US3409669A - 2-(cyclohexylamino)-2-methyl-propylguanidine-1 and the salts and hydrate thereof - Google Patents

2-(cyclohexylamino)-2-methyl-propylguanidine-1 and the salts and hydrate thereof Download PDF

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US3409669A
US3409669A US413315A US41331564A US3409669A US 3409669 A US3409669 A US 3409669A US 413315 A US413315 A US 413315A US 41331564 A US41331564 A US 41331564A US 3409669 A US3409669 A US 3409669A
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Dyke Wilfred James Cecil
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UCB Pharma Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)

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  • R represents a cycloalkyl group of from 5 to 7 carbo
  • R represents a cycloalkyl group of from 5 to 7 carbo
  • certain guanidine compounds which are described in detail below, possess particularly especially against renal and According to the present invention we provide compounds of the general formula R N-R I R-NH-o-cm-NH-c R2 I'd-R5 and their hydrates and with one or more alkyl groups having 1-4 carbon atoms.
  • R is a hydrogen atom or an alkyl group having 1-4 carbon atoms.
  • R is an alkyl group having 1-4 carbon atoms.
  • R R and R which may be the same or different, are hydrogen atoms or alkyl groups having 1-4 carbon atoms.
  • R is methyl and R is hydrogen or methyl.
  • R R is cyclohexyl and R R and R cial y noteworthy in this respect.
  • R R and/or R is an alkyl group thismay, be a straight chained or branched chained alkyl group, e.g. a methyl, ethyl, butyl group etc.
  • the compounds exist as optical isomers and racemic mixtures and zoates, salicylates, nates, p-toluene sulphonates etc.
  • the new guanidines according to the invention may be emulsifyture of the invention, there is provided a process for the preparation of compounds of the general formula meanings and R is is reacted, where R tive of the general formula N-R3 a s- (where R is an alkyl or aralkyl group, atom or an alkyl group having and R have the above meanings) or a salt thereof, with cyanamide, with N-nitrosoguanidine with an N-alkyl-N- nitrosoguanidine or with a cyanogen halide followed by reaction of the cyanogen-halide-reaction product with ammonia or an amine, or is reacted, where R is a group with mercuric oxide and ammonia or an amine.
  • the salt of the thiourea derivative may, for example, be a mineral acid salt such as a hydrohalide, nitrate or sulphate.
  • the reaction with the thiourea derivative may be effected in the presence or absence of a solvent, suitable solvents, where present, including water and watermiscible organic solvents such as water miscible alcohols, ethers, ketones, or carboxylic acids, e.g. methanol, ethanol, propanol, dioxan, tetrahydrofuran, acetone, methyl ethyl ketone, acetic acid etc.
  • the reaction temperature is not especially critical and normal temperature is generally convenient, although higher temperatures, e.g. up to the boiling point of the medium, can also be used.
  • the compounds of Formula I as defined above can be prepared by reacting the compound of Formula II wherein R is hydrogen with a compound of the general formula R is a hydrogen 1-4 carbon atoms and R and R R and salt thereof.
  • the amines of general Formula II used in the above methods can be conveniently prepared by reduction of the corresponding nitriles of the general formula
  • the above nitriles can be prepared, for example, by condensation of an amine RNI-I with an aldehyde or ketone R CO--R followed by treatment with a cyanide.
  • the aldehyde or ketone is preferably in the form of its bisulphite adduct, e.g. sodium acetaldehyde bisulphite, sodium acetone bisulphite etc.
  • the cycloalkyl amine is advantageously added dropwise to a solution of the bisulphite adduct in an aqueous solvent such as water.
  • the cyanide is preferably an alkali metal cyanide, e.g. sodium, potassium cyanide etc.
  • the amine RNH may be condensed with a cyanhydrin of the aldehyde in ketone R ---COR to give the nitrile directly.
  • the reduction of the nitrile is preferably effected with a metal hydride reducing agent, e.g. lithium aluminium hydride in a solvent medium e.g. ether or tetrahydrofuran.
  • a metal hydride reducing agent e.g. lithium aluminium hydride in a solvent medium e.g. ether or tetrahydrofuran.
  • the amines of Formula II above may also be prepared by condensation of a cycloalkanone with a diamine followed by reduction of the resulting Schiffs base.
  • the substituents R R and R may be introduced subsequently, by alkylation, for example using conventional techniques such as reaction with an alkyl halide, sulphate or aromatic-sulphonate alkylating agent.
  • the methods of preparation of the new compounds described herein will in general give rise to the compounds in the form of salts.
  • the free base may be prepared from the salt by treatment with a strong anion exchange resin or treatment with caustic alkali or silver oxide.
  • Other salts may be formed from the free base so obtained.
  • conventional ion exchange techniques may be used, e.g. using anion exchange resin.
  • the 2-(cyclohexylamine)propylamine used in the above preparation was made as follows: Sodium acetaldehyde bisulphite (364 grams) was dissolved in water (800 millilitres) and to the solution, cyclohexylamine (198 grams) was added dropwise at room temperature during the course of thirty minutes, with mechanical stirring. The mixture was allowed to stand for a further one hour after which it was treated with a solution of sodium by evaporation and the product 2-(cyclohexylamino) propylamine distilled at reduced pressure. It has B.P. 105-7/18 mm., and n 1.4742. Yield 122 grams.
  • EXAMPLE 2 A mixture of S-methylisothiourea sulphate (15.8 grams), 2-cyclohexylamino-Z-methyl-propylamine 16.6 grams) and water (50 millilitres) was allowed to stand overnight at room temperature. The evolution of methyl mercaptan was completed by heating the solution on a water bath for another hour. After cooling, the crystals of 2-cyclohexylamino-2-methyl-propylguanidine sulphate which had separated, were recrystallised from a mixture of alcohol and water and had M.P. 203-6 C. Yield 18 grams.
  • the 2-cyclohexylamino-2-methyl-propylamine required was prepared in the following way: A solution of 120 grams of acetone sodium bisulphite in 400 millilitres of water was slowly treated with 66 grams of cyclohexylamine. After standing for one hour the mixture was treated with 36 grams of sodium cyanide dissolved in 70 millilitres of water. The upper layer of 2-cyclohexylamino-2-methyl-propionitrile which formed was removed, and the lower layer extracted three times with ether. The ether extracts were combined and added to the original upper layer of nitrile. The other solution so obtained was dried over anhydrous sodium sulphate. The residue, after removal of the yield 47 grams standing, and had M.P. 52 C.
  • EXAMPLE 3 A solution of sodium propionaldehyde bisulphite was prepared by careful addition, with ice cooling, of propionaldehyde (58 grams) to aqueous sodium bisulphite (300 millilitres of 37%). To the solution, cyclohexylamine (99 grams) was added dropwise during the course of. 30 minutes at room temperature under mechanical stirring which was continued for a further 60 minutes. A solution of sodium cyanide (100 grams) in water (200 millilitres) was then added and the resultant mixture was stirred for a further 3 hours and then allowed to stand overnight. The so formed. 2-cyclo-hexylamino-nbutyronitrile was extracted with ether and the ether extract dried over anhydrous sodium sulphate.
  • the active ingredient in this composition is 2-(cyclohexylamino)propylguanidine sulphate or 2-(cyclohexylamino)-2-methyl propylguanidine sulphate.
  • EXAMPLE 6INJECTION (10 MG./ML.) Formula Active ingredient Water for injection B.P. to 100 ml.
  • the active ingredient was dissolved in the sulphuric acid which had previously been made up to 70 ml. with water for injection. After adjusting the pH to 7.4 with the sodium hydroxide, the solution was made up to 100 ml. for ln ection and sterilised by filtration through a /3 sintered glass filter or a sterilising grade membrane filter before being aseptically packed in sterile 1 ml. ampoules.
  • the active ingredient in this composition is 2-(cycl0- hexylamino)propylguanidine sulphate, or 2-(cyclohcxylamino)-2-methyl propylguanidine sulphate.

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Description

United States Patent 3,409,669 (CYCLOHEXYLAMINO) 2 METHYL PROPYL- GUANIDINE-l AND THE SALTS AND HYDRATE THEREOF Wilfred James Cecil Dyke, Upton-by-Chester, England, assignor to Evans Medical Limited, Liverpool, England,
Filed Nov. 23, 1964, SerJNo. 413,315
application Great Britain, Dec. 13, 1963,
2 Claims. (Cl. 260564) ABSTRACT THE DISCLOSURE The guanidine derivatives of the present invention are those which are encompassed by the following formula:
N0 Drawing. Claims priority,
wherein R represents a cycloalkyl group of from 5 to 7 carbo Applicant has found that certain guanidine compounds, which are described in detail below, possess particularly especially against renal and According to the present invention we provide compounds of the general formula R N-R I R-NH-o-cm-NH-c R2 I'd-R5 and their hydrates and with one or more alkyl groups having 1-4 carbon atoms.
R is a hydrogen atom or an alkyl group having 1-4 carbon atoms.
R is an alkyl group having 1-4 carbon atoms.
R R and R which may be the same or different, are hydrogen atoms or alkyl groups having 1-4 carbon atoms.
may be straight or branched chain alkyl groups i.e. methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl groups. The preferred compounds are those in which R is methyl and R is hydrogen or methyl.
3,409,669 Patented Nov. 5, 1968 The su'bstituents R R and R gen.
are preferably all hydroticularly marked and the compound in which R R is cyclohexyl and R R and R cial y noteworthy in this respect.
previously proposed guanidine hypotensives and is substantially equally effective by either route.
Where R R and/or R is an alkyl group thismay, be a straight chained or branched chained alkyl group, e.g. a methyl, ethyl, butyl group etc.
Where the groups R are different, the compounds exist as optical isomers and racemic mixtures and zoates, salicylates, nates, p-toluene sulphonates etc.
The new guanidines according to the invention may be emulsifyture of the invention, there is provided a process for the preparation of compounds of the general formula meanings and R is is reacted, where R tive of the general formula N-R3 a s- (where R is an alkyl or aralkyl group, atom or an alkyl group having and R have the above meanings) or a salt thereof, with cyanamide, with N-nitrosoguanidine with an N-alkyl-N- nitrosoguanidine or with a cyanogen halide followed by reaction of the cyanogen-halide-reaction product with ammonia or an amine, or is reacted, where R is a group with mercuric oxide and ammonia or an amine.
The salt of the thiourea derivative may, for example, be a mineral acid salt such as a hydrohalide, nitrate or sulphate. The reaction with the thiourea derivative may be effected in the presence or absence of a solvent, suitable solvents, where present, including water and watermiscible organic solvents such as water miscible alcohols, ethers, ketones, or carboxylic acids, e.g. methanol, ethanol, propanol, dioxan, tetrahydrofuran, acetone, methyl ethyl ketone, acetic acid etc. The reaction temperature is not especially critical and normal temperature is generally convenient, although higher temperatures, e.g. up to the boiling point of the medium, can also be used.
According to a modification of the process of the invention the compounds of Formula I as defined above can be prepared by reacting the compound of Formula II wherein R is hydrogen with a compound of the general formula R is a hydrogen 1-4 carbon atoms and R and R R and salt thereof.
R have the above meanings) or a The reaction of the amine II with cyanamide gives compounds having an unsubstituted guanidine group; the reaction of the amine II with an unsubstituted N-nitroso guanidine gives an unsubstituted guanidine group but the nitrosoguanidine may carry an N-alkyl substituent to yield an N-alkyl guanidine.
The amines of general Formula II used in the above methods can be conveniently prepared by reduction of the corresponding nitriles of the general formula The above nitriles can be prepared, for example, by condensation of an amine RNI-I with an aldehyde or ketone R CO--R followed by treatment with a cyanide. The aldehyde or ketone is preferably in the form of its bisulphite adduct, e.g. sodium acetaldehyde bisulphite, sodium acetone bisulphite etc. The cycloalkyl amine is advantageously added dropwise to a solution of the bisulphite adduct in an aqueous solvent such as water. The cyanide is preferably an alkali metal cyanide, e.g. sodium, potassium cyanide etc.
Alternatively the amine RNH may be condensed with a cyanhydrin of the aldehyde in ketone R ---COR to give the nitrile directly.
The reduction of the nitrile is preferably effected with a metal hydride reducing agent, e.g. lithium aluminium hydride in a solvent medium e.g. ether or tetrahydrofuran.
The amines of Formula II above may also be prepared by condensation of a cycloalkanone with a diamine followed by reduction of the resulting Schiffs base.
Where the preparative method leads to an unsubstituted guanidine group, the substituents R R and R may be introduced subsequently, by alkylation, for example using conventional techniques such as reaction with an alkyl halide, sulphate or aromatic-sulphonate alkylating agent.
The methods of preparation of the new compounds described herein will in general give rise to the compounds in the form of salts. The free base may be prepared from the salt by treatment with a strong anion exchange resin or treatment with caustic alkali or silver oxide. Other salts may be formed from the free base so obtained. Alternatively if it is desired to change the anion of an acid addition salt, conventional ion exchange techniques may be used, e.g. using anion exchange resin.
In order that the invention may be well understood we give the following examples by way of illustration only (all temperatures are in C.)
EXAMPLE 1 To a solution of 15.4 grams of S-rnethyl-isothiourea sulphate in 50 millilitres of water was added 15.6 grams of 2-(cyclohexylarnino) propylamine. After standing the mixture overnight at room temperature, during which time methyl mercaptan was evolved, the reaction was completed by heating on a boiling water bath for one hour. After cooling, the solution deposited crystals, which after collecting and drying, weighed 22.6 grams and had M.P. 198. These were recrystallised from water. There was thus obtained 2-(cyclohexylamino)propyl-guanidine sulphate of M.P. 206 (corr.).
The 2-(cyclohexylamine)propylamine used in the above preparation, was made as follows: Sodium acetaldehyde bisulphite (364 grams) was dissolved in water (800 millilitres) and to the solution, cyclohexylamine (198 grams) was added dropwise at room temperature during the course of thirty minutes, with mechanical stirring. The mixture was allowed to stand for a further one hour after which it was treated with a solution of sodium by evaporation and the product 2-(cyclohexylamino) propylamine distilled at reduced pressure. It has B.P. 105-7/18 mm., and n 1.4742. Yield 122 grams.
EXAMPLE 2 A mixture of S-methylisothiourea sulphate (15.8 grams), 2-cyclohexylamino-Z-methyl-propylamine 16.6 grams) and water (50 millilitres) was allowed to stand overnight at room temperature. The evolution of methyl mercaptan was completed by heating the solution on a water bath for another hour. After cooling, the crystals of 2-cyclohexylamino-2-methyl-propylguanidine sulphate which had separated, were recrystallised from a mixture of alcohol and water and had M.P. 203-6 C. Yield 18 grams.
The 2-cyclohexylamino-2-methyl-propylamine required was prepared in the following way: A solution of 120 grams of acetone sodium bisulphite in 400 millilitres of water was slowly treated with 66 grams of cyclohexylamine. After standing for one hour the mixture was treated with 36 grams of sodium cyanide dissolved in 70 millilitres of water. The upper layer of 2-cyclohexylamino-2-methyl-propionitrile which formed was removed, and the lower layer extracted three times with ether. The ether extracts were combined and added to the original upper layer of nitrile. The other solution so obtained was dried over anhydrous sodium sulphate. The residue, after removal of the yield 47 grams standing, and had M.P. 52 C. A solution of the 2-cyclohexylamino-2-methyl-propionitrile (44 grams) in dry ether (75 millilitres) was gradually added to a suspension of lithium aluminium hydride (13 grams) in 600 mi lilitres of ether. The reaction mixture was refluxed, with mechanical stirring, for 3 hours and then left to stand overnight. Water millilitres) was carefully added, followed by sodium hydroxide (13 millilitres) and finally water millilitres). After cooling the filtered solution was dried over sodium sulphate. The ether was removed by evaporation and the residual oil fractionated to yield 24 grams of 2-cyclohexylamino-Z-methyl propylamine of B.P. 1l2-114 C./18 mm., n 1.4721.
EXAMPLE 3 A solution of sodium propionaldehyde bisulphite was prepared by careful addition, with ice cooling, of propionaldehyde (58 grams) to aqueous sodium bisulphite (300 millilitres of 37%). To the solution, cyclohexylamine (99 grams) was added dropwise during the course of. 30 minutes at room temperature under mechanical stirring which was continued for a further 60 minutes. A solution of sodium cyanide (100 grams) in water (200 millilitres) was then added and the resultant mixture was stirred for a further 3 hours and then allowed to stand overnight. The so formed. 2-cyclo-hexylamino-nbutyronitrile was extracted with ether and the ether extract dried over anhydrous sodium sulphate. After removal of the ether, the nitrile was purified by distillation and had B.P. 10 108/12 mm., n 1.437. A solution of the so obtained 2-cyclohexyl-n-butyronitrile (35.2 grams) in dry ether millilitres) was slowly added ether, the 2-cyclohexylamino-n-butylamine was distilled and had B.P. 110/15 mm., n 1.476. Yield 22.3 grams. A mixture of 2 cyclohexylamino n butylamine (17 grams), S-methylisothiourea sulphate (15.4 grams), and water (50 millilitres) was heated on a boiling water bath for 2 hours. During this time methyl mercaptan was evolved and a solid deposited. After cooling the solid product, 2 cyclohexylamino-n-butylguanidine sulphate, was collected on a filter and after recrystallisation from 150 millilitres of 33% aqueous alcohol had M.P. C.
Yield 19.7 grams.
EXAMPLE 4 2-cyclohexylaminopropylamine (7.8 grams), S-ethyl- N-rnethylisothiouronium sulphate (11 grams) and alcohol (5 millilitres) lilitres of water. The aqueous solution was passed down a chromatographic column of De-Acidite FF (OH form) and the emergent liquor concentrated under reduced Water to 100 m1.
Method of preparation a No. 3 sintered glass filter.
5 ml. (one teaspoonful) of the elixir contains 10 mg. of the active ingredient.
The active ingredient in this composition is 2-(cyclohexylamino)propylguanidine sulphate or 2-(cyclohexylamino)-2-methyl propylguanidine sulphate.
EXAMPLE 6INJECTION (10 MG./ML.) Formula Active ingredient Water for injection B.P. to 100 ml.
Method of preparation active ingredient was dissolved in sufficient water for injection to make 100 ml. The solution was sterilised by filtration through a 5/3 sintered glass filter or sterilising grade membrane filter and aseptically packed in sterile 1 ml. ampoules.
EXAMPLE 7--INJECTION (25 MG./ML.) Formula Active ingredient g 2.5 Sulphuric acid, dilute B.P.C. ml 4.0
Sodium hydroxide solution B.P. (Appendix I) q.s.
pH 7.4 Water for injection B1. to 100 ml.
Method of preparation The active ingredient was dissolved in the sulphuric acid which had previously been made up to 70 ml. with water for injection. After adjusting the pH to 7.4 with the sodium hydroxide, the solution was made up to 100 ml. for ln ection and sterilised by filtration through a /3 sintered glass filter or a sterilising grade membrane filter before being aseptically packed in sterile 1 ml. ampoules.
The active ingredient in this composition is 2-(cycl0- hexylamino)propylguanidine sulphate, or 2-(cyclohcxylamino)-2-methyl propylguanidine sulphate.
EXAMPLE 8-TABLET Formula Active ingredient 60 mesh (B.S.) powder mg 25.0 Lactose, B.P. "mg... 87.5 Starch, B.P. maize mg 37.5 10% w./v. maize starch paste q.s. Magnesium stearate percent w./w 1.0
Method of preparation The active ingredient, lactose and starch were damped with starch paste and mixed thoroughly. The wet granules inch EXAMPLE 9-INJECTION (IOMC L/ ML.)
Formula Active ingredient g. 'l'.O Sulphuric acid, dilute B.P.C. ml. 2.0 Sodium hydroxide solution B.P. (Appendix I) q.s. 7.4
Water for injection to ml.
Method of preparation, as in Example 7.
I claim:
1. A compound selected from the group consisting of 2-(cyclohexylamino)-2-methyl-propyl-guanidine-1, a hydrate thereof and a physiologically acceptableacid addition salt thereof.
2. 2-(cyclohexylamino)-2-methyl-propyl-guanidine-1.
References Cited UNITED STATES PATENTS 3,291,829 12/1966 Mull 260 -564 CHARLES B. PARKER, Primary Examiner. ROBERT V. HINES, Assistant Examiner.
US413315A 1963-12-13 1964-11-23 2-(cyclohexylamino)-2-methyl-propylguanidine-1 and the salts and hydrate thereof Expired - Lifetime US3409669A (en)

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US5262568A (en) * 1990-03-02 1993-11-16 State Of Oregon Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists
US5312840A (en) * 1986-07-10 1994-05-17 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education Substituted guanidines having high binding to the sigma receptor and the use thereof
US5336689A (en) * 1990-03-02 1994-08-09 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists
US5385946A (en) * 1986-07-10 1995-01-31 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon Method for treating hypertension with disubstituted granidine compounds
US5403861A (en) * 1991-02-08 1995-04-04 Cambridge Neuroscience, Inc. Substituted guanidines and derivatives thereof as modulators of neurotransmitter release and novel methodology for identifying neurotransmitter release blockers
US5574070A (en) * 1990-05-25 1996-11-12 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University Substituted guanidines having high binding to the sigma receptor and the use thereof
US5741661A (en) * 1991-02-08 1998-04-21 Cambridge Neuroscience, Inc. Substituted guanidines and derivatives thereof as modulators of neurotransmitter release and novel methodology for identifying neurotransmitter release blockers
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US6242198B1 (en) 1996-07-25 2001-06-05 Cambridge Neuroscience, Inc. Methods of treatment of eye trauma and disorders
US6251948B1 (en) 1990-03-02 2001-06-26 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon Tri-and tetra-substituted guanidines and their use as excitatory amino acid antagonists
US6756389B2 (en) 1996-08-09 2004-06-29 Cambridge Neuroscience, Inc. Pharmaceutically active compounds and methods of use
US6787569B1 (en) 1994-02-03 2004-09-07 Cambridge Neuroscience, Inc. Therapeutic guanidines
US7351743B1 (en) 1994-02-03 2008-04-01 Wyeth Therapeutic guanidines

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Cited By (47)

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Publication number Priority date Publication date Assignee Title
US5312840A (en) * 1986-07-10 1994-05-17 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education Substituted guanidines having high binding to the sigma receptor and the use thereof
US5385946A (en) * 1986-07-10 1995-01-31 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon Method for treating hypertension with disubstituted granidine compounds
US5478863A (en) * 1986-07-10 1995-12-26 State Of Oregon, Oregon Health Sciences University Of Oregon Substituted guanidines having high binding to the sigma receptor and the use thereof
US5604228A (en) * 1986-07-10 1997-02-18 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University Substituted guanidines having high binding to the sigma receptor and the use thereof
US5637622A (en) * 1990-03-02 1997-06-10 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists
US5336689A (en) * 1990-03-02 1994-08-09 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists
US6251948B1 (en) 1990-03-02 2001-06-26 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon Tri-and tetra-substituted guanidines and their use as excitatory amino acid antagonists
US5559154A (en) * 1990-03-02 1996-09-24 Oregon State Board Of Higher Education Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists
US5262568A (en) * 1990-03-02 1993-11-16 State Of Oregon Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists
US5798390A (en) * 1990-03-02 1998-08-25 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists
US5767162A (en) * 1990-03-02 1998-06-16 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon Tri-and tetra-substituted guanidines and their use as excitatory amino acid antagonists
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GB1110947A (en) 1968-04-24
DE1214674B (en) 1966-04-21
FR3889M (en) 1966-01-31
CH471071A (en) 1969-04-15
BE656923A (en) 1965-06-10
NL6413937A (en) 1965-06-14
SE331090B (en) 1970-12-14

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