US3683023A - Amino-guanidine derivatives - Google Patents

Amino-guanidine derivatives Download PDF

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US3683023A
US3683023A US828366A US3683023DA US3683023A US 3683023 A US3683023 A US 3683023A US 828366 A US828366 A US 828366A US 3683023D A US3683023D A US 3683023DA US 3683023 A US3683023 A US 3683023A
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guanidine
percent
blood pressure
theory
yield
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US828366A
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Werner Winter
Max Thiel
Kurt Stach
Wolfgang Schaumann
Karl Dietmann
Klaus Ritter
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/52—Nitrogen atoms not forming part of a nitro radical with hetero atoms directly attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/16—Compounds containing any of the groups, e.g. aminoguanidine

Definitions

  • R and R are each hydrogen or lower alkyl
  • alkylene containing two to three carbon atoms and when joined together form alkylene containing two to three carbon atoms, and X is phenyl substituted by at least one halogen atom, and the salts thereof with pharmaceutically acceptable acids.
  • R and R which may be the same or different, are each hydrogen atoms or lower alkyl and when R, and R are joined together form alkylene containing two or three carbon atoms and X is phenyl substituted by one or more halogen atoms; and the salts thereof with physiologically compatible acids.
  • the new compounds (I) are valuable pharmaceuticals and canbe successfully used for the regulation of. the blood pressure and are particularly suitable for use in the treatment of hypertonias.
  • the new guanidine derivatives (I) can be prepared, for example, by the reaction of a hydrazine having the formula:
  • R has the same significance as given above, or if R, and R are hydrogen'or lower alkyl, by the reaction of a compound having the-formula:
  • R is hydrogen or lower alkyl and X and have the same meanings as given above, with a compound having the formula:
  • Tetrahydrofuran has proved to be particularly useful as a polar, inert solvent.
  • reaction products is carried out by converting the same by the conventional methods into their physiologically compatible salts, for example, by neutralization with an appropriate organic or inorganic acid.
  • physiologically compatible salts there may be mentioned, in particular, the hydrochlorides, hydrobromides, sulfates, phosphates, tartrates, citrates and oxalates of the free bases (I).
  • EXAMPLE 2 (3-chloroanilino)-guanidine 7.1 g m-chlorophenyl-hydrazine (0.05 mol) were first heated, while passing nitrogen through the mixture, with 7.7 g S-methyl-isothiuronium bromide for 30 minutes at C and then for 30 minutes at C.
  • the compounds of the invention constitute potent antihypertensive agents.
  • the compounds have proved particularly effective in the treatment of patients with severe or sustained elevation of blood pressure, particularly diastolic pressure.
  • the compounds are suitable for use in almost all forms of fixed and progressive hypertensive disease, including that in which blood pressure is moderately elevated.
  • the compounds have also proved efiective in renal hypertension, including hypertension secondary to pyelonephritis, glomerulonephritis and renal amylordosis.
  • the compounds can be administered orally, as pills, tablets, capsules, powders and the like.
  • the preferred form of oral administration is as a tablet containing 10 to 25 mg of active compound.
  • the compounds can also be administered parenterally.
  • injection solutions containing 10 mg/ml of injection solution are preferred.
  • the dosage schedule is entirely dependent on the condition of the patient, his response to the treatment and whether or not he is ambulatory or hospitalized.
  • the treatment should be begun with small doses (10 mg) and increased gradually depending upon the patients response.
  • the dosage can be increased at 5 to 7 day intervals until an average daily dose of 25 to 50 mg is reached. Only one dose a day is usually required.
  • Rats each weighing 250-300 g were used as test animals. Experimental hypertension was induced in these animals by administering to them over a 4 week period ll-desoxycorticosterone-acetate (5 mg-twice weekly subcutaneously and by supplying them with a feed containing 10 percent sodium chloride. After this period, during which experimental high blood pressure had been achieved, an arterial tonometer catheter was surgically implanted into the carotid artery of each of the animals. Blood pressure measurements were carried out using an electromechanical pressure converter (Statham element) and a direct writing system (Schwarzer system) for recording the same. After the control values had been determined, the animals were given the test substance dissolved in physiological saline, the test drugs being supplied by an esophageal catheter.
  • guanethidine (Ismelin Ciba) [2-(octahydro-l-azocinyl)-ethyl]-guanidine sulfate was used.

Abstract

Amino-guanidine derivatives constituting blood pressure regulating agents and being characterized by their ability to decrease blood pressure having the formula: WHEREIN R1 and R2 are each hydrogen or lower alkyl, and when joined together form alkylene containing two to three carbon atoms, and X is phenyl substituted by at least one halogen atom, and the salts thereof with pharmaceutically acceptable acids.

Description

United States Patent Winter etal.
[54] AMINO-GUANIDINE DERIVATIVES [72] Inventors: Werner Filed:
May 27, 1969 Appl. No.: 828,366
Foreign Application Priority Data July 9, 1968 Germany ..P I7 68 867.4
U.S. Cl......260/564 F, 260/256.4 R, 260/308 R,
260/309.6, 260/310 R, 260/50l.l4, 260/564.
Int. Cl.....' ..C07c 129/08 Field of Search ..260/564 F Aug. 8, 1972 [56] References Cited UNITED STATES PATENTS 3,383,409 I 5/1968 Bream et al. ..260/50l.l4
OTHER PUBLICATIONS Chemical Abstracts, Vol. 67, 32382(a) I967).
Primary Examiner-Leon Zitver Assistant Examiner-Gerald A. Schwartz Attorney-Burgess, Dinklage & Sprung ABSTRACT Amino-guanidine derivatives constituting blood pressure regulating agents and being characterized by their ability to decrease blood pressure having the formula:
I wherein R and R are each hydrogen or lower alkyl,
and when joined together form alkylene containing two to three carbon atoms, and X is phenyl substituted by at least one halogen atom, and the salts thereof with pharmaceutically acceptable acids.
5 Claims, No Drawings wherein R and R which may be the same or different, are each hydrogen atoms or lower alkyl and when R, and R are joined together form alkylene containing two or three carbon atoms and X is phenyl substituted by one or more halogen atoms; and the salts thereof with physiologically compatible acids.
In accordance with the invention it has now been found that the new compounds (I) are valuable pharmaceuticals and canbe successfully used for the regulation of. the blood pressure and are particularly suitable for use in the treatment of hypertonias.
The new guanidine derivatives (I) can be prepared, for example, by the reaction of a hydrazine having the formula:
X NH NI-I (II) wherein X has the same significance as given above, either with an isourea derivative having the formula:
Nit
NH-Rz (III) wherein Z is a reactive group which can easily be split off and R, and R have the same significances as given above, or, if R is hydrogen, with a cyanamide having the formula:
R,-NI-l-CN iv wherein R, has the same significance as given above, or if R, and R are hydrogen'or lower alkyl, by the reaction of a compound having the-formula:
wherein R is hydrogen or lower alkyl and X and have the same meanings as given above, with a compound having the formula:
reacted with the compounds (VI) either by heating in a polar, inert solvent or, without the use of a solvent, simply by melting the components together, preferably in an atmosphere of nitrogen or in a vacuum.
Tetrahydrofuran has proved to be particularly useful as a polar, inert solvent.
The isolation of the reaction products is carried out by converting the same by the conventional methods into their physiologically compatible salts, for example, by neutralization with an appropriate organic or inorganic acid.
As examples of physiologically compatible salts, there may be mentioned, in particular, the hydrochlorides, hydrobromides, sulfates, phosphates, tartrates, citrates and oxalates of the free bases (I).
The following examples are given for the purpose of illustrating the present invention; the same are however, not to be construed as in any way limiting the scope thereof.
EXAMPLEI (3-chloroanilino)-guanidine 28.4 g (0.2 mol) m-chlorophenyl-hydrazine were heated under reflux with 29.4 g (0.2 mol) N-guanylyield 93.7 percent of theory.
( 2,4-dichloroanilino)-guanidine The hydrochloride melted with decomposition, after recrystallization from tetrahydrofuran/isopropanol, at 235-237C; yield 61 percent of theory. (2,3-dichloroanilino)-guanidine The hydrochloride melted with decomposition, after recrystallization from tetrahydrofuran, at 25 3-254C; yield: 76.6 percent of theory. (4-fluoroanilino)-guanidine The hydrochloride melted with decomposition, after recrystallization from isopropanol/ether, at 2l5-216 C; yield 77.5 percent of theory.
EXAMPLE 2 (3-chloroanilino)-guanidine 7.1 g m-chlorophenyl-hydrazine (0.05 mol) were first heated, while passing nitrogen through the mixture, with 7.7 g S-methyl-isothiuronium bromide for 30 minutes at C and then for 30 minutes at C.
' Thereafter, the base was freed by adding an aqueous chloroanilino)-guanidine hydrochloride having a melting point of l98l99C. The yield amounted to 5 g (45 percent of theory).
The following compounds were obtained in an analogous manner: (2,5-dichloroanilino)-guanidine The hydrobromide melted, after recrystallization from ethyl acetate/methanol, at 202203C; yield: 51 percent of theory. (The crude hydrobromide was recrystallized directly from the melt obtained.) (2,4,6-trichloroanilino)-guanidine The hydrobromide melted, after recrystallization from methanol/ether, at 246-247C; yield: 53 percent of theory. (The crude hydrobromide was recrystallized directly from the melt obtained.) (2,6-dichloroanilino)-guanidine The hydrobromide melted, after recrystallization from alcohol/ether, at 226227C; yield: 61 percent of theory. (The crude hydrobromide was recrystallized directly from the melt obtained.)
EXAMPLE 3 v 2-(2,4-dibromophenyl-hydrazino)-A -imidazoline 6.65 g (0.025 mol) 2,4-dibromophenyl-hydrazine were melted together with 4.95 g (0.025 mol) S- methyl-ethylene-thiourea hydrobromide in a vacuum (12 mm Hg) at l30l40C. After 2 hours had elapsed, the cooled melt was recrystallized from isopropanol. There were obtained 8 g (77.7 percent of theory) 2-( 2 4-dibromophenyl-hydrazino)- -imidazoline hydrobro mide, which had a melting point of 240C.
The following compounds were obtained in an analogous manner: 2-(2,5-dichlorophenyl-hydrazino)-A -imidazoline The hydrobromide melted, after recrystallization from alcohol, at 262263C; yield: 53.3 percent of theory. 2-( 2,6-dichlorophenyl -hydrazino)-A -imidazoline The hydrobromide melted, after recrystallization from alcohol/ether, at 293-294C; yield: 61.3 percent of theory. 2-(2,4-dichlorophenyl-hydrazino)-A -imidazoline The hydrobromide melted, after recrystallization from isopropanol, at 230C; yield: 69.3 percent of theory.
2-( 3 ,4-dichlorophenyl-hydrazino)-A -imidazoline The hydrobromide melted, after recrystallization from isopropanol, at 217C; yield: 53 percent of theory. 2-(2,3-dichlorophenyl-hydrazino)-A -imidazoline The hydrobromide melted, after recrystallization from isopropanol, at 237C; yield: 59 percent of theory. 2-(2,4,6-tribromophenyl-hydrazino)-A -imidazoline The hydrobromide melted, after recrystallization from isopropanol, at 246247C; yield: 46 percent of theory.
2-(4-fluorophenyl-hydrazino)-A -imidazoline The hydrobromide melted, after recrystallization from isopropanol, at l83l85C; yield: 78 percent of theory.
The following compounds were also obtained in an analogous manner but in this instance the reaction was carried out while passing through nitrogen: 2-(3-chlorophenyl-hydrazino)-A -imidazoline The hydrochloride melted, after amorphous reprecipitation, from alcohol/ether, at l67-l70C; yield: 53 percent of theory. 2-(2,4,6-trichlorophenyl-hydrazino)-A -imidazoline The hydrochloride melted, after recrystallization from alcohol, at 262-263C; yield: 52 percent of theory.
The compounds of the invention constitute potent antihypertensive agents. The compounds have proved particularly effective in the treatment of patients with severe or sustained elevation of blood pressure, particularly diastolic pressure. The compounds are suitable for use in almost all forms of fixed and progressive hypertensive disease, including that in which blood pressure is moderately elevated. The compounds have also proved efiective in renal hypertension, including hypertension secondary to pyelonephritis, glomerulonephritis and renal amylordosis.
The compounds can be administered orally, as pills, tablets, capsules, powders and the like. The preferred form of oral administration is as a tablet containing 10 to 25 mg of active compound.
The compounds can also be administered parenterally. injection solutions containing 10 mg/ml of injection solution are preferred.
The dosage schedule is entirely dependent on the condition of the patient, his response to the treatment and whether or not he is ambulatory or hospitalized. The treatment should be begun with small doses (10 mg) and increased gradually depending upon the patients response. The dosage can be increased at 5 to 7 day intervals until an average daily dose of 25 to 50 mg is reached. Only one dose a day is usually required.
In order to establish the effectiveness of the aminoguanidine compounds of the invention as agents for reducing blood pressure a series of tests as follows were carried out.
Rats, each weighing 250-300 g were used as test animals. Experimental hypertension was induced in these animals by administering to them over a 4 week period ll-desoxycorticosterone-acetate (5 mg-twice weekly subcutaneously and by supplying them with a feed containing 10 percent sodium chloride. After this period, during which experimental high blood pressure had been achieved, an arterial tonometer catheter was surgically implanted into the carotid artery of each of the animals. Blood pressure measurements were carried out using an electromechanical pressure converter (Statham element) and a direct writing system (Schwarzer system) for recording the same. After the control values had been determined, the animals were given the test substance dissolved in physiological saline, the test drugs being supplied by an esophageal catheter. l, 2 and 3 hours after administration of the test drug, the animals blood pressure was again determined. All of the values as reported in the table which follows represent average values for arterial pressure. The average values determined at the beginning of the experiment, i.e., prior to drug administration amounted to -180 mm Hg. Groups of 10 animals were used in connection with each drug, therefore the average values are averages determined for 10 animals.
As comparison compound, guanethidine (Ismelin Ciba) [2-(octahydro-l-azocinyl)-ethyl]-guanidine sulfate was used.
The following compounds were used in the tests:
A- [2-( octahydrol -azocinyl )-ethyl ]-guanidinesulfate B- 2-(2,4,6-trichlorophenylhydrazino)- imidazoline-N-hydrochloride C 2(3-chlorophenylhydrazino)-imidazoline-A hydrochloride TABLE Blood Pressure Decrease Maximal Decrease in Average Dose in Arterial Blood Pressure mg./kg. in mm. Hg
Compound Oral G 50 21 H 50 38 l 50 33 J 50 46 K 50 44 As can be seen from the above table, 50 mg/kg of the comparison compound guanethidine resulted in a decrease in average arterial blood pressure of 26 mm Hg, while in all but two instances, the compounds of the invention produced a substantially more marked decrease. In the two instances where the decrease did not exceed that of the control preparation, the values were not significantly different.
It is to be noted in this connection that the use of guanethidine can lead to disturbing and serious clinical problems in particular adverse reactions resulting from sympathetic blockage. These side effects are not observed in connection with the claimed compounds.
We claim:
1. (2,5-dichloroanilino)-guanidine.
2. (2,4,6-trichloroanilino)-guanidine.
3. (2,4-dichloroanilino)-guanidine.
4. (2,6-dichloroanilino)-guanidine.
5. (4,fluoroanilino)-guanidine.
I Inventor(s) Boehr. 329
I UNITED sir/mes PA'IENT 0mm: 9 CER'IIFICATE OF CORREQTKGN name; No. 3, 83,023
Warner Winter et a1 It is certified that error appears in the above-identified patent I 01; l head, I
v and thatsaid Letters Patent are hereby corrected as shown below:
after inventor listing, please insert the name of the assignee; viz Boehringer Mannheim GMBH, of Mannheim,
EDWARD M.'FLETGHER,JR. Attes ting Officer Germany.
Col. 2 line 3.4,
For 9 -"chloroanilino-" Read g-chlo'roanilino cdilughqu l ine. 32,..- I For I I -imt'tdazoline" Read A -imidazo1ine Signed and sealed this 20th day of February 1973.
- (SEAL? Attest':
ROBERT GOTTSCHALK Commissioner of Patents

Claims (4)

  1. 2. (2,4,6-trichloroanilino)-guanidine.
  2. 3. (2,4-dichloroanilino)-guanidine.
  3. 4. (2,6-dichloroanilino)-guanidine.
  4. 5. (4,fluoroanilino)-guanidine.
US828366A 1968-07-09 1969-05-27 Amino-guanidine derivatives Expired - Lifetime US3683023A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4184492A (en) * 1975-08-07 1980-01-22 Karl Storz Endoscopy-America, Inc. Safety circuitry for high frequency cutting and coagulating devices
US4209624A (en) * 1976-10-26 1980-06-24 Cooper Laboratories, Inc. Process for preparing substituted bis(amidinoureas)
US6136987A (en) * 1998-10-29 2000-10-24 Rhein Chemie Rheinau Gmbh Use of arylguanidinium xanthogenates as vulcanization accelerators and process for the production thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU190639B (en) * 1983-12-12 1986-09-29 Gyogyszerkutato Intezet Kv,Hu Process for production of new aminoguanidin derivatives
EP0325936A3 (en) * 1988-01-16 1990-01-17 Ono Pharmaceutical Co., Ltd. Aminoguanidine derivatives and inhibitory agents on maillard reaction containing them as active ingredients

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3383409A (en) * 1966-11-10 1968-05-14 Wander Ag Dr A Beta-(2, 6-dihalophenyl) ethylamino guanidines and the salts thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE558299A (en) *

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3383409A (en) * 1966-11-10 1968-05-14 Wander Ag Dr A Beta-(2, 6-dihalophenyl) ethylamino guanidines and the salts thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, Vol. 67, 32382(a) (1967). *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4184492A (en) * 1975-08-07 1980-01-22 Karl Storz Endoscopy-America, Inc. Safety circuitry for high frequency cutting and coagulating devices
US4209624A (en) * 1976-10-26 1980-06-24 Cooper Laboratories, Inc. Process for preparing substituted bis(amidinoureas)
US6136987A (en) * 1998-10-29 2000-10-24 Rhein Chemie Rheinau Gmbh Use of arylguanidinium xanthogenates as vulcanization accelerators and process for the production thereof
MY119688A (en) * 1998-10-29 2005-06-30 Rhein Chemie Rheinau Gmbh Use of arylguanidinium xanthogenates as vulcanization accelerators and process for the production thereof

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NL6910469A (en) 1970-01-13
CA954142A (en) 1974-09-03
AT292010B (en) 1971-08-10
FI50114B (en) 1975-09-01
DE1768867B2 (en) 1973-05-24
DE1768867A1 (en) 1972-01-13
DE1768867C3 (en) 1973-12-20
FI50114C (en) 1975-12-10
GB1217805A (en) 1970-12-31
CH511817A (en) 1971-08-31

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