-(pyridin-2-yl)propyl, 3- (3,4-dichlorophenyl)-3-(pyridin-2-yl)propyl, 3-(4-fluorophenyl)-3-(pyridin-3-yl)propyl, 2-[N-(5-bromo-3-methyl-pyridin-2-yl)-benzylamino]ethyl, 2- [N-(5-bromo-3-methyl-pyridin-2-yl)-(4-chlorobenzyl) amino]-ethyl, 4- (5-bromo-3-methyl-pyridin-2-yl)butyl, 3—(5-bromo—3—methyl—pyridin-2—yl)propyl, 4-(5-bromo-pyridin-2-yl) butyl, 3- (5-bromo-pyridin-2-yl) propyl, 3-(4-chlorophenyl)-3-phenylpropyl, 3-(4-fluorophenyl)-3-phenylpropyl, 3,3-bis-(4-fluorophenyl)propyl or 3,3-bis-(4-chlorophenyl)propyl.
The use of the individual compounds indicated below is particularly preferred: N1-[3-(lH-Imidazol-4-yl)propyl]-N2-[2-[(pyridin-330 yl)methylthio]ethyl]-guanidine N1 - [ 3 - (1H-imidazο 1 -4 -y 1) propyl ] -N2-(3,3-diphenylpropyl) guanidine N1- [ 3- (lH-imidazol-4-yl) ]propyl] -N2- [2-[ (pyridin-2-yl) amino]ethyl]-guanidine N1-[3-[(5-bromo-3-methyl-pyridin-2-yl) amino]propyl]-N2-[3 7 IE 91995 (lH-imidazol-4-yl) propyl]-guanidine N1- [ 3 - (lH-imidazol-4-yl) propyl]-N2-[2-(diphenylmethoxy) ethyl]-guanidine (Compound A) N1-[3-(3,5-difluorophenyl)-3-(pyridin-2-yl)propyl]-N2-[35 (lH-imidazol-4-yl)propyl]-guanidine (Compound B) N1-[2-[N-(5-bromo-3-methyl-pyridin-2-yl)-benzylamino] ethyl]-N2-[3-(lH-imidazol-4-y1) propyl]-guanidine (Compound C) N1- [ 4 - (5-bromo-3-methyl-pyridin-2-yl)butyl]-N2-[3 (1H10 imidazol-4-yl)propyl]-guanidine (Compound D).
The compounds used according to the invention are known compounds which may be prepared by the processes described in the above-mentioned documents.
The neuropeptide-Y antagonistic action of the compounds used according to the invention was demonstrated by the method of Motulsky and Michel (H.J. Motulsky, M.C. Michel, Am. J. Physiol. 255. 880 (1988)).
In this method, the rise in intracellular Ca++ concentration in HE'L cells (human erythroleukemia cells) induced by NPY was measured fluorimetrically, using fura-2 as indicator. Under the given conditions, NPY produces a concentration-dependent rise in the intracellular Ca++ concentration by stimulation of the specific NPY receptor.
To measure the inhibitory action of the antagonists to be tested, the latter are added to the incubation medium at concentrations of from 10~4 to 10-6 and the NPY activity curve is then again determined.
The guanidine compounds used according to the invention shift the NPY concentration activity curve to the right. According to Schild-Plot analysis, the shift to the right is competitive so that the substances antagonise the NPY action by competition on the specific NPY receptor.
The following Table shows the values measured in terms of pA2 values: IE 91995 I Compound | pA2 | | Inhibition of the rise in Ca++ I A I 4.0 | B | 4.72 I I I c I 5.88 | I | D I 5.04 I_I; The following compounds were used for the above described test, the results of which are shown in the Table: Compound A: N1-[3-(lH-imidazol-4-yl)propyl]-N2-[2(diphenylmethoxy)ethyl]-guanidine IE 91995 Compound B: N1-[ 3-(3,5-dif luorophenyl)-3-(pyridin-2-yl) propyl]-N2-[3-(lH-imidazol-4-yl)propyl] guanidine NH Compound C: N1-[2-[N-(5-bromo-3-methyl-pyridin-2-yl)5 benzylamino]-ethyl]-N2-[3-(lH-imidazol-4-yl)propyl]-guanidine Compound D: N1-[4-(5-bromo-3-methyl-pyridin-2-yl)butyl]N2-[3-(lH-imidazol-4-yl) propyl]-guanidine The invention is described in the Examples.
IE 91995 Example 1 N1-[3-(lH-Imidazol-4-yl)propyl]-N2-[2-[(pyridin-3-yl)methylthio]-ethyl]guanidine-trihydrochloride CH2-5-CH2 NH -CH2-NH-C-NH-CH2-CH2-CH x 3 HCI 0.85 g (2 mmol) of N-Benzoyl-N'-[3-(imidazol-4-yl)5 propyl]-N''-{2-[(pyrid-3-yl)methylthio]ethylJguanidine are heated under reflux in 45 ml of 18% hydrochloric acid for 6 hours. When the reaction mixture is cold, the benzoic acid formed is removed by extraction with ether, the aqueous phase is evaporated to dryness in a vacuum and the residue is dried in a high vacuum. 0.78 g (91%) of a dry, highly hygroscopic foam is obtained.
C15H22N6S*3HC1 (427.8) Molar mass (MS): Calc.: 318.16267; found: 318.16299 MS: m/z (rel. Int. [%]) = 318 (M+, 3), 168(17), 125(29), 95(51), 93(100), 92(57), 44(89). 201H-NMR data (d6-DMSO, TMS as internal standard) 6 = 1.87 (m) 2 H, 2.62 (t) 2 H, 2.73 (t) 2 H, 3.0-3.7 (m) 4 H, 4.10 (s) 2 H, 7.3 - 8.3 (m) 6 H, 4 H replaceable by D20 8.5-9.1 (m) 4 H, ppm.
E 91995 Example 2 N1-[3-(lH-Imidazol-4-y1) propyl]-N2-(3 ,3-diphenylpropyl) guanidine-dihydrochloride CH-CHNH ch2-nh-c-nh-ch2-ch2 x 2 HCI 0.84 g (1.8 mmol) of N-Benzoyl-N3-(imidazol-45 yl) propyl]-N11 -(3,3-diphenylpropyl)guanidine are heated under reflux in 45 ml of 20% hydrochloric acid for 7 hours. The product is worked up as in Example 1.
Yield: 0.67 g (86%) of a hygroscopic, non-crystalline solid.
C22H27N5·2HC1 (434.4) MS: m/Z (rel. Int. [%]) = 362 ([M+H]+, 84), 167(54), 109(100), 91(60) (FAB method). 1H-NMR data: δ = 1.81 (m) 2 H, (dg-DMSO, TMS 2.27 (dt) 2 H, 15 as internal standard) 2.68 (t) 2 H. 3.02 (m) 2 H, 3.16 (m) 2 H, 4.10 (t) 1 H, 7.15 - 7.6 (m) 13 H, 20 2 H, d2o, replaceable by 7.80 (m) 2 H, replaceable by D2O, 8.99 (d) 1 H, ppm.
Example 3 N1-[3-(lH-Imidazol-4-yl)propyl]-N2-[2-(pyridin-2-ylamino)-ethyl]-guanidine-trihydrochloride 91995 l$L NH NHCH2CH2-NH-C-MH-CH2CH2CH2^NI H HC1 0.93 g (76%) of a colourless, hygroscopic solid are obtained from 1.21 g (3.1 mmol) of N1-benzoyl-N2-[3-(lHimidazol-4 -yl ) propyl ] -N3 - [2- (pyridin-2-yl-amino) -ethyl] guanidine and 20 ml of cone, hydrochloric acid.
C14H24C13N7 (396-75) 1H-NMR data: 6 = 1.80 - 2.21 (m) 2 H, (CD3OD, TMS as 2.69 - 3.00 (m) 2 H, internal standard) 3.37 (t) 2 H, 3.57 - 3.83 (m) 4 H, 4.8 (broad) 8 H, replace able by D2O, 6.96 (t) 1 H, 7.22 (d) 1 H, 7.44 (s) 1 H, 7.83 - 8.16 (m) 2 H, 8.87 (s) 1 H, ppm • Example 4 N1- [ 3- [ (5-Bromo-3-methyl-pyridin-2-yl)amino]-propyl]-N2[3-(lH-imidazol-4-yl)propyl]-guanidine-hydroiodide 1.50 g (3.37 mmol) of 3-[(5-Bromo-3-methyl-pyridin2-yl)amino)propyl]-isothiuronium iodide and 0.42 g (3.37 mmol) of 3-(lH-imidazol-4-yl)propylamine are boiled under reflux in 20 ml of acetonitrile for 3 hours.
After cooling, the reaction mixture is concentrated by evaporation under vacuum and the residue is purified chromatographically on silica gel, using ethyl acetate/methanol (70:30) as solvent. Concentration of the main fraction by evaporation under vacuum yields 0.41 g (23%) of a colourless, amorphous solid.
C16H25BrIN7 (522.24) 1H-NMR data: 6 = 1.93 (m) 4 H (CD3OD, TMS as 2.12 (s) 3 H internal standard 2.69 (t) 2 H 15 3.2 - 3. 6 (m) 6 H 4.9 (broad) 6 H, replaceable by ' d2o, 6.95 (s) 1 H 7.40 (d) 1 H 20 7.69 (s) 1 H 7.93 (d) 1 H, ppm.
IE 91995 Example 5 N1-[3-(lH-Imidazol-4-yl)propyl]-N2-[2-(diphenylmethoxy)ethyl]-guanidine-hydroiodide H x ΗΪ a) N1-Benzoyl-N2-[2-(diphenylmethoxy)ethyl]-thiourea 7.8 g (34 mmol) of 2-(diphenylmethoxy)-ethylamine and 5.6 g (34 mmol) of benzoyl isothiocyanate are stirred in 60 ml of ethyl acetate for 2 hours at room temperature. The precipitated solid is suction filtered, washed with ethyl acetate and recrystallised from ethanol. 11.1 g (83%) of colourless crystals, m.p.126-127 Pc, are obtained.
C23H22N2°2S (390.5) b) S-Methyl-N-[2-(diphenylmethoxy)ethyl]-isothiuronium iodide 11.1 g (28 mmol) of N-^-benzoyl-N2-[ 2-(diphenyl15 methoxy)ethyl]-thiourea are boiled up with 4.15 g (30 mmol) of potassium carbonate in 200 ml of methanol and 60 ml of water for 40 minutes. After removal of the solvent by evaporation under vacuum, the residue is taken up with 20 ml of water and the aqueous phase is extracted four times with 30 ml of dichloromethane. The combined organic phases are dehydrated with sodium sulphate, filtered and concentrated by evaporation under vacuum. The residue is taken up with 100 ml of ethanol and with 2.1 ml (33 mmol) methyl iodide IE 91995 stirred up for 20 hours at room temperature. 11.4 g (94%) of a colourless, highly viscous oil are obtained after removal of the solvent by evaporation under vacuum.
C17H21IN2OS (428.3) c) N1-[3-(lH-Imidazol-4-yl)propyl]-N2-[2-(diphenyl methoxy)ethyl]-guanidine hydroiodide 1.73 g (4 mmol) of S-methyl-N-[2-(diphenylmethoxy)ethyl]-isothiuronium iodide and 0.50 g (4 mmol) of 3-(lHimidazol-4-yl)-propylamine are boiled under reflux in 20 ml of acetonitrile for 3 hours. After removal of the solvent by evaporation under vacuum and chromatographic purification on silica gel, using dichloromethane/methanol (80:20) of solvent, 1.41 g (70%) of a colourless, amorphous solid are obtained.
C22H28IN5O (505.4) 1H-NMR data: 5 = 1.7 - 2.1 (m) 2 H, (CD3OD, TMS as 2.7 (t) 2 H, internal standard) 3.1- 3.8 (m) 6 H 4.9 (broad) 5 H, replaceable by D20, 5.6 (s) 1 H, 7.0 (s) 1 H, 7.2- 7.6 (m) 10 H 8.0 (s) 1 H, ppm.
Example 6 N1-[3-(3,5-Difluorophenyl)-3-(pyridin-2-yl)propyl]-N2[3-(lH-imidazol-4-yl)propyl]guanidine-trihydrochloride E 91995 a) N1-Benzoyl-N2-[3-(3,5-difluorophenyl)-3-(pyridin-2-yl)propyl]-N3-[3-(lH-imidazol-4-yl)propyl]guanidine 1.24 g of 3-(3,5-Difluorophenyl)-3-(pyridin-2-yl)propylamine and 1.59 g (5 mmol) of N-benzoyl-diphenyl5 imidocarbonate are stirred together with 20 ml of methylene chloride at room temperature for 20 minutes.
The solvent is then distilled off under vacuum and the oily residue is taken up with 30 ml of pyridine and is heated to 100aC for 45 minutes after the addition of 0.65 g (5.2 mmol) of 3-(lH-imidazol-4-yl)propylamine.
The reaction mixture is concentrated by evaporation under vacuum and the residue is taken up with 5% hydrochloric acid and extracted with ether. It is then made alkaline with ammonia and shaken with methylene chloride and the organic phase is washed with water, dehydrated over sodium sulphate and concentrated by evaporation under vacuum.
The reaction product is isolated and purified by preparative layer chromatography on silica gel 60 PF254 containing gypsum (Solvent: chloroform/methanol 99.5:0.5, ammoniacal atmosphere). 1.3 g (52%) of a colourless, amorphous solid are obtained after concentration of the eluates by evaporation.
C28H28F2N6° (502.6) IE 91995 1H-NMR data: 5 = 1.96 (m) 2 H, (CDC13, TMS as 2.3 (broad) 1 H, internal standard) 2.6 - 2.8 (m) 3 H, 3.34 (broad) 2 H, 3.5 (broad) 1 H, 3.9 (broad) 1 H, 4.17 (dd) 1 H, 6.6 - 7.8 (in) 11 H, 8.12 (d) 2 H, 8.58 (d) 1 H, 10.3 - 10.9 (broad) 1 H, replaceable by d2o, ppm. b) N1-[3-(3,5-Difluorophenyl)-3-(pyridin-2-yl)propyl]-N215 [3-(lH-imidazol-4-yl)propyl]guanidine 0.76 g (1.5 mmol) of N1-benzoyl-N2-[3-(3,5difluorophenyl)-3-(pyridin-2-yl)propyl]-N3-[3-(lHimidazol-4-yl)propyl]guanidine are heated under reflux in 40 ml of 20% hydrochloric acid for 10 hours. The hydro20 chloric acid solution is then extracted three times with ether, concentrated to dryness under vacuum and dried in a high vacuum.
Yield: 0.65 g (85%) of the trihydrochloride in the form of a hygroscopic, amorphous solid.
C21H24F2N6'3HC1 (507.8) MS (FAB method): m/z (rel. Int. [%]) = 399 ([M+H]+,80), 232 (100), 204 (18), 109 (60), 100 (36), 95 (11).
SE 91995 1H-NMR data: δ = 1.85 (m) 2 H, (DMSO-d6, TMS as 2.35 - 2 .65 (m) 2 H, internal standard) 2.72 (t) 2 H, 3.0 - 3. 3 (m) 4 H, 5 4.78 (t) 1 H. 7.16 (dd ) 1 H, 7.36 (d) 2 H, 7.51 (s) 1 H, 7.62 (s) 2 H, replace- 10 able by d2°, 7.76 (dd) 1 H, 8.02 (m) 3 H, 2 H replaceable by D2O, 8.32 (dd) 1 H, 8.75 (d) 1 H, 9.05 (s) 1 H, 14.45 (broad) 1 H, replaceable by D2O, 14.8 (broad) 1 H, replaceable by D2O ppm.
Example 7 N1-[2-[N-(5-Bromo-3-methyl-pyridin-2-yl)-benzylamino]ethyl]-N2-[3-(lH-imidazol-4-yl) propyl]guanidine-trihydrochloride Br CH.
NH N-CH2CH2NH-C-NH-CH2CH2CH2 CH2 H x 3 HC1 IE 91995 1.15 g (2.0 mmol) of N^—benzoyl-N2-[2-[N-(5-bromo3-methylpyridin-2-yl)-benzylamino]ethyl ]-N3-[3-(lHimidazol-4-yl)propyl]-guanidine are boiled in 20 ml of cone, hydrochloric acid for 20 hours. The aqueous solution is concentrated by evaporation to about half its volume and extracted with 3 x 20 ml of diethylether.
The aqueous phase is then filtered, concentrated to dryness under vacuum and concentrated twice more by evaporation under vacuum, each time with 20 ml of absolute ethanol. The residue is recrystallised from isopropanol.
Yield: 0.82 g (71%) of a colourless, highly hygroscopic solid.
C22H31BrCl3N7 (579.80) 3-H-NMR data: 6 = 1.80 - 2.18 (m) 2 (CD3OD, TMS as 2.61 (s) 3 H, internal standard) 2.89 (t) 2 H, 3.34 (t) 2 H, 3.60 (m) 2 H, 3.83 (m) 2 H, 4.15 (t) 2 H, 4.9 (broad) 7 H, 7.37 - 7.55 (m) 6 8.84 (d) 1 H, 8.92 (d) 2 H, ppm.
Example 8 N1 - [ 4 - (5-Bromo-3-methyl-pyridin-2-yl) butyl]-N2[3 - (1Himidazol-4-yl) propyl]guanidine-trihydrochloride 8r ch3 nh CH2-CH2CH2CH2-NH-C-NH-CH2CH2CH2y-N x 3 HC1 Nz ί IE 91995 1.00 g (2 mmol) of N1-Benzoyl-N2[4-(5-bromo-3methyl-pyridin-2-yl)butyl]-N3-[3-(lH-imidazol-4-yl)propyl]-guanidine are boiled in 20 ml of cone, hydrochloric acid for 18 hours. The aqueous solution, diluted to 40 ml after cooling, is extracted with 4 x 20 ml of diethyl .ether,. filtered and concentrated by evaporation under vacuum. The residue is taken up twice with 20 ml of absolute ethanol and concentrated by evaporation. The crude product obtained is then converted into the base with sodium methylate and chromatographed on aluminium oxide, using ethyl acetate/methanol (1:1). The main fraction is taken up with 5 ml of water after concentration by evaporation, 0.5 ml of cone, hydrochloric acid are added and the product is concentrated by evaporation under vacuum. After it has been again concentrated by evaporation with 20 ml of absolute ethanol, 0.62 g (60%) of the title compound are obtained in the form of a colourless hygroscopic solid.C17H28BrC13N6 (502.71) 20 ^-H-NMR data: δ = 1.68 - 2.22 (m) 6 H, (CD3OD, TMS as 2.61 (s) 3 H, internal standard) 2.91 (t) 2 H, 3.05 - 3.52 (m) 6H, 4.95 (broad) 7 H, 25 7.61 (s) 1 H, 8.89 (d) 1 H, 9.10 (d) 2 H, ppm.
IE

Claims (21)

1. The use of guanidine derivatives corresponding to the general formula II wherein R 1 stands for a phenyl group which may be unsubstituted or mono- or disubstituted with halogen
2. - [N-(5-bromo-3-methyl-pyridin-2-yl)- (4-chlorobenzyl) amino]-ethyl, 2-[N-(5-bromo-3-methyl-pyridin-2-y1)-benzylamino]ethyl, 2- [b is-(4-chlorophenyl) methoxy]ethyl, 2 - (Diphenylmethoxy) -ethyl, 2-[bis- (4-fluorophenyl) methoxy]-ethyl, 2- [N-(5-bromo-3-methyl-pyridin-2-yl)- (4-chlorobenzyl) amino]-ethyl, 30 4-(5-bromo-3-methyl-pyridin-2-yl) butyl, 2-[N-(5-bromo-3-methyl-pyridin-2-yl)-benzylamino]ethyl, 2- (Diphenylmethoxy)ethyl, 2-[bis-(4-fluorophenyl)methoxy]-ethyl, 3.3- bis-(4-chlorophenyl)propyl. 3.3- bis-(4-fluorophenyl) propyl and 3-(4-fluorophenyl)-3-phenylpropyl, IE 91995 3-(4-chlorophenyl)-3-phenylpropyl, 3- (5-bromo-pyridin-2-yl)propyl, 3- (3,4-dichlorophenyl)-3-(pyridin-2-yl)propyl, 25 3-(4-fluorophenyl)-3-(pyridin-3-yl)propyl, 3-(4-chlorophenyl)-3-(pyridin-2-yl) propyl, 3-(3,5-difluorophenyl)-3-(pyridin-2-yl)propyl, 3- (3,4-difluorophenyl)-3-(pyridin-2-yl)propyl,
3. The use of N 1 -[3-(lH-imidazol-4-yl)propyl]-N 2 -[2[(pyridin-3-yl)methylthio]ethyl]-guanidine and the physio5 logically acceptable salts thereof for the purpose according to Claim 1. 3.3- bis-(4-chlorophenyl)propyl. 3.3- bis-(4-fluorophenyl)propyl or 3-(4-chlorophenyl)-3-phenylpropyl, 35 3-(4-fluorophenyl)-3-phenylpropyl, IE 91995 3-(5-bromo-pyridin-2-yl)propyl, 3- (5-bromo-3-methyl-pyridin-2-yl)propyl, 3-(4-fluorophenyl)-3-(pyridin-3-yl)propyl, 3-(4-chlorophenyl)-3-(pyridin-2-yl)propyl, 25 3-(3,4-dichlorophenyl)-3-(pyridin-2-yl)propyl, 3-(3,5-difluorophenyl)-3-(pyridin-2-yl) propyl, 3-(3,4-difluorophenyl)-3-(pyridin-2-yl)propyl, 3- (4-fluorophenyl)-3-(pyridin-2-y1) propyl, 4. -(5-bromo-pyridin-2-yl)butyl, 4- (5-bromo-3-methyl-pyridin-2-yl) butyl, 30 3-(5-bromo-3-methyl-pyridin-2-yl)propyl,
4. The use of N 1 -[3-(lH-imidazol-4-yl)propyl]-N 2 -(3,3diphenylpropyl)guanidine and the physiologically acceptable salts thereof for the purpose according to Claim 1. 4- (5-bromo-pyridin-2-yl)butyl,
5. Physiologically acceptable salts thereof for the purpose according to Claim 11. 5 wherein R 1 stands for a phenyl group which is unsubstituted or mono- or disubstituted with halogen atoms, C]_Cg-alkyl groups or C1-C3~alkoxy groups or a pyridine ring which is unsubstituted or mono- or disubstituted with halogen atoms,-—---10 C1-C3-alkyl groups or C1-C3-alkoxy groups, R 2 stands for a hydrogen atom, a ¢^-03-alkyl group, a phenyl group optionally mono- or disubstituted with halogen atoms, C1-C 3 -alkyl groups or C 1 -C 3 -alkoxy groups or a benzyl or heteroarylmethyl group which is unsubstituted or mono- or 5 denotes a hydrogen atom or a phenyl group optionally monoor disubstituted with halogen atoms, C 1 -C 3 -alkyl groups or C^-C-j-alkoxy groups, R 5 stands for a hydrogen atom or a methyl or hydroxy group and Z stands for a single bond, an oxygen atom or a sulphur atom and p has the value 2 or 3,
6. The use of N 1 -[3-[(5-bromo-3-methyl-pyridin-2-yl)15 amino] propyl ] -N 2 -[3- (lH-imidazol-4-yl)propyl]-guanidine and the physiologically acceptable salts thereof for the purpose according to claim 1.
7. The use of N 1 -[3-(lH-imidazol-4-yl)propyl]-N 2 -[2(diphenylmethoxy)ethyl]-guanidine and the physiologically
8. The use of N 1 -[3-(3,5-difluorophenyl)-3-(pyridin-2yl) propyl]-N 2 -[3-(lH-imidazol-4-yl)propyl]-guanidine and the physiologically acceptable salts thereof for the 25 purpose according to Claim 1.
9. The use of N 1 -[2-[N-(5-bromo-3-methyl-pyridin-2yl) -benzylamino] -ethyl ] -N 2 -[3-(lH-imidazol-4-yl)propyl ] guanidine and the physiologically acceptable salts thereof for the purpose according to Claim 1. 30 10. The use of N 1 -[ 4- (5-bromo-3-methyl-pyridin-2yl) butyl ] -N 2 - [3-( lH-imidazol-4-yl) propyl] -guanidine and the physiologically acceptable salts thereof for the purpose according to Claim 1.
10. Or a methyl group, and the physiologically acceptable salts thereof for the preparation of a pharmaceutical product for the treatment of high blood pressure. 10 5. The use of N 1 -[3-(lH-imidazol-4-yl)propyl]-N 2 [2-[(pyridin-2-yl)-amino]ethyl]-guanidine and the physiologically acceptable salts thereof for the purpose according to Claim 1. 10 m has the value 2 or 3 and R' denotes a hydrogen atom or a methyl group, and their physiologically acceptable salts, for the preparation of a pharmaceutical product having an NPY-antagonistic action. 10 atoms, -alkyl groups or C 1 -C 3 -alkoxy groups or a pyridine ring which may be unsubstituted or mono- or disubstituted with halogen atoms, C 1 -C 3 -alkyl groups or C 1 -C3~alkoxy groups, R 2 stands for a hydrogen atom, a Ci-C 3 -alkyl group, a phenyl group optionally mono- or
11. The use of guanidine derivatives corresponding to 35 the general formula II 91995 (II) in which R denotes the group R J 'N-(CH 2 ) n R 4
12. The use according to Claim 11, characterised in 15 that in the general formula II, R stands for one of the following groups:
13. The use of N 1 -[3-(lH-imidazol-4-yl)propyl]-N 2 -[ΣΕ ( pyr idin- 3 -yl ) methylthio ] ethyl ] -guanidine and the
14. The use of N 1 -[3-(lH-imidazol-4-yl)propyl]-N 2 -(3,3diphenylpropyl)guanidine and the physiologically acceptable salts thereof for the purpose according to Claim 11. 10
15. The use of N 1 -[3-(lH-imidazol-4-yl)propyl]-N 2 [2-[(pyridin-2-yl)amino]-ethyl]-guanidine and the physiologically acceptable salts thereof for the purpose according to Claim 11. 15 disubstituted with halogen atoms, Ci-C 3 -alkyl groups or Ci-C3-alkoxy groups, and n has the value 2, 3 or 4 , or in which R denotes the group 15 2. The use according to Claim 1, characterised in that in the general formula II, R stands for one of the following groups: 15 disubstituted with halogen atoms, C 1 -C 3 -alkyl groups or C 1 -C 3 -alkoxy groups, or a benzyl or heteroarylmethyl group which may be unsubstituted or mono- or disubstituted with halogen atoms, C 1 -C 3 -alkyl groups or C 1 -C 3 -alkoxy groups, and n has the value 2, 3 or 4,
16. The use of N 1 -[3-[(5-bromo-3-methyl-pyridin-2-yl)15 amino] -propyl] -N 2 - [ 3 - (lH-imidazol-4-yl) propyl] -guanidine and the physiologically acceptable salts thereof for the purpose according to Claim 11.
17. The use of N 1 -[3-(lH-imidazol-4-yl)propyl]-N 2 -[2(diphenylmethoxy)ethyl]-guanidine and the physiologically
18. The use of N 1 -[3-(3,5-difluorophenyl)-3-(pyridin-2y 1) propyl]-N 2 -[3-(lH-imidazol-4-yl) propyl]-guanidine and the physiologically acceptable salts thereof for the 25 purpose according to Claim 11.
19. The use of N 1 -[2-[N-(5-bromo-3-methyl-pyridin-2yl) -benzylamino) ethyl ] -N 2 - [ 3 - (lH-imidazol-4-yl) propyl] guanidine and the physiologically acceptable salts thereof for the purpose according to Claim 11. 30
20. The use of N 1 -[ 4 - ( 5-bromo-3-methy l-pyridin-2yl)butyl] -N 2 -[3- (lH-imidazol-4-yl) propyl]-guanidine and the physiologically acceptable salts thereof for the purpose according to Claim 11. 20 acceptable salts thereof for the purpose according to Claim 11. 20 3-(4-fluorophenyl)-3-(pyridin-2-yl) propyl, 20 R 3 4 I R 4 -C-Z-(CH 2 ) p R5 IE 91995 wherein R 3 stands for a pyridine ring or phenyl ring which is unsubstituted or mono- or disubstituted with halogen atoms, C1-C3-alkyl groups or C1-C3-alkoxy groups, R 4 denotes a hydrogen atom or a phenyl group optionally mono5 or disubstituted with halogen atoms, Ο^^-Οβ-alkyl groups or C1-C 3 -alkoxy groups, R 5 stands for a hydrogen atom or a methyl or hydroxyl group and Z stands for a single bond, an oxygen atom or a sulphur atom and p has the value 2 or 3, m has the value 2 or 3 and R' denotes a hydrogen atom 20 acceptable salts thereof for the purpose according to Claim 1. 20 2-[Bis-(4-chlorophenyl) methoxy]ethyl, 20 or in which R denotes the group R 3 4 I r 4 -c-z-(CH 2 )pL 25 R 5 IE 91995 □ wherein R stands for a pyridine ring or phenyl ring which may be unsubstituted or mono- or disubstituted with halogen atoms, C 1 -C 3 -alkyl groups or C 1 -C 3 -alkoxy groups, R 4
21. The use as claimed in any of the preceding claims substantially as hereinbefore described by way of Example.
IE99591A 1990-03-30 1991-03-26 The use of guanidine derivatives for the preparation of a pharmaceutical product having NPY antagonistic activity IE65252B1 (en)

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