MXPA00008764A - Halogenated amidino amino acid derivatives useful as nitric oxide synthase inhibitors - Google Patents

Abstract

Halogenated amidino amino acid derivatives useful as nitric oxide synthase inhibitors of Formula (I) or a pharmaceutically acceptable salt thereof, wherein all substituentsare described in the specification.

Description

DERIVATIVES OF AMINO HALOGENATED AMINO ACIDS, USEFUL AS INHIBITORS OF NITRIC SYNTHETIC OXIDE Background of the Invention Field of the Invention The present invention relates to amino acid derivatives of amidino and their use in therapy, in particular to their use as inhibitors of nitric oxide synthase.

Description of the prior art It is known since the early 80's that the vascular relaxation caused by acetylcholine is dependent on its presence in the vascular endothelium and this activity was attributable to a labile humoral factor called the Endothelial Derived Relaxation Factor (EDRF). The activity of nitric oxide (NO) as a vessel / dilator has been known for more than 100 years. In addition, NO is the active component of a-ilnitrite, glyceryl trinitrate and other nitrovasodilators. The recent identification of the EDRF as NO has coincided with the discovery of a REF .: 122180 biochemical pattern by which NO is synthesized from the amino acid L-arginine by the enzyme NO synthase.

Nitric oxide is an endogenous stimulant of soluble guanylate cyclase. In addition to endothelium-dependent relaxation, NO is involved in a number of biological actions that include phagocytic cell cytotoxicity and cell-to-cell communication in the central nervous system (see Moneada et al., Biochemical Pharmacology, 38, 1709-1715, 1989; Moneada et al., Pharmacological Reviews, 43, 109-142, 1991). Excess NO production appears to be involved in a number of pathological conditions, particularly conditions involving systemic hypotension, such as toxic shock, septic shock and therapy with certain cytokines (Kervin et al., J. Medicinal Chemistry, 38, 4343-4362 , nineteen ninety five) .

The synthesis of NO from L-arginine can be inhibited by the L-arginine analogue, LN-monomethyl-arginine (L-NMMA) and the therapeutic use of L-NMMA for the treatment of toxic shock and other types of systemic hypotension has been proposed (WO 91/04024 and GB-A-2240041). The therapeutic use of certain other inhibitors of NO synthase apart from L-NMMA for the same purpose has been proposed in WO 91/04024 and in EP-A-0446699.

Recently it has become obvious that there are at least three types of NO synthase as follows: (i) a constitutive Ca ++ / calmodulin-dependent enzyme, located in the endothelium, that releases NO in response to the receptor or to a physical stimulation in response to the receptor or to physical stimulation. (ii) a Ca ++ / calmodulin dependent enzyme, located in the brain, that releases NO in response to the receptor or to physical stimulation. (iii) a Ca ++ -dependent enzyme that is induced after activation of vascular smooth muscle, macrophages, endothelial cells, and a number of other cells by endotoxin and cytokines. Once this inducible NO synthase is expressed, it generates NO continuously for long periods.

The NO released by the two constituent enzymes acts as a transduction mechanism underlining several physiological responses. The NO produced by the inducible enzyme is a cytotoxic molecule for tumor cells and invading microorganisms. It also appears that the adverse effects of excess NO production, in particular pathological vasodilation and tissue damage, can largely result from the effects of NO synthesized by inducible NO synthase (Knowles and Moneada, Biochem J., 298, 249 -258, 1994 Billiar et al, Annals of Surgery, 221, 339-349, 1995; Davies et al., 1995).

There is also growing evidence that NO may be involved in cartilage degeneration which occurs under certain conditions such as arthritis and it is also known that NO synthesis is increased in rheumatoid arthritis and in osteoarthritis (McLnnes et al. collaborators, J. Exp. Med, 184, 1519-1524, 1996; Sakurai et al., J. Clin.

Investig., 96, 2357-2363, 1995). Accordingly, conditions in which there is an advantage in inhibiting NO production from L-arginine include autoimmune and / or inflammatory conditions affecting the joints, for example arthritis, and also inflammatory bowel diseases, cardiovascular ischemia, diabetes , diabetic retinopathies, nephropathy, cardiomyopathy, congestive heart failure, myocarditis, arteriosclerosis, migraine, reflux esophagitis, diarrhea, irritable bowel syndrome, cystic fibrosis, emphysema, asthma, chronic obstructive pulmonary disease, bronchiectasea, herniated vertebral discs, obesity, psoriasis, rosacea, contact dermatitis, hyperalgesia (allodynia), cerebral ischemia [focal ischemia, thrombotic shock, global ischemia (secondary to cardiac arrest)], multiple sclerosis due to anxiety and other central nervous system disorders involving NO , for example Parkinson's disease and disease Alzheimer's, rhinitis, cancer therapy, and other NO-mediated disorders that include opium tolerance, in patients requiring prolonged opioid analgesics, and benzodiazepine tolerance in patients taking benzodiazepines, and other addictive behaviors, for example, nicotine and eating disorders (Kerwin et al., J. Medicinal Chemistry, 38, 4343-4362, 1995; Knowles and Moneada, Biochem J. 298, 249-258, 1994; Davies et al., 1995; Pfeilschifter et al., Cell Biology International, 20, 51-58, 1996).

Additional conununications in which there is an advantage in inhibiting NO production of L-arginine include, systemic hypotension associated with septic shock and / or toxic shock induced by a wide variety of agents; therapy with cytokines such as TNF, IL-1 and IL-2; and as an auxiliary for short-term immunosuppression in transplant therapy (E. Kelly et al, J. Partent, Ent Nutri, 19, 234-238 and 1995, S. Moneada and E. Higgs, FASEB et al., Crit. Care ed., 23, 1018-1024, 1995).

More recently, NO has been identified as being a neurotransmitter in pain patterns of the spinal cord. The administration of NO synthase inhibitors to patients with chronic pain syndromes, and more specifically chronic tension type headache has been shown to reduce the level of pain. (The Lancet, 353: 256-257, 287-289, 1999).

Some of the NO synthase inhibitors proposed for therapeutic use up to now, and in particular L-NMMA, are non-selective; they inhibit both the constitutive NO synthases and the NOs to the inducible synthases. The use of such nonselective NO synthase inhibitors requires that great care be taken in order to avoid potentially serious consequences of overinhibition of the constitutive NO synthase including hypertension and possible thrombosis and tissue damage. In particular, in the case of the therapeutic use of L-NMMA for the treatment of toxic shocks it has been recommended that the patient must undergo continuous monitoring of blood pressure throughout the treatment. Thus, while nonselective NO synthase inhibitors have therapeutic utility provided that appropriate precautions are taken, inhibitors of NO synthase are selective in the sense that they inhibit inducible NO synthase to a considerable extent. larger than the constitutive isoforms of NO synthase that should be of an even greater and easier to use therapeutic benefit (S. Monead and E. Higgs, FASEB J. 9, 13119-1330, 1995).

WO 96/35677, WO 96/33175, WO 96/15120, WO 95/11014, WO 95/11231, WO 95/25717, WO 95/24382, W094 / 12165, WO94 / 14780, WO93 / 13055, EP0446699A1 and US Patent No. 5, 132, 453 disclose compounds that inhibit nitric oxide synthesis and preferentially inhibit the inducible isoform of nitric oxide synthase. The descriptions of which are incorporated herein by reference in their entirety as if they were written thereon. WO 95/34534, WO 96/19440 and WO 97/32844 describe derivatives of amidino sulfoxide and sulfone, acetamidine derivatives of the amidino amino acid and hydroxyamidino derivatives, respectively, useful as inhibitors of nitric oxide synthase, the latter preferably inhibit the inducible form on the constitutive forms of NO synthase.

BRIEF DESCRIPTION OF THE INVENTION In a broad aspect, the present invention is directed to inhibit or modulate the synthesis of nitric oxide in a subject in need of such inhibition or modulation by administration of a compound that preferentially inhibits or modulates the inducible isoform of nitric oxide synthase on the forms constitutives of nitric oxide synthase. It is also another object of the present invention to decrease the levels of nitric oxide in a subject in need of such a decrease.

The present invention is directed towards the halogenation of amidino amino acid derivatives to exhibit the inhibition of activity and bioactivity by iNOS. Halogenation alters the basicity of the amidine moiety, and increases potency and provides a longer half-life in vivo as iNOS inhibitors.

The compounds of the present invention are represented by halogenated amidino compounds, of formula (I): (D) or a pharmaceutically acceptable salt thereof thereof, wherein: R1 is selected from the group consisting of hydrogen, Ci-Cio alkyl, C2-C? Alkenyl, and C2-C? Alkynyl; R2 is selected from the group consisting of hydrogen, Ci-Cio alkyl, C2-C? Alkenyl, C2-C? Alkynyl, and either R or S α-amino acid; R 3 and R 4 are independently selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl and N 0 2; wherein R1, R2, R3 and R4 may be optionally substituted from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano , nitro, amino, carboxyl, carboxyalkyl, carboxaryl, amidino, and guanidino; Rll is selected from the group consisting of hydroxyl and R or S alpha-amino acid; G is selected from the group consisting of C? -C? 0 alkylene, C2-C? 0 alkenylene, and C2-C? Alkynylene, each of which is optionally substituted with one or more selected from the group consists of halogen, hydroxyl, trifluoromethyl, nitro, cyano, amino, C? -C? alkyl, = CH2, C2-C? 0 alkenyl, C2-C? 0 alkynyl, and Ci-Cio alkoxy, each of which may be optionally substituted from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, amino , carboxyl, carboxyalkyl, carboxaryl, amidino, guanidino, trifluoromethyl and nitro; G is selected from the formula (CH2) P- (CX1X2) r- (CH2) sQ- (CH2) t- (CX3X) u- (CH2) v where p, r, s, t, u and v are independently O a 3 and Q is oxygen, C = 0, S (0) a where a is O to 2, with the proviso that when a is 1 or 2, G must contain halogen, or NR12 where R12 is hydrogen or C? -C? 0 which may be optionally substituted with one or more selected from the group consisting of Ci-Cio alkyl, Ci-Cio alkoxy, hydroxyl, trifluoromethyl, nitro, cyano, amino, and halogen; G is selected from the formula - (CH2) - (CX5X6) and- (CH2) zA- (CH2) k- (CX7X8) :-( CH2) h where w, y, z, k, j, h are independently O to 3 and A is carbocyclic radical or 3 to 6 membered heterocyclic radical which may be optionally substituted with one or more selected from the group consisting of halogen, Ci-Cio alkyl, C1-C10 alkoxy, hydroxyl, trifluoromethyl, nitro , cyano, and amino, each of which may be optionally substituted by halogen or C1-C10 alkyl, with the proviso that when G is selected from the formula - (CH2) - (CX5X6) y- (CH2) zA - (CH2) k- (CX7X8) j- (CH2) h, Y must contain halogen; X1, X2, X3, X4, X5, X6, X7, X8 are independently not present, hydrogen, halogen, C? -C? 0 alkyl, = CH2, C2-C? 0 alkenyl, or C2-C alkynyl 0, wherein the alkyl of C? -C? 0, = CH2, C2-C? 0 alkenyl, and the C2-C? Alkynyl may be optionally substituted with one or more of the group consisting of lower alkyl lower alkenyl, lower alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, hydroxyl, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, amino, carboxyl, carboxyalkyl, carboxyryl, amidino, guanidino, trifluoromethyl, and nitro; Y is selected from the group consisting of heterocycle, haloalkyl of C? -C? 0, dihaloalkyl of C? C? O, trihaloalkyl of C? -C? 0, Ci-Cio alkyl, C3-C? 0 cycloalkyl, C2-C? 0 alkenyl, and C2-C? 0 alkynyl, each of which is optionally substituted with one or more selected from the group consisting of halogen, hydroxyl, trifluoromethyl, nitro, cyano, amino, C 1 -C 10 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, and C 1 alkoxy; ? -C? 0; Y may be NR9R10 wherein R9 and R10 are independently selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C ciclo cycloalkyl, C2-C al alkenyl, C C-C alqu alkynyl, nitro, amino, aryl, and alkaryl of C? -C? 0; with the proviso that at least one of G or Y contains halogen.

The compounds of the present invention can exist in geometric or stereoisomeric forms. The present invention contemplates all such compounds, which include geometric isomers cis- and trans-, geometric isomers z- and E-, enantiomers R- and S-, diastereomers, d-isomers, 1-isomers, racemic mixtures thereof and other mixtures thereof, which fall within the scope of the invention.

It is an object of the present invention to provide compounds that have utility as inhibitors of nitric oxide synthase. These compounds also preferentially inhibit the inducible form on the form Constitutive by at least 3 times. It is also an object of the present invention to provide compounds that are more selective than those known in the art.

Detailed description of the invention Preferably, the compounds of the present invention are halogenated amidino compounds of formula (I) wherein: (D or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of hydrogen; C 1 -C 0 alkyl, C 2 -C 0 alkenyl, and C 2 -C 0 alkynyl; R 2 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, C 2 -C 8 alkynyl, and either R or S alpha-amino acid; R3 and R4 are independently selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C2 alkenyl, C2-C2 alkynyl, and N02; wherein R1, R2, R3 and R4 may be optionally substituted from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano , nitro, amino, carboxyl, carboxyalkyl, carboxaryl, amidino and guanidino; R11 is selected from the group consisting of hydroxyl and R or S alpha-amino acid; G is selected from the group consisting of C?-C? Alalkylene, C2-C? Al alkenylene, and C2-C? Alqu alkynylene, each of which is optionally substituted with one or more selected from the group consisting of halogen , hydroxyl, trifluoromethyl, nitro, cyano, amino, C1-C10 alkyl, = CH2, alkenyl C2-C ?o, C2-C? Alkynyl, and C1-C10 alkoxy, each of which may be optionally substituted from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, amino, carboxyl, carboxyalkyl, carboxaryl, amidino, guanidino, trifluoromethyl, and nitro; G is selected from the formula (CH2) p- (CX1X2) r- (CH2) sQ- (CH2) t- (CX3X4) w- (CH2) v where p, r, s, t, u, v are independently O to 3 and Q is oxygen, C = 0, S (0) where a is O to 2, with the proviso that when a is 1 or 2, G must contain halogen, or NR12 where R12 is hydrogen or alkyl of C? -C? 0 which may be optionally substituted with one or more selected from the group consisting of C? -C? 0 alkyl, Ci-Cio alkoxy, hydroxyl, trifluoromethyl, nitro, cyano, amino, and halogen; G is selected from the formula - (CH2) w- (CX5X6) and- (CH2) S-A- (CH2) k- (CX7X8) D- (CH2) h wherein w, y, z, k, j, h on independently 0 to 3 and A is a carbocyclic radical or heterocyclic radical of 3 to 6 members which may be optionally substituted with one or more selected from the group consisting of halogen, d- alkyl C, C? -C? 0 alkoxy, hydroxyl, trifluoromethyl, nitro, cyano, and amino, each of which may be optionally substituted with halogen or C? -C? 0 alkyl, with the proviso that when G is selected from the formula - (CH2) w- (CX5X6) and- (CH2) zA- (CH2) k- (CX7X8) j- (CH2) h, Y must contain halogen; X1, X2, X3, X4, X5, X6, X7, X8 are independently not present, hydrogen, halogen, C? -C? 0 alkyl, = CH2, C2-C? 0 alkenyl, or C2-C alkynyl wherein, the alkyl of C? -C? 0, = CH2, C2-C10 alkenyl, or the C2-C? alkynyl, may be optionally substituted with one or more of the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, hydroxyl, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, amino, carboxyl, carboxyalkyl, carboxaryl, amidino, guanidino, trifluoromethyl, and nitro; Y is selected from the group consisting of heterocycle, haloalkyl of C? -C? 0, dihaloalkyl of C? Cio, trihaloalkyl of C? -C? Or C? -C? Alkyl, cycloalkyl of C3-C? 0, C2-C? al alkenyl, and C2-C? alkynyl, each of which is optionally substituted with one or more selected from the group consisting of halogen, hydroxyl, trifluoromethyl, nitro, cyano, amino, C1 alkyl -C10, C2-C? Alkenyl, C2-C? Alkynyl, and C1-C10 alkoxy; And it may be NR9R10 wherein R9 and R10 are independently selected from the group consisting of hydrogen, C? -C? Alkyl, C3-C? Cycloalkyl, C2-C? Alkenyl, or C2-C alkynyl? 0 nitro, amino, aryl, and alkaryl C? -C? 0; with the proviso that at least one of G or Y contains a halogen.

More preferably, the compounds of the present invention are of the formula (I) wherein; G is selected from the formula (CH2) p- (CXXX2) r- (CH2) sQ- (CH2) t- (CX3X4) w- (CH2) v wherein p, r, s, t, u, v are independently 0-3 and Q is oxygen, C = 0, S (0) a where a is 0 to 2, with the proviso that when a is 1 or 2, G must contain a halogen, or NR12 where R12 is hydrogen or Ci-Cio alkyl, which may be, optionally substituted with one or more selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 0 alkoxy hydroxyl, trifluoromethyl, nitro, cyano, amino , and halogen; and Y is selected from the group consisting of haloalkyl of C1-C10, dihaloalkyl of C1-C10, trihaloalkyl of C1-C10, alkyl of C1-C10, cycloalkyl of C3-C? or, alkenyl of C2-C? 0, and C2-C alkynyl? 0.

More preferably, the compounds of the present invention are of the formula (I); where: R1, R2 are H, R3, R4 are independently H, or N02; G is selected from the formula (CH2) P- (CXXX2) - (CH2) sQ- (CH2) t- (CX3X4) w- (CH2) v where p, r, s, t, u, v are independently 0-3 and Q is oxygen, C = 0, S (0) a where a is 0 to 2, with the proviso that when a is 1 or 2, G must contain a halogen, or NR12 where R12 is hydrogen or C? -C? 0 alkyl, which may be optionally substituted with one or more selected from the group consisting of Ci-Cio alkyl, Ci-Cio alkoxy, hydroxyl, trifluoromethyl, nitro, cyano, amino, and halogen; and Y is selected from the group consisting of Ci-Cβ alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, and C2-C6 alkynyl, each of which is optionally substituted with one or more halogens, or NHR9 wherein R9 is hydrogen, C?-C6 alkyl, C3-C6 cycloalkyl, C2-Ce alkenyl, or C2-C6 alkynyl.

More preferably, the compounds of the present invention are of the formula (I); wherein: R1, R2, R3 and R4 are H; and Y is C? -C6 alkyl, optionally substituted with at least one halogen.

More preferably, the compounds of the present invention are selected from the group consisting of: N- (2-fluoro-l-iminoethyl) -3-aminopropyl-L-cysteine dihydrochloride; N- (2-fluoro-1-iminoethyl) -2-aminoethyl-D, L-homocysteine dihydrochloride; N- (2-fluoro-1-iminoethyl) -2-aminoethyl-L-homocysteine dihydrochloride.

As used herein, the term "alkyl", alone or in combination, means a branched or unbranched acyclic alkyl radical containing from 1 to 10, preferably from 1 to 8 carbon atoms and more preferably 1 to 6 carbon atoms. carbon. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl and the like.

The term "alkenyl" refers to an unsaturated, branched or unbranched acyclic hydrocarbon radical that contains at least one double bond. Such radicals containing from 2 to 10 carbon atoms, preferably from 2 to 8 carbon atoms and more preferably from 2 to 6 carbon atoms. Examples of suitable alkenyl radicals include propylenyl, isobutenyl, pentenylen-1-yl, buten-1-yl yl hexen-1-yl-2-2-methylbuten-1, 3-methylbuten-l-yl, hepten-1- ilo, and octen-1-yl, and the like.

The term "alkynyl" refers to an unsaturated branched or unbranched acyclic hydrocarbon radical in a manner that contains one or more triple bonds. Such radicals containing 2 to 10 carbon atoms, preferably having 2 to 8 carbon atoms and more preferably having 2 to 6 carbon atoms. Examples of suitable alkynyl radicals include radicals ethynyl, propynyl, 1-butin- yl, pentyn-1-yl pentyn-2-yl methylbutyn-1-yl hexyne-1-yl-butyn-2,, 3,, hexyne -2-yl, hexin-3-yl, 3, 3-dimethylbutyn-1-yl and the like.

The term "heterocyclic radical" means an unsaturated cyclic hydrocarbon radical with 3 to about 6 carbon atoms, wherein 1 to about 4 carbon atoms are replaced by nitrogen, oxygen or sulfur. The "heterocyclic radical" may be fused to an aromatic hydrocarbon radical. Suitable examples include pyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1, 3-dioxolanyl, 2-imidazolinyl, imidazolidinyl , 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1, 2, 3-oxadiazolyl, 1,2,3-triazolyl, 1, 3-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1, -dioxanilo, morpholinyl 1, -ditianilo, thiomorpholinyl, pyrazinyl, piperazinyl, 1, 3, 5-triazinyl, 1, 3, 5-trithianyl, benzo (b) thiophenyl, benzimidazolyl, quinolinyl, and the like.

The term "aryl" means an aromatic hydrocarbon radical of 4 to 16 carbon atoms, preferably 6 to about 12 carbon atoms, more preferably 6 to 10 carbon atoms. Examples of suitable aromatic hydrocarbon radicals include phenyl, naphthyl, and the like.

The terms "cycloalkyl" or "cycloalkenyl" means a "alicyclic radical in a ring with 3 to 10 carbon atoms, preferably from 3 to 6 carbon atoms. Examples of suitable alicyclic radicals include cyclopropyl, cyclopropylenyl, cyclobutyl, cyclopentyl, I ciciohexilo , 2-cyclohexen-1-ynylenyl, cyclohexenyl and the like.

The term "alkoxy", alone or in combination, means an alkyl ether radical wherein the term alkyl is as defined above and more preferably containing 1 to 4 carbon atoms. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.

The term "alkylene" refers to hydrocarbons containing 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, and more preferably 1 to 6 carbon atoms.

The term "alkenylene" and "alkynylene" refers to hydrocarbons containing 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms.

The term "halogen" means fluorine, chlorine, bromine or iodine.

The term "prodrug" refers to a compound that becomes more active in vivo.

As used herein, reference to "treatment" of a patient is intended to include prophylaxis.

The present invention includes compounds of formula (I) in the form of salts, in particular the acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts are normally pharmaceutically acceptable however salts of pharmaceutically unacceptable salts may be useful in the preparation and purification of the compound in question. In that way, preferred salts include those formed from hydrochloric, hydrobromic, sulfuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, succinic, oxalic, fumaric, maleic, oxaloacetic, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic and isethionic acids. The salts of the compounds of formula (I) can be worked up by the reaction of the appropriate compound in the form of the free base with the appropriate acid.

While it may be possible for the compounds of formula (I) to be administered as the chemical raw material, it is preferable to present them as a pharmaceutical composition. Accordingly, in a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more of other therapeutic ingredients. The vehicles must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not be perjucidial to the recipient thereof.

The formulatiinclude those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, and intraarticular), inhalation, rectal, and topical (including dermal, buccal, sublingual, and intraocular) administration, however the most suitable route may depend on for example the condition and disorder of the recipient. The formulatican conveniently be presented in the form of unit doses and can be prepared by any of the methods well known in the pharmaceutical art. All methods include the step of bringing into association a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof ("active ingredient") with the carrier that citutes one or more accessory ingredients. In general, the formulatiare prepared by bringing into uniform and intimate association with the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

Formulatiof the present invention suitable for oral administration may be presented as discrete units such as capsules, lozenges or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be present as a bolus, electuary or paste.

A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricant, active surface or dispersant. The molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated to provide slow or controlled release of the active ingredient therein.

Formulatifor parenteral administration include sterile aqueous and non-aqueous injectable solutiwhich may contain anti-oxidants, buffers, bacteriostats and solutes which return to isotonic formulation with the blood of the projected receptor; and sterile aqueous or non-aqueous suspensiwhich may include suspending agents and thickening agents. The formulatimay be presented in unit doses or in multi-dose containers, for example sealed vials and flasks, and may be stored under freeze-dried (lyophilized) conditithat require only the addition of the sterile liquid carrier, eg, saline, water for injection, immediately before use. Extemporaneous injectable solutiand suspensican be prepared from sterile powders, granules and tablets of the kind previously described.

Formulatifor rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.

Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoring base such as sucrose and acacia or tragacanth, and lozenges comprising the active ingredient in a base such as gelatin and glycerin or sucrose and acacia.

Preferred unit dose formulations are those which contain an effective dose, as mentioned above, or an appropriate fraction thereof, of the active ingredient.

Of course, in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art which take into consideration the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

The compounds of the invention can be administered orally or via injection at a dose from 0.001 to 2500 mg / kg per day. The dose range for human adults is generally from 0.005 mg to 10 g / day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention that is effective at such doses or as a multiple thereof, for example, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.

The compounds of formula (I) are preferably administered orally or by injection (intravenous or subcutaneous). The precise amount of compound administered to a patient will be the responsibility of the attending physician. However, the dose used will depend on a number of factors, including the age, and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the conditions and their severity.

All references, patents or applications, US or foreign, cited in the application are incorporated herein by reference as if they were part of this.

The following are general synthetic sequences that are useful in the preparation of the compounds of the present invention.

Scheme I: a.CuS04; b. R: C (-NH) Oet. HCl; c. ion exchange resins Scheme 2: (Ph3P) 2PdCl2. b. DAST. C. H2, Pd / C. d.

CH3C (= NH) 0et.HCl, ii. HCl.

Scheme 3: to. R'C = (NOH) Cl Scheme: 3, 5-dimethylpyrazole-l-carboxamidine Scheme 5: to. NaBH, .b.DAST Esguema 6: Esguema 7: 3. #} üL Scheme 8 G = heterocycle yiwc '' CObCH, i. Pdo / ester N-acetyl dehydroalanin methyl ii. Chiral reduction iii. Hydrolysis iv. LiBEt3H v. YC (NH) 0Et vi. Hydrolysis Scheme 9: Without further elaboration, it is believed that one skilled in the art can, using the preceding description, use the present invention in its broadest interpretation. Therefore, the following specific preferred embodiments are constructed as merely illustrative and not limiting of the remainder of the disclosure in any manner that is disclosed. EXAMPLES Example 1 4,4-difluoro-N 5 - (1-iminoethyl) -L-ornithine dihydrochloride. 4, 4-difluoro-ornithine is prepared, as described in J.Org. Chem. 61, 1996, pp 2497-2500 and then treated in the same manner as described in J. Antibiotics 25, 1972, p. 179 to form its copper complex. The copper complex of 4,4-difluoro ornithine is treated with ethyl acetimidate hydrochloride as described in Analytical Biochemistry 62, 1974, p. 291 to form the delta amidine. The copper complex is then broken as described in J. Antibiotics 25, 1972, p. 179 to form the title compound.

Example 2. 4,4-Difluoro-N6- (1-iminoethyl) -L-lysine dihydrochloride.

The Boc-L-Ala (Znl) -Ome is reacted with Z-beta-Ala-Cl under the conditions described in J. Org. Chem. 57, 1992, pp. 3397-3404 to give a protected 4-keto-L-lysine which is then dissolved in DCM and treated with DAST to produce protected 4,4-difluoro-L-lysine. The epsilon carbobenzoxy protecting group is then removed under the conditions of catalytic hydrogenolysis. The resulting compound is reacted with methyl acetimidate hydrochloride to produce the epsilid amidine which was reacted with 2N HCl to give the title compound.

Example 3. 5,5-Difluoro-N6- (1-iminoethyl) -L-lysine hydrochloride. ,5-Difluoro-lysine is prepared as described in J. Med. Chem. 20, 1977, pp 1623-1627 and then treated in the same manner as described in J. Antibiotics 25, 1972, p. 179 to form its copper complex. The copper complex of 5,5-difluoro lysine is treated with ethyl acetimidate hydrochloride as described in Analytical Biochemistry 62, 1974, p. 291 to form the epsilon amidine. The copper complex is then broken as described in J. Antibiotics 25, 1972, p. 179 to form the title compound. Example 4. N6- (2, 2, 2-trichloro-l-iminoethyl) -L-lysine dihydrochloride Ex.-4a) A three-necked flask was charged with 10 ml of dimethylformamide and 0.26 g (0.001 mole) of a-N-Boc-L-Lys-Ome. To this solution 0.35 g was added (0.002 moles) of methyl trichloroacetimidate and 0.53 ml (0.003 moles) of diisopropylethylamine. It was allowed to stir and heat at 25 ° C overnight. Concentration in vacuo removed the dimethylformamide. The residue was treated with trifluoroacetic acid for 30 minutes. This was diluted with water and purified via chromatography on a C-18 column to yield 0.24 g (80%) of Ex-4a. Mass Spectrum FAB, M + H = 304.

Ex.-4b) To a flask containing 0.12 g of Ex.-4a was added 10 ml of methanol and 5 ml of lithium hydroxide IN. This mixture was stirred for 10 minutes and then concentrated in vacuo. This material was purified via C-18 column chromatography to result in 0.1 g (95%) of the title compound. Mass Spectrum FAB, M + H = 290.

Example 5. N6- (2, 2, 2-trifluoro-1-iminoethyl) -L-lysine dihydrochloride Ex.-5a) A three-necked flask was fitted with a dry ice-acetone condenser and charged with 100 ml of ethanol and 6.5 9 (0.027 mole) of a-N-Boc-L-Lys-OH.

This was cooled to -78 ° C and 5 g (0.053 moles) of trifluoroacetonitrile were added via a gas dispersion tube. After the addition was complete, 2.7 g (0.027 mol) of triethylamine was added. This solution was kept under stirring and heated to 25 ° C overnight. Concentration in vacuo resulted in 11 g of 5a as a colorless viscous oil. XH-NMR (D20) 1.05 (t, 9H), 1.25- 1.75 (m, 6H), 1.35 (s, 9H), 2.8 (q, 6H), 2.95 (t, 2H), 3.7 (t, ÍH); 19F-NMR (D20) -68. 9 (s): Mass Spectrum, M + Li = 348 Ex-5b) To a flask containing 0.5 g of Ex-5a, 10 ml of dioxane (saturated with HCl) was added. This mixture was stirred for 30 minutes and then concentrated in vacuo to result in a white sticky foam. This material was dissolved in water and lyophilized to yield the title compound as a hygroscopic foam. 1 H-NMR (D 20) 1.15 (t, triethylamine hydrochloride), 1.3-1.5 (m, 2H), (m, 2H), 1.8-1.9 (m, 2H), 3.05 (q, triethylamine hydrochloride), 3.35 ( t, 2H), 3.9 (t, ÍH); 19F-NMR (D20) - 71.4 (s): mass spectrum, M + H = 242.

Example 6. N6- (2, 2-difluoro-1-iminoethyl) -L-lysine dihydrochloride Ex-6a) To a mixture of methanol and a catalytic amount of black palladium were added 0.5 g (1.4 mmol) of the product of Example Ex-20a. An excess of ammonium formate was added to this mixture. This mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered through celite and concentrated to result in a colorless oil.

Ex-6b) The product of Ej-6a was dissolved in 2N HCl and kept stirring at room temperature for three hours. This solution was diluted with water and lyophilized to yield 0.3 g (95%) of the title compound as a colorless oil. XH-NMR (D20) 1.3-1.6 (m, 2H), 1.6-1.75 (m, 2H), 1.8-2.0 (m, 2H), 3.35 (t, 2H), 4.0 (t, ÍH), 6.55 (t, lH); Elemental Analysis calculated for C8H? 502N3C? 2F2 + 5H20 + 4NH4C1 + 0 4 lysine: C, 18. 16; H, 7 24; N, 15. 8! Found: C, 18 13; H, 6.99; N, 15 69 Example 7 (±) -E-2-amino-6- (l-imino-2-fluoroethylamino) -hex-4-enoic acid dihydrochloride NttHCI NHj Ex-7a) Under argon, to 65.8 g of trans-1,4-dichloro-2-butene were added in portions 47 g of potassium phthalimidine with mechanical stirring maintaining the temperature between 100 ° C and 110 ° C. The reaction mixture was then stirred for 2 hours maintaining the temperature between 145 ° C and 150 ° C. It was then cooled to 20 ° C and extracted with 3 X 400 ml of ether. The ether layer was separated and dislodged to give a solid. This solid was recrystallized from ethanol to yield yellow crystals of N- (trans-4-chloro-2-butenyl) phthalimide, weight 36 g, 61% yield. Analysis calculated for C? 2H? 0ClNO2 (Molecular weight 237.25): C, 61.26; H, 4.29; N, 6.02; Cl, 14.94; Found C, 61.18; H, 4.30; N, 5.98; Cl, 14.62.

Ex-7b) Under argon, 3.7 g of metallic sodium was dissolved in 200 ml of absolute ethanol at 60 ° C to 65 then allowed to cool to 30 ° C. A sample of 27.4 g of ethyl acetamidomalonate was then added with good agitation. After 30 minutes, 30g of Ej-7a were added in 3 portions. The reaction mixture was heated under reflux for 4 hours, cooled and filtered. The filtrate was evaporated and the residue was taken up in 100 ml of ethyl acetate and washed with 100 ml of water. The organic layer was then dried, filtered and concentrated. 100 ml of hexane were then added and 27 g of the crude title product were obtained after filtration as a white solid. This solid trans-2-acetamido-2-carbethoxy-6-, phthalimido-4-ethyl acetate was purified by column chromatography on silica gel or recrystallization from ethanol. Analysis calculated for C2? H24N207 (Molecular Weight 416.15): C, 60.63; H, 5.81; N, 6.77; Found C, 60.51; H, 5.81; N, 6.64.

Ex-7c) A mixture of 25 g of ethyl trans-2-acetamido-2-carbethoxy-6-phthalimido-4-hexenoate and 200 ml of 37% HCl was heated under reflux for 20 hours and then maintained at 0 -2 ° C for 20 hours. It was then filtered to remove the phthalic acid and the filtrate was reduced to dryness in vacuo. 100 ml of absolute ethanol were then added and evaporated evaporated under vacuum. The residual solid was taken up in 100 ml of absolute ethanol and filtered to give 13 g of trans-2,6-diamino-4-hexenoic acid dihydrochloride.

Ex-7d) As described in J. Amer. Chem. Soc. Vol. 95, 6800, (1973), 10 g of trans-2,6-diamino-4-hexenoic acid hydrochloride were taken in 600 ml of 95% ethanol and passed through a 100 g of alumina (Alcoa F-20). The column was eluted with 2 L of 95% ethanol and then the eluent was reduced to ~ 200 ml in vacuo. The precipitate was filtered and dried to give monohydrochloride 4,5-dehydrolysin.

Ex-7e) 11 g of trans-4,5-dehydrolysin monohydrochloride were dissolved in 10 ml of water at 100 ° C. 7 g of copper carbonate were then added in small portions for 30 minutes. The reaction mixture is then cooled to 20 ° C and filtered. 1.5 equivalents of ethyl fluoroacetimidate hydrochloride were then added in portions to the above filtrate at 4 ° C-5 ° C. The pH of the reaction mixture is maintained at ~10.5 by the addition of 2N NaOH.

After 2 h of stirring the reaction mixture is passed through an ion exchange resin and eluted with 0.5 N aqueous ammonia. The ammonia solution was then acidified carefully to pH 4 with 2N HCl and evaporated to give Example 7.

Example 8 (±) -2-amino-6- (l-imino-2-fluoroethylamino) -hex-4-ynoic acid hydrochloride Ex-8) A mixture of 92.8 g of 1-dichloro-2-butyne and 108 g of hexamethylenetetramine was refluxed under argon in 500 ml of chloroform for 18 h. The reaction mixture was then cooled and filtered to give 168 g of the 1,4-Dichloro-2-butyne hexamethylenetetramine complex as a brown solid.

Ex-8b) The solution of the product of Ej-8a (60 g) in 500 ml of absolute ethanol saturated with HCl was refluxed under argon for 18 hours and cooled to 20 ° C. The formed precipitate was filtered and the mother liquor was concentrated to give a yellow waxy solid.

This was recriztalized with ether to give 41 g of l-Amino-4-chloro-2-butyne hydrochloride as a yellow solid.

Analysis calculated for CH7C12N (Molecular Weight: 141.59): C, 34.78; H, 5.05; N, 10.09; Cl, 50.08; Found: C, 31.61; H, 5.70; N, 12.49; Cl, 45.53.

Ex-8c) 14.1 g of l-amino-4-chloro-2-butyne hydrochloride were taken in 70 ml of dioxane and 35 ml of water. 4 g of NaOH were added and the reaction mixture was stirred for 30 minutes followed by the addition of 21.8 g of di-t-butylcarbonate at 20 ° C. The reaction mixture was stirred at 20 ° C to 25 ° C for 8 hours and then the lower organic layer was separated. The upper aqueous layer was extracted with 100 ml of dichloromethane. The organic layers were combined and washed with 50% aqueous solution of NaHCO 3, dried over anhydrous MgSO 4, treated with Darco, filtered over celite and concentrated to give a brown oil. This oil was chromatographed to give 9 g of 1-t-butyloxycarbonylamino-4-chloro-2-butyne as a white solid.

Analysis calculated for CgH14ClN02 (Molecular Weight 205. 25); C, 53.25; H, 6.92; N, 6.96; Cl, 17.27; Found C, 52.67; H, 6.16; Cl, 17.22.

Ex-8d) 12.1 g of l-butyloxycarbonylamino-4-chloro-2-butyne were refluxed for 16 hours with a mixture of 8 g of diethyl acetamidomalonate and sodium ethoxide prepared from 900 mg of sodium in 100 ml of absolute ethanol. The ethanol is then removed under vacuum and the residual mass is divided between water and ethyl acetate / ether (1: 1). The organic layer is treated with 0.5 N NaOH and 0.5 N HCl and washed with water. It is then dried over Na 2 SO 4, filtered and concentrated. The product is crystallized from ethyl acetate / petroleum ether to give approx. 7 g of ethyl 2-acetylamino-6-t-butyloxycarbonylamino-2-ethoxycarbonyl-4-hexinoate.

Ex-8e) Following the procedure described in Tetrahedron Lett Vol. 21, 4263, (1980) the partial saponification of 10.2 g of ethyl-2-acetylamino-6-t-butyloxycarbonylamino-2-ethoxycarbonyl-4-hexanoate, is brought to in ethanol with 1.5 equivalents of KOH in water at 20-25 ° C for 3 hours to give 2-acetylamino-6-t-butyloxycarbonylamino-2-ethoxycarbonyl-4-hexynoic acid in ~ 90% yield.

Ex-8f) The decarboxylation of 17 g of ej-8e is effected by reflux in 300 ml of dioxane for 24 hours. The reaction mixture is then cooled to room temperature and the solvent removed in vacuo. The residual mass is then taken in 80 ml of ethanol and 1.2 equivalents of KOH in water is added for further saponification in 15 h to give 10.5 g of 2-acetylamino-6-t-butyloxycarbonylamino-4-hexynoic acid.

Ex-8g) 10 g of 2-acetylamino-6-t-butyloxycarbonylamino-4-hexynoic acid are taken in 50 ml of acetic acid and 25 ml of 4N HCl in dioxane and stirred for 2 hours at 25 ° C. The reaction mixture is dried to give 2-acetylamino-6-amino-4-hexynoic acid.

Ex-8h) 2.86 g of ethylfluoroacetimidate hydrochloride, 1 equivalent of 2-acetylamino-6-amino-4-hexynoic acid and 6.84 g of DBU are taken in 200 ml of absolute ethanol and stirred for 16 hours at 20 ° C under argon. The solvent is removed under vacuum and 100 mL of water are added. This reaction mixture is filtered through an acid ion exchange column and the product is eluted with 10% pyridine / water to obtain Acido (±) -2-acetylamino-6- (1-imino-2-fluoroethylamino) dihydrochloride. hex-4-inoic.

Ex-8i) a sample of (±) -2-acetylamino-6-fluoroethylamino (-hex-4-inoic) hydrochloride (3 g) is treated with concentrated HCl and then pyridine to give (±) - acid dihydrochloride 2-Amino-6- (l-imino-2-fluoro-ethylamino) -hex-4-inoic by removal of the solvent under vacuum.

Example 9 1- (1-Imino-2-fluoroethylaminoethyl) -2- (aminoethyl-1-carboxylic) cyclopropane dihydrochloride.

Ex-9a) A solution of 0.05 moles of dimethylsulfonium methylide is generated in situ in a mixture of DMSO / THF mixture by the reaction of trimethylisulfonium iodide and NaH. Immediately, a solution of 0.05 moles of Ej-7b in 30 ml of DMSO is added at 0 ° C and the reaction mixture is heated to 20 ° C in 2 hours. The reaction mixture is washed with saturated ammonium chloride solution and extracted with ethyl acetate, after drying. The ethyl acetate is evaporated to give Ej-9a.

Ex-9b) The title compound is prepared from Ex-9a, similar to the procedure for Ex-7b.

Example 10. 2-Amino-5-exomethylene-6- (1-imino-2-fluoroethylamino) -hexaoic acid exo-lOa) is prepared from the hexanoate of Ethyl-2-acetamido-2-carbethoxy-5-keto-6 -fatimido as described in J. Med. Chem. 20, 1977, pp. 1623-1627 and then subjected to the Witting reaction with methylenetriphenyl phosphorane to give ethyl-2-acetamido-2-carbethoxy-5-exomethylene hexanoate. -6-phthalimido.

Ex-lOb) The title compound is prepared from eE-lOa similar to the procedure for Ex-7b.

EXAMPLE 11 2-Amino-5-cyclopropyl-6- (1-imino-2-fluoroethylamino) -hexanoic acid dihydrochloride Ex-lla) A sample of the Ej-10a was treated with an equimolar amount of methylenedimethyl sulfurane. After the usual treatment, ethyl-2-acetamido-2-carbethoxy-5-cyclopropyl-6-phthalimidohexanoate is obtained.

Ex-llb) The title compound is prepared from the Example similar to the procedure for Ex-7b.

Example 12. 2-Amino-5-methyl-6- (l-imino-2-fluoroethylamino) -hexanoic acid dihydrochloride Ex-12a) A sample of 10a is reduced or hydrogenated in position 5 to give ethyl-2-acetamido-2-carbethoxy-5-methyl-6-fatlimido hexanoate.

Ex-12b) The title compound is prepared from Ex-12a similar to the procedure for Ex-7b.

Example 13. 2-amino-4-exomethylene-6- (1-imino-2-fluoroethylamino) -hexanoic acid hydrochloride Ex-13a) A sample of 4-oxo-lysine is prepared as described in J. Chem Soc Perkin I, (1825, (1972). This is subjected to the Witting reaction with methylenetriphenyl phosphorane to give 4-methylene lysine.

Ex-13b) The title compound is prepared from Ej-13a following the procedure as described for the preparation of Ej-7d.

Example 14. N-l-Imino-2-fluoroethyl-4-oxalisine dihydrochloride Ex-14a) A sample of 0-2 aminoethyl or serine 4-oxalisine dihydrochloride is prepared as described in Recl. Trav. Chim. Pays-Bas, 81, 713-719 (1962). This is then converted to the title compound following the procedure described in Ex-7d.

Example 15 N-l-imino-2-fluoroethyl-5-oxahomolysin dihydrochloride Ex-15a) A sample of 2-amino-4- (2-aminoethoxy) butyric acid is prepared as described in J. Antibiot; 29, 38-43 (1976). This is then converted to the title compound following the procedure described for the preparation of Ej-7 from Ej-7d.

Example 16 -f luoro-N6- (1-iminoethyl) -D, L-lysine dihydrochloride Ex-16a) 5-fluoro-lysine (45 mg), (Oakwood) was treated in the same manner described in J. Antibiotics 25, 1972, p. 179 to form its copper complex. The 5-fluoro-lysine copper complex was treated with ethyl acetamidate hydrochloride as described in Analitical Biochemistry 62, 1974, p. 291 to form the epsilon amidine.

The copper complex was then fractionated as described in J. Antibiotics 25, 1972, p. 179 to form the title compound. This material was purified via chromatography with C-18 column to yield 32 mg (46%) of the title compound. C, H, N Calculated for C8H16N302F + 2.55 HCl + .20 NH4C1 + .5 H20: C, 30.21; H, 6.51; N, 14.00 Found: C, 29.91; H, 6.28; N, 14.01.

Example 17 N- (1-iminoethyl) -2-amino-l, 1-difluoroethyl-L-cysteine dihydrochloride N-Boc-L-cysteine is reacted with 2-chloro-l, 1-difluoro-ethene in the same manner as described in J. Chem. Miniprint 12, 1990; p. 2868 to form N-Boc- S- (2-chloro-l, 1-difuoroethyl) -L-cysteine. N-Boc-S- (2-chloro-1,1-difluoroethyl) -L-cysteine is reacted with potassium phthalimide in DMF at 100 ° C to form the phthalimide. The phthalimide is treated with hydrazine in ethanol to form the amine. The amine is treated with ethyl acetamidate hydrochloride to form the amidine. This material is purified via chromatography on a C-18 column to give the compound Boc,. The Boc group is removed with HCl / dioxane (4N) in acetic acid to yield the title compound Example 18 N- (1-iminoethyl) -2-amino-l, 1-difluoroethyl-D, L-homocysteine dihydrochloride Ex-18a) A solution of N-Boc-D, L-homocysteine (5 mmoles) in NaOH (5 ml, 2N) was added to a stirred solution of 1,2-dichloro-1,1-difluoroethane (5 mmoles). ) in DMF. The resulting solution was then heated to 50 ° C for 16 hours. The reaction solution was poured into EtOAc and extracted with citric acid (5%) and brine, dried (Na2SO4) and concentrated in vacuo. The material was purified by flash column chromatography to produce N-Boc-S- (2-chloro-l, 1-difluoroethyl) -D, L-homocysteine. The Example is prepared in the same manner as described for example 1 starting with N-Boc-S- (2-chloro-l, 1-difluoroethyl) -D, L-homocysteine.

Example 19 N5- (1-iminoethyl) -2,5-diaminopentanoic acid dihydrochloride Ex-19a) A solution of diethyl acetamidomalonate (21.7 g, 0.1 mole) was added to a stirred solution of sodium ethoxide (4 mmol) in ethanol (50 ml). After the addition, the resulting solution was cooled to 0 ° C, followed by the slow addition of 4,4,4-trifluorocrotonitrile (13.3 g, 0.11 mol) over 20 minutes. The reaction solution was stirred for 1.5 hours at room temperature. The reaction solution 5e, then poured over EA and extracted with brine, dried over Na 2 SO 4 and concentrated in vacuo to yield a clear liquid which solidified on standing to yield 32.2 g of a white solid.

Ex-19b) The nitrile (11.4 g, 34 mmol) was hydrogenated in ethanol with RaNi at 60 psi at 68 ° C for 3 hours. The reaction solution was concentrated in vacuo. EtOH and MTBE were added to the oil and the resulting white solid was collected to yield 1.5 g. C, H, N calculated for CnH? 5N204F3; C, 44.45; H, 5.43; N, 9.42.

Found C, 44.60; H, 5.18; N, 9.23.

Ex-19c) Lactam (1.0 g, 3.4 mmol) in HCl was refluxed for 4.5 hours. The reaction solution was concentrated in vacuo. The residue via C-18 chromatography to give the amino acid (500 mg). C, H, N, Cl calculated for C6HuN202F3.2.01 HCl.0.6 H20; C, 25.35; H, 5.04; N, 9.86; Cl, 25.07.

Found C, 25.08; H, 4.97; N, 9.80; Cl 25.40.

Ex-19d) The amine (0.37 g, 1.3 mmol) was treated with ethyl acetimidate hydrochloride (0.17 g, 1.4 mmol) to form the amidine by the method of Example 3. The materials purified via C-18 chromatography to give as result amidine (98 mg). C, H, N calculated for C8H? 4N302F3.2.0 HCl.1.5 H20; C, 28.17; H, . 61; N, 12.32.

Found C, 28.20; H, 5.37; N, 12.23.

Example 20. N6- (2-chloro, 2, 2-difluoro-l-iminoethyl) -L-lysine dihydrochloride Ex-20a) A three neck flask was fitted with a dry ice / acetone condenser and charged with 100 ml of ethanol and 5 g (0.02 mole) of N6-Boc-L-Lys-OH. This was cooled to -78 ° C and 5 g (0.045 moles) of chlorodifluoroacetonitrile were added via a gas dispersion tube. After the addition was complete, 0.5 g (0.5 mol) of triethylamine were added. This solution was maintained in agitation and heat at 25 ° C overnight.

Concentration in vacuo resulted in a residue which was dissolved in water and placed on a Dowex 50 ion exchange column. The column was washed with water and the product was eluted with 10% pyridine aqueous solution. Removal of the solvent in vacuo resulted in 1.26 g of the Boc-protected product as a white solid. Further purification was carried out on a sample using reverse phase chromatography to result in the Boc-protected product as a white solid. Analysis by mass spectrum for C? 3H220CnF2: M + H = 358. The elemental analysis calculated for Cj.3H2204N3CnF2 + H20: C, 36.78; H, 5.14; N, 8.58; Found: C, 36.39; H, 5.38; N, 8.3 Ex-20b) 20 ml of 2N HCl was added to a flask containing 0.185 g of the product of Ej-20a. This mixture was stirred for 2.5 hours, diluted with water and lyophilized to yield the title compound as a colorless oil. XH-NMR (D20) 1.2-1.5 (m, 2H), 1.5-1.7 (m, 2H), 1.7-2.0 (m, 2H), 3.35 (t, 2H), 3.9 (t, ÍH); Elemental analysis calculated for C8H? 602N2Cl3F2 + 4 H20 + 0.15 lysine: C, 24.75; H, 6.14; N, 10.67.

Found: C, 24.96; H, 6.26; N, 10.39 Example 21 N6- (2-fluoro-1-iminoethyl) -L-lysine dihydrochloride Ex-21a) To a solution of 5 g (0.18 mole) of Na-Cbz-lysine in 50 ml of ethanol was added 3.8 g (0.027 mole) of ethyl fluoroacetimidine. This was stirred at 25 ° C for 24 hours. The reaction mixture was concentrated to give an oily residue. Chromatography (C-18, acetonitrile / water) eluted two fractions containing the Cbz-protected title product. The first fraction containing 1.5 g of a 2: 1 ratio of cbz-protected product to be derived from Cbz-lysine and a second fraction containing 0.4 g of the Cbz-protected product. 1H-NMR (D20) 1.2-1.4 (m, 2H), 1.6-1.7 (m, 3H), 1.7-1.8 (m, HH), 3.2 (t, 2H), 4.1 (t, HH), 5.0 (s) , 2H), 5.1 (d, 2H), 7.3 (s, 5H); Elemental analysis calculated for C? 6H2204N3F? + CF3C02H + 2.5 H20: C, 43.38; H, 5.66; N, 8.43 Found: C, 43.65; H, 5.30; N, 8.25 Ex-21b) A solution of 1.5 g of the first fraction of the product of Ej-21a in 20 ml of 2N HCl was stirred at reflux for 2.5 hours. Withdrawn the heat and concentrated in vacuo to yield 0.5 g of the title product as a colorless oil.

XH-NMR (D20) 1.3-1.5 (m, 2H), 1.5-1.7 (m, 2H), 1.7-2.0 (m, 2H), 3.25 (t, 2H), 3.95 (t, ÍH), 5.15 (d 2H); Elemental analysis calculated for C8H? 802N3F? Cl2 + 5H20 + 0.5 lysine: C, 27.65; H, 7.59; N, 11.73 Found: C, 27.74; H, 7.15; N, 11.56 Example 22 5-Fluoro-N6- (1- (thiofen-2-yl) -1-iminomethyl) D, L-lysine Ex-22a) To a mixture of 2-cyanothiophene and 1 equivalent of ethanol is bubbled anhydrous HCl gaseous to result in ethyl imidate.

Ex-22b) The product of Ej-22a is added to a solution of 5-fluorolisine in ethanol and allowed to stir until the reaction is complete. Purification with chromatography resulted in the title product.

Example 23 N- (2-fluoro-1-iminomethyl) -3-aminopropyl-L-cysteine dihydrochloride Ex-23a) 2.5 g (5 mmoles) of S- (Ntw-Boc-3-aminoethyl) -Na-Fmoc-L-cysteine were dissolved in 25 ml of dichloromethane and deprotected by addition of 8 ml of trifluoroacetic acid with 2.5 minutes of stirring at room temperature. The solvent was evacuated in vacuo to give S- (3-aminoethyl) -Na-Fmoc-L-cysteine.

Ex-23b) The product of Ex-23a was allowed to react with 1.05 g (10 mmol) ethyl fluoroacetimidate hydrochloride in 40 ml of ethanol in the presence of 2.6 ml (15 mmol) of diisopropylethylamine (DIPEA) with stirring for 18 hours at room temperature. The Fmoc-protected product was isolated on reverse phase preparative HPL using a gradient of acetonitrile in H20 containing 0.05% TFA (10-50% AcN in 30 minutes). Obtaining 1.2 g (2.6 mmoles, 52%) of white solid material. FAB MS: M + H = 460 Ex.23c) 1.2 g (2.6 mmoles) of the product of Ex-3b It was decprotected in a mixture of 5 ml of diethylamine and 20 ml of DMF with stirring for 15 minutes. The solvent was evaporated under reduced pressure and the remaining oil was purified on reverse phase preparative HPLC using a gradient of acetonitrile in H20 containing 0.05% TFA (0-30% AcN in 30 minutes) to yield 0.426 mg (0.93 mmol) 36%) of the title product. FAB MS: M + H = 238 2H NMR (D20): 1.77-1.92 (; 2H), 2.49-2.61 (m; 2H), 2. 86-3.05 (m, 4H), 3.38-3.48 (m, 2H), 4.02-4.08 (m, ÍH), 5.04-5.110 s; ÍH) and 5.19- 5.25 (s, ÍH).

Example 24 N- (2-fluoro-1-iminoethyl) -2-aminoethyl-L-cysteine dihydrochloride Ex-24a) 20 g (50 mmol) of S- (Nw-Z-2-aminoethyl) -Na-Boc-L-cysteine (oil) was dissolved in 100 ml of methanol and the Z group was removed in the presence of sodium sulfate. g of NH4OOCH and 1 g of black Pd with stirring for 24 hours under N2. The product was isolated on reverse phase preparative HPLC using a gradient of acetonitrile in water containing 0.05% TFA (0-40% AcN in 30 minutes) to yield 5.6 g (42%) of S- (2-aminoethyl) - Na-Boc-L-cysteine. FAB MS: M + H = 265 Ej-24b) 1.4 g (5.3 mmoles) of the product of Ej-24a. They were dissolved in 25 ml of ethanol and allowed to react with 1.05 g (10 mmol) of ethyl fluoroacetimidate hydrochloride in the presence of 2.6 ml (15 mmol) of DIPEA with stirring. 18 hours at room temperature. The solvent was evaporated under reduced pressure and the oily remnant was purified on preparative reverse phase HPLC using a gradient of acetonitrile in water containing 0.05% TFA (10-50% AcN in 30 minutes) to yield 0.95 g (2.94 mmol); 55%) of the Boc-protected product. FAB MS: M + H = 324 Ex-24c) 0.95 g (2.94 mmoles) of the product of Ej-24b were dissolved in 25 ml of IN HCl and stirred for 12 hours at room temperature. This was diluted with 200 ml of water and lyophilized to yield 0.46 g (1.55 mmol, 53%) of the title compound as an oil. FAB MS: M + H = 224 XH NMR (D20): 2.71- 2.85 (m, 2H), 2.96-3.18 (m, 2H), 3.42-3.56 (m, 2H), 4.18-4.28 (m, ÍH), 5.18-5.22 (s, ÍH) and 5.25-5.30 (s, ÍH).

Example 25 N- (2-fluoro-l-iminoethyl) -2-aminoethyl-D, L-homocysteine dihydrochloride Ex-25a) 4.7 g (20 immoles) of Na-Boc-homocysteine They were dissolved in 50 ml of DMF and 1.6 g (40 mmol) of NaH (60% dispersion in mineral oil) were added to the solution. After 15 minutes of stirring at room temperature, 4.1 g (20 mmoles) of 2-bromoethylamine bromohydrate were added slowly to the mixture. The stirring was continued for 16 hours at room temperature. The DMF was removed under reduced pressure and the residue was isolated on preparative reverse phase HPLC using a gradient of acetonitrile in water containing 0.05% TFA (0-40% AcN in 30 minutes) to yield 4.05 g (10.3 mmol; %) of S- (aminoethyl) -Na-Boc-L-cysteine as an oil. FAB MS: M + H = 279 XH NMR (D20): 1.25-1.35 (m, 9H), 1.78-2.10 (m, 2H), 2.44-2.67 (m, 2H), 2.69-2.80 (m, 2H), 3.04-3.15 (m, 2H) and 4.06-4.22 (m, ÍH).

Ex-25b) 1.5 g (3.8 mmol) of the product of example Ex-25a were dissolved in 20 ml of ethanol and reacted with 0.63 g (6 mmol) of ethyl fluoroacetimidate hydrochloride in the presence of 1.05 ml (6 mmol) of DIPEA with stirring for 18 hours at room temperature. The solvent was evaporated under reduced pressure and the remaining oil was purified on reverse phase preparative HPLC using a gradient of acetonitrile in water containing 0.05% TFA (0-40% AcN in 30 minutes) to yield 1.4 g (3.1 mmol; 82%) of the Boc-protected product as an oil. FAB MS: M + H = 338 XH NMR (D20): 1.24-1.34 (m, 9H), 1.75-2.12 (m, 2H), 2.43-2.83 (m, 4H), 3.41-3.55 (t, 2H), 4.04-4.22 (m, ÍH), 5.08-5.14 (s, ÍH) and 5.23-5.28 (s, ÍH).

Ex-25c) 1.4 g (3.1 mmol) of the product of example Ex-25b were dissolved in 25 ml of IN HCl and stirred for 12 hours at room temperature. This was diluted with 300 ml of H20 and lyophilized to yield 0.91 g (2.93 mmol, 95%) of the title product as an oil. FAB MS: M + H = 238 XH NMR (D20): 1.98-2.25 (m, 2H), 2.60-2.84 (m, 4H), 3.43-3.56 (m, 2H), 4.06-4.16 (t, ÍH), 5.08-5.14 (s, ÍH) and 5.23-5.28 (s, ÍH).

Example 26 N- (2-fluoro-1-iminoethyl) -2-aminoethyl-L-homocysteine Ex-26a) hydrochloride The title product was prepared as in Example 25 using Na-Boc-L-homocysteine to yield 7.5 g (24.2 mmol, 96%) of the title compound as an oil. FAB MS: M + H = 238 1H NMR (D20): 1.98-2.25 (m, 2H), 2.60- 2.84 (m, 4H), 3.43-3.56 (m, 2H), 4.06-4.16 (t, ÍH), 5.08-5.14 (s, ÍH) and 5.23-5.28 (s, ÍH).

Example 27 N- (2-chloro-2,2-difluoro-1-iminoethyl) 3-aminoethyl-D, L-homocysteine dihydrochloride Ex-27a) 2.8 g (10 mmoles) of the product of ej-25a They were dissolved in 40 ml of ethanol and 1.75 ml (10 mmoles) of DIPEA were added to the solution. Difluoro-chloro-acetonitrile (F2C1CN) gas was bubbled into the mixture in an ice bath for 10 minutes. It was stirred for 24 hours at room temperature and then the solvent was evaporated in vacuo. The remaining oil was purified on reverse phase preparative HPLC using a gradient of acetonitrile in water containing 0.05% of TFA (5-40% AcN in 30 minutes) to produce 2.4 g (6.2 mmoles, 62%) of the Boc-protected product as an oil. FAB MS: M + H = 390 Ex-27b) 2.4 g (6.2 mmoles) of the product of Ex-27a Dissolve in 50 ml of IN HCl and stir for 12 hours at room temperature. This is diluted with 200 mL of water and lyophilized to yield 1.4 g (4.8 mmol, 77%) of the title product as an oil. FAB MS: M + H = 290 Example 28 N- (2, 2-difluoro-1-iminoethyl) -2-aminoethyl-D, L-homocysteine dihydrochloride Ex-28a) 2.4 g (6.2 mmoles) of the product of Ex-27a They were dissolved in 50 ml of MeOH and treated with 1 g of H4NOOCH and 0.2 g of black Pd with stirring under N2 for 48 hours. The catalyst was filtered and the Boc-protected product was purified on preparative reverse phase chromatography using a gradient of acetonitrile in water containing 0.05% TFA (10-50% AcN in 30 minutes) to yield 1.06 g of a white solid ( 2.26 mmoles, 23% in total). FAB MS: M + H = 356 Ex-28b) 1.06 g (2.26 mmol) of the product of Ex-28a were dissolved in 20 ml of IN HCl and stirred for 12 hours at room temperature. This was diluted with 200 ml of water and lyophilized twice to yield 0.69 g (2.1 mmol, 96%) of the title product as an oil. FAB MS: M + H = 256 XH NMR (D20): 2.02-2.28 (m, 2H), 2.55-2.90 (m, 4H), 3. 48-3.65 (m, 2H), 4.03-4.18 (m, ÍH) and 6.40-6.80 (t, ÍH).

Example 29 N- (2-fluoro-1-iminoethyl) -3-aminopropyl-D, L-homocysteine dihydrochloride Ex-29a) Na-Boc-homocysteine is dissolved in DMF and NaH (60% dispersion in mineral oil) is added to the solution. After stirring for 15 minutes at room temperature, 2-bromopropylamine hydrobromide is added slowly to the mixture. Stirring is continued for 16 hours at room temperature. The DMF is removed under reduced pressure and the residue is isolated on reverse phase preparative HPLC using a gradient of acetonitrile in water containing 0.05% TFA to yield S- (aminopropyl) -Na-Boc-homocysteine.

Ex-29b) The product of Ej-29a is dissolved in 20 ml of ethanol and reacted with ethyl fluoroacetimidate hydrochloride in the presence of DIPEA with stirring, for 18 hours at room temperature. The solvent is evaporated under reduced pressure and the remaining oil is purified on reverse phase preparative HPLC using a gradient of acetonitrile in water containing 0.05% TFA to result in the Boc-protected product.

Ex-29c) The product of Ej-29b is dissolved in 1N HCl and stirred for 12 hours at room temperature. This is diluted with water and lyophilized to yield the title product.

Example 30 N- (2-fluoro-1-iminoethyl) -2-aminoethyl-D, L-bishomocysteine dihydrochloride Ex-30a) Na-Cbz-glutamic acid, a-benzyl ester is dissolved in THF and treated with Borane. Isolation gives the protected glutamic alcohol.

Ex-30b) The product of Ej-30a is treated with triphenyl phosphine and carbon tetrabromide. The isolation results in the benzyl ester of 2-Cbz-amino, 5-bromopentanoic acid.

Ex-30c) The product of Ej-30b is dissolved in THF and allowed to react with sodium hydride followed by 2-Boc-amino mercaptoethane. Isolation results in the benzyl ester of S- (Boc-aminoethyl) -Na-Cbz-Bishomocysteine.

Ex-30d) The product of Ex-30c is Boc-protected with HCl to result in the benzyl ester of S- (aminoethyl) -Na-Cbz-bishomocysteine.

Ex-30e) The product of Ej-30d is allowed to react with ethyl fluoroacetimidate hydrochloride as in Ex-25b to result in the protected Cbz product as a benzyl ester.

Ex-30f) Deprotection of the product of Ej-30e via hydrogenation results in the title product.

EXAMPLE 31 2- [N- (2-Fluoro-1-iminoethyl) -aminomethyl] -5- [2 (S) -aminopropionic acid-3-yl] -thiophene dihydrochloride.

Ex-31a) A 2-bromothiophen-5-carboxamide is allowed to react with methyl N-acetyldehydroalanin ester under Heck coupling conditions to result in 2- (2- (acetylamino) methylpropenoic-3-yl ester) thiophen -5-carboxamide.

Ex-31b) The product of Ex-31a is subjected to chiral hydrogenation conditions to result in 2- (2 (S) - (acetylamido) methyl propanoic-3-yl) thiophene-5-carboxamide ester.

Ex-31c) The product of Ex-31b is subjected to the conditions of half saponification to result in 2- (2 (S) - (acetylamino) propanoic acid-3-yl) thiophene-5-carboxamide.

Ex-31d) The product of Ex-31c is allowed to react with LiBEt 3 H to result in 2 (S) - (acetylamino) propanoic acid-3-yl) thiophene-5-aminomethyl.

Ex-31e) The product of Ej-31d is allowed to react with ethyl fluoroacetimidate hydrochloride as in Example Ex-24b to result in the acetyl-protected product.

Ex-31f) The deprotection of the product of ej-31e via hydrolysis results in the title product.

Example 32 N - (2-chloro-l-iminoethyl) -L-lysine dihydrochloride Ex-32) The method of Example 20 was used to prepare the title product. Loop spectral analysis for C8H? 6N302Cl ?: M + H = 222.

Biological Data The activity of the compounds listed above as inhibitors of NO synthase is or can be determined by the following tests: Citrulline Test for Nitric Oxide Synthase The activity of nitric oxide synthase is measured by monitoring the conversion of [3 H] -arginine to [3 H] -citrulline. The inducible mouse nitric oxide synthase (miNOS) was prepared from an extract of RAW 264.7 cells treated with LPS and partially purified by DEAE-Sepharose chromatography. The nitric oxide synthase constitutive of rat cerebellum (mNOS) was prepared from a rat cerebellum extract and partially purified by DEAE-Sepharose chromatography. The enzyme and inhibitors were incubated at 37 ° C for 15 minutes in a reaction volume of 100 ml with the following components added to the start mixture: 50 mM Tris (pH 7.6), 1 mg / ml bovine serum albumin, 1 mM DTT, 2 mM CaCl2, 10 mM FAD, 10 mM tetrahydrobiopterin, 30 mM L-arginine containing L- [[2, 3-3H] -arginine at 300 cpm / pmole and 1 mM NADPH For the constitutive NOS, 50 nM of calmodulin was also added. The reaction was terminated by the addition of cold stop buffer containing 10 mM EGTA, 10 mM HEPES, pH 5.5 and 1 mM citrulline. The [3 H] -citrulline was separated by chromatography on a Dowex 50W X-8 cation exchange resin and the radioactivity determined with a liquid scintillation counter.

Raw Cell Nitrite Assay RAW 264.7 cells are plated for confluence, in 96-well tissue culture plates to develop overnight (17 hours) in the presence of LPS to induce NOS. A follow-up of 3 to 6 wells were untreated and served as controls for subtraction of non-specific backgrounds. The medium is removed from each well and the cells are washed twice with Krebs-Ringers-Hepes (25 mM, pH 7.4) with 2 mg / ml of glucose. The cells are then placed on ice and incubated with 50 ml of buffer containing L-arginine (30 mM) +/- inhibitors for 1 hour. The test is initiated by heating the plate at 37 ° C in a water bath, for 1 hour. The production of nitrite by intracellular iNOS is linear with time. To complete the cell assay, the cell plate is placed on ice and the nitrite-containing buffer is removed and analyzed for nitrite, using the previously published fluorescence nitrite determination. T.P. Misko et al., Analytical Biochemistry, 214, 11-16 (1993). All values are the average of the wells in triplicate and are compared to a supporting substrate induced in the group of cells (100% of value).

In vivo assays The rats are treated with an intraperitoneal injection of 10 mg / kg endotoxin (LPS) with or without oral administration of the nitric oxide synthase inhibitors. Plasma nitrites are measured 5 hours post-treatment. The results showed that the administration of the nitric oxide synthase inhibitor decreases the plasma production of nitrites / a reliable indicator of the production of nitric oxide, induced by endotoxin. IP is the abbreviation for 2-iminopiperidine. LPS is the abbreviation for endotoxin. From the previous description, an expert in the field can easily find out the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make several changes and modifications of the invention to adapt it to various uses and conditions. It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Having described the invention as above, the content of the following is claimed as property.

Claims (12)

1. A compound of formula (I) (D or a pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from the group consisting of hydrogen, Ci-Cio alkyl, and C2-C? alkenyl, and C2-C alqu alkynyl; R2 is selected from the group consisting of hydrogen, Ci-Cio alkyl, C2-C al alkenyl, and any, R or S alpha-amino acid; R3 and R4 are independently selected from the group consisting of hydrogen, Ci-Cio alkyl, alkenyl of wherein R1, R2, R3 and R4 may be optionally substituted from the group consisting of C?-C8 alkyl, C2-alkenyl C8, C? -C8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, Ci-C? Alkoxy, aryloxy, tyl, C? -C8 thioalkoxy, halogen, cyano / nitro, carboxyl, carboxyalkyl, carboxyryl, amidino / and guanidino; R11 is selected from the group consisting of hydroxyl and R or S alpha-amino acid; G is selected from the group q ^ consisting of C1-C10 alkylene / C2-C2 alkenylene, and C2-C alkynylene or each of which is optionally substituted with one or more selected, - from the group consists of halogen, hydroxyl, trifluoromethyl, nitro, cyano, amino, Ci-Cio alkyl = CH2, C2-C alkenyl or C2-C alkynyl] and Ci-Cio alkoxy each of which may optionally be substituted wherever possible with one or more of the group consisting of C? -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl / cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, C? -C8 alkoxy, aryloxyl, lime, C?-C8 halogen thioalkoxy, cyano, nitro, amino, carboxyl, carboxyalkyl, carboxaryl, amidino, guanidino, trifluoromethyl; G is selected from the formula (CH2) P- (CXXX2) t- (CH2) SQ - (CH2) t- (CX3X4) u- (CH2) v where, p, r, s, t, u, v are independently 0 to 3 and Q is oxygen, C = 0, S (0) a, where a is 0 to 2, provided, when a is 1 or 2 , G must contain halogen, or NR12, wherein R12 is hydrogen or Ci-Cio alkyl, which may be optionally substituted wherever possible, with one or more selected from the group consisting of C1-C10 alkyl, alkoxy C1-C10 hydroxyl, trifluoromethyl, nitro, cyano, amino and halogen; G is selected from the formula - (CH2) w- (CX5X6) and- (CH2) ZA- (CH2) k- (CXX8) j- (CH2) h / where, y, z, k, j, h are independently 0 to 3 and A a carbocyclic radical of 3 to 6 members or a heterocyclic radical which may be optionally substituted with one or more selected from the group consisting of halogen, Ci-Cio alkyl, Ci-Cio alkoxy, hydroxyl, trifluoromethyl, nitro, cyano and amino, each of which may be optionally substituted if it is wherever possible with halogen, Ci-Cio alkyl, provided, when G is selected from the formula - (CH2) "- (CX5X6 ) y- (CH2) 2-A- (CH2) k- (CX7X8) j- (CH2) h, Y must contain halogen; X1, X2, X3, X4, X5, X6, X7, X8 are independently not present, or are hydrogen, halogen, Ci-Cio alkyl = CH2, C2-C? Or alkenyl or C2-C? 0 alkynyl wherein alkyl of C? -C? o / = CH2, C2-C? alkenyl or C2-C? alkynyl or they may be optionally substituted by one or more of the group consisting of C? -C8 alkyl C2-C8 alkenyl, alkynyl of C2-C8, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, C? -C8 alkoxy, aryloxy, tyl, C? -C8 thioalkoxy, halogen, cyano, nitro, amino, carboxyl, carboxyalkyl, carboxyryl, amidino, guanidino , trifluoromethyl; Y is selected from the group consisting of heterocyl, C1-C10 haloalkyl, C1-C10 dihaloalkyl, C1-C10 trihaloalkyl C1-C10 alkyl, C3-C3 cycloalkyl, C2-C3 alkenyl and alkynyl C2-C? O / each of which is optionally substituted with one or more selected from the group consisting of halogen, hydroxyl, trifluoromethyl, nitro, cyano, amino, Ci-Cio alkyl, C2-C? Alkenyl, C2-C? alkynyl and Ci-Cι alkoxy; And it may be NR9R10 wherein R9 and R10 are independently selected from the group consisting of hydrogen, Ci-Cio cycloalkyl C3-C6 alkyl or alkenyl C2-C? O / alkynyl of C2-C? 0, nitro, amino, aryl, and alkaryl of Ci-Cio; With the provision that at least one of G and Y contains halogen.

2. A compound as claimed in the claim 1, characterized in that,: G is selected from the group consisting of alkyl Ci-Cio alkenylene of C2-C? O / and C2-C? Alkynylene, each of which is optionally substituted with one or more selected from the group consisting of halogen, hydroxyl, trifluoromethyl, nitro, cyano, amino, C1-C10 alkyl, = CH2, C2-C2 alkenyl, C2-C2 alkynyl, and C1-C10 alkoxy, each of which may be optionally substituted wherever possible with one or more selected from the group which consists of C? -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl, C? -C8 alkoxy, aryloxy, tyl, C? -C8 thioalkoxy, halogen, cyano, nitro, amino, carboxyl, carboxyalkyl, carboxiaryl, amidino, guanidino, trifluoromethyl; or G is selected from the formula (CH2) p- (CXXX4) r- (CH2) SQ- (CH2) t- (CX3X4) U- (CH2) V where p, r, s, t, u, v are independently 0-3, Q is oxygen, C = 0, S (0) a, where a is 0 to 2, with the provision that when a is 1 or 2, G must contain a halogen, or NR12 where R12 is hydrogen or Ci-Cio alkyl, which may be optionally substituted with one or more selected from the group consisting of C? -C? 0 alkyl, Ci-Cio alkoxy, hydroxyl, trifluoromethyl, nitro, cyano, amino and halogen.

3. A compound as claimed in claim 2, characterized in that: G is selected from the group consisting of alkylene C1-C10, C2-C? Alkenylene, C2-C? Alkynylene, each of which is optionally substituted with one or more selected from the group consisting of halogen, hydroxyl, trifluoromethyl, nitro, cyano, amino, C 1 -C 10 alkyl, = CH 2, C 2 -C 0 alkenyl, C 2 -C 10 alkynyl, and C 1 -C 10 alkoxy, each of which may be optionally substituted wherever possible with one or more of the group consisting of C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 8 alkoxy, aryloxy, tyl, C 1 -C 8 thioalkoxy, halogen, cyano, nitro, amino, carboxyl, carboxyalkyl, carboxaryl, amidino, guanidino, trifluoromethyl; and Y is selected from the group consisting of heterocycle, haloalkyl of C? -C? 0, dihaloalkyl of C1-C10, trihaloalkyl of C1-C10, alkyl of C1-C10 cycloalkyl of C3-C? or, alkenyl of C2-C and C2-C alkynyl, each of which is optionally substituted with one or more selected from the group consisting of halogen, hydroxyl, trifluoromethyl, nitro, cyano, amino, C1-C10 alkyl, C2-alkenyl C 0 and C 1 -C 4 alkoxyl 4. A compound as claimed in claim 3, characterized in that: R 1, R 2 are H, R 3, R 4 are H or N 0 2; G is selected from the group consisting of C? -C? Alkylene, C2-C? 0 alkenylene, and C2-C? Alkynylene, each of which is optionally substituted with one or more selected from the group consists of halogen, hydroxyl, trifluoromethyl, nitro, cyano, amino, C? -C? 0 alkyl, = CH2, C2-C? alkenyl, C2-C? alkynyl, and C? -C alkoxy? or, each of which may be optionally substituted wherever possible with one or more of the group consisting of C? -C? alkyl, C2-C8 alkenyl, C2-C8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl , hydroxyl, C? -C8 alkoxy, aryloxy, tyl, C2-C8 thioalkoxy, halogen, cyano, nitro, amino, carboxyl, carboxyalkyl, carboxyryl, amidino, guanidino, trifluoromethyl; and Y is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, each of which is optionally substituted with one or more halogens, or NHR9 wherein R9 is hydrogen, CI-CT cycloalkyl C3-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

5. A compound as claimed in claim 4, characterized in that: R1, R2, R3 and R4 are each H; G is C1-C5 alkylene substituted with at least one halogen; and Y is Ci-Cd alkyl.

6. A compound as claimed in claim 1, characterized in that: R1, R2, R3 and R4 are each H; Y is C1-C10 haloalkyl or C1-C10 alkyl; and G is selected from the formula (CH2) p- (CX ^ 2) r- (CH2) SQ- (CH2) t- (CX3X4) U- (CH2) V, where p, r, s, t, u, v, are independently 0-3 and Q is oxygen, C = 0, S (0) a where a is 0 to 2, with the provision that when a is 1 or 2. G must contain a halogen, or NR12 where R 12 is hydrogen or C 1 -C 10 alkyl, which may be optionally substituted with one or more selected from the group consisting of C 1 -C 10 alkyl, C 1 -C 10 alkoxy, hydroxyl, trifluoromethyl, nitro, cyano, amino, and halogen . N6- (2,2,2-trichloro-l-iminoethyl) -L-lysine dihydrochloride; N6- (2, 2-difluoro-l-iminoethyl) -L-lysine dihydrochloride; (±) -E-2-Amino-6- (l-imino-2-fluoroethylamino) -hex-4-enoicacid dihydrochloride; (±) -2-Amino-6- (l-imino-2-fluoroethylamino) -hex-4-ynoic acid dihydrochloride; 1- (1-imino-2-fluoroethylaminomethyl) -2- (1-carboxylic aminoethyl) cyclopropane dihydrochloride; 2-Amino-5-exomethylene-6- (1-imino-2-fluoroethylamino) -hexanoic acid dihydrochloride; 2-Amino-5-cyclopropyl-6- (1-imino-2-fluoroethylamino) -hexanoic acid dihydrochloride; 2-Amino-5-methyl-6- (l-imino-2-fluoroethylamino) -hexanoic acid hydrochloride; 2-Amino-4-exomethylene-6- (1-imino-2-fluoroethylamino) -hexanoic acid dihydrochloride; N-l-imino-2-fluoroethyl-4-oxalisine dihydrochloride; N-l-imino-2-fluoroethyl-5-oxahomolysin dihydrochloride; 5-fluoro-N6- (1-iminoethyl) -D, L-lysine dihydrochloride; N- (1-iminoethyl) -f-amino-1,1-difluoroethyl-L-cysteine dihydrochloride; N- (1-iminoethyl) -2-amino-1, 1-difluoroethyl-D, L-homocysteine dihydrochloride; N5- (1-iminoethyl) -2,5-diaminopentanoic acid dihydrochloride; N6- (2-chloro-2, 2-difluoro-1-iminoethyl) -L-lysine dihydrochloride; N6- (2-fluoro-l-iminoethyl) -L-lysine dihydrochloride; 5-fluoro-N6- (1- (thiophen-2-yl) -1-iminomethyl) D, L-Lysine; N- (2-fluoro-1-iminoethyl) -3-aminopropyl-L-cysteine dihydrochloride; N- (2-fluoro-1-iminoethyl) -2-aminoethyl-L-cysteine dihydrochloride; N- (2-fluoro-1-iminoethyl) -2-aminoethyl-D, L-homocysteine dihydrochloride; N- (2-fluoro-1-iminoethyl) -2-aminoethyl-L-homocysteine dihydrochloride; N- (2-chloro-2,2-difluoro-1-iminoethyl) -3-aminoethyl-D, L-homocysteine dihydrochloride; N- (2, 2-difluoro-1-iminoethyl) -2-aminoethyl-D, L-homocysteine dihydrochloride; N- (2-fluoro-1-iminoethyl) -3-aminopropyl-D, L-homocysteine dihydrochloride; N- (2-fluoro-1-iminoethyl) -2-aminoethyl-D, L-bishomocysteine dihydrochloride; N- (2-fluoro-1-iminoethyl) -2-aminoethyl-L-homocysteine dihydrochloride; N- (2-chloro-2,2-difluoro-1-iminoethyl) -3-aminoethyl-D, L-homocysteine dihydrochloride; N- (2, 2-difluoro-1-iminoethyl) -2-aminoethyl-D, L-homocysteine dihydrochloride; N- (2-fluoro-1-iminoethyl) -3-aminopropyl-D, L-homocysteine dihydrochloride; N- (2-fluoro-1-iminoethyl) -2-aminoethyl-D, L-bishomocysteine dihydrochloride; 2- [N- (2-fluoro-1-iminoethyl) -aminomethyl] -5- [2 (S) -aminopropionic acid 3-yl] -thiophene dihydrochloride; and N6- (2-chloro-l-iminoethyl) -L-lysine dihydrochloride.

8. A compound of claim 7, characterized in that it is selected from the group consisting of: N- (2-fluoro-1-iminoethyl) -3-aminopropyl-L-cysteine dihydrochloride; N- (2-fluoro-1-iminoethyl) -2-aminoethyl-L-cysteine dihydrochloride; N- (2-fluoro-1-iminoethyl) -2-aminoethyl-D, L-homocysteine dihydrochloride; and N- (2-fluoro-1-iminoethyl) -2-aminoethyl-L-homocysteine dihydrochloride.

9. The use of a compound of claims 1,2,3,4,5,6,7 or 8, for the preparation of a medicament for the inhibition of nitric oxide synthesis in a subject in need of such inhibition.

10. The use of a compound of claims 1,2,3,4,5,6,7 or 8, for the preparation of a medicament for selectively inhibiting the synthesis of nitric oxide produced by the NO cassette by the nitric oxide produced by the constitutive forms of NO tape in a subject in need of such selective inhibition.

11. The use of a compound of claims 1,2,3,4,5,6,7 or 8 for the preparation of a medicament for decreasing the levels of nitric acid in a subject in need of such a decrease.

12. A pharmaceutical composition, characterized in that it comprises a compound of claims 1,2,3,4,5,6,7 or 8, together with one or more pharmaceutically acceptable carriers.