CA2037433A1 - Use of guanidine derivatives for the preparation of a pharmaceutical product having pny antagonistic activity - Google Patents
Use of guanidine derivatives for the preparation of a pharmaceutical product having pny antagonistic activityInfo
- Publication number
- CA2037433A1 CA2037433A1 CA002037433A CA2037433A CA2037433A1 CA 2037433 A1 CA2037433 A1 CA 2037433A1 CA 002037433 A CA002037433 A CA 002037433A CA 2037433 A CA2037433 A CA 2037433A CA 2037433 A1 CA2037433 A1 CA 2037433A1
- Authority
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- Canada
- Prior art keywords
- propyl
- pyridin
- guanidine
- ethyl
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- 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)
-
- 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
-
- 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
-
- 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
- A61P9/12—Antihypertensives
Abstract
Abstract The use of guanidine derivatives having the following basic structure
Description
2~37~33 The use of guanidine derivatives for the preparation of a pharmaceutical product having NPY
antagonistic activity Descri~tion 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 systematic 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 production 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 ~0 structure l/
( `
2~37~33 which have histamine-H2 agonistic and histamine-H
antagonistic activities are known from DE-OS 35 12 084, 35 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 caxdiac insufficiency.
10 It has now been found that the compounds described above surprisingly also have neuropeptide-Y antagonistic activities independently of the above mentioned cardio-tonic and positive inotropic activity.
- The present invention therefore relates to the use of guanidine derivatives corresponding to the general formula II
~111 R~ ~ ~(CI
¢~
N~
R il in which R denotes the group Rl \
N-(cH2)n wherein Rl denotes a phenyl group which may be unsub-stituted or mono- or disubstituted with halogen atoms, 2~3 ~4~3 C1-C3-alkyl groups or Cl-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 unsub-stituted or mono- or disubstituted with halogen atoms, Cl-C3-alkyl groups or Cl-C3-alkoxy groups, and n has the value 2, 3 or 4, or in which R denotes the group R4-c-z-(cH2) ~5 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 s mono- or disubstituted with halogen atoms, C1-C3-alkyl groups or C1-C3-alkoxy groups, R5 stands for a h ydrogen 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 preparatlon 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-Y-antagonistic activity.
2037~33 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 Rl \ N-(CH2)n~
In this group, Rl 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 C1-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, C1-C3-alkyl groups such as methyl or ethyl groups and C1-C3-alkoxy groups such as methoxy, ethoxy or propoxy groups, preferably methoxy groups.
Linkage of the pyridine ring denoted by Rl to the nitrogen 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.
R2 stands for a hydrogen atom, a C1-C3-alkyl group, in particular a methyl, ethyl or propyl group, a phenyl 2(~3r~ ~33 group, which may be unsubstituted or mono- or disubstitut-ed, a benzyl group, which may be unsubstituted or mono- or disubstituted, or a hetero aryl methyl gxoup, 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 sub-stituents 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 mono-substitution 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 furanomethyl or a pyridinomethyl group. The heteroarylmethyl group may also be u~substituted or, preferably, mono- or disubstitut-ed. The substituents may be halogen atoms such as fluorine, chlorine or bromine atoms, C1-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 R4 f z (CH2,p 2~37~33 In this group, R3 may denote an unsubstituted or a mono-or disubstituted phenyl group or an unsubstituted or mono-or disubstituted pyridine ring. In the case of substitu-- tion, 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 Cl-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 mono-or disubstituted pyridine ring, preferably an unsub-stituted 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, Cl-C3-alkyl groups such as methyl or ethyl groups and C1-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 sub-stituted 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, ~37~33 preferably 3, and R' denotes a hydrogen atom or a methylgroup, 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-3-yl)methylthio]ethyl]-guanidine Nl-[3-(lH-imidazol-4-yl)propyl]-N2-(3,3-diphenylpropyl)-guanidine Nl-[3-(lH-imidazol-4-yl)]propyl]-N2-[2-[(pyridin-2-yl)-amino]ethyl]-guanidine Nl-[3-[(5-bromo-3-methyl-pyridin-2-yl)amino]propyl]-N2-[3-~3~3~
~lH-imidazol-4-yl)propyl]-guanidine Nl-[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-(lH-imidazol-4-yl)propyl]-guanidine (Compound C) N1-[4-(5-bromo-3-methyl-pyridin-2-yl)butyl]-N2-[3(lH-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 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 ~child-Plot analysls, 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:
2~3~33 ¦ Compound I PA2 ¦ Inhibition of the rise in Ca++ ¦
antagonistic activity Descri~tion 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 systematic 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 production 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 ~0 structure l/
( `
2~37~33 which have histamine-H2 agonistic and histamine-H
antagonistic activities are known from DE-OS 35 12 084, 35 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 caxdiac insufficiency.
10 It has now been found that the compounds described above surprisingly also have neuropeptide-Y antagonistic activities independently of the above mentioned cardio-tonic and positive inotropic activity.
- The present invention therefore relates to the use of guanidine derivatives corresponding to the general formula II
~111 R~ ~ ~(CI
¢~
N~
R il in which R denotes the group Rl \
N-(cH2)n wherein Rl denotes a phenyl group which may be unsub-stituted or mono- or disubstituted with halogen atoms, 2~3 ~4~3 C1-C3-alkyl groups or Cl-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 unsub-stituted or mono- or disubstituted with halogen atoms, Cl-C3-alkyl groups or Cl-C3-alkoxy groups, and n has the value 2, 3 or 4, or in which R denotes the group R4-c-z-(cH2) ~5 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 s mono- or disubstituted with halogen atoms, C1-C3-alkyl groups or C1-C3-alkoxy groups, R5 stands for a h ydrogen 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 preparatlon 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-Y-antagonistic activity.
2037~33 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 Rl \ N-(CH2)n~
In this group, Rl 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 C1-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, C1-C3-alkyl groups such as methyl or ethyl groups and C1-C3-alkoxy groups such as methoxy, ethoxy or propoxy groups, preferably methoxy groups.
Linkage of the pyridine ring denoted by Rl to the nitrogen 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.
R2 stands for a hydrogen atom, a C1-C3-alkyl group, in particular a methyl, ethyl or propyl group, a phenyl 2(~3r~ ~33 group, which may be unsubstituted or mono- or disubstitut-ed, a benzyl group, which may be unsubstituted or mono- or disubstituted, or a hetero aryl methyl gxoup, 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 sub-stituents 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 mono-substitution 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 furanomethyl or a pyridinomethyl group. The heteroarylmethyl group may also be u~substituted or, preferably, mono- or disubstitut-ed. The substituents may be halogen atoms such as fluorine, chlorine or bromine atoms, C1-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 R4 f z (CH2,p 2~37~33 In this group, R3 may denote an unsubstituted or a mono-or disubstituted phenyl group or an unsubstituted or mono-or disubstituted pyridine ring. In the case of substitu-- tion, 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 Cl-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 mono-or disubstituted pyridine ring, preferably an unsub-stituted 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, Cl-C3-alkyl groups such as methyl or ethyl groups and C1-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 sub-stituted 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, ~37~33 preferably 3, and R' denotes a hydrogen atom or a methylgroup, 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-3-yl)methylthio]ethyl]-guanidine Nl-[3-(lH-imidazol-4-yl)propyl]-N2-(3,3-diphenylpropyl)-guanidine Nl-[3-(lH-imidazol-4-yl)]propyl]-N2-[2-[(pyridin-2-yl)-amino]ethyl]-guanidine Nl-[3-[(5-bromo-3-methyl-pyridin-2-yl)amino]propyl]-N2-[3-~3~3~
~lH-imidazol-4-yl)propyl]-guanidine Nl-[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-(lH-imidazol-4-yl)propyl]-guanidine (Compound C) N1-[4-(5-bromo-3-methyl-pyridin-2-yl)butyl]-N2-[3(lH-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 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 ~child-Plot analysls, 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:
2~3~33 ¦ Compound I PA2 ¦ Inhibition of the rise in Ca++ ¦
5 ¦ A ¦ 4.0 I l I
. I B ¦ 4.72 I C 1 5.88 ¦ D 1 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 N l !
Nll IIN ~
(3 N
2 ~3 3 r~ ~; 3 3 Compound B: Nl-[3-(3,5-difluorophenyl)-3-(pyridin-2-yl~-propyl]-N2-[3-(lH-imidazol-4-yl)propyl]-guanidine F ~ F
Nll N N ~N,~
~,N H 11 ~1 Compound C: Nl-[2-[N-(5-bromo-3-methyl-pyridin-2-yl)-5benzylamino]-ethyl]-N2-[3-(1H-imidazol-4-yl)-propyl]-guanidine [~
B r~ --I IN N l!--N~--\J
Compound D: N1-[4-(5-brcmo-3-methyl-pyridin-2-yl)butyl]-N2-[3-(lH-imidazol-4-yl)propyl]-guanidine ar~CIl3 N~l `Nll NN
The invention is described in the Examples.
2~37~33 Example 1 N1-[3-(lH-Imidazol-4-yl)propyl]-N2-[2-[(pyridin-3-yl)-methylthio]-ethyl]guanidine-trihydrochloride -S-CH2-C~2-~l~-C-NH-C~2-CH2-C~2~ l x 3 HCl 0.85 g (2 mmol) of N-Benzoyl-N'-[3-(imidazol-4-yl)-propyl]-N " -~2-[(pyrid-3-yl)methylthio]ethyl)guanidine 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).
H-NMR data ~ = 1.87 (m) 2 H, (d6-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 H, 4 H
replaceable by D20 8.5 - 9.1 (m) 4 H, ppm.
'~3~3 Example 2 Nl-[3-(lH-Imidazol-4-yl)propyl]-N2-(3,3-diphenylpropyl)-guanidine-dihydrochloride H-cH2-cH2-NH-c-NH-cH2-cH2-c~2 ~ ~ x 2 HCl 0.84 g (1.8 mmol) of N-Benzoyl-N'- r 3-(imidazol-4-yl)propyl]-N''-(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.
C22H27Ns-2HCl (434-4) MS: m/z (rel. Int. [%]) = 362 ([M+H]+, 84), 167(54), 109(100), 91(60) (FAB method).
H~NMR data: ~ = 1.81 (m) 2 H, (d6-DMS0, 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, 2 H, replaceable by D20, 7.80 (m) 2 H, replaceable by D2O, 8.99 (d) 1 H, ppm.
Example 3 Nl-[3-(lH-Imidazol-4~yl)propyl]-N2-!2-(pyridin-2-yl-amino)-ethyl~-guanidine-trihydrochloride ~037~33 ~ NHCH2CH2-NH-C-NH-CH2cH2cH2 ~
x 3 HCl 0.93 g (76~) of a colourless, hygroscopic solid are obtained from 1.21 g (3.1 mmol) of N1-benzoyl-N2-[3-(lH-imidazol-4-yl)propyl]-N3-[2-(pyridin-2-yl-amino)-ethyl]-guanidine and 20 ml of conc. hydrochloric acid.
C14H24C13N7 (396-75) H-NMR data: ~ = 1.80 - 2.21 (m) 2 H, (CD30D, 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 D20, 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 ~37~3 ~r ~'~;~3 N~
N I IN /--~111 1 IN ~ ~>
x Il~ N~
1.50 g (3.37 mmol) of 3-[~5-Bromo-3-methyl-pyridin-2-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.
C16H2sBrIN7 (522-24) H-NMR data: ~ = 1.93 (m) 4 H
(CD30D, TMS as 2.12 (s) 3 H
internal standard 2.69 (t) 2 H
3.2 - 3.6 (m) 6 H
4.9 (broad) 6 H, replaceable by D20, 6.95 (s) 1 H
7.40 (d) 1 H
7.69 (s) 1 H
7.93 (d) 1 H, ppm.
~37~3~
Example 5 Nl-[3-(lH-Imidazol-4-yl)propyl]-N2-[2-(diphenylmethoxy)-- ethyl]-guanidine-hydroiodide IH
~; ~IH CJI CH l\IH-~-,YHCH C~l OCH
H x H~
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.126-1270C, are obtained.
C23H22N2o2s (390.5) '.J
b) S-Methyl-N-[2-(diphenylmethoxy)ethyl]-isothiuronium iodide 11.1 g -(28 mmol) of Nl-benzoyl-N2-[2-(diphenyl-methoxy)ethyl]-thiourea are boiled up with 4.15 g (30 mmol) of potassium carbonate in 200 ml of methanol and 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 e~Japoration under ~ac~um. The residue is ta~en up with 100 ml of e~anol ana with 2.1 ml(33 ~mol) ~ethyl iodide 2~337~33 stirred up for 20 hours at room temperature. 11.4 g (94%) of a colourless, hi~hly viscous oil are obtained after removal of the solvent by evaporation under vacuum.
C17H21IN2S (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-(lH-imidazol-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.
C22H2gINsO (505-4) H-NMR data: ~ = 1.7 - 2.1 (m) 2 H, (CD30D, 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-(pyrldin-2-yl)propyl]-N2-[3-(lH-imidazol-4-yl)propyl]guanidine-trihydrochloride 3 ~
F ~ F
~ CH-CH2-CH2-NH-C-~H-CH2-CH2-CH2 ~ NH ~ 3 HCl a) Nl-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-diphenyl-imidocarbonate are stirred together with 20 ml ofmethylene 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 1009C 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 prepara-tive layer chromatography on silica gel 60 PF254 contain-ing gypsum (Solv~nt: 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.
C28H28F2N60 (502.6) 2~3~33 H-NMR data: ~ = 1.96 (m) 2 H, (CDCl3, 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 (m) 11 H, 8.12 (d) 2 H, 8.58 (d) 1 H, 10.3 - 10.9 (broad) 1 H, replaceable by D2O, ppm.
-' b) Nl-[3-(3,5-Difluorophenyl)-3-(pyridin-2-yl)propyl]-N2-[3-(lH-imidazol-4-yl)propyl]guanidine 0.76 g (1.5 mmol) of Nl-benzoyl-N2-[3-(3,5-difluorophenyl) -3 - (pyridin-2-yl) propyl] -N3 - [3 - (lH-imidazol-4-yl)propyl]guanidine are heated under reflux in 40 ml of 20% hydrochloric acid for 10 hours. The hydro-20 chloric acid solution is then extracted three times withether, 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.
25 C21H24F2N6 3HCl (507.8) MS (FAB method): m/z (rel. Int. [%]) = 399 ([M+H]+,80), 232 (100), 204 (18), 109 (60), 100 (36), 95 (11).
~6~7~3 H-NMR data: ~ = 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, 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-able by D2O, 7.76 (dd) 1 H, 8.02 (m) 3 H, 2 H, replaceable by D20, 8.32 (dd) 1 H, 8.75 (d) 1 H, 9.05 (s) 1 H, 14.45 (broad) 1 H, replaceable by D20, 14.8 (broad) 1 H, replaceable by D2O ppm.
Example 7 Nl-[2-[N-(5-Bromo-3-methyl-pyridin-2-yl)-benzylamino]-ethyl]-N2-[3-(lH-imidazol-4-yl)propyl]guanidine-tri-hydrochloride 3r CH3 NH
`N-cH2cH2NH-c-NH-cH2cH2cH2-¢ ~ ,c 3 HCl 2~'7433 1.15 g (2.0 mmol) of Nl-benæoyl-N2-[2-[N-(5-bromo-3-methylpyridin-2-yl)-benzylamino]ethyl]-N3-[3-(lH-imidazol-4-yl)propyl]-guanidine are boiled in 20 ml of conc. 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: ~ = 1.80 - 2.18 (m) 2 H
15 (CD30D, 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 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-(lH-imidazol-4-yl)propyl]guanidine-trihydrochloride Br~ CH B NH
N J--CH2~CH2CH2CH2-NH-C-I`~H-C~rl2CH2CH2-¢ N x 3 HCl ~1 H
~037433 1.00 g (2 mmol) of Nl-Benzoyl-N2[4-(5-bromo-3-- methyl-pyridin-2-yl)butyl]-N3-[3-(lH-imidazol-4-yl)-propyl]-guanidine are boiled in 20 ml of conc. hydro-chloric acid for 18 hours. The aqueous solution, diluted to 40 ml after cooling, is extracted with 4 x 20 ml of diethylether, 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 concentra-tion by evaporation, 0.5 ml of conc. hydrochloric acid are added and the product is concentrated by evaporation under vacuum. After it has been again concentrated by evapora-tion 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 lH-NMR data: ~ = 1.68 - 2.22 (m) 6 H, (CD30D, 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, 7.61 (s) 1 H, 8.89 (d) 1 H, 9.10 (d) 2 H, ppm.
. I B ¦ 4.72 I C 1 5.88 ¦ D 1 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 N l !
Nll IIN ~
(3 N
2 ~3 3 r~ ~; 3 3 Compound B: Nl-[3-(3,5-difluorophenyl)-3-(pyridin-2-yl~-propyl]-N2-[3-(lH-imidazol-4-yl)propyl]-guanidine F ~ F
Nll N N ~N,~
~,N H 11 ~1 Compound C: Nl-[2-[N-(5-bromo-3-methyl-pyridin-2-yl)-5benzylamino]-ethyl]-N2-[3-(1H-imidazol-4-yl)-propyl]-guanidine [~
B r~ --I IN N l!--N~--\J
Compound D: N1-[4-(5-brcmo-3-methyl-pyridin-2-yl)butyl]-N2-[3-(lH-imidazol-4-yl)propyl]-guanidine ar~CIl3 N~l `Nll NN
The invention is described in the Examples.
2~37~33 Example 1 N1-[3-(lH-Imidazol-4-yl)propyl]-N2-[2-[(pyridin-3-yl)-methylthio]-ethyl]guanidine-trihydrochloride -S-CH2-C~2-~l~-C-NH-C~2-CH2-C~2~ l x 3 HCl 0.85 g (2 mmol) of N-Benzoyl-N'-[3-(imidazol-4-yl)-propyl]-N " -~2-[(pyrid-3-yl)methylthio]ethyl)guanidine 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).
H-NMR data ~ = 1.87 (m) 2 H, (d6-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 H, 4 H
replaceable by D20 8.5 - 9.1 (m) 4 H, ppm.
'~3~3 Example 2 Nl-[3-(lH-Imidazol-4-yl)propyl]-N2-(3,3-diphenylpropyl)-guanidine-dihydrochloride H-cH2-cH2-NH-c-NH-cH2-cH2-c~2 ~ ~ x 2 HCl 0.84 g (1.8 mmol) of N-Benzoyl-N'- r 3-(imidazol-4-yl)propyl]-N''-(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.
C22H27Ns-2HCl (434-4) MS: m/z (rel. Int. [%]) = 362 ([M+H]+, 84), 167(54), 109(100), 91(60) (FAB method).
H~NMR data: ~ = 1.81 (m) 2 H, (d6-DMS0, 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, 2 H, replaceable by D20, 7.80 (m) 2 H, replaceable by D2O, 8.99 (d) 1 H, ppm.
Example 3 Nl-[3-(lH-Imidazol-4~yl)propyl]-N2-!2-(pyridin-2-yl-amino)-ethyl~-guanidine-trihydrochloride ~037~33 ~ NHCH2CH2-NH-C-NH-CH2cH2cH2 ~
x 3 HCl 0.93 g (76~) of a colourless, hygroscopic solid are obtained from 1.21 g (3.1 mmol) of N1-benzoyl-N2-[3-(lH-imidazol-4-yl)propyl]-N3-[2-(pyridin-2-yl-amino)-ethyl]-guanidine and 20 ml of conc. hydrochloric acid.
C14H24C13N7 (396-75) H-NMR data: ~ = 1.80 - 2.21 (m) 2 H, (CD30D, 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 D20, 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 ~37~3 ~r ~'~;~3 N~
N I IN /--~111 1 IN ~ ~>
x Il~ N~
1.50 g (3.37 mmol) of 3-[~5-Bromo-3-methyl-pyridin-2-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.
C16H2sBrIN7 (522-24) H-NMR data: ~ = 1.93 (m) 4 H
(CD30D, TMS as 2.12 (s) 3 H
internal standard 2.69 (t) 2 H
3.2 - 3.6 (m) 6 H
4.9 (broad) 6 H, replaceable by D20, 6.95 (s) 1 H
7.40 (d) 1 H
7.69 (s) 1 H
7.93 (d) 1 H, ppm.
~37~3~
Example 5 Nl-[3-(lH-Imidazol-4-yl)propyl]-N2-[2-(diphenylmethoxy)-- ethyl]-guanidine-hydroiodide IH
~; ~IH CJI CH l\IH-~-,YHCH C~l OCH
H x H~
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.126-1270C, are obtained.
C23H22N2o2s (390.5) '.J
b) S-Methyl-N-[2-(diphenylmethoxy)ethyl]-isothiuronium iodide 11.1 g -(28 mmol) of Nl-benzoyl-N2-[2-(diphenyl-methoxy)ethyl]-thiourea are boiled up with 4.15 g (30 mmol) of potassium carbonate in 200 ml of methanol and 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 e~Japoration under ~ac~um. The residue is ta~en up with 100 ml of e~anol ana with 2.1 ml(33 ~mol) ~ethyl iodide 2~337~33 stirred up for 20 hours at room temperature. 11.4 g (94%) of a colourless, hi~hly viscous oil are obtained after removal of the solvent by evaporation under vacuum.
C17H21IN2S (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-(lH-imidazol-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.
C22H2gINsO (505-4) H-NMR data: ~ = 1.7 - 2.1 (m) 2 H, (CD30D, 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-(pyrldin-2-yl)propyl]-N2-[3-(lH-imidazol-4-yl)propyl]guanidine-trihydrochloride 3 ~
F ~ F
~ CH-CH2-CH2-NH-C-~H-CH2-CH2-CH2 ~ NH ~ 3 HCl a) Nl-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-diphenyl-imidocarbonate are stirred together with 20 ml ofmethylene 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 1009C 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 prepara-tive layer chromatography on silica gel 60 PF254 contain-ing gypsum (Solv~nt: 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.
C28H28F2N60 (502.6) 2~3~33 H-NMR data: ~ = 1.96 (m) 2 H, (CDCl3, 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 (m) 11 H, 8.12 (d) 2 H, 8.58 (d) 1 H, 10.3 - 10.9 (broad) 1 H, replaceable by D2O, ppm.
-' b) Nl-[3-(3,5-Difluorophenyl)-3-(pyridin-2-yl)propyl]-N2-[3-(lH-imidazol-4-yl)propyl]guanidine 0.76 g (1.5 mmol) of Nl-benzoyl-N2-[3-(3,5-difluorophenyl) -3 - (pyridin-2-yl) propyl] -N3 - [3 - (lH-imidazol-4-yl)propyl]guanidine are heated under reflux in 40 ml of 20% hydrochloric acid for 10 hours. The hydro-20 chloric acid solution is then extracted three times withether, 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.
25 C21H24F2N6 3HCl (507.8) MS (FAB method): m/z (rel. Int. [%]) = 399 ([M+H]+,80), 232 (100), 204 (18), 109 (60), 100 (36), 95 (11).
~6~7~3 H-NMR data: ~ = 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, 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-able by D2O, 7.76 (dd) 1 H, 8.02 (m) 3 H, 2 H, replaceable by D20, 8.32 (dd) 1 H, 8.75 (d) 1 H, 9.05 (s) 1 H, 14.45 (broad) 1 H, replaceable by D20, 14.8 (broad) 1 H, replaceable by D2O ppm.
Example 7 Nl-[2-[N-(5-Bromo-3-methyl-pyridin-2-yl)-benzylamino]-ethyl]-N2-[3-(lH-imidazol-4-yl)propyl]guanidine-tri-hydrochloride 3r CH3 NH
`N-cH2cH2NH-c-NH-cH2cH2cH2-¢ ~ ,c 3 HCl 2~'7433 1.15 g (2.0 mmol) of Nl-benæoyl-N2-[2-[N-(5-bromo-3-methylpyridin-2-yl)-benzylamino]ethyl]-N3-[3-(lH-imidazol-4-yl)propyl]-guanidine are boiled in 20 ml of conc. 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: ~ = 1.80 - 2.18 (m) 2 H
15 (CD30D, 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 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-(lH-imidazol-4-yl)propyl]guanidine-trihydrochloride Br~ CH B NH
N J--CH2~CH2CH2CH2-NH-C-I`~H-C~rl2CH2CH2-¢ N x 3 HCl ~1 H
~037433 1.00 g (2 mmol) of Nl-Benzoyl-N2[4-(5-bromo-3-- methyl-pyridin-2-yl)butyl]-N3-[3-(lH-imidazol-4-yl)-propyl]-guanidine are boiled in 20 ml of conc. hydro-chloric acid for 18 hours. The aqueous solution, diluted to 40 ml after cooling, is extracted with 4 x 20 ml of diethylether, 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 concentra-tion by evaporation, 0.5 ml of conc. hydrochloric acid are added and the product is concentrated by evaporation under vacuum. After it has been again concentrated by evapora-tion 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 lH-NMR data: ~ = 1.68 - 2.22 (m) 6 H, (CD30D, 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, 7.61 (s) 1 H, 8.89 (d) 1 H, 9.10 (d) 2 H, ppm.
Claims (20)
1. The use of guanidine derivatives corresponding to the general formula II
(II) in which R denotes the group wherein R1 stands for a phenyl group which may be unsubstituted or mono- or disubstituted wlth halogen atoms, C1-C3-alkyl groups or C1-C3-alkoxy groups or 2 pyridine ring which may be unsubstituted or mono- or disubstituted with halogen atoms, C1-C3-alkyl groups or C1-C3-alkoxy groups, R2 stands for a hydrogen atom, a C1-C3-alkyl group, a phenyl group optionally mono- or disubstituted with halogen atoms, C1-C3-alkyl groups or C1-C3-alkoxy groups, or a benzyl or heteroarylmethyl 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 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, C1-C3-alkyl groups or C1-C3-alkoxy groups, R5 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, 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.
(II) in which R denotes the group wherein R1 stands for a phenyl group which may be unsubstituted or mono- or disubstituted wlth halogen atoms, C1-C3-alkyl groups or C1-C3-alkoxy groups or 2 pyridine ring which may be unsubstituted or mono- or disubstituted with halogen atoms, C1-C3-alkyl groups or C1-C3-alkoxy groups, R2 stands for a hydrogen atom, a C1-C3-alkyl group, a phenyl group optionally mono- or disubstituted with halogen atoms, C1-C3-alkyl groups or C1-C3-alkoxy groups, or a benzyl or heteroarylmethyl 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 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, C1-C3-alkyl groups or C1-C3-alkoxy groups, R5 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, 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.
2. The use according to Claim 1, characterised in that in the general formula II, R stands for one of the following groups:
2-(Diphenylmethoxy)ethyl, 2-[bis-(4-fluorophenyl)-methoxy]-ethyl, 2-[Bis-(4-chlorophenyl)methoxy]ethyl,
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.
3. The use of N1-[3-(1H-imidazol-4-yl)propyl]-N2-[2-[(pyridin-3-yl)methylthio]ethyl]-guanidine and the physio-logically acceptable salts thereof for the purpose according to Claim 1.
4. The use of N1-[3-(1H-imidazol-4-yl)propyl]-N2-(3,3-diphenylpropyl)guanidine and the physiologically accept-able salts thereof for the purpose according to Claim 1.
3. The use of N1-[3-(1H-imidazol-4-yl)propyl]-N2-[2-[(pyridin-3-yl)methylthio]ethyl]-guanidine and the physio-logically acceptable salts thereof for the purpose according to Claim 1.
4. The use of N1-[3-(1H-imidazol-4-yl)propyl]-N2-(3,3-diphenylpropyl)guanidine and the physiologically accept-able salts thereof for the purpose according to Claim 1.
5. The use of N1-[3-(1H-imidazol-4-yl)propyl]-N2-[2-[(pyridin-2-yl)-amino]ethyl]-guanidine and the physio-logically acceptable salts thereof for the purpose according to Claim 1.
6. The use of Nl-[3-[(5-bromo-3-methyl-pyridin-2-yl) amino]propyl]-N2-[3-(1H-imidazol-4-yl)propyl]-guanidine and the physiologically acceptable salts thereof for the purpose according to claim 1.
7. The use of Nl-[3-(1H-imidazol-4-yl)propyl]-N2-[2-(diphenylmethoxy)ethyl]-guanidine and the physiologically acceptable salts thereof for the purpose according to Claim 1.
8. The use of Nl-[3-(3,5-difluorophenyl)-3-(pyridin-2-yl)propyl]-N2-[3-(1H-imidazol-4-yl)propyl]-guanidine and the physiologically acceptable salts thereof for the purpose according to Claim 1.
9. The use of N1-[2-[N-(5-bromo-3-methyl-pyridin-2-yl)-benzylamino]-ethyl]-N2-[3-(lH-imidazol-4-yl)propyl]-guanidine and the physiologically acceptable salts thereof for the purpose according to Claim 1.
10. The use of N1-[4-(5-bromo-3-methyl-pyridin-2-yl)butyl]-N2-[3-(1H-imidazol-4-yl)propyl]-guanidine and the physiologically acceptable salts thereof for the purpose according to Claim 1.
11. The use of guanidine derivatives corresponding to the general formula II
(II) in which R denotes the group wherein R1 stands for a phenyl group which is unsub-stituted or mono- or disubstituted with halogen atoms, C1-C3-alkyl groups or C1-C3-alkoxy groups or a pyridine ring which is unsubstituted or mono- or disubstituted with halogen atoms, C1-C3-alkyl groups or C1-C3-alkoxy groups, R2 stands for a hydrogen atom, a C1-C3-alkyl group, a phenyl group optionally mono- or disubstituted with halogen atoms, C1-C3-alkyl groups or C1-C3-alkoxy groups or a benzyl or heteroarylmethyl group which is 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 wherein R3 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, R4 denotes a hydrogen atom or a phenyl group optionally mono-or disubstituted with halogen atoms, C1-C3-alkyl groups or C1-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 for the treatment of high blood pressure.
(II) in which R denotes the group wherein R1 stands for a phenyl group which is unsub-stituted or mono- or disubstituted with halogen atoms, C1-C3-alkyl groups or C1-C3-alkoxy groups or a pyridine ring which is unsubstituted or mono- or disubstituted with halogen atoms, C1-C3-alkyl groups or C1-C3-alkoxy groups, R2 stands for a hydrogen atom, a C1-C3-alkyl group, a phenyl group optionally mono- or disubstituted with halogen atoms, C1-C3-alkyl groups or C1-C3-alkoxy groups or a benzyl or heteroarylmethyl group which is 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 wherein R3 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, R4 denotes a hydrogen atom or a phenyl group optionally mono-or disubstituted with halogen atoms, C1-C3-alkyl groups or C1-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 for the treatment of high blood pressure.
12. The use according to Claim 11, characterised in that in the general formula II, 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 and 3,3-bis-(4-chlorophenyl)propyl.
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 and 3,3-bis-(4-chlorophenyl)propyl.
13. The use of N1-[3-(lH-imidazol-4-yl)propyl]-N2-[2-[(pyridin-3-yl)methylthio]ethyl]-guanidine and the physioloqically acceptable salts thereof for the purpose according to Claim 11.
14. The use of N1-[3-(1H-imidazol-4-yl)propyl]-N2-(3,3-diphenylpropyl)guanidine and the physiologically accept-able salts thereof for the purpose according to Claim 11.
15. The use of N1-[3-(1H-imidazol-4-yl)propyl]-N2-[2-[(pyridin-2-yl)amino]-ethyl]-guanidine and the physio-logically acceptable salts thereof for the purpose according to Claim 11.
16. The use of N1-[3-[(5-bromo-3-methyl-pyridin-2-yl)-amino]-propyl]-N2-[3-(1H-imidazol-4-yl)propyl] guanidine and the physiologically acceptable salts thereof for the purpose according to Claim 11.
17. The use of N1-[3-(1H-imidazol-4-yl)propyl]-N2-[2-(diphenylmethoxy)ethyl]-guanidine and the physiologically acceptable salts thereof for the purpose according to Claim 11.
18. The use of N1-[3-(3,5-difluorophenyl)-3-(pyridin-2-yl)propyl]-N2-[3-(1H-imidazol-4-yl)propyl]-guanidine and the physiologically acceptable salts thereof for the purpose according to Claim 11.
19. The use of N1-[2-[N-(5-bromo-3-methyl-pyridin-2-yl)-benzylamino)ethyl]-N2-[3-(1H-imidazol-4-yl)propyl]-guanidine and the physiologically acceptable salts thereof for the purpose according to Claim 11.
20. The use of Nl-[4-(5-bromo-3-methyl-pyridin-2-yl)butyl]-N2-[3-(1H-imidazol-4-yl)propyl]-guanidine and the physiologically acceptable salts thereof for the purpose according to Claim 11.
Applications Claiming Priority (2)
| 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 |
| EP901062000.0 | 1990-03-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2037433A1 true CA2037433A1 (en) | 1991-10-01 |
Family
ID=8203843
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002037433A Abandoned CA2037433A1 (en) | 1990-03-30 | 1991-03-01 | Use of guanidine derivatives for the preparation of a pharmaceutical product having pny 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) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5939462A (en) * | 1997-02-14 | 1999-08-17 | Bayer Corporation | NPY5 receptor antagonists and methods for using same |
| US5958709A (en) * | 1993-12-28 | 1999-09-28 | Synaptic Pharmaceutical Corporation | Processes for identifying compounds that bind to the human Y4 receptor |
| US5968819A (en) * | 1994-12-02 | 1999-10-19 | Synaptic Pharmaceutical Corporation | DNA encoding a hypothalamic atypical neuropeptide Y/peptide YY receptor (Y5) |
| 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 |
| US5989834A (en) * | 1994-02-03 | 1999-11-23 | Synaptic Pharmaceutical Corporation | Uses of nucleic acid encoding neuropeptide Y/peptide YY (Y2) receptors nucleic acid encoding |
| US6048900A (en) * | 1998-02-13 | 2000-04-11 | Bayer Corporation | Amide derivatives and methods for using the same as selective neuropeptide Y receptor antagonists |
| US6245817B1 (en) | 1997-02-14 | 2001-06-12 | Bayer Corporation | NPY5 receptor antagonists and methods for using same |
| 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) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0672054A4 (en) * | 1991-12-19 | 1996-02-07 | Garvan Inst Med Res | A novel molecule which inhibits neuropeptide tyrosine biological function. |
| AU7692996A (en) * | 1995-12-01 | 1997-06-27 | Ciba-Geigy Ag | Receptor antagonists |
| AU7692896A (en) * | 1995-12-01 | 1997-06-27 | Novartis Ag | Quinazolin-2,4-diazirines as NPY receptor antagonist |
| ZA974147B (en) * | 1996-05-14 | 1997-11-14 | Novo Nordisk As | Somatostatin agonists and antagonists. |
| ATE218859T1 (en) * | 1996-08-23 | 2002-06-15 | Agouron Pharma | LIGANDS OF NEUROPEPTIDE Y |
| 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 |
| EP0937065A1 (en) * | 1996-10-31 | 1999-08-25 | Novo Nordisk A/S | Constrained somatostatin agonists and antagonists |
| CA2251580A1 (en) * | 1997-02-14 | 1998-08-20 | Bayer Corporation | Amides as npy5 receptor antagonists |
| KR20010020610A (en) * | 1997-07-03 | 2001-03-15 | 해피 페너 ; 해리 에이치. 페너 2세 | 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. |
| AU2935200A (en) | 1999-04-30 | 2000-11-17 | Pfizer Products Inc. | Compounds for the treatment of obesity |
| CN1461304A (en) | 2000-09-20 | 2003-12-10 | 先灵公司 | Substituted imidazoles as dual histamine H1 and H3 agonists or antagonists |
| ATE411983T1 (en) * | 2000-09-20 | 2008-11-15 | Schering Corp | SUBSTITUTED IMIDAZOLES AS HISTAMINE H1 AND H3 AGONISTS OR ANTAGONISTS |
| MXPA03002448A (en) | 2000-09-20 | 2003-06-19 | Schering Corp | Substituted imidazoles as dual histamine h1 and h3 agonists or antgonists. |
| JP2004509869A (en) | 2000-09-20 | 2004-04-02 | シェーリング コーポレイション | Substituted imidazoles as dual histamine H1 and H3 agonists or antagonists |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0199845B1 (en) * | 1985-04-02 | 1990-08-01 | HEUMANN PHARMA GMBH & CO | Imidazolylalkylguanidin derivatives, process for their preparation and pharmaceutical compositions containing them |
| 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 DE DE59006842T patent/DE59006842D1/en not_active Expired - Fee Related
- 1990-03-30 AT AT90106200T patent/ATE109979T1/en active
- 1990-03-30 ES ES90106200T patent/ES2058651T3/en not_active Expired - Lifetime
- 1990-03-30 DK DK90106200.0T patent/DK0448765T3/en active
- 1990-03-30 EP EP90106200A patent/EP0448765B1/en not_active Expired - Lifetime
-
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 PT PT97138A patent/PT97138A/en not_active Application Discontinuation
- 1991-03-25 HU HU91979A patent/HU207945B/en not_active IP Right Cessation
- 1991-03-26 IE IE99591A patent/IE65252B1/en not_active IP Right Cessation
- 1991-03-26 JP JP3061914A patent/JPH0789939A/en active Pending
- 1991-03-27 KR KR1019910004812A patent/KR910016329A/en not_active Application Discontinuation
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5958709A (en) * | 1993-12-28 | 1999-09-28 | Synaptic Pharmaceutical Corporation | Processes for identifying compounds that bind to the human Y4 receptor |
| US5976814A (en) * | 1993-12-28 | 1999-11-02 | Synaptic Pharmaceutical Corporation | DNA encoding a human neuropeptide Y/peptide YY/pancreatic polypeptide receptor (Y4) and uses thereof |
| US6913892B1 (en) | 1993-12-28 | 2005-07-05 | H. Lundbeck A/S | Method of obtaining compositions comprising Y4 specific compounds |
| US5989834A (en) * | 1994-02-03 | 1999-11-23 | Synaptic Pharmaceutical Corporation | Uses of nucleic acid encoding neuropeptide Y/peptide YY (Y2) receptors nucleic acid encoding |
| US6645774B1 (en) | 1994-12-02 | 2003-11-11 | Synaptic Pharmaceutical Corporation | Methods of modifying feeding behavior using compounds with afinity for the human hypothalamic atypical neuropeptide Y/peptide YY receptor (Y5) |
| US5968819A (en) * | 1994-12-02 | 1999-10-19 | Synaptic Pharmaceutical Corporation | DNA encoding a hypothalamic atypical neuropeptide Y/peptide YY receptor (Y5) |
| 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 |
| US6818445B2 (en) | 1994-12-02 | 2004-11-16 | 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) |
| US6316203B1 (en) | 1994-12-02 | 2001-11-13 | Synaptic Pharmaceutical Corporation | Methods of screening and preparing a composition using DNA encoding a hypothalamic atypical neuropeptide Y/peptide YY receptor (Y5) |
| US6410792B1 (en) | 1997-02-14 | 2002-06-25 | Bayer Corporation | Amide derivatives and methods for using the same as selective neuropeptide Y receptor antagonists |
| US5939462A (en) * | 1997-02-14 | 1999-08-17 | Bayer Corporation | NPY5 receptor antagonists and methods for using same |
| US6245817B1 (en) | 1997-02-14 | 2001-06-12 | Bayer Corporation | NPY5 receptor antagonists and methods for using same |
| 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) |
| US6048900A (en) * | 1998-02-13 | 2000-04-11 | Bayer Corporation | Amide derivatives and methods for using the same as selective neuropeptide Y receptor antagonists |
Also Published As
| Publication number | Publication date |
|---|---|
| HU910979D0 (en) | 1991-10-28 |
| ES2058651T3 (en) | 1994-11-01 |
| KR910016329A (en) | 1991-11-05 |
| PT97138A (en) | 1991-11-29 |
| IE910995A1 (en) | 1991-10-09 |
| IL97424A (en) | 1995-05-26 |
| EP0448765A1 (en) | 1991-10-02 |
| IL97424A0 (en) | 1992-06-21 |
| IE65252B1 (en) | 1995-10-18 |
| HU207945B (en) | 1993-07-28 |
| HUT57044A (en) | 1991-11-28 |
| AU7206891A (en) | 1991-10-03 |
| AU637882B2 (en) | 1993-06-10 |
| ATE109979T1 (en) | 1994-09-15 |
| EP0448765B1 (en) | 1994-08-17 |
| DK0448765T3 (en) | 1994-09-19 |
| ZA911471B (en) | 1991-11-27 |
| JPH0789939A (en) | 1995-04-04 |
| DE59006842D1 (en) | 1994-09-22 |
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