IE65252B1 - 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 activityInfo
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- IE65252B1 IE65252B1 IE99591A IE99591A IE65252B1 IE 65252 B1 IE65252 B1 IE 65252B1 IE 99591 A IE99591 A IE 99591A IE 99591 A IE99591 A IE 99591A IE 65252 B1 IE65252 B1 IE 65252B1
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- propyl
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- pyridin
- ethyl
- imidazol
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- 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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- 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
- A61K31/415—1,2-Diazoles
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- 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
- A61K31/435—Heterocyclic 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- 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
- A61P9/12—Antihypertensives
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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. 3 2 , 597 (1989)) also proved the participation of NPY in the development 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 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 (II) in which R denotes the group ,N-(CH2)nwherein R^ 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 C1-C3-alkyl group, a phenyl optionally mono- or disubstituted with halogen atoms, C1-C3-alkyl groups or C1-C3-alkoxy groups, or a benzyl or hetero aryl methyl group which may be unsubstituted or mono- or disubstituted with halogen atoms, Cj-C3-alkyl groups or (^-03-alkoxy groups, and n has the value 2, 3 or 4, or in which R denotes the group R34 I r4-c-z-(CH2)pR5 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, C]_-C3-alkyl groups or C-^-03-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 R1 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.
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 R1 ^N-(CH2)nR2 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 C3-C3-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, 03-03-alkyl groups such as methyl or ethyl groups and C3-C3-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-, 3or 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-i_-C3-alkyl group, in particular a methyl, ethyl or propyl group, a phenyl 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 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 thiopheny lmethyl, a furanylmethyl or 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, Cj_-C3-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 R34 I r4-c-z-(ch2)pL P R5 o 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 CjC3-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 monoor 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, C^-C3-alkyl groups such as methyl or ethyl groups and C^-C^-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, 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-y1) 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-3yl)methylthio]ethyl]-guanidine N1-[3-(lH-imidazol-4-yl) 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-[37 -ι ις (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-[3(lH-imidazol-4-yl)propyl]-guanidine (Compound B) N1-[2-[N-(5-bromo-3-methyl-pyridin-2-yl)-benzylamino] ethyl]-N2-[3-(ΙΗ-imidazol-4-yl)propyl]-guanidine (Compound C) n1- [ 4 - (5-bromo-3-methyl-pyridin-2-yl) butyl]-N2-[3(1Himidazol-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~x concentration in HEL 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 ΤΓ S O'*" O A 2 V S VI θ S I 1 | Compound 1 1 1 pA2 1 I Inhibition of the rise in Ca++ | _l_1 5 1 1 A I i | 4.0 I 1 1 I 1 1 B I 1 | 4.72 I 1 1 1 1 1 c 1 | 5.88 1 1 10 1 1 D 1 1 | 5.04 1 1 1 The following compounds were used for the above described test, the results of which are shown in the 15 Table: Compound A: N1-[3-(lH -imidazol-4-yl) propyl]-N2-[2- (diphenylmethoxy) ethyl]-guanidine Compound Β: N3·-[ 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)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.
Example 1 N1-[3-(lH-Imidazol-4-yl) propyl]-Ν2-[2-[(pyridin-3-yl)methylthio]-ethyl]guanidine-trihydrochloride NH CH^-S- CH2-CH2-NH-C-NH-CH2-CH2CH x 3 HCI 0.85 g (2 mmol) of N-Benzoyl-N'-[3-(imidazol-4-yl)5 propyl]-N'1-{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*3HCl (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). 1H-NMR data δ = 1.87 (m) 2 H, (dg-DMSO, TMS as 2.62 (t) 2 H, internal standard) 2.73 (t) 2 H, 3.0-3 .7 (m) 4 H, 4.10 (s) 2 H, 7.3 - 8. 3 (m) 6 replaceable by D£0 8.5 - 9.1 (m) 4 H, ppm.
Example 2 N1-[3-(lH-Imidazol-4-yl) propyl ] -N2- (3,3-dipheny lpropyl) guanidine-dihydrochloride -CH-CHNH ch2-nh-c-nh-ch2-ch2 -CH x 2 HCl 0.84 g (1.8 mmol) of N-Benzoyl-N'-[3-(imidazol-4yl) propyl]-N(3,3-diphenylpropyl)guanidine are heated under reflux in 45 ml of 20% hydrochloric acid for 7 up as in Example 1. hygroscopic, non-crystalline hours. The product is worked Yield: 0.67 g (86%) of a solid.
C22H27N5’2HC1 (434.4) MS: m/z (rel. Int. [%]) = 109(100), 91(60) (FAB method) 1H-NMR data: 6 (dg-DMSO, TMS as internal standard) 362 ([M+H]+, 84), 167(54), 1.81 (m) 2 H, 2.27 (dt) 2 H, 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, H, replaceable by D20, 7.80 (m) 2 H, replaceable by D20, 8.99 (d) 1 H, ppm.
Example 3 N1-[3-(lH-Imidazol-4-yl)propyl]-N2-[2-(pyridin-2-ylamino)-ethyl]-guanidine-trihydrochloride NH NHCH2CH2-NH-C-NH-CH2CH2CH2 x 3 HCI 0.93 g (76%) of a colourless, hygroscopic solid are obtained from 1.21 g (3.1 mmol) of N^-benzoyl-N2-[3-(1Himidazol-4-yl) propyl ] -N3-[2 -(pyridin-2-yl-amino) -ethyl] guanidine and 20 ml of cone, hydrochloric acid. 5c14h24c13n7 (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, 10 4.8 (broad) 8 H, replace able by D20, 6.96 (t) 1 H, 7.22 (d) 1 H, 7.44 (s) 1 H, 15 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 x> A XII 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 Example 5 N1-[3-(lH-Imidazol-4-yl)propyl]-N2- [2-(diphenylmethoxy)ethyl]-guanidine-hydroiodide NH N-CH CH NH-C-NHCH CH OCH; \\ 2 2 2 2 2 in χ ΗΪ a) N-^-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°C, are obtained.
C23H22N2O2S (390.5) b) S-Methyl-N-[2-(diphenylmethoxy)ethyl]-isothiuronium iodide 11.1 g (28 mmol) of N1-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 mi of ethanol and with 2.1 ml (33 mmol) methyl iodide ι ς 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: 8 = 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, replace- able 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 F. cx γ nh CH-CH2-CH2-NH-C-NH-CH2-CH2-CH2 Yt-NH x 3 HCl a) N1-Benzoyl-N2-[3-(3,5-difluorophenyl)-3-(pyridin-2-yl)propyl]-N3-[3- (ΙΗ-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 100®C 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) l-H-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, 5 3.5 (broad) 1 H, 3.9 (broad) 1 H, 4.17 (dd) 1 H, 6.6 - 7.8 (m) 11 H, 8.12 (d) 2 H, 10 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- (1Himidazol-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). 1H-NMR data: (DMSO-d6, TMS as internal standard) = 1.85 (m) 2 H, 2.35 - 2.65 (m) 2 H, 2.72 (t) 2 H, 3.0 - 3.3 (m) 4 H, 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 D2O, 7.76 (dd) 1 H, 8.02 (m) 3 H, 2 replaceable by D20, 8.32 (dd) 1 H, 15 8.75 9.05 (d) 1 H, (s) 1 H, 14.45 (broad) 1 H, replaceable by D20, 14.8 (broad) 1 H, replaceable by D20 ppm.
Example 7 N1-[2-[N-(5-Bromo-3-methyl-pyridin-2-yl)-benzylamino]ethylJ-N2-[3-(lH-imidazol-4-yl) propyl]guanidine-trihydrochloride Br CHNH N-CH2CH2NH-C-NH-CH2CH2CH2 CH2 x 3 HCI 1.15 g (2.0 mmol) of N1-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) 1H-NMR data: δ = 1.80 - 2 . 18 ( 15 (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, 20 4.15 (t) 2 H, 4.9 (broad) 7 H, 7.37 - 7.55 (m) 6 H 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 Br NH N/-CH2-CH2CH2CH2-NH-C-NH-CH2CH2CH2-y—N x 3 HCl I H 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) 1H-NMR data: (CD3OD, TMS as internal standard) = 1.68 - 2, ,22 (m) 6 H, 2.61 (s) 3 H, 2.91 (t) 2 H, 3.05 - 3. .52 (m) 6H, 4.95 (broad) 7 H, 7.61 (s) 1 H, 8.89 (d) 1 H, 9.10 (d) 2 H, ppm.
Claims (10)
1. The use of guanidine derivatives corresponding to general formula II in which R represents the group: R 1\ R 2 z N—(CH 2 )n where is an unsubstituted phenyl group or a phenyl group substituted once or twice by halogen atoms, alkyl groups or alkoxy groups or an unsubstituted pyridine ring or a pyridine ring substituted once or twice by halogen atoms, Cj_^ alkyl groups or alkoxy groups, R^ is a hydrogen atom, a alkyl group, a phenyl group optionally substituted once or twice by halogen atoms, alkyl groups or alkoxy groups, an unsubstituted benzyl or heteroarylmethyl group or a benzyl or heteroarylmethyl group substituted once or twice by halogen atoms, alkyl groups or Cj β alkoxy groups and n has a value of 2, 3 or 4, or in which R represents the group: Ra R4-C-Z-(CH 2 )p Rs where R is an unsubstituted phenyl ring or pyridine ring or a phenyl ring or pyridine ring substituted once or twice by halogen atoms, alkyl groups or alkoxy groups, R is a hydrogen atom or a phenyl group optionally substituted once or twice by halogen atoms, ς alkyl groups or alkoxy groups, R is a hydrogen atom or - 23 a methyl group and Z is a single bond, an oxygen atom or a sulfur atom and p has a value of 2 or 3, m has a value of 2 or 3 and R' is a hydrogen atom or a methyl group, and physiologically acceptable salts thereof for the production of a * medicament with an NPY-antagonistic effect.
2. The use claimed in Claim 1, characterized in that, in general formula II, R represents one of the following groups: 2-(diphenylmethoxy)-ethyl, 2-[bis-(4-f1uorophenyl)-methoxy]-ethyl, 2- [bis-(4-chlorophenyl)-methoxy]-ethyl, 3. - (4-fluorophenyl)-3-(pyridin-2-yl)-propyl, 3-(3,4-di fluorophenyl)-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-dichiorophenyl)-3-(pyridin-2-yl)-propyl, 3- (4-fluorophenyl)-3-(pyridin-3-yl)-propyl, 2-[N-(5-bromo-3-methylpyridi n-2-yl)-benzyl ami no]-ethyl, 2- [N-(5-bromo-3-methylpyridin-2-yl)-(4-chlorobenzyl)-amino]-ethyl, 4. - (5-bromo-3-methylpyridin-2-yl)-butyl, 3- (5-bromo-3-methylpyridin-2-yl)-propyl, 4- (5-bromopyridin-2-yl)-butyl, 3-(5-bromopyridin-2-yl)-propyl, 3-(4-chlorophenyl)-3-phenylpropyl, 3-(4-f1uorophenyl)-3-phenylpropyl, 3,3-bi s-(4-f1uorophenyl)-propyl or 3,3-bi s-(4-chlorophenyl)-propyl.
3. The use of N^-[3-(lH-imidazol-4-yl)-propyl]-N^-[2-[(pyridin-3yl)-methylthio]ethyl]-guanidine and physiologically acceptable salts thereof for the purpose according to Claim 1.
4. The use of N^-[3-(lH-imidazol-4-yl)-propyl]-N^-(3,3-diphenylpropyl)-guanidine and physiologically acceptable salts thereof for the purpose according to Claim 1.
5. The use of N^-[3-(lH-imidazol-4-yl)-propyl]-N^-[2-[(pyridin-2yl)-amino]ethyl]-guanidine and physiologically acceptable salts thereof for the purpose according to Claim 1. - 24
6. The use of N 1 -[3-[(5-bromo-3-methylpyridin-2-yl)-amino]propyl]2 N -[3-(lH-imidazol-4-yl)-propyl]-guanidine and physiologically acceptable salts thereof for the purpose according to Claim 1. 5
7. The use of N 1 -[3-(lH-imidazol-4-yl)-propyl]-N 2 -[2-(diphenylmethoxy)-ethyl]-guanidine and physiologically acceptable salts thereof for the purpose according to Claim 1.
8. The use of N 1 -[3-(3,5-difluorophenyl)-3-(pyridin-2-yl)-propyl]2 10 N -[3-(lH-imidazol-4-yl)-propyl]-guanidine and physiologically acceptable salts thereof for the purpose according to Claim 1.
9. The use of N 1 -[2-[N-(5-bromo-3-methylpyridin-2-yl)2 benzyl ami no]ethyl]-N -[3-(ΙΗ-imidazol-4-yl)-propyl]-guanidine and 15 physiologically acceptable salts thereof for the purpose according to Claim 1.
10. The use of N^-[4-(5-bromo-3-methylpyridin-2-yl)butyl]-N 2 -[3(lH-imidazol-4-yl)-propyl]-guanidine and physiologically acceptable 20 salts thereof for the purpose according to Claim 1.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP90106200A EP0448765B1 (en) | 1990-03-30 | 1990-03-30 | Use of guanidine derivatives for the manufacture of a medicament with NPY-antagonistic activity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE910995A1 IE910995A1 (en) | 1991-10-09 |
| IE65252B1 true IE65252B1 (en) | 1995-10-18 |
Family
ID=8203843
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE99591A IE65252B1 (en) | 1990-03-30 | 1991-03-26 | The use of guanidine derivatives for the preparation of a pharmaceutical product having NPY antagonistic activity |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0448765B1 (en) |
| JP (1) | JPH0789939A (en) |
| KR (1) | KR910016329A (en) |
| AT (1) | ATE109979T1 (en) |
| AU (1) | AU637882B2 (en) |
| CA (1) | CA2037433A1 (en) |
| DE (1) | DE59006842D1 (en) |
| DK (1) | DK0448765T3 (en) |
| ES (1) | ES2058651T3 (en) |
| HU (1) | HU207945B (en) |
| IE (1) | IE65252B1 (en) |
| IL (1) | IL97424A (en) |
| PT (1) | PT97138A (en) |
| ZA (1) | ZA911471B (en) |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2126212A1 (en) * | 1991-12-19 | 1993-07-08 | Albert Tseng | A novel molecule which inhibits neuropeptide tyrosine biological function |
| US5516653A (en) * | 1993-12-28 | 1996-05-14 | Synaptic Pharmaceutical Corporation | DNA encoding a human neuropeptide Y/peptide YY/pancreatic polypeptide receptor (Y4) and uses thereof |
| US5545549A (en) * | 1994-02-03 | 1996-08-13 | Synaptic Pharmaceutical Corporation | DNA encoding a human neuropeptide Y/peptide YY (Y2) receptor and uses thereof |
| US5602024A (en) * | 1994-12-02 | 1997-02-11 | Synaptic Pharmaceutical Corporation | DNA encoding a hypothalamic atypical neuropeptide Y/peptide YY receptor (Y5) and uses thereof |
| US5989920A (en) | 1994-12-02 | 1999-11-23 | Synaptic Pharmaceutical Corporation | Methods of modifying feeding behavior compounds useful in such methods and DNA encoding a hypothalmic atypical neuropeptide Y/peptide YY receptor Y5 |
| WO1997020823A2 (en) * | 1995-12-01 | 1997-06-12 | Novartis Ag | 2-amino quinazoline derivatives as npy receptor antagonists |
| AU7692896A (en) * | 1995-12-01 | 1997-06-27 | Novartis Ag | Quinazolin-2,4-diazirines as NPY receptor antagonist |
| AU2764797A (en) * | 1996-05-14 | 1997-12-05 | Novo Nordisk A/S | Somatostatin agonists and antagonists |
| EP0984778B1 (en) * | 1996-08-23 | 2002-06-12 | Agouron Pharmaceuticals, Inc. | Neuropeptide-y ligands |
| FR2754709B1 (en) | 1996-10-23 | 1999-03-05 | Sanofi Sa | COSMETIC COMPOSITION CONTAINING AN ANTAGONIST OF GAMMA NEUROPEPTIDE RECEPTORS AND ALPHA 2 ANTAGONISTS THAT MAY BE INCORPORATED IN SUCH A COMPOSITION |
| AU4772497A (en) * | 1996-10-31 | 1998-05-22 | Novo Nordisk A/S | Constrained somatostatin agonists and antagonists |
| AU6267198A (en) * | 1997-02-14 | 1998-09-08 | Bayer Corporation | Amides as npy5 receptor antagonists |
| CA2251368A1 (en) * | 1997-02-14 | 1998-08-20 | Bayer Corporation | Amide derivatives as selective neuropeptide y receptor antagonists |
| US6245817B1 (en) | 1997-02-14 | 2001-06-12 | Bayer Corporation | NPY5 receptor antagonists and methods for using same |
| US6048900A (en) | 1998-02-13 | 2000-04-11 | Bayer Corporation | Amide derivatives and methods for using the same as selective neuropeptide Y receptor antagonists |
| US6713265B1 (en) | 1997-06-04 | 2004-03-30 | Synaptic Pharmaceutical Corporation | Methods of modifying feeding behavior, compounds useful in such methods, and DNA encoding a hypothalamic atypical neuropeptide Y/peptide YY receptor (Y5) |
| CA2294898A1 (en) | 1997-07-03 | 1999-01-14 | Neurogen Corporation | Certain diarylimidazole derivatives; a new class of npy specific ligands |
| ES2161594B1 (en) * | 1998-12-17 | 2003-04-01 | Servier Lab | NEW DERIVATIVES OF HYDRAZIDE, ITS PREPARATION PROCEDURE AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| WO2000066578A1 (en) | 1999-04-30 | 2000-11-09 | Pfizer Products Inc. | Compounds for the treatment of obesity |
| EP1318994B1 (en) | 2000-09-20 | 2008-02-27 | Schering Corporation | Substituted imidazoles as dual histamine h1 and h3 agonists or antagonists |
| ES2233708T3 (en) | 2000-09-20 | 2005-06-16 | Schering Corporation | IMIDAZOLS REPLACED AS AGONISTS OR DUAL ANTAGONISTS OF HISTAMINE H1 AND H3. |
| ATE411983T1 (en) * | 2000-09-20 | 2008-11-15 | Schering Corp | SUBSTITUTED IMIDAZOLES AS HISTAMINE H1 AND H3 AGONISTS OR ANTAGONISTS |
| DE60135471D1 (en) | 2000-09-20 | 2008-10-02 | Schering Corp | H3 AGONISTS OR ANTAGONISTS |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3579000D1 (en) * | 1985-04-02 | 1990-09-06 | Heumann Pharma Gmbh & Co | IMIDAZOLYLALKYLGUANIDINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS. |
| DE3631334A1 (en) * | 1986-09-15 | 1988-03-17 | Heumann Pharma Gmbh & Co | NEW IMIDAZOLYLGUANIDE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
-
1990
- 1990-03-30 AT AT90106200T patent/ATE109979T1/en active
- 1990-03-30 DK DK90106200.0T patent/DK0448765T3/en active
- 1990-03-30 ES ES90106200T patent/ES2058651T3/en not_active Expired - Lifetime
- 1990-03-30 EP EP90106200A patent/EP0448765B1/en not_active Expired - Lifetime
- 1990-03-30 DE DE59006842T patent/DE59006842D1/en not_active Expired - Fee Related
-
1991
- 1991-02-28 ZA ZA911471A patent/ZA911471B/en unknown
- 1991-03-01 CA CA002037433A patent/CA2037433A1/en not_active Abandoned
- 1991-03-04 IL IL9742491A patent/IL97424A/en not_active IP Right Cessation
- 1991-03-04 AU AU72068/91A patent/AU637882B2/en not_active Ceased
- 1991-03-25 HU HU91979A patent/HU207945B/en not_active IP Right Cessation
- 1991-03-25 PT PT97138A patent/PT97138A/en not_active Application Discontinuation
- 1991-03-26 JP JP3061914A patent/JPH0789939A/en active Pending
- 1991-03-26 IE IE99591A patent/IE65252B1/en not_active IP Right Cessation
- 1991-03-27 KR KR1019910004812A patent/KR910016329A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| ATE109979T1 (en) | 1994-09-15 |
| EP0448765B1 (en) | 1994-08-17 |
| DK0448765T3 (en) | 1994-09-19 |
| KR910016329A (en) | 1991-11-05 |
| AU7206891A (en) | 1991-10-03 |
| CA2037433A1 (en) | 1991-10-01 |
| HU910979D0 (en) | 1991-10-28 |
| IE910995A1 (en) | 1991-10-09 |
| IL97424A0 (en) | 1992-06-21 |
| DE59006842D1 (en) | 1994-09-22 |
| AU637882B2 (en) | 1993-06-10 |
| ZA911471B (en) | 1991-11-27 |
| IL97424A (en) | 1995-05-26 |
| JPH0789939A (en) | 1995-04-04 |
| PT97138A (en) | 1991-11-29 |
| EP0448765A1 (en) | 1991-10-02 |
| HU207945B (en) | 1993-07-28 |
| HUT57044A (en) | 1991-11-28 |
| ES2058651T3 (en) | 1994-11-01 |
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| MM4A | Patent lapsed |