AU637882B2

AU637882B2 - The use of guanidine derivatives for the preparation of a pharmaceutical product having pny antagonistic activity

Info

Publication number: AU637882B2
Application number: AU72068/91A
Authority: AU
Inventors: Kurt Henning Dr Ahrens; Heidrun Dr. Engler; Martin C. Dr. Michel; Johann Peter Dr. Morsdorf; Helmut Dr. Schickaneder
Original assignee: Heumann Pharma GmbH and Co
Current assignee: Heumann Pharma GmbH and Co
Priority date: 1990-03-30
Filing date: 1991-03-04
Publication date: 1993-06-10
Anticipated expiration: 2011-03-04
Also published as: ATE109979T1; EP0448765B1; DK0448765T3; KR910016329A; IE65252B1; AU7206891A; CA2037433A1; HU910979D0; IE910995A1; IL97424A0; DE59006842D1; ZA911471B; IL97424A; JPH0789939A; PT97138A; EP0448765A1; HU207945B; HUT57044A; ES2058651T3

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

PATENTS ACT 1952 b 78 8Form Form COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Short Title: Int. Cl: Application Number: Lodged: 0 O

S

:gmplete Specification-Lodged: Accepted: S.0 *Lapsed: Published:

S*

Priority:

S..

Related Art: 4 e**t S.

0 Siee S S

L

:I"Na;Aie of Applicant: Aress of Applicant: Actual Inventor: Address for Service: TO BE COMPLETED BY APPLICANT HEUMANN PHARMA GmbH CO.

Postfach 2260, D-8500 Germany Nuremberg 1, DR. MARTIN C. MICHEL, DR. JOHANN PETER MORSDORF, DR. HEIDRUN ENGLER, DR. HELMUT SCHICKANEDER, DR. KURT-HENNING AHRENS Peter Maxwell Associates, Blaxland House, Ross Street, NORTH PARRAMATTA N.S.W. 2151 Complete Specification for the invention entitled: THE USE OF GUANIDINE DERIVATIVES FOR THE PREPARATION OF A PHARMACEUTICAL PRODUCT HAVING PNY ANTAGONISTIC ACTIVITY The following statement is a full description of this invention, including the best method of perf'trming it known to me:-* SNote: The description is to be typed in double spacing, pica type face, in an area not exceeding 250 mm in depth and 160 mmrn in width, on tough white paper of good quality and it is to be inserted inside this form.

14599/78-L Printed by C.J. THOMPSON, Commonwealth Government Printer. Canberra 4 o 5 Neuropeptide Y (NPY) is a peptide of 36 amino acids 9 which was originally isolated from pigs' brains Tatemoto, Proc. Natl. Sci., USA 79, 5485 (1982)) but 0 has also been found in the human central and peripheral nervous system.

NPY controls the vascular sympathetic tone together with noradrenalin. The 4 -fsys-tma-t4 use of NPY leads to prolonged rise in the vascular resistance. Boublik et al 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 4 pre4rtionr of high blood pressure.

NPY antagonists therefore constitute a potential new method in the treatment of high blood pressure, but no NPY antagonists have hitherto been known.

Guanidine derivatives having the following basic structure

I!

-2which have histamine-H 2 agonistic and histamine-H 1 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 cardioconic 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.

According to the invention, there is provided a method 15 for the treatment of a medical condition treatable by neuropeptide-Y antagonists, said method comprising administering to a patient in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of one or more of a guanidine derivative 20 corresponding to the general formula II

(CH

2N HR NH H.

(II)

-3in which R denotes the group

R

1 N-

(CH

2 nwherein R1 stands for a phenyl. group which may be unsubstituted or mono- i~r disubstituted with halogen atoms, 0 1

-C

3 -alkyJ. groups or C 1 -0 3 -alkoxy groups or a pyridine ring which may be unsubstituted or mono- or disubstituted with halogen atoms, 0 1

-C

3 -alkyi. groups or

CI-C

3 -alkoxy groups, R 2 stands for a hydrogen atom, a Cl-C 3 -alky. group, a phenyl group optionally mono- or 0 disubstituted with halogen atoms, Cl-C 3 alkyl groups or 0* 0 1 -0 3 -alkoxy groups, or a benzyl or heteroarylmethyl group which may be unsubstituted or raono- or disubstituted with halogen atoms, Cl-C 3 alkyl groups or 01-03- .~*alkoxy groups, and n has the value 2, 3 or 4, or in which R denotes the group 4

R

wherein R 3 stands for a pyridine ring or phenyl ring which may be unsubstituted or mono- or disubstituted with halogen atoms, 0 1 -0 3 -alkyJ. groups or 0 1

-C

3 -alkoxy groups,

R

4 denotes a hydrogen atom or a phenyl group optionally mono- or disubstituted with halogen atoms, C 1-03 -alkyl groups or Cl-0 3 -alkoxy grus.R

I

-3a- *1 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, or a physiologically acceptable salt thereof.

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.

Therefore, according to another aspect of the invention there is provided a method for the treatment of high blood pressure, comprising administering to a patient in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of one or more of a guanidine derivative corresponding to the general formula II to. 20

RH

in which R denotes the.group Im S*N-(CH2)n R2 wherein R 1 stands for a phenyl group which is unsubstituted or mono- or disubstituted with halogen atoms, C-C 3 -alkyl groups or C-0 3 -alkoxy groups or a pyridine ring which is groups or Cl-C3-alkoxy groups or a pyridine ring which is -3bunsubstituted or mono- or disubstituted with halogen atoms,

C

1

-C

3 -alkyl groups or Ci-C 3 -alkoxy groups, R2 stands for a hydrogen atom, a C1-C 3 -alkyl group, a phenyl group optionally mono- or disubstituted with halogoen atoms,

C

1

-C

3 -alkyl groups or C1-C 3 -alkoxy groups or a benzyl or heteroarylmethyl group which is unsubstituted or mono- or disubstituted with halogen atoms, C 1

-C

3 -alkyl groups or

C

1

-C

3 -alkoxy groups, and n has the value 2, 3 or 4, or in which R denotes the group

R

3

R

4 -C-Z-(CH2)p-

R

wherein R 3 stands for a pyridine ring or phenyl ring which 4 is unsubstituted or mono- or disubstituted with halogen atoms, C1-C 3 -alkyl groups or C 1

-C

3 -alkoxy groups, S R 4 denotes a hydrogen atom or a phenyl group optionally mono- or disubstituted with halogen atoms, C-C 3 -alkyl groups or C1-C 3 -alkoxy groups, R 5 stands for a hydrogen 20 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 valu.e 2 or 3, m has the value 2 or 3 and R' denotes a hydrogen atom or a methyl group, or a physiologically acceptable salt thereof.

Another object of this invention is therefore the use of the above-defined guanidine derivatives for the preparation of a pharmaceutical product for the treatment of high blood pressure.

In the general formula II indicated above, R may denote the group

R

1

N-(CH

2 )n- R2 1. 0 In this group, R 1 stands for an unsubstituted or mono- or disubstituted phenyl group. In the case of substitution, o 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 C 1

-C

3 -alkyl groups, preferably methyl or ethyl groups, and 1 or 2

C

1

-C

3 -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 R 1 may also be an unsubstituted or S* 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, C 1

-C

3 -alkyl groups such as methyl or ethyl groups and Cl-C 3 -alkoxy groups such as methoxy, ethoxy or propoxy groups, preferably methoxy groups.

Linkage of the pyridine ring denoted by R 1 to the nitrogen atom in the group R may take place in the 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.

R

2 stands for a hydrogen atom, a C 1

-C

3 -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 R 2 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 R 1 In the case of substitution, the benzyl group may S. 10 be substituted with 1 or 2 halogen atoms such as fluorine, chlorine or bromine atoms, preferably chlorine or fluorine S atoms, or C 1

-C

3 -alkoxy groups, such as methoxy or ethoxy st* groups, preferably methoxy groups. In the case of monosubstitution of the benzyl group denoted by R 2 the 15 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 R 2 stands for a hetero aryl methyl group, this groupis preferably a thiophenylmethyl, a4r or 20 a pyr-id-in-et group. The heteroarylmethyl group may also be unsubstituted or, preferably, mono- or disubstituted. The substituents may be halogen atoms such as fluorine, chlorine or bromine atoms, C 1

-C

3 -alkyl groups such as methyl or ethyl groups and linear C 1

-C

3 -alkoxy 25 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

R

3

R

4

-C-Z-(CH

2 p-

RS

j Vrsc In this group, R 3 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 C 1

-C

3 -alkyl groups, preferably methyl or ethyl groups, and 1 or 2 C 1

C

3 -alkoxy groups, such as methoxy or ethoxy groups.

Monosubstitution and disubstitution are preferred.

10 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 R 3 may also be an unsubstituted or a mono- 15 or disubstituted pyridine ring, preferably an unsubstituted pyridine ring or a monosubstitted pyridine ring.

The substituents of the pyridine ring may be, for example, halogen atoms such as fluorine, chlorine o. bromine atoms, preferably bromine or chlorine atoms, most preferably bromine atoms, C 1

-C

3 -alkyl groups such as methyl or ethyl groups and C 1

-C

3 -alkoxy groups such as methoxy, ethoxy or Spropoxy groups, preferably methoxy groups.

Linkage of the pyridine ring denoted by R 3 to the carbon atom in the group R may take place in the 3- or 25 4-position of the pyridine ring, the 2- or 3-position being preferred. Linkage in the ?-position of the pyridine ring is particularly preferred.

R

4 denotes a hydrogen atom or an unsubstituted or mono- or disubstituted phenyl group. In the case of substitution, the phenyl group denoted by R 4 is substituted in the same manner as the phenyl group denoted by R 3 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 RI 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 follcwing groups: 2-(Diphenylmethoxy)ethyl, 2-[bis-(4-fluorophenyl)methoxy] ethyl, 2-[bis- (4-chlorophenyl)methoxylethyl, 004furpey)?(prdn2y~rpl 103-('.4-luorohenyl)-?-(pyridin-2-pylpopl 3- (3 ,4-difluorophenyl) (pyridin-2-yl) propyl, 0.00lrohnl--(yii--y~rpl 3- 5-diflorophenyl) (pyridin-2-yl) propyl, 150 4-clorophenyl) (pyridin-3-yl) propyl, 2-f N-(5-bromo-3-methyl-pyridin-2-yl) -benzylamino]ethyl, 2-[N-(5-bromo-3-methyl-pyridin-2-yl)-(4-chlorobenzyl)amino] -ethyl, 4-0-rm--ehlprdn2y)btl -(5-bromo-3-methyl-pyridin-2-yl)pbutyl, 4- (5-bromo-pyridin-2-yl) butyl, 3- (5-bromo-pyridin-2-yl) propyl, 3- (4-chlorophenyl) -3-phenylpropyl, 0000 3 (4-fluorophenyl) -3-phenylpropyl, 25 3,3-bis-(4-fluorophenyl)propyl or 3, 3-bis- (4-chiorophenyl) propyl.

The use of the individual compounIs indica-,ed below is particularly preferred: Nl-f3-(lH-Imidazol-4-yl)propyl] -N 1 -f2--f (pyridin-3yl) methylthio] ethyl) -guanidine Nl-f3-(lH-imidazol-4-yl)propyl]-N 2 -(3,3-diph3flylpropyl)guariidine

N

1 -[3-(1H-imidazol-4-yl) ]propyl]-N 2 -f2-C (pyridin-2-yl)amino] ethyl] -guaklidine Nl-f3-f (5-bromo-3-methyl-pyridin-2-yl)aminolpropyl]-N 2 (lH-imidazol-4-yl)propyl]-guanidine N1-[3-(1H-imidazol-4-yl)propyl]-N 2 -[2-(diphenylmethoxy)ethyl]-guanidine (Compound A)

N

1 -[3-(3,5-difluorophenyl)-3-(pyridin-2-yl)propyl]-N 2 (lH-imidazol-4-yl)propyl]-guanidine (Compound B) N1 [2-[N-(5-bromo-3-methyl-pyridin-2-yl) -benzylamino]ethyl]-N 2 -[3-(1H-imidazol-4-yl)propyl]-guanidine (Compound C) Nl-[4-(5-bromo-3-methyl-pyridin-2-yl)butyl]-N 2 -[3(1H- 10 imidazol-4-yl)propyl]-guanidine (Compound D).

The compounds used according to the invention are known compounds which may be prepared by the processes 0* described in the above-mentioned documents.

0. The neuropeptide-Y antagonistic action of the o* 15 compounds used according to the invention was demonstrated by the method of Motulsky and Michel 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) f 20 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 25 to be tested, the latter are added to the incubation medium at concentrations of from 10 4 to 10 6 and the NPY activity curve is then again determined.

The guanidine compounds used according to the invention shift the NPY concentration activity curve to the right. According to Schild-Plot analysis, the shift to the right is competitive so that the substances antagonise the NPY action by competition on the specific NPY receptor.

The following Table shows the values measured in terms of pA 2 values: Compound pA 2 IInhibition of the rise in Ca++ A B 4.72 I C 5.88 D 5.04 *;The following compounds were used for the above *described test, the results of which are shown in the goo.

Table: Compound A: Nl-[3-(lH-imidazol-4-yl)propyl]-N 2 (diphenylmethoxy) ethyl] -guanidine Hi mNil Ia Compound B: Nl-[3-(3,5-difluorophenyl)-3-(pyridin-2-yl)propyl]-N 2 -[3-(lH-imidazol-4-yl)propyl]guanidine F F Nil I It Comoun C: Nl-2[N H Iom-3mthlprdn2y) bezylmino-etyl 3 (11-imdazl-4-l) Compound C: N 1 -CE 5-bromo-3-methyl-pyridin-2-yl) uyin* 5 beuzylam-io]-ty]N- 3-(H-imidazol-4-yl)prpl -andn Br~i I11 Ni *.e~eN Ni CIIt Th ineto isdsrbdi h xmls Example 1

N

1 (1H-Imidazol-4-yl)propyl -N 2 2- (pyridin-3-yl) methylthio]-ethyl]guanidine-trihydrochloride N NH N

CH

2 -S-CH2-CH 2

-NH-C-NH-CH

2

-CH

2 -CH-2 x 3 HC1 0.85 g (2 mmol) of N-Benzoyl-N'-[3-(imidazol-4-yl)- 5 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 10 the residue is dried in a high vacuum. 0.78 g of a dry, highly hygroscopic foam is obtained.

C

15

H

22

N

6 S'3HC1 (427.8) Molar mass Calc.: 318.16267; found: 318.16299 MS: m/z (rel. Int. 318 168(17), 125(29), 95(51), 93(100), 92(57), 44(89).

1 H-NMR data 6 1.87 2 H, (d 6 -DMSO, TMS as 2.62 2 H, internal standard) 2.73 2 H, eg internal standard) 2.73 2 H, 3.0-3.7 4 H, 4.10 2 H, 7.3 8.3 6 H, 4 H replaceable by D 2 0 9.1 4 H, ppm.

Example 2[ Nl-[ 3- (1H-imid azol-4-yl) propyl]-N 2 3-diphenylpropyl) guanidine-dihydrochioride

NH

-CH-CH 2 -CH 2 NH-C-,NH- C H 2 -CH 2

CH.

2 x 2 HC1

H

0.84 g (1.8 mmol) of N-Benzoyl-N'-C3-(imidazol-4- 'Vow. 5~ yl)propyl]-N' '-(3,3-diphenylpropyl)guanidine are heated undar reflux in 45 ml of 20% hydrochloric acid for 7 hours. The product is worked up as in Example 1.

Yield: 0.67 g of a hygroscopic, non-crystalline solid.

as e

C

22

H

27

N

5 *2HC1 (434.4) MS: m/z (rel. Int. 362 84) 167(54), 109(100), 91(60) (FAB method).

1 H-NMR data: 6 =1.81 (mn) 2 H, *6*(d 6 -DMSO, TMS 2.27 (dt) 2 H, as internal standard) 2.68 2 H.

3.02 (mn) 2 H, 3.16 (mn) 2 H, 6.0 4.10 1 H, 7.15 7.6 (in) 13 H, 2 H, replaceable by 7.80 (mn) 2 H, replaceable by D 2 0, 8.99 1 H, ppm.

Examnle 3 amino) -ethyl]I-guanidine-trihydrochloride

NH

0 11 0.93 g of a colourless, hygroscopic solid are obtained from 1.21 g (3.1 mmol) of N'-benzoyl-N 2 -l3-(lHimidazol-4-yl)propyl]-N 3 -2-(pyridin-2-y-amino) -ethyl]guanidine and 20 ml of conc. hydrochloric acid.

C

14

H

24 C1 3

N

7 (396.75)

B

41 41.

B.

b S. 0 9 Q

U.

1 H-NM. data:

(CD

3 OD, TMS as internal standard) 6 1.80 2.21 (in) 2 H, 2.69 3.00 (in) 2 H, 3.37 2 H, 3.57 3.83 (in) 4 H, 4.8 (broad) 8 H, replace able by D 2 0, 6.96 2. H, 7.22 1 H, 7.44 1 H, 7.83 8.16 (in) 2 H, 8.87 1 H, ppm.

Example 4 Nl-r3-c (5-Bromo-3-methyl-pyridin-2-yl) amino] -propyl]-N 2 S3 (1H- imidaz o 1-4 propyl j -guanidine-hydro iodide

NIN

I IN il N 141> x III 'NI log~ 0 9 9041 0 6

,B

98 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-(1H-imidazol-4-yl)propylamine are boiled under reflux in 20 ml of aceconitrile 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 of a colourless, amorphous solid.

C

16

H

25 BrIN 7 (522.24) 1 H-NMR data:

(CD

3 0D, TMS as internal standard 6 1.93 4 H 2.12 3 H 2.69 2 H 3.2 3.6 6 H 4.9 (broad) 6 H, replaceable by D 2 0, 6.95 1 H 7.40 1 H 7.69 1 H 7.93 1 H, ppm.

Example N1-[3-(1H-Imidazol-4-yl)propyl]-N2-[2-(diphenylmethoxy)ethyl]-guanidine-hydroiodide

INH

CH CH NH-C-NHCH CH OCH 222 22 H x HI a) N 1 -Benzoyl-N 2 -[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 of colourless crystals, m.p.126-127 C, are obtained.

C

23

H

22

N

2 0 2 S (390.5) b) S-Methyl-N-[2-(diphenylmethoxy)ethyl]-isothiuronium iodide 11.1 g (28 mmol) of N 1 -benzoyl-N 2 -[2-(diphenylmethoxy)ethyl]-thiourea are boiled up with 4.15 g (30 mmol) of potassium carbonate in 200 n.l 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 evaporation under vacuum. The residue is taken up with 100 ml of ethanol and with 2.1 ml (33 rrol) methyl iodide stirred up for 20 hours at room temperature. 11.4 g of a colourless, highly viscous oil are obtained after removal of the solvent by evaporation under vacuum.

C

17

H

21

IN

2 0S (428.3) c) N1-[3-(iH-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-(1Himidazol-4-yl)-propylamine are boiled under reflux in 10 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 of a colourless, amorphous solid are obtained.

C

22

H

2 8IN 5 0 (505.4)

S

oo9 oo 0 S. S 1 H-NMR data:

(CD

3 0D, TMS as internal standard) SR 20

OO

6 1.7 2.1 2 H, 2.7 2 H, 3.1 3.8 6 H 4.9 (broad) 5 H, replaceable by D 2 0, 5.6 1 H, 1 H, 7.2 7.6 10 H 1 H, ppm.

Example 6

N

1 -[3-(3,5-Difluorophenyl)-3-(pyridin-2-yl)propyl]-N 2 [3-(lH-imidazol-4-yl)propyl]guanidine-trihydrochloride

CH-CH

2

-CH

2

-NH-C-NH-CH

2

-CH

2 -CH2 NH 3 HC

-N

a) N 1 -Benzoyl-N 2 -[3-(3,5-difluorophenyl)-3-(pyridin-2-yl)propyl]-N 3 -[3-(lH-imidazol-4-yl)propyl]guanidine 1.24 g of 3-(3,5-Difluoro nenyl)-3-(pyridin-2-yl)propylamine and 1.59 g (5 mmol) of N-benzoyl-diphenyl- 5 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 S heated to l009C for 45 minutes after the addition of s* 10 0.55 g (5.2 mmol) of 3-(1H-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

S

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-

S

tive layer chromatography on silica gel 60 PF 2 5 4 containing gypsum (Solvent: chloroform/methanol 99.5:0.5, 20 ammoniacal atmosphere). 1.3 g of a colourless, amorphous solid are obtained after concentration of the eluates by evaporation.

C

2 8

H

2 8

F

2

N

6 0 (502.6) 1 H-N.fl data: (CDC1 3 TMS as internal standard) 61.96 (in) 2 H, 2.3 (broad) 2. H, 2.6 2.8 (in) 3 H, 3.34 (broad) 2 H, (broad) 2. H, 3.9 (broad) 2. H, 4.17 (dd) I H, 6.6 7.8 (mn) 11 H, 8.12 2 H, 8.58 21 H, 10.3 10.9 (broad) 2. H, replaceable by

D

2 0, ppm.

4*@

S

0S 0e S S

S

OS S *5

S

S*S

*5

S

5@@5 S *5 S 55 SS 0

S

55.5

S

b) Nl-[3-(3,5-Difluorophenyl)-3-(pyridin-2-yl)propyl]-N 2 2.5 (1H-iiidazol-4-yl)propyl]guanidine 0.76 g (1.5 mino]) of Nl-benzoyl-1 2 difluoropheny)-3-(pyridin-2-yl)propy.]-N 3 imidazol-4-yl)propyljguanidine are heated under reflux in ml of 20% hydrochloric acid for 2.0 hours. The hydro- 20 chlo:ric acid solution is then extracted three times with ether, concentrated to dryness under vacuum and dried in a high vacuum.

Yield: 0.65 g of the trihydrochloride in the form of a hygroscopic, amorphous solid.

25 C 2 lH 24

F

2

N

6 *3HC1 (507.8) MS (FAB method): in/z (rel. Int. 399 232 (100); 204 2.09 2.00 95 1 H-NI4R data: (DMSO-d 6 TI4S as internal standard) 0 Are 15 ode* 555.

6=1.85 (in) 2 H, 2.35 2.65 (Mn) 2 H, 2.72 2 H, 3.3 (in) 4 H, 4.78 1 _11 7.16 (dd'i 1 H, 7.36 2 H, 7.51 1 H, 7.62 2 H, replaceable by D 2 0, 7.76 (dd) 1 H, 8 .02 (mn) 3 H, 2 H, replaceable by D 2 0, 8.32 (dd) 1 H, 8.75 1 H, 9.05 1 H, 14.45 (broad) 1 H, replaceable by D 2 0, 14.8 (broad) 2. H, replaceable by D 2 0 ppm.

S

555050 a

*S.S

0O 55 S 00 05 Se S

S

SSSO

S

003 Examole. 7 Nl-f2-[N-(5-Bromo-3-inethyl-pyridin-2-yl)-benzylamino]ethy1]_N 2 -(3-(lH-imidazol-4-yl)propy1]guanidine-trihydrochloride Br NH 3 IM

H

1.15 g (2.0 mmol) of Nl-benzoyl-N 2 3-methylpyridin-2--yl) -benzylamino] ethyl] -N 3 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 dietalylether.

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 of a colourless, highly hygroscopic solid.

**0

C

22

H

3 lBrC1 3

N

7 (579.80) IH-NMR data:

(CD

3 OD, TMS as internal standard) 6'1.80 2.18 (in) 2 H 2.61- 3 H1, 2.89 2 H, 3.34 2 H, 3.60 (in) 2 H, 3.83 (mn) 2 H, 4.15 2 H, 4.9 (broad) 7 H, 7.37 7.55 (mn) 6 H 8. 84 1 H, 8.92 2 H, ppm.

20

S

0O*S a. a S. a a a a..

S

Examp~le 8 Nl-14-(5-Brono-3-inethyl-pyridin-2-yl.)butyl]-N 2 i3-(lHimidazol-4-yl) propyl]guanidine-trihydrochlorike Br CH 3

N

N CH 2

-CH

2 CHCH2NHC MHCH2CH2CH2 7 N> C

H

1.00 g (2 mmol) of N 1 -Benzoyl-; 2 [4-(5-bromo-3methyl-pyridin-2-yl)butyl]-N 3 -[3-(1H-imidazol-4-yl) propyl]-guanidine are boiled in 20 ml of conc. hydrochloric acid for 18 hours. The aqueous solution, diluted to 40 ml after cooling, is extracted with 4 x 20 ml of diethyl 4 ier, 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 The main fraction is taken up with 5 ml of water after concentration by evtporation, 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 evaporation with 20 ml of absolute ethanol, 0.62 g of the title compound are obtained in the form of a colourless, hygroscopic solid.

C

1 7

H

2 8 BrC1 3

N

6 (502.71) 20 1 H-NMR data: 6 1.68 2.22 6 H,

(CD

3 0D, TMS as 2.61 3 H, internal standard) 2.91 2 H, 1 3.05 3.52 6H, 4.95 (broad) 7 H, 7.61 1 H, 8.89 1 H, 9.10 2 H, ppm.

Claims

1. A method for the treatment of a medical condition treatable by neuropeptide-Y antagonists, said method comprising administering to a patient in need of such treatr mnt a pharmaceutical composition comprising a therapeutically effective amount of one or more of a guanidine derivative corresponding to the general formula II (II) (cH 2 )m N R d a in which R denotes the group R 1 N-(CH2)n- R2 n r** wherein R 1 stands for a phenyl group which may be unsubstituted or mono- or disubstituted with halogen atoms, Ci-C 3 -alkyl groups or C 1 -C 3 -alkoxy groups or a pyridine ring which may be unsubstituted or mono- or disubstltuted with halogen atoms, C1-C 3 -alkyl groups or C 1 -C 3 -alkoxy groups, R 2 stands for a hydrogen atom, a C1-C 3 -alkyl group, a phenyl group optionally mono- or disubstituted with halogen atoms, 0 1 -C 3 -alkyl groups or C 1 -0 3 -alkoxy groups, or a benzyl or heteroarylmethyl group which may be unsubstituted or mono- or disubstituted -23- with halogen atoms, Ci-C 3 -alkyl groups or C1-C3- alkoxy groups, and n has the value 2, 3 or 4, or in which R denotes the group R 3 R4C-Z-(CH2) p R wherein R 3 stands for a pyridine ring or phenyl ring which may be unsubstituted or mono- or disubstituted with halogen atoms, C 1 -C 3 -alkyl groups or Cl-C 3 -alkoxy groups, R 4 denotes a hydrogen atom or a phenyl group optionally Q mono- or disubstituted with halogen atoms, C 1 -C3-alkyl 0 groups or C1-C 3 -alkoxy groups, R 5 stands for a hydrogen atom or a methyl or hydroxy group and Z stands for a single bond, an oxygen atom or a sulphur atom and p has the value 2 or 3, m has the value 2 or 3 and R' denotes a hydrogen atom or a methyl group, or a physiologically acceptable salt thereof.

2. The method according to claim 1, characterised in that in the general formula II, R stands for one of the following groups: 2-(Diphenylmethoxy)ethyl, 2-[bls-(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-dtfluorophenyl)-3-(pyridin-2-yl)propyl, 3-(4-chlorophenyl)-3-(pyridin-2-yl)propyl, -24- 3- 4-dich3.orophenyl (pyridin-2-yl )propyl, 3- (4-f luorophenyl (pyridin-3-yl )propyl, 2- EN- (5-bromo-3--methy- -pyridin-2-yl )-benzylamino] ethyl, -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-bronio-pyridi -2-yl )butyl, 3- (5-bromo-pyridin-2-yl )propyJ. 3- (4-chiorophenyl )-3-phenylpropyl, 3- (4-f luorophenyl) -3-phenylpropyl, 3,-i-4furohnlpoy or 3,3-bis-(4-florophenyl)propyl.o is 3-is-(4-hloroenyl)propyl -2[-(prdn3 4 The method of claim 1 wherein the guanidine derivative is Nl-[3-(1H-imidazol-4-yl)propyl]-N 2 -E2-[(pyridin-2-y) ylmethltoethyl]-guanidine or a physiologicallyetbesl acteptble sltthref 6 The method of claim 1 wherein the guanidine derivative is Nl-[3-(5-irmdazol-4yl-prdn2)aiopropylj- 2 (33 is N2-3-(H-imidazol-4-yl)propyl]-N 2 -E2-[n opridn-ay) -26- physiclogically acceptable salt thereof.

7. The method of claim 1 wherein the guanidine derivative is N 1 -[3-(1H-imidazol-4-yl)propyl]-N 2 (diphenylmethoxy)ethyl]-guanidine or a physiologically acceptable salt thereof.

8. The method of claim 1 wherein the guanidine derivative is N1-[3-(3,5-difluorophenyl)-.3-(pyridin-2-yl)propyl]-N 2 (3-(1H-imidazol-4-yl)propl]-guanidine or a physiologically acceptable salt thereof.

9. The method of claim 1 wherein the guanidine derivative is N 1 -[2-[N-(5-bromo-3-methyl-pyridin-2-yl)-benzylamino]- ethyl]-N 2 -[3-(1H-imidazol-4-yl)propyl]- guanidine or a physiologically acceptable salt thereof. The method of claim 1 wherein the guanidine derivative V. is N 1 -[4-(5-bromo-3-methyl-pyridin-2-yl)butyl]-N 2 imidazol-4-yl)propyl]-guanidine or a physiologically 4, 4. acceptable salt thereuf.

11. A method for the treatment of high blood pressure, co;prising administering to a patient in need of such treatment a pharmaceutical composition comprising a .therapeutically effective amount of one or more of a guanidine derivative corresponding to the general formula II NH S (CH 2 )r N R 614j) (2/I -V~b -26- in which R denotes the group R 1 R N- (CH 2 )n- R2 wherein R 1 stands for a phenyl group which is unsubstituted or mono- or disubstituted with halogen atoms, C1-0 3 -alkyl groups or C 1 -C 3 -alkoxy groups or a pyridine ring which is unsubstituted or mono- or disubstituted with halogen atoms, C 1 -0 3 -alkyl groups or C 1 -C 3 -alkoxy groups, R 2 stands for a hydrogen atom, a C 1 -C 3 -alkyl group, a phenyl group optionally mono- or disubstituted with halogoen atoms, C 1 -0 3 -alkyl groups or C 1 -C 3 -alkoxy groups or a benzyl or heteroarylmethyl group which is unsubstituted or mono- or disubstituted with halogen atoms, Ci-C 3 -alkyl groups or C 1 -C 3 -alkoxy groups, and n has the value 2, 3 or 4, or in which R denotes the group R R3 R4-C-Z-(CH 2 )p- groups or Cf-C 3 -alkoxy groups, R 5 stands for a hydrogen 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 C1-03-alkoxy groups, R 4 denotes a hydrogen atom or a phenyl group optionally mono- or disubstituted with halogen atoms, Ci-C3-alkyl groups or C1-03-alkoxy groups, R 5 stands for a hydrogen W'atom or a methyl or hydroxyl group and Z stands for a single -27- bond, an oxygen atom or a sulphur atom and p has the value 2 or 3, m has the value 2 or 3 and RI denotes a hydrogen atom or a methyl group, or a physiologically acceptable salt thereof.

12. The method according to claim 11, characterised 4 n that in the general formula II, R stands for one of the following groups: 2-(Diphenylmethoxy)-ethyl, 2-[bis-(4-fluorophenyl)-methoxyj- ethyl, 2-[bis-(4-chlorophenyl)methoxyJ ethyl, 3- (4-f luorophenyl) (pyridin-2-yl )propyl, 3-34dfloohny)@0~rii--y~rpl 3 -(3,5-difluorophenyl)-3-(pyridin-2-yl)propyl, Vo 3-(3,4-dilorophenyl)-3-(pyridin-2-yl)propyl, 3-(4-lorophenyl)-3-(pyridin-3-yl)propyl, 3-(3,-dicho-3-pheyl-pyridin-2-poyl),pl 3- (4-f roopheiny)-3-- yridn--yty)roy 2--(-bromo-3t-pyridin-2-yl) -bezyopnoytll 2-3-Ni-(-romor3-meylpridilndy)(-h~obny)ai1] 3- -bio-4-hetahl-ylidin-yl) rpl -28- *see b e 0, C beC C *r C CCC. 0 C .00. 0 C C C CC CC C CCC C C CC CCC <i* /r D j. e

13. The method of claim 11 wherein the guanidine derivative is N 1 -[3-1H-imidazol-4-yl)propyl)-N 2 -[2-(pyridin-3- yl)methylthio]ethyl]-guanidine or a physiologically acceptable salt thereof.

14. The method of claim 11 wherein the guanidine derivative is N 1 -[3-(1H-imidazol-4-yl)propyl]-N 2 diphenylpropyl)guanidine or a physiologically acceptable salt thereof. The method of claim 11 wherein the guanidine derivative is N 1 -[3-(H-imidazol-4-yl)propyJ.-N 2 -(2-(pyridin-2- yl)amino]-ethyl]-guanidine or a physiologically acceptable salt theic of.

16. The method of claim 11 wherein the guanidine derivat~lve is N 1 -[3-((5-bromo-3-methyl-pyridin-2-yl)-amino)-propyl]- N 2 -(3-(1H-imidazol-4-yl)propyl3-guanidine or a physiologically acceptable salt thereof.

17. The method of claim 11 wherein the guanidine derivative is N 1 -[3-(H-imidazol-4-yl)propylj-N 2 (diphenylmethoxy)ethyl]-guanidine or a physiologically acceptable salt thereof.

18. The method of claim 11 wherein the guanidine derivative is N 1 -[3-(3,5-difluorophenyl)-3-(pyridin-2-yl)propyl]-N 2 [3-(1H-imidazol-4-yl)propylj-guanidine or a physiologically acceptable salt thereof.

19. The method of claim 11 wherein the guanidine derivative is N l.2-(N-(5-bromo-3-methyl-pyridin-2-yl)- benzylamino)ethyl]-N 2 -(3-(1H-imidazol-4-yl)propyl3- guanidine or a physiologically acceptable salt thereog. -29- The method of claim 11 wherein the guanidine derivative is N 1 4-(5-bronio-3-methyl-pyridin-2-yl)butyl -N 2 3- (1H-imidazol-4-yl)propyl -guanidine or a physiologically acceptable salt thereof. Dated this 12th January, 1993. HEUMANW PHARMA GmbH CO. Patent Attorneys for the Applicant: FF.TER MAXWELL ASSOCIATES 9 9 9 9 9. 9. 9

99.. 99 9 49 9 9. 9 9.. 99 99 9 9. .9 99999 9 9 99 4 999 9 9 9 iI'