HU211980A9 - Amidino derivatives - Google Patents

Description

The invention is illustrated in detail by the following examples.

Examples

Example 1 (S) -N ⁵ - (1-Amino-ethyl) -omidine hydrochloride

L-Ornithine Hydrochloride (10.1 g; 60 mmol) was dissolved in hot water (10 mL), and copper (II) carbonate (7 g) was added portionwise to the solution under stirring at 100 ° C. The dark blue solution was cooled to room temperature, filtered, and the residue was washed with water (20 mL).

The filtrate and washings were combined and the solution was stirred at 5 ° C while ethyl acetimidate hydrochloride (11.1 g, 90 mol) was added portionwise; at the time of addition, the pH of the solution was maintained at 10.5 by the addition of 2N aqueous sodium hydroxide solution. The solution was then allowed to stand at room temperature for one hour, then acidified to pH 3 with 2N aqueous hydrochloric acid solution and loaded onto a column of Bio-Rad AG 5OW-X8 cation exchanger (150 mL) in hydrogen form. The column was washed with water until a neutral value of the eluate was eluted and then eluted with 0.5 N aqueous ammonium hydroxide. The ninhydrin-positive fractions were combined and the resulting solution was concentrated at 40 ° C for a short time under reduced pressure to remove ammonia. The solution was then carefully acidified to pH 4 with 2N aqueous hydrochloric acid and then evaporated to dryness under reduced pressure.

Crystallisation of the residue was carried out by dissolving the material in a little water and adding a large amount of ethanol to the solution and allowing the mixture to stand for several hours at 4 ° C. The precipitated material was filtered off, washed with ethanol and finally dried under reduced pressure in a vacuum desiccator. After drying, the title compound was obtained as a colorless crystalline solid.

Mp 226-228 ° C.

Example 2] Amino-ethyl) -lysine hydrochloride

Basically, according to the procedure of Example 1, L-lysine hydrochloride (7.3 g, 40 mmol) was converted to a partial complex which was reacted with ethyl acetimidate hydrochloride (7.5 g, 60 mmol). The title compound isolated by the method described in Example 1 was obtained as a hygroscopic amorphous powder.

Example 3 (+) - E-2-Amino-6- (] -imino-ethylamino-hex-4-ene v hydrochloride

Using the procedure of Example 1, 4 -4-dehydro-lysine hydrochloride was converted to the title compound. The product was obtained in an amorphous state which was homogeneous by thin layer chromatography on acetonitrile / water / acetic acid (5: 3: 2).

The NMR spectrum (D ₂ O) and the mass spectrum confirmed the proposed structure.

Example 4 (S) -S-2- (1-Aminoethylamino) ethylcysteine hydrochloride

Using the procedure of Example 1, (5) -5-2- (1-aminoethyl) -cysteine hydrochloride (2 g, 10 mmol) was converted to the copper complex and the complex was then treated with ethyl acetate / hydrochloride (1.88 g, 15 mmol). ). The product was isolated according to the method described in Example 1. The title compound was obtained as a pale yellow amorphous solid which was found to be homogeneous by thin layer chromatography on acetonitrile / water / acetic acid (5: 3: 2).

The NMR spectrum (D ₂ O) and the mass spectrum confirmed the proposed structure.

Refer to 5-11. the compounds of Example 1B are essentially

Example 1 was prepared by reacting the copper complex of the corresponding amino acid of formula (II) with the desired ethyl alkanimidate hydrochloride.

EXAMPLE 5 (S) -N ⁶ - (1-lmino-pmpyl) -lysine hydrochloride

The title compound was isolated as a hygroscopic, amorphous, white powder. The product was found to be homogeneous by thin layer chromatography on acetonitrile / water / acetic acid (5: 3: 2).

Mass Spectrum: (M + 1 ⁺ ) ⁺ 202.0.

Example 6 (S) -N ⁶ - (α-Amino-cyclopropylmethyl) -1-lysine hydrochloride

The title compound was isolated as a hygroscopic, amorphous white powder. The product was found to be homogeneous by thin layer chromatography on acetonitrile / water / acetic acid (5: 3: 2).

Mass Spectrum: (M + 1 ^{+ 1} ) ⁺ 214.0.

Example 7 (±) -2-Amino-7- (J-iminoethylamino) -heptanoic acid hydrochloride

The title compound was isolated as an amorphous material. The product was found to be homogeneous by thin layer chromatography on acetonitrile / water / acetic acid (5: 3: 2).

Mass Spectrum: (M + 1) ⁺ 202.0.

1 H-NMR (200 MHz, D ₂ O) δ ppm: 1.22-1.43 (m, 2)

CH ₂ , 1.50-1.70 (m, CH ₂ ), 1.75-1.90 (m, CH ₂ ), 2.1 (s, CH ₃ ), 3.10-3.20 (t , CH ₂ ), 3.60-3.72 (t, CH)

Example 8 (± -Z-2-Amino-6- (1-iminoethylamino) -hex-4-enoic acid)

hydrochloride

The title compound was crystallized from a mixture of ethanol and water to give a colorless color

EN 211 980 A9 may also be stored in freeze-dried (lyophilized) form in ampoules and vials; such a form requires only the addition of water for injections of the sterile liquid carrier such as saline just prior to use. Prescription injectable solutions can be prepared from sterile powders, granules or tablets as described above.

The rectal (rectal) pharmaceutical compositions can be prepared in the form of a suppository using conventional carriers such as cocoa butter or polyethylene glycol.

Topical (topical) pharmaceutical compositions for use in the mouth, such as buccal or sublingual, include, but are not limited to, the following; square tablets containing the active ingredient in a flavored base such as sucrose and acacia or tragacanth; as well as pastilles comprising the active ingredient in a base such as gelatin and glycerol or sucrose and acacia.

Preferred unit dosage formulations comprise an effective dose of the active ingredient, hereinafter described, and an appropriate portion thereof.

It should be emphasized that in addition to the ingredients mentioned above, the pharmaceutical compositions of the present invention may further comprise conventional agents known in the art for the particular formulation type; for example, compositions for oral administration may also include flavoring agents.

The compounds of the invention may be administered orally or by injection at a dose of 0.1-500 mg / kg / day. For adult human organisms, the dosage range will generally be from 5 mg to 35 g per day, preferably from 5 mg to 2 g per day. Tablets and other similar units in the form of discrete units generally contain a compound of the present invention in an effective dosage amount, or in an amount that is multiple to said effective dose; for example, the units contain the active ingredient in an amount of from 5 mg to 500 mg, usually from about 10 mg to 200 mg.

The compounds of formula (I) are preferably administered orally or (intravenously or subcutaneously) by injection. Determining the exact amount of compound to be administered to a patient is the responsibility of the treating physician. The dose to be used will depend on a number of factors, such as the age and sex of the patient, the nature and severity of the disorder being treated. The route of administration may vary depending on the circumstances, the nature and severity of the condition.

Compounds of formula (I) may be prepared by an amino acid of formula (II)

NH ₂

I

H _{2 is} a protected derivative of NQ-CH-COOH (II) or an amino acid of formula (I) with a compound of formula (III)

R ¹

I

HN = C-L (ΙΠ)

where L is a leaving group and R ¹ and Q are as defined above, and then deprotected.

Suitable leaving groups L include, for example, -OR ⁵ and -SR ⁵ wherein R ⁵ is a lower alkyl group, for example a C 1-4 alkyl group, preferably methyl or ethyl.

The compound of formula (II) is generally used in a form in which the amino acid functionality is protected by suitable protecting groups; for further details, see, for example, the following references; TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 2nd Edition, Wiley and Sons Inc., 1991. As a final step of the process, the protecting groups can be removed in a conventional manner (see the above reference) to give the corresponding compounds of formula (I). obtained. For example, the amino acid functionality can be protected as the corresponding salt slurry, and deprotection can be carried out on an ion exchange column which is typically used to remove the inorganic ions from the reaction mixture.

The compounds of formula (III) may be used in the form of the free base or an acid addition salt such as the hydrochloride salt or the hydroiodide salt.

The reaction is generally carried out in a suitable solvent in the presence of a base such as an alkali metal hydroxide such as sodium hydroxide, preferably at a pH of about 9 to 11 and generally at a temperature between 0 ° C and the reflux temperature of the solvent, preferably 0 ° C to 50 ° C. temperature. The preferred solvent is water, but the reaction can be carried out alone in a polar solvent, such as a low alcohol such as methanol or ethanol, or in an amide such as M / N-dimethylformamide, or mixtures of said organic solvent with water. The latter solution may be particularly advantageous under certain circumstances.

The compounds of formula (II) are generally known derivatives which can be converted into the appropriately protected compounds by known methods. The imidate and thioimide derivatives of the formula (wherein L is -R ⁵ and -SR ^{5 in} the above order) are also generally known compounds, and the reaction of such compounds with primary amines is discussed in detail, for example. the following literature source; The Chemistry of Amidines and Imidates, Vol. 2, Saul Patai and Zvi Rappaport, Vol. Wiley and Sons Inc., 1991.

Pharmaceutically acceptable salts, esters and amides thereof.

A particularly preferred group of compounds of formula (I) are those compounds in which the formula is present

R ¹ is methyl;

Q is - (CH ₂ ) _n - wherein n is 3 or 4;

-CH ₂ CH = CHCH ₂ -;

- (CH ₂ ) ₂ SCH ₂ -; or

CH ₂ ACH ₂ - wherein A is cyclopropyl; and pharmaceutically acceptable salts, esters and amides thereof. Particularly preferred unique examples of the compounds of formula (I) include:

(S> —TV ⁵ - (1-imino-ethyl / ornithine:

(1-imino-ethyl / lysine;

(±) - £ -2-amino-6- (l-imino-ethylamino) hex-4-enoic acid;

and (5) -5-2- (1-iminoethylamino / ethylcysteine);

and pharmaceutically acceptable salts, esters and amides thereof. The invention also encompasses compounds of Formula (I) in the form of salts, in particular acid addition salts. Salts with organic and inorganic acids are among the suitable salts. Such salts are normally acceptable from a pharmaceutical point of view, but some pharmaceutically acceptable salts may also be used in the preparation and purification of the compounds in question. Preferred salts include derivatives formed with the following acids: hydrogen chloride, hydrogen bromide. sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, succinic acid, oxalic acid, fumaric acid, maleic acid, oxalic acid, methanesulfonic acid, ethanesulfonic acid, para-toluenesulfonic acid, benzenesulfonic acid and isethionic acid. The salts of the compounds of formula (I) can be prepared by reacting the corresponding compound in the free base form with the corresponding acid.

Although it is possible to administer the compounds of formula (I) alone, i.e., in the form of a chemical product, the corresponding derivatives are preferably used as pharmaceutical compositions. Accordingly, a further object of the present invention is to provide a pharmaceutical composition comprising a compound of formula (I) or a compound of formula (IA), or a pharmaceutically acceptable salt or solvate thereof, with one or more pharmaceutically acceptable carriers and optionally one or more pharmaceutically acceptable salts thereof. with several other therapeutic components. The carrier (s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation. or has no adverse effect on host organizations.

The pharmaceutical compositions include compositions for oral, parenteral (e.g., subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (e.g., dermal, buccal, i.e. oral, sublingual and intraocular) administration, but the most appropriate route is the condition and disorder of the recipient organism. The compositions are preferably formulated in unit dosage form. The preparation of the compositions can be carried out according to any of the methods well known in the art of pharmacy. All methods include the step of contacting a compound of Formula I with a pharmaceutically acceptable salt or solvate (i.e., "active ingredient") of a compound of Formula I with one or more excipients. carrier. Generally, the compositions are prepared by uniformly mixing the active ingredient with liquid carriers or finely divided solid carriers or a mixture of the former type of carrier and then, if necessary, converting the product to the desired formulation.

Compositions of the invention suitable for oral administration may be prepared, for example, in the following forms: discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient; powder or granules; a solution or suspension in an aqueous or non-aqueous liquid; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The administration of the active ingredient can also be carried out in the form of a bolus, syrup or paste formulation.

Tablets may be prepared by compression or molding, optionally using one or more excipients. In the manufacture of compressed tablets, the active ingredient is compressed in a suitable apparatus, optionally in the form of a powder or granules, mixed with a binder, lubricant, lubricant, surfactant or dispersant. Molded tablets are prepared by pouring the active ingredient in a suitable liquid dampened mixture with a diluent. Optionally, the tablets may be coated or grooved, and the formulation may also be performed to release the active ingredient in the tablets slowly or in a controlled manner.

Pharmaceutical compositions suitable for parenteral administration include, for example, aqueous and non-aqueous sterile injectable solutions which may contain antioxidants, buffers, bacteriostats, and solutes to render the formulation isotonic with the blood of the recipient organism to be treated; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. The pharmaceutical compositions may be contained in unit dose or multiple dose containers, e.g.

EN 211,980 A9

As used herein, the term "treatment" of a patient also includes prophylactic (prophylactic) treatment.

Certain compounds of formula (I) are novel, and accordingly, the present invention provides compounds of formula (LA) and salts, pharmaceutically acceptable esters and amides thereof.

R ¹ NH ₂ II

HN = C-NH-Q-CH-COOH (IA) in the formula

R ¹ is C 1-6 straight or branched alkyl, C 2-6 alkenyl,

C 2-6 alkynyl, C 3-6 cycloalkyl or C 3-6 cycloalkyl (C 1 -C 6) alkyl;

Q is C3-C6 alkylene, optionally substituted with one or more C1-C3 alkyl, optionally substituted with one or more C1-C3 alkyl substituted C3-C6 alkenylene,

- (CH ₂ ) _p X (CH ₂ ) _q - wherein p is 2 or 3; q is 1 or 2; and

X is S (O) _X wherein x is 0, 1 or 2; oxygen; or

NR ² , wherein

R ² is hydrogen or C 1-6 alkyl; or

- (CH ₂ ) _r A (CH ₂ ) _s - wherein r is 0, 1 or 2; s is 0, 1 or 2; and

A is a 3- to 6-membered carbocyclic or heterocyclic ring optionally substituted with one or more suitable substituents, such as C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen, nitro, cyano, trifluoro (C 1 -C 6 alkyl). ), amino, C 1-6 alkylamino or di (C 1-6 alkyl) amino;

with the proviso that when R 'is methyl, Q is not CH ₂ CH ₂ CH ₂ CH ₂ or

CH ₂ CH ₂ CH ₂ .

The present invention also relates to the use of the compounds of formula IA as defined above, or pharmaceutically acceptable salts, esters or amides thereof, for use in the manufacture of a medicament for the treatment of conditions in which L (N) oxide synthase L is administered. Inhibition of nitric oxide production from -arginine is an advantage.

Specific examples of R ¹ include, for example, methyl, ethyl, η-propyl, isopropyl, cyclopropyl, propenyl, η-butyl, tert-butyl, cyclobutyl and cyclopropylmethyl.

Specific examples of carbocyclic or heterocyclic rings in Group A include, for example, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclohexenyl, cyclopentenyl, cyclobutenyl, phenyl, pyridyl, piperidinyl, pyrrolyl, and the like. , pyrrolidinyl, furanyl, tetrahydrofuranyl, thiazolyl, imidazolyl and oxazolyl. In any of these examples, the ring may optionally be substituted with one or more suitable substituents; the corresponding substituents have already been mentioned above.

Examples of alkylene, alkenylene or alkynylene groups in Q include groups of the following formula: - (CH ₂ ) _n - wherein n is 3, 4 or 5;

- (CH ₂ ) _V CH = CH (CH ₂ ) _W -; and - (CH ₂ ) "CH = CH (CH ₂ ) _W -; wherein each of the latter formulas is v is 0, 1, 2 or 3; and w is 0, 1, 2 or 3;

provided that the sum of (v + w) is 2, 3 or 4.

Preferred groups of the compounds of formula I are those compounds in which the formula is present

R ¹ is methyl;

Q is - (CH ₂ ) _n - wherein n is 3, 4 or 5, more preferably 3 or 4; -CH ₂ CH = CHCH ₂ -;

- (CH ₂ ) p X (CH ₂ ) q - wherein p is 2 or 3; q is 1 or 2;

X is S (O) _X wherein x is 0, 1 or 2, more preferably 0; oxygen; or

NR ² , wherein

R ² is hydrogen or C 1-6 alkyl, more preferably C 1-3 alkyl; or

- (CH ₂ ) A (CH ₂ ) _S - wherein r is 1 or 2; s is 1 or 2; and

A is a 6-membered carbocyclic or heterocyclic ring, more preferably one of the individual rings listed above, most preferably cyclobutyl, phenyl or pyridyl;

with the proviso that it is

NH ₂

I

-CH-COOH has the natural L or (S) chirality; as well as a

EN 211,980 A9

X is S (O) _X wherein x is 0, 1 or 2; oxygen; or

NR ² , wherein

R ² is hydrogen or C 1-6 alkyl; or

- (CH ₂ ) A (CH ₂ ) _S - wherein r is 0, 1 or 2;

s is 0, 1 or 2; and

A is a 3- to 6-membered carbocyclic or heterocyclic ring optionally substituted with one or more suitable substituents, such as C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halogen, nitro, cyano, trifluoro-C 1-6 alkyl ), an amino group, a C 1-6 alkylamino group, or a di (C 1-6 alkyl) amino group.

The compounds of formula I are present in the molecule

- may include multiple asymmetric centers, depending on the exact meaning of the different groups. The general formula (I) includes all possible isomers. When Q is CH ₂ CH = CHCH ₂ -, the formula (I) includes both E and Z isomers. All compounds of formula (I) contain an asymmetric center

NH _;

I

In the -CH-COOH group, although the natural L or (S) chirality of arginine is preferred, the formula (I) also encompasses all possible isomers in this way.

The carbocyclic or heterocyclic ring in Group A may be saturated, ethylenically unsaturated or aromatic. In the case of a heterocyclic ring, the ring may contain one or more heteroatoms. generally selected from nitrogen, oxygen or sulfur.

In the case of pharmaceutically acceptable compounds of formula (I), acceptable esters and amides of the COOH terminal group is a group of k ^ OOR ³ wherein R ³ is e. C 1-6 alkyl, aryl or aryl (C 1-3 alkyl or COOR ⁴ wherein R ^{4 is} a residue of an appropriate natural or synthetic amino acid).

The present invention relates to the use of the compounds of formula (I) as defined above, or the pharmaceutically acceptable salts, esters or amides thereof, for use in the manufacture of a medicament for the treatment of conditions in which L (N) oxide synthase L is administered. Inhibition of production of nitric oxide from arginine is an advantage.

Another object of the invention is a method of treating human or animal subjects suffering from conditions in which the inhibition of nitric oxide production from L-arginine by the action of nitrogen (II) oxide synthase is advantageous, characterized by that to alleviate said conditions, the subject is administered an effective amount of a compound of formula (I), a pharmaceutically acceptable salt, ester or amide thereof.

The activity of a compound as an inhibitor of nitric oxide synthase can be determined by a assay that induces a macrophage cell line (J774) with lipopolysaccharide (LPS) and gamma interferon for expression of nitrogen (II) oxide synthase. then the nitrogen (II) oxide formed is measured by reaction with hemoglobin or nitrite. Although the test is fairly simple and can be performed comfortably, it has the disadvantage of not being able to distinguish between selective and non-selective nitrogen (II) oxide synthase inhibitors. Selectivity can be determined using an assay based on in vitro use of rat aortic rings. The basal tone of the tissue is used to indicate the activity of constitutive nitric oxide synthase, while the lipopolysaccharide-induced loss of the nitrogen (II) -oxide-regulated tone is used to indicate the activity of the inducible enzyme in vascular smooth muscle cells. To demonstrate selectivity, an assay based on measurement of rat blood pressure (constitutive enzyme) and measurement of blood pressure (inducible enzyme) in rats treated with lipopolysaccharide may also be used. The compounds of formula (I) exhibit nitrogen (II) -oxidase inhibitory activity in the J774 cell line and, in the case of a number of compounds, have been found to be selective inhibitors in the rat aortic ring; it has been observed that these compounds are inhibitors of about 10-40 times more potent inhibitors of inducible nitrogen (II) oxide synthase than they can inhibit constitutive nitrogen (II) oxide synthase.

Claims (1)

Conditions in which the inhibition of the formation of nitrogen (II) oxide from L-arginine is an advantage include, for example, the following: a wide range of agents induced by septic and / or toxic much associated systemic hypotension; cytokines such as TNF, IL-1 and IL-2, and an adjuvant for short-term immunosuppression therapy during transplantation therapy. In the meantime, however, evidence of the existence of a third nitric oxide synthase enzyme, which plays a role in the degeneration of cartilage in certain conditions, such as arthritis, is growing; it is known that nitric oxide synthesis is increased in rheumatoid arthritis. Other examples of conditions in which inhibition of the formation of nitrogen (II) oxide from L-arginine are further include autoimmune diseases and / or inflammatory conditions such as arthritis. EN 211,980 A9 FIELD OF THE INVENTION The present invention relates to novel amidino derivatives, processes for their preparation, pharmaceutical compositions containing amidino derivatives, and pharmaceutical uses of the compounds and compositions, in particular nitric oxide synthase inhibitors. It has been known since the early 1980s that acetylcholine-induced vascular relaxation is dependent on the presence of endothelium and this activity is attributed to a labile humoral factor, namely endothelial-derived relaxing factor (EDRF). Nitrogen (II) oxide (NO) vasodilator activity has been known for more than 100 years and nitrogen (II) oxide is an active component of amyl nitrite, glyceryl nitrite and other nitro vasodilators. The recent identification of endothelial realization factor as nitrogen (II) oxide is consistent with the recognition of the pathway. wherein the nitrogen (II) oxide is synthesized from the L-arginine amino acid using the nitrotene (II) oxide synthase enzyme. Nitrothene (II) oxide is an endogenous stimulant of soluble guanylate cyclase. and is involved in a number of biological processes related to endothelium-dependent relaxation, including cytotoxicity of phagocytic cells and communication between cells in the central nervous system (see Moncada et al. Biochemical Pharmacology. 38, 1709-1715 (1989); and Moncada et al., Pharmacological Reviews, 43, 109-142 (1991)]. According to the present opinion, excessive nitrogen (II) oxide production may play a role in many conditions, especially in conditions that involve systematic hypotension, such as toxic shock or therapeutic procedures with certain cytokines. Synthesis of nitrogen (II) oxide from L-arginine is the L-arginine analogue LA-monomethyl-arginine (inhibited by LNMMAj; the use of L-TV monomethyl-arginine for the treatment of toxic shock and other types of systemic hypotension in the past) [WO 91/04024 International Patent Application (PCT); British Patent Application GB-A-2240041], WO 91/04024 International Patent Application (PCT) and EP-A-O446699. European Patent Application No. 5,192,196 also suggested the therapeutic use of certain other N-oxide synthase inhibitors other than L-N-monomethyl-arginine for the same purpose. It has recently become apparent that there are at least two types of nitrogen (II) oxide synthase: (i) a constitutive, Ca 2 / calmodulin dependent enzyme that releases nitrogen (II) oxide to a receptor or physical response; (ii) an enzyme independent of Ca ⁺⁺ which is induced by endotoxin or cytokine activation of vascular smooth muscle, macrophages, endothelial cells and many other cells. The inducible nitric oxide synthase synthesizes foxide over a long period of time. Nitrogen (II) oxide released by a constitutive enzyme acts through a transduction mechanism that forms the basis of many physiological responses. Nitrogen (II) oxide produced by the inducible enzyme functions as a cytotoxic molecule for tumor cells and invading microorganisms. It is also clear that the adverse effects of excessive nitrogen (II) oxide production - in particular on the effects of pathological vasodilation and tissue damage - primarily from the effects of nitrogen (II) oxide synthesized by inducible nitric oxide synthase. Nitric oxide synthase inhibitors that have been proposed for therapeutic use so far are non-selective in the sense of inhibiting both constitutive and inducible nitric oxide synthase. The use of such non-selective nitrogen (II) oxide synthase inhibitors requires extreme caution in order to avoid the potential consequences of over-inhibition of constitutive nitric oxide synthase. For example, hypotension, thrombosis and tissue damage. In the therapeutic use of L-A-monomethyl-arginine in the treatment of toxic shock, it is particularly recommended that the patient's blood pressure be monitored continuously during treatment. Since the therapeutic use of non-selective nitrogen (II) oxide synthase inhibitors requires increased caution as mentioned above, it can be reasonably assumed that selective nitrogen (II) oxide synthase inhibitors, i.e., nitrogen (II) oxide synthase inhibitors that are inducible nitrogen (II ) inhibit oxide synthase to a much greater extent than constructive nitric oxide synthase. - with significantly higher therapeutic benefits and much easier application. The present invention relates to amidino derivatives of formula (I). and their salts, pharmaceutically acceptable esters and amides thereof; R ¹ NH ₂ I I HN = C-NH-Q-CH-COOH (I) where R ¹ is C 1-6 straight or branched alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or C 3-6 cycloalkyl (C 1 -C 6) alkyl; Q is C3-C6 alkylene, optionally substituted with one or more C1-C3 alkyl groups, optionally substituted with one or more C1-C3 alkyl substituted C3-C6 alkenylene, optionally substituted with one or more C1-C3 alkyl groups. C3-6alkynylene, - (CH ₂ ) p X (CH ₂ ) _q - wherein p is 2 or 3; q is 1 or 2; and (19) Country code: PATENT DESCRIPTION (11) Registration number: 211,980 A9 HU Koi HUNGARIAN [COMPANY HUNGARIAN (21) File number of the application: P / P 00132 (22) Date of notification: 05.05.1995. Patent Number: 92/10018 Country Code: ZA Starting date for calculating the protection period for the underlying foreign patent: 1992. 12. 23. The protection can be maintained for 20 years from this day. (51) Int. Cl. ⁶ C 07 C 257/14 C 07 C 257/16 C 07 C 323/58 A 61 K 31/155 PATENT OFFICE Start of domestic protection: 01.07.1994. (72) Inventors: Beams, Richard Mansfield, Beckenham, Kent (GB) Hodson, Harold Francis, Beckenham, Kent (GB) Palmer. Richard Michael John. Beckenham, Kent (GB) (73) Patent: The Wellcome Foundation Ltd., London (GB) (74) Representative: ADVOPATENT Patent Office, Budapest (54) amidino Temporary protection is provided in sections 3-9. . EN 211,980 A9 Scope of the description: 10 pages