Background of the invention Neurodegenerative diseases are caused by malfunctions within the motor sector of the nervous system. These malfunctions, which are caused by the presence or absence of hormones, are a direct result of neural cell deterioration within the brain. Thus, biological problems of the brain, or rather predicaments arising between cellular connections within the brain, and the treatment of such conditions, illustrate how the brain organizes movement and behavior.

The brain is the body's communication headquarters. It obtains a myriad of information from various parts of the sensory system and processes this information in an organized fashion. It then relays sensory input to different parts of the motor system. Such messages from the brain dictate specific muscular and behavioral patterns. Thus, this neural system is highly depended on a cause and effect system, where the slightest offset to the assembly-line fashion of cellular interaction results in major behavioral abnormalities. Moreover, there are two particular areas of the brain that are specifically related to motor malfunctions: the substania nigra and the striatum (the caudate nucleus and the putamen). The cells of the nigra synapse with cells of the striatum, which serves as the controller of motor functions such as walking, balance, and muscular movement.

Information from the nigra cells passes through the synapses with the aid of a specific hormone, dopamine, which is a significant chemical transmitter in the brain. Because the existence of dopamine is essential to the function of the

substania nigra, it is also essential for the various muscular activities controlled by the striatum, such as walking, balance, etc.

Neurodegenerative diseases, like Parkinson's Disease and Huntington's disease, thus, illustrate two very different behavioral patterns that are subsequently caused by two opposite and extreme biological abnormalities, where the nigra-striatum neural communication assemblage is hampered. Parkinson's disease (PD) results from a depletion in the amount of dopamine produced by the brain. At the onset of the disease, dopamine-secreting cells of the substania nigra, either because of genetic factors or environmental toxins, experience mass cell death. Thus, the nigra cells are unable to form synapses through which they secrete and relay dopamine to the striatum in a neural circuit within the basal ganglia. The striatum is also a coordination center for chemical messengers. When there is a decrease in dopamine levels, the striatum experiences a chemical imbalance. Since the basal ganglia plays a largely inhibitory role on the spinal motor centers, the loss of control of the nigra of the striatum as well as the disabilities of the striatum due to abnormal dopamine levels cause inhibition of muscular movements. Therefore, as a consequence of microscopic dysfunctions, macroscopic abnormalities arise.

Neurodiseases can be classified as follows : NEUROLOGICAL DISEASES, such as PAIN STROKE AND OTHER CEREBROVASCULAR TRAUMAS EPILEPSY AND OTHER CONVULSIONS NEUROMOTOR DISEASES, such as Parkinson's Disease Auto-immune Neurodegenerative Diseases Genetic Neurodegenerative Diseases Paralysis and the Prospects for Restored Muscle Function SLEEP DISORDERS NEUROTOXICITIES INFECTIONS TUMORS MENTAL RETARDATION DRUG AND ALCOHOL ADDICTION MENTAL DISEASES, such as PSYCHOSES Schizophrenia

Affective Disorders Alzheimer's Disease and Other Dementias Autism Dissociative Disorders NEUROTIC, BEHAVIORAL AND PERSONALITY DISORDERS Anxiety Disorders Mild Depression Personality Disorders COPING PROBLEMS Prion diseases are a special kind of neurodegenerative diseases which belong to the subgroup of infectious diseases.

Prions are infectious agents which do not have a nucleic acid genome. It seems that a protein alone is the infectious agent. A prion has been defined as"small proteinaceous infectious particle which resists inactivation by procedures that modify nucleic acids". The discovery that proteins alone can transmit an infectious disease has come as a considerable surprise to the scientific community. Prion diseases are often called"transmissible spongiform encephalopathies", because of the post mortem appearance of the brain with large vacuoles in the cortex and cerebellum. Probably most mammalian species develop these diseases. Prion diseases are a group of neurodegenerative disorders of humans and animals and the prion diseases can manifest as sporadic, genetic or infectious disorders. Examples for prion diseases acquired by exogenous infection are the Bovine spongiform encephalitis (BSE) of cattle and the new variant of Creutzfeld-Jakob disease (vCJD) caused by BSE. Further examples include kuru, Gerstmann-Straussier-Scheinker disease of humans as well as scrapie of animals. For many years, the prion diseases were thought to be caused by viruses despite intriguing evidence to the contrary. The unique characteristic common to all of these disorders, whether sporadic, dominantly inherited, or acquired by infection, is that they involve the aberrant metabolism of the prion protein (PrP). In many cases, the cellular prion protein (PrP°) ["c"refers to cellular] is converted into the scrapie isoform (PrPSc) ["Sc"refers to Scrapie] by a posttranslational process that involves a conformational change. Often, the human prion diseases are transmissible to experimental animals and all of the inherited prion diseases segregate with PrP gene mutations.

These prion diseases in animals and humans have a long incubation period and a long clinical course, and are always fatal leading via decerebration to death within an average period of 7 months (CJD). Neuropathological features consist of neuronal vacuolization, neuronal death and gliosis with hyperastrocytosis. The precise diagnosis of transmissible neurodegenerative diseases can be established only by the examination of the central nervous system after biopsy or autopsy.

Clinical symptoms of the disease are progressive dementia, myoclonus and prominent ataxia with the additional clinical features of dysautonomia and delirious psychomotor excitement and with relatively preserved verbal responses.

Between 1980 and, roughly, 1996, about 750,000 cattle infected with BSE were slaughtered for human consumption in Great Britain (Anderson, R. M. et al. Nature 382,779-788, 1996; Ferguson, N. M., Donnelly, C. A., Woolhouse, M. E. J. & Anderson, R. M. Phil. Trans. R. Soc. Lond. B 352,803-838, 1997). The annual incidence of vCJD (3,10, 10,18, 14 and 33 deaths in 1995-2000, respectively) can be interpreted as a first sign of a steady or exponential increase over the next years. The suggestion by the European Union Scientific Steering Committee that up to 500,000 people could have been exposed to BSE from a single infected bovine has fuelled speculation that millions of consumers are at risk.

Recent findings demonstrate that the pathogenic PrPsc of vCJD can be found in the lymph system (e. g. tonsils, lymph nodes) in humans suggesting a high risk of horizontal spread via lymph and/or blood transmission, dramatically increasing the number of people at risk.

The medical need in prion diseases today can be clearly defined as the establishment of a diagnostic system, that can detect the disease as early as possible in living humans and/or animals, to estimate the medical need for the treatment in the future and to identify the infected animals to remove them from the food chain. The medical need for prion diseases in the future (approximately starting in 5-10 years) will be medical treatment that inhibits the disease symptoms, the manifestation and/or progression of the disease.

It is object of the present invention to provide novel and also known compounds which can be used as pharmaceutically active agents, especially for prophylaxis and/or treatment of neurodiseases, especially prion diseases and prion infections, methods wherein said compounds are used in order to treat said neurodiseases and

compositions containing at least one inventive compound and/or pharmaceutically acceptable salt thereof as a pharmaceutically active ingredient.

The object of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, and the examples of the present application.

One aspect of the present invention relates to compounds of the general formula (I) : wherein: Xi represents-CHGhy, -C (CH3) Ghy, or-C (CH3) =N-NH-Y ; X2 represents-H,-OCH3,-CHGhy,-C (CH3) Ghy, or-C (CH3) =N-NH-Y; Ghy represents a guanidino group: =N-NH-C (NH) NH2; Z is -A-(CH2)n-CH=CH-(CH2)p-A'-B, -A-(CH2)n-C6H4-(CH2)p-A'-B, - A- (CH2) n-C5H3N- (CH2) p-A'-B,- (CH2) nB,-A- (CH2) n-CR'R"- (CH2) p-A'-B,<BR> - A- (CH2) n-CH=CH- (CH2) p-B,-A- (CH2) n-A'-,-A- (CH2) n-C6H4- (CH2) p-B,<BR> -A-(CH2)n-C5H3N-(CH2)pB@ -A-(CH2)n-CR'CR"-(CH2)p-B, or -A- (CH2)n-B; R', R"are independently of each other-OH,-SH,-NH2, methyl, ethyl or propyl ; A and A'are independently of each other-NH (CO)-,-NH-,- (CO) NH-, - NH (CO) NH- or-0- ; B represents-NH (CO) NH2,-NH-C (=NH)-NH2,-CN,-OH,-NH2, - CONH2,-COOH,-COOCH3,-COOC2H5, Y represents X'is independently of X1-CHGhy,-C (CH3) Ghy, or-C (CH3) =N-NH-Y; X'2 is independently of X2-H,-OCH3,-CHGhy,-C (CH3) Ghy, or - C (CH3) =N-NH-Y ; n and p are independently of each other an integer of 0 to 10; under the proviso that A * A' ; and pharmaceutical acceptable salts thereof.

Another aspect of the present invention relates to the use of compounds of the general formula (I) : wherein: Xi represents-CHGhy, -C (CH3) Ghy, or-C (CH3) =N-NH-Y; X2 represents-H,-OCH3,-CHGhy,-C (CH3) Ghy, or-C (CH3) =N-NH-Y; Ghy represents a guanidino group: =N-NH-C (NH) NH2;

Z is-A- (CH2) n-CH=CH- (CH2) p-A'-B,-A- (CH2) n-C6H4- (CH2) p-A'-B, -A-(CH2)n-C5H3N-(CH2)p-A'-B, -(CH2)nB, -A-(CH2)n-CR'R"-(CH2)p-A'-B, -A-(CH2)n-CH=CH-(CH2)p-B, -A-(CH2)n-A'-, -A-(CH2)n-C6H4-(CH2)p-B, A- (CH2) n-CsH3N- (CH2) p-B,-A- (CH2) n-CR'R"- (CH2) p-B, or-A- (CH2) n-B ; R', R"are independently of each other-OH,-SH,-NH2, methyl, ethyl or propyl ; A and A'are independently of each other -NH(CO)-, -NH-, -(CO)NH-, -NH(CO)NH- or -O-; B represents-NH (CO) NH2,-NH-C (=NH>NH2,-CN,-OH,-NH2, -CON H2s-COOH,-COOCH3,-COOC2Hs

Y represents

X'iisindependenttyofXi-CHGhy.-C (CH3) Ghy, or-C (CH3) =N-NH-Y; X'2 is independently of X2-H,-OCH3,-CHGhy,-C (CH3) Ghy, or -C (CH3) =N-NH-Y; n and p are independently of each other an integer of 0 to 10; under the proviso that A # A@; and pharmaceutically acceptable salts thereof as pharmaceutical active agents.

The inventive compounds are preferably used for prophylaxis andlor treatment of infectious diseases, or in a more general sense, for prophylaxis and/or treatment of neurodegenerative diseases.

A further aspect of the present invention is directed to the use of the aromatic guanylhydrazone compounds of the general formula (1) : wherein: Xi represents-CHGhy, -C (CH3) Ghy, or-C (CH3) =N-NH-Y; X2 represents-H,-OCH3,-CHGhy, -C(CH3)Ghy, or-C(CH3)=N-NH-Y; Ghy represents a guanidino group: =N-NH-C (NH) NH2; Z is-H, -NH (CO) NHB,-CóH4B,-NHC (NH) NHC (NH) NH2,-C5NH3B, - C (CH3) Ghy,-CHGhy,-NH (CO)-Ph,-CO-NHPh,-CH=CH-COOH, -A-(CH2)n-CH=CH-(CH2)p-A@-B, -A-(CH2)n-C6H4-(CH2)p-A'-B, AQCH2) n-CsH3N (CH2) p-A'-B,-A- (CH2) n-CR'R"- (CH2) p-A'-B, -NH(CO)B, -NHB, -(CO)NHB, -COB, -SB, -OB, -CO-OB, -O-COB, -NH(CO)OB, -O (CO)NHB, -A-(CH2)n-CH=CH-(CH2)p-B, -A-(CH2)n-C6H4-(CH2)p-B, -A-(CH2)n-C5H3N-(CH2)p-B, -(CH2)nB, - A- (CH2) n-CR'R"- (CH2) p-B,-A- (CH2) n-B,-A- (CH2) n-A'-B,-NH2,

R', R"are independently of each other-OH, SH,-NH2, methyl, ethyi or propyl ; A and are independently of each other -NH(CO)-, -NH-, -(CO)NH-, -NH(CO)NH- or -O-; B represents-NH (CO) NH2,-NH-C (=NH)-NH2,-CN,-OH,-NH2, -CONH2,-COOH,-COOCH3,-COOC2H5, Y represents

X't is independently of X1-CHGhy,-C (CH3) Ghy, or-C (CH3) =N-NH-Y; X'2 is independently of X2-H,-OCH3,-CHGhy,-C (CH3) Ghy, or -C (CH3) =N-NH-Y; n and p are independently of each other an integer of 0 to 10; and pharmaceutical acceptable salts thereof as pharmaceutically active agents for the preparation of a pharmaceutical composition for prophylaxis and/or treatment of

neurological diseases, prion diseases and/or mental diseases.

Guanylhydrazone derivatives are known from US-A-5 599 984, US-A-5 750 573 and US-A-5 849 794 as active agents for the treatment of inflammatory diseases. EP 97948263.5 discloses the use of guanylhydrazone compounds for treating diseases associated with T-cell activation.

As used herein, the term"neurodiseases"comprises neurological and mental diseases selected from the group comprising addiction, alzheimer's disease, anxiety disorders, autism, blindness, cerebral palsy, chronic fatigue syndrome, Chorea Huntington, coping problems, down syndrome ; mild depression, mental retardation, personality disorders, dyslexia, eating disorders, epilepsy, infectious diseases, prion diseases, prion infections, multiple sclerosis, muscular dystrophy, neurology, neurotoxicities, pain, parkinson's disease, schizophrenia, sleep disorders, stress, stroke, tourette syndrome, tumors, progressive supranuclear palsy (PSP), Parkinsonism dementia complex of Guam (PDC), Pick's disease (PiD), Pallid- ponto-nigral degeneration (PPND), Amyotrophic Iteral sclerosis (ALS).

Thus, one embodiment of the present invention disclosed herein is directed to a method for preventing and/or treating neurodiseases in an individual which method comprises administering to the individual an amount of at least one compound according to any one of claims 2 to 9 and/or pharmaceutical acceptable salts thereof effective to treat said neurodisease. Most preferred is the administration of compounds Nos. 1 to 21.

The name"prion"is used to describe the causative agents which underlie the transmissible spongiform encephalopathies. A prion is proposed to be a novel infectious particle that differs from viruses and viroids. It is composed solely of one unique protein that resists most inactivation procedures such as heat, radiation, and proteases. The latter characteristic has led to the term protease- resistant isoform of the prion protein. The protease-resistant isoform has been proposed to slowly catalyze the conversion of the normal prion protein into the abnormal form.

The term"isoform"in the context of prions means two proteins with exactly the same amino acid sequence that are folded into molecules with dramatically different tertiary structures. The normal cellular isoform of the prion protein (PrP) has a high a-helix content, a low p-sheet content, and is sensitive to protease digestion. The abnormal, disease-causing isoform (PrPS) has a lower

a-helix content, a much higher p-sheet content, and is much more resistant to protease digestion.

Preferred is the use of a compound of formula (I) wherein the guanylhydrazone substituents characterized as, Xi and X2, or within the residue B as X'1 and X'2, are in meta or para position. In the case that X2 (X'2) is not hydrogen the meta position of Xi and X2 (X'1 and X'2) to Z is most preferred, because of steric reasons.

Furthermore, the use of compounds of the general formula (l) is preferred wherein Z represents-A- (CH2) n-A'-B or-A- (CH2) n-B and n is an integer of 1 to 10 or these compounds wherein Z represents-A- (CH2) n-CH=CH- (CH2) p-A'-B, -A-(CH2)n-CH=CH-(CH2)p-B, -A-(CH2)n-C6H4-(CH2)p-A'-B, <BR> <BR> - A- (CH2) n-CeH4- (CH2) p-B,-A- (CH2) n-CR'R"- (CH2) p-A'-B,<BR> - A- (CH2) n-CR'R"- (CH2) p-B,-A- (CH2) n-C5H3N- (CH2) p-A'-B, or-A- (CH2) n-C5H3N- (CH2) p-B and n and p are independently of each other integer of 1 to 5. A, A', and B represent the residues as mentioned above.

More preferred is the use of the inventive guanylhydrazone compounds wherein Z is -NH (CO)- (CH2),- (CO) NHB and n is an integer of 3 to 10 and these compounds wherein Z stands for-NH (CO}- (CH2) n-C6H4tCH2) ptCO) NHBs - NH (COHCH2) n-CH=CH- (CH2) p- (CO) NHB, -NH (COHCH2) n-CR'R"« CH2) ptCO) NHB, or -NH (CoHCH2) n-CD5H3NdCH2) ptCO) NHB and n and p are independently of each other integer of 1 to 5. B represents another benzene substituted with one or two guanylhydrazone residues as shown above.

Also preferred are compounds wherein Y represents More preferred are compounds wherein Y represents Most preferred are compounds wherein Y represents

Most preferred is the use of the inventive compounds selected from the group comprising: Compound 1: N- (4-acetylphenyl)-N'- (3, 5-diacetylphenyl) urea tris (amidinohydrazone), Compound 2: N, N'-bis (3-acetylphenyl) pentane diamide bis (amidinohydrazone), Compound 3: N, N'-bis (3, 5-diacetylphenyl) pentane diamide tetrakis (amidinohydrazone), Compound 4: N, N'-bis (3, 5-diacetylphenyl) decane diamide tetrakis (amidinohydrazone), Compound 5: N, N'-bis (3, 5-diacetylphenyl) butane diamide tetrakis (amidinohydrazone), Compound 6: N, N'-bis (3, 5-diacetylphenyl) hexane diamide tetrakis (amidinohydrazone), Compound 7: N, N'-bis (3, 5-diacetylphenyl) heptane diamide tetrakis (amidinohydrazone),

Compound 8: N, N'-bis (3, 5-diacetylphenyl) isophthalic acid diamide tetrakis (amidinohydrazone), Compound 9: 4, 4'-diacetyl-N, N'-diphenyl urea bis (amidinohydrazone), Compound 10: 4-acetyl-N- [3- (3- acetylphenylcarbamoyl) propyl] benzamide bis- (guanylhydrazone), Compound 11 : N, N'-bis-(3, 5-diacetylphenyl) sebacamide tetrakis-[(2- pyrimidyl) hydrazone], Compound 12 : N, N'-bis- (3, 5-diacetylphenyl) sebacamide tetrakis- [ (4, 5- dihydroimidazol-2-yl) hydrazone], Compound 13: 9- (3, 5-diacetylphenylcarbamoyl) nonanoic acid bis- (guanylhydrazone), Compound 14: N- (3, 5-diacetylphenyl) sebacamide bis- (guanylhydrazone), Compound 15: 3-acetyl-N- [8- (3, 5-diacetylphenylcarbamoyl)- octyl] benzamide tris- (guanylhydrazone), Compound 16: 4-acetyl-N [8- (3, 5-diacetylphenylcarbamoyl) octyl]- benzamide tris-(guanylhydrazone), Compound 17 : N- (3, 5-diacetylphenyl)-9-cyanononanamide bis- (guanylhydrazone), Compound 18: N, N'-bis (3, 5-diacetylphenyl) urea tetrakis (amidinohydrazone), Compound 19: N, N'-bis (3, 5-diacetylphenyl) pyridine-2, 6-dicarboxylic acid diamide tetrakis (amidinohydrazone), Compound 20: N, N'-bis (3, 5-diacetylphenyl) pyridine-3, 5-dicarboxylic acid diamide tetrakis (amidinohydrazone), Compound 21: 3, 3'-diacetyl-N, N'-diphenyl urea bis (amidinohydrazone), and pharmaceutically acceptable salts of one of these compounds.

An integral part of signa) transduction is the interaction of ligands their receptors and intracellular signal transduction molecules. Ligands are messengers that bind to specific receptors on the surface of target cells. As a result of the binding, the receptors trigger the activation of a cascade of downstream signaling molecules, thereby transmitting the message from the exterior of the cell to its nucleus. When the message reaches the nucleus, it initiates the modulation of specific genes, resulting in the production of RNA and finally proteins that carry out a specific biological function. Disturbed activity of signal transduction molecules may lead to the malfunctioning of cells and disease processes.

Specifically, interference of the pathogenic PrPSt from prion diseases with neuronal cells is necessary for the prion protein to induce its neuropathological features such as neuronal vacuolization, neuronal death and gliosis with hyperastrocytosis.

The novel and known aromatic guanylhydrazone compounds of the general formula (I) represent a new class of pharmaceuticals highly useful for the prophylaxis and treatment of prion infections and prion diseases.

Thus, a further aspect of the present invention describes the use of a compound of the general formula (I) and/or pharmaceutical acceptable salts thereof for the manufacture of a pharmaceutical formulation for prophylaxis and/or treatment of prion infections and/or diseases induced or caused by prion infection.

As used herein the term"prion diseases"refers to transmissible spongiform encephalopathies. This group of neurologic diseases affects humans and many species of animals causing a"sponge-like"degeneration of brain tissue. Among other unique features, all of these diseases are associated with the accumulation of an abnormal form of the prion protein in nerve cells that eventually leads to the death of the host. While prion diseases can all be transmitted from one host to another, it remains contentious as to whether a virus-like infectious agent or the abnormal prion protein itself, the prion, causes the conversion of normal to abnormal protein.

Probably most mammalian species develop prion diseases. Specific examples for animals include: * Scrapie sheep, goat TME (transmissible mink encephalopathy) : mink CWD (chronic wasting disease): muledeer, deer, elk BSE (bovine spongiform encephalopathy) : cows, cattles Humans are also susceptible to several prion diseases. Examples are: CJD Creutzfeld-Jacob Disease

. GSS Gerstmann-Straussler-Scheinker syndrome FFI Fatal familial Insomnia . Kuru Alpers Syndrome The human prion diseases include kuru, sporadic Creutzfeldt-Jakob disease (sCJD), familial CJD (fCJD), iatrogenic CJD (iCJD), Gerstmann-Straussler- Scheinker (GSS) disease, fatal familial insomnia (FFI), and, more recently, new variant CJD (nvCJD or vCJD). In addition to these human diseases, prion-related diseases, have been recognized in several animal hosts. Scrapie is a naturally occurring disease of sheep and goats that causes ataxia, behavioral changes, and a severe pruritus that leads to scraping behavior, from which the disease was named. Additional prion diseases in animals include transmissible mink encephalopathy (TME), chronic wasting disease (CWD) of deer and elk, feline spongiform encephalopathy (FSE), and bovine spongiform encephalopathy (BSE), among others.

The transmissible nature of prion disease was first demonstrated experimentally in 1936 when Cuillé and Chelle transmitted scrapie to a healthy goat by the intraocular administration of scrapie-infected spinal cord. Thirty years later, sCJD was transmitted to chimpanzees. The pathologic feature common to all these diseases is a prominent vacuolation of the gray matter of the brain that produces a "sponge-like"appearance on light microscopy. This histopathologic appearance, coupled with the transmissible nature of these diseases, led to their collective designation as"transmissible spongiform encephalopathies"or TSEs.

The etiologic agent of the TSEs was proposed to be a"slow virus"to explain its transmissible nature and the prolonged incubation period observed during experimental transmission studies. Early experiments suggested that protein may be a critical component of the infectious agent. These studies established the basis for a new form of a transmissible pathogen, one that is composed ostensibly of only protein and lacks any replicative elements such as nucleic acid.

The term"prion"was coined to indicate an infectious agent with proteinlike properties. The unusual properties of the pathogen were demonstrated in early experiments in which conditions that degrade nucleic acids, such as exposure to

ionizing and ultraviolet radiation, did not reduce the infectivity of scrapie fractions.

On the other hand, treatments that degrade protein, such as prolonged exposure to proteases, correlated with a reduction in infectivity. A protein with relative resistance to protease digestion was found to be consistently present in the brains of animals and humans with TSE. Surprisingly, this protein was found to be one that is normally encoded by a chromosomal gene of the host.

Thus, the question raised, how a normally expressed protein could also be a transmissible pathogen ? It was hypothesized and later demonstrated that PrP exists in two major isoforms: the nonpathogenic or cellular form, designated PrP, and the pathogenic or scrapie-inducing form, designated PrPsc. Both prPc and prpSC have the same amino acid sequence, yet they differ in their biochemical properties: PrPC is soluble in nondenaturing detergents and completely degraded by proteases, whereas PrPsc is insoluble in nondenaturing detergents and shows a relative resistance to proteases. Structural studies of PrPC and PrPSC indicate a difference in the conformation of the two isoforms: PrPc is predominantly helical, whereas PrPsc contains at least 40% pleated sheet structure. Conversion to this sheet structure appears to be the fundamental event in prion disease. The ultimate mechanism of how cells die coincident with the generation of prions is still unclear. Simple accumulation of pathogenic protein may not be sufficient to explain disease, however, it may constitute a critical step in cellular dysfunction.

It was shown that the aromatic guanylhydrazone compounds of the general formula (I) are highly effective for the prophylaxis and/or treatment of prion infections and/or prion diseases selected from the group comprising Scrapie, TME, CWD, BSE, CJD, vCJD, GSS, FFI, Kuru, and Alpers Syndrome. Preferably, the aromatic guanylhydrazone derivatives are used for preventing and/or treating BSE, vCJD, or CJD.

The aromatic guanylhydrazone compounds of the general formula (I) and/or pharmaceutical acceptable salts thereof are administered in a dosage corresponding to an effective concentration in the range of 0. 01-100 uM, preferably in the range of 0.01-50 uM, more preferably in the range of 0.5-10 , uM, still more preferably in the range of, and most preferably in the range of 0. 5- 5, uM.

A question is how PrPC does convert to PrP" ? Potential mechanisms that initiate conversion of PrPC to PrPsc include a germ line mutation of the human prion

protein gene (PRNP), a somatic mutation within a particular neuron, and spontaneous conversion of PrPC to an aberrant conformation that is not refolded appropriately to its native structure. The prion protein gene (PRNP) is the single gene on the short arm of chromosome 20 in humans which encodes the normal cellular isoform of the prion protein. Regardless of the initiating event, once an "infectious unit"has been generated, PrPsc appears to act as a conformational template by which PrPC is converted to a new molecule of PrPsc through protein- protein interaction of PrPsc and PrP. This concept is supported by several studies which show that mice with the normal PrP gene deleted (PrP knockout mice) do not develop prion disease after inoculation with scrapie. Furthermore, transgenic (Tg) mice that express a chimeric PrP gene made of human and mouse segments develop protease-resistant chimeric mouse-human prpSC in their brains when inoculated with brain extracts from humans with prion disease.

These findings clearly illustrate that prions do not self-replicate but instead convert nonpathogenic PrPC to pathogenic PrPSc.

In its sporadic or nonfamilial form, CJD is the most common of the human prion diseases. Confusion and forgetfulness which progress rapidly to severe cortical dementia in combination with ataxia, myoclonus, and an abnormal electroencephalogram (EEG) represents the"classic tetrad"of CJD. However, a host of other neurologic signs and symptoms, including diffuse or focal weakness, painful neuropathy, chore-iform movements, hallucinations, cortical blindness, primary language disturbance, supranuclear ophthalmoplegia, and alien hand syndrome, among others, have been observed. As the disease progresses from the early stage, ataxia commonly limits the patient's mobility.

Familial CJD (fCJD) includes those cases with a dominantly inherited mutation of the PRNP gene, in which the pathologic features of spongiform change occur in the absence of GSS-type plaques. Although, familial cases of CJD tend to have a clinical and pathologic phenotype similar to that of sCJD.

The original description of a patients with the onset of ataxia and dysarthria followed by variable degrees of pyramidal and extrapyramidal symptoms and late developing dementia defines the classic presentation of GSS. The duration of said disease ranges from 2 to 10 years. Death usually results from secondary infection, often from aspiration pneumonia because of impaired swallowing. The presence of plaque deposits regionally or diffusely throughout the cortex that are

immunoreactive to anti-human PrP antibodies is the hallmark of this form of prion disease.

FFI is a genetic disorder which manifests itself by many symptoms due to the degeneration of a certain part of the brain, the thalamus. The affected area of the brain is the area responsible for sleep, the thalamus. The thalamus is the center which communications from the brain to the body and the body to the brain pass through for proper directions to where a signal should be received. When sleep takes place, it is thought that the thalamus becomes less efficient at this signal transfer function allowing for the vegetative state of sleep to come over an individual. Consequently, the symptoms of fatal familial insomnia are directly related to the malfunction of the responsibilities of the thalamus, namely sleep.

There are four stages of the disease before an individual's life ends. The first stage is progressive insomnia, the trade mark of fatal familial insomnia. By now, there is no cure for this illness.

The term"familial"means : affecting several members of the same family, usually as a result of an underlying genetic mutation.

The occurrence of vCJD is sobering because it appears to represent a situation in which the prion has"jumped"species, in this case from cow to human. Because the pathologic features and clinical presentation of vCJD differ significantly from those of sCJD, it is considered a new"strain"of human prion disease. The same "protein signature"was observed following experimental transmission of BSE to several animal hosts, supporting the idea that vCJD results from the infection of humans with BSE. vCJD occurs primarily in younger individuals (average age 27) with a somewhat protracted course of approximately 16 months. The brain shows diffuse vacuolation and the presence of distinctive dense core PrP- containing plaques surrounded by a halo of spongiform change.

Kuru is the condition which first brought prion diseases to prominence in the 1950s. Found in geographical isolated tribes in New Guinea. Established that ingesting brain tissue of dead relatives for religious reasons was likely to be the route of transmission.

Alpers Syndrome is the name given to prion diseases in infants.

Scrapie is the accepted, albeit somewhat colloquial, name for the naturally occurring transmissible spongiform encephalopathy of sheep and goats found worldwide. Scrapie also infects laboratory mice and hamsters making it one of the most important sources of new scientific information about this group of disorders. Scrapie was the first example of this type of disease to be noticed and has been known about for many hundreds of years. There are two possible methods of transmission in sheep: a) Infection of pasture with placenta tissue carrying the agent followed by ingestion, or b) direct sheep-lamb transmission.

CWD is a fatal neurodegenerative disease of deer and elk, now known to be a transmissible spongiform encephalopathy. To date, affected animals have been found exclusively in the United States.

BSE Bovine spongiform encephalopathy or"mad cow disease"appears to have originated from scrapie that has been recognized in Europe since the mid-18th century. It has since spread to most sheep-breeding countries and is widespread in the United Kingdom, where until 1988 the rendered carcasses of livestock (including sheep) were fed to ruminants and other animals as a protein-rich nutritional supplement.

During rendering, carcasses from which all consumable parts had been removed were milled and then decomposed in large vats by boiling at atmospheric or higher pressures, producing an aqueous slurry of protein under a layer of fat (tallow).

After the fat was removed, the slurry was desiccated into a meat and bone meal product that was packaged by the animal food industry and distributed to owners of livestock and other captive animals (e. g. , zoo and laboratory animals, breeding species, pets).

The present invention provides also a method for preventing and/or treating prion infections and/or diseases induced by prion infections in an individual which comprises administering to the individual an amount of at least one compound of the general formula (I) and/or pharmaceutically acceptable salts thereof effective to treat said prion infection and/or prion disease.

The term"individual"preferably refers to mammals, especially humans or ruminants. Ruminants are, for instance, muledeer, elk, cow, cattle, sheep, goat,

deer, or buffalo. Minks are an example for mammals which do not belong to the specie of ruminants.

As used herein the term"ruminants"refers to an animal, for instance, cattle, sheep, goat, deer, elk, or buffalo that has four separate stomach chambers, and is therefore able to digest a wide range of organic and plant foods. The term "ruminants"refers also to exotic ruminants, like captive nyala, gemsbok, Arabian oryx, eland, kudu, scimitar-horned oryx, ankole, or bison which are also accessible to develop Spongiform encephalopathy.

As described above, said prion infection and/or prion disease is selected from the group comprising Scrapie, TME, CWD, BSE, vCJD, CJD, GSS, FFI, Kuru, and Alpers Syndrome. Preferably, the method is used for prophylaxis and/or treatment of BSE, vCJD, or CJD.

Thereby, the aromatic guanylhydrazone compounds of the present invention and/or pharmaceutically acceptable salts thereof are administered in a dosage corresponding to an effective concentration in the range of 0. 01-50 uM, preferably in the range of 0. 01-10 uM, more preferably in the range of 0. 01-1 uM, and most preferably in the range of 0.01-0. 1 uM.

Still a further aspect of the present invention is directed to pharmaceutical compositions comprising at least one aromatic guanylhydrazone compound of the general formula (i) as an active ingredient together with a pharmaceutically acceptable carrier, excipient or diluents.

The aromatic guanylhydrazone compounds of the present invention are basic and form pharmaceutical acceptable salts with organic and inorganic acids.

Examples of suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphorsulfonic acid, china acid, mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic

acid, d-o-tolyltartaric acid, tartronic acid, a-toluic acid, (o, m, p)-toluic acid, naphthylamine sulfonic acid, and other mineral or carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner.

It is also possible to obtain acid addition salts with amino acids like methionine, tryptophane, lysine or arginine, especially with aromatic guanylhydrazone compounds of the general formula (I) wearing a carboxylic acid residue.

Depending upon the substituents on the inventive aromatic guanylhydrazone compounds, one may be able to form salts with bases too. Thus, for example, if there are carboxylic acid substituents in the molecule, salts may be formed with inorganic as well as organic bases such as, for example, NaOH, KOH, NH40H, tetraalkylammonium hydroxide, and the like.

The compounds of the general formula (I) can also be administered in form of their pharmaceutical active salts optionally using substantially nontoxic pharmaceutically acceptable carriers, excipients or diluents. The medications of the present invention are prepared in a conventional solid or liquid carrier or diluents and a conventional pharmaceutically-made adjuvant at suitable dosage level in a known way. The preferred preparations are in administratable form which is suitable for oral application. These administratable forms, for example, include pills, tablets,, film tablets, coated tablets, capsules, powders and deposits.

Furthermore, the subject of the present invention also includes pharmaceutical preparations for parenteral, including dermal, intradermal, intragastrical, intracutaneous, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutaneous, rectal, subcutaneous, sublingual, topical or transdermal application, which in addition to typical vehicles and diluents contain a aromatic guanylhydrazone compound of the general formula (I) and/or a pharmaceutically acceptable salt thereof as active ingredient.

Within the disclosed methods the pharmaceutical compositions of the present invention, containing aromatic guanylhydrazone derivatives of the general formula (I) as active ingredients, will typically be administered in admixture with suitable carrier materials selected with respect to the intended form of administration, i. e. oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders

for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral nontoxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like. Moreover, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture.

Powders and tablets may be comprised of from about 5 to about 95 percent inventive composition.

Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among the lubricants, there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include starch, methylcellulose, guar gum and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate. Some of the terms noted above, namely disintegrants, diluents, lubricants, binders and the like, are discussed in more detail below.

Additionally, the compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects, i. e. antihistaminic activity and the like. Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.

Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injections or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutical acceptable carrier such as inert compressed gas, e. g. nitrogen.

For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides such as cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein by stirring or similar mixing. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidifies.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The inventive aromatic guanylhydrazone compounds of the present invention may also be deliverable transdermally. The transdermal compositions may take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

The term capsule refers to a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredients. Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins. The capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.

Tablet means compressed or molded solid dosage form containing the active ingredients with suitable diluents. The tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction well known to a person skilled in the art.

Oral gels refers to the active ingredients dispersed or solubilized in a hydrophillic semi-solid matrix.

Powders for constitution refers to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juices.

Suitable diluents are substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol, starches derived from wheat, corn rice and potato, and celluloses such as microcrystalline cellulose. The amount of diluents in the composition can range from about 5 to about 95% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight.

The term disintegrants refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments. Suitable disintegrants include starches,"cold water soluble"modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses and cross-linked microcrystalline celluloses such as sodium croscarmellose, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures. The amount of disintegrant in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 5 to about 10% by weight.

Binders characterize substances that bind or"glue"powders together and make them cohesive by forming granules, thus serving as the"adhesive"in the formulation. Binders add cohesive strength already available in the diluents or bulking agent. Suitable binders include sugars such as sucrose, starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate ; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose ; polyvinylpyrrolidone ; and inorganics such as magnesium aluminum silicate. The amount of binder in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight.

Lubricant refers to a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride,

sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D, L- leucine. Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press. The amount of lubricant in the composition can range from about 0.2 to about 5% by weight of the composition, preferably from about 0.5 to about 2%, more preferably from about 0.3 to about 1.5% by weight.

Glidents are materials that prevent caking and improve the flow characteristics of granulations, so that flow is smooth and uniform. Suitable glidents include silicon dioxide and talc. The amount of glident in the composition can range from about 0. 1% to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight.

Coloring agents are excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount of the coloring agent can vary from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1%.

Description of figures Fig. 1 shows selected guanylhydrazone derivatives which are suitable pharmaceutically active compounds for prophylaxis and/or treatment of neurodiseases; Fig. 2 shows a selected guanylhydrazone derivative which is a suitable pharmaceutically active compound for prophylaxis and/or treatment of neurodiseases, especially of prion infections and prion diseases. it is readily apparent to those skilled in the art that other suitable modifications and adaptations of the compositions and methods of the invention described herein are evident and may be made without departing from the scope of the invention or the embodiments disclosed herein. Having now described the present invention in detail, the same will be more clearly understood by reference to the following examples, which are included for purposes of illustration only and are not intended to be limiting of the invention.

Examples Example 1 Materials and methods Cell culture and expression of 3F4-taaged PrP (3F4-ScN2a) The mouse neuroblastoma cell line 3F4-ScN2a represents a stably transfected clone of ScN2a cells (PrPsc infected N2a cells) which overexpress 3F4-epitope- tagged murine PrP. Residues 109 and 112 of murine PrP were replaced by methionine to introduce the epitope for reactivity with the monoclonal anti-PrP antibody 3F4. Cells were maintained in Dulbecco's modified Eagle's (DMEM) or Opti-MEM medium containing 10 % fetal calf serum, antibiotics and glutamin. For generation of stable transfectants we used the vector pcDNA3.1/Zeo (Invitrogen ; Leek, The Netherlands). Lipofection of cells with recombinant plasmids was done using standard procedures and recombinant clones were selected by addition of 300 lug Zeocin/ml medium.

Treatment of cells with inhibitors Al tested compounds were solubilized in DMSO (dimethylsulfoxide), and prepared as 10 mM stock solutions. The drugs were applied to the cells described above for three days in final concentrations between 2 and 20 uM.

Immunoblot and proteinase K (PK) analysis Confluent cell cultures were lysed in cold lysis buffer (10 mM Tris-HCI, pH 7.5 ; 100 mM NaCI ; 10 mM EDTA; 0.5 % Triton X-100; 0.5 % DOC) (EDTA: ethylene diamine tetraacetate; Triton X-100: t-octylphenoxypolyethoxyethanol ; DOC: deoxycholic acid). Postnuclear lysates were split between those with and without proteinase K digestion. Samples without proteinase K digestion were supplemented with proteinase inhibitors (5 mM PMSF, 0.5 mM Pefabloc, and aprotinin) (PMSF: phenylmethylsulfonyl fluoride) and directly precipitated with ethanol. Samples for proteinase K digestion were incubated with 20 pg/ml proteinase K for 30 min at 37°C ; digestion was stopped with proteinase inhibitors, and samples were ethanol precipitated. After centrifuging for 30 min at 3,500 rpm the pellets were redissolved in TNE buffer (10 mM Tris-HCI pH7.5, 100 mM NaCI, 1 mM EDTA) and gel loading buffer was then added. After boiling for 5 min an aliquot was analyzed on 12.5 % PAGE. For Western blot analysis, the proteins were electrotransferred to PVDF membranes (polyvinylidendifluorid). The membrane was blocked with 5 % non-fat dry milk in TBST (0. 05 % Tween 20,100

mM NaCI, 10 mM Tris-HCI, pH 7.8) (Tween 20: polyoxyethylenesorbitan monolaurate ; Tris-HCI : Tris-(hydroxymethylfaminomethane-hydrochloride), incubated overnight with the primary antibody at 4°C and stained using the enhanced chemiluminescence blotting kit from Amersham Corporation. Specific immuno-staining of the PrP° and PrPSc forms were obtained with the prion protein specific antibody 3F4 (Signet Pathologies, U. S. A.).

Results Determination of the amount of the pathogenic form of the prion protein PrPSc upon treatment of prion infected cells with different types of small molecule protein kinase inhibitors resulted in the identification of a compound class of guanylhydrazones comprising the compounds Nos. 1,4, 5,9, 12,15, 17,19, and 20.

These compounds significantly reduced the amount of PrPsc in prion infected cells in a concentration range between 2 and 20 uM (final concentration). The compounds 1,4, 5,19, and 20 inhibit almost completely the activity of prion propagation within said concentration range without being toxic to the used cell cultures.

The following table 1 shows the inhibition of the activity of prion propagation: Table 1: Inhibition of prion propagation Compound No. Inhibition of propagation 1 90% 4 100% 5-90% 12 80% 19 100% Therefore these molecules described here serve as potential inhibitors for the medical intervention and treatment of neurological and/or mental diseases, such as alzheimer's disease, anxiety disorders, autism, Chorea Huntington, mild depression, stroke, stress, epilepsy, parkinson's disease, schizophrenia, and infectious diseases such as prion infections. Said prion infections and prion diseases may comprise diseases such as Transmissible spongiform encephalitis (TSE) infections which include Bovine spongiform encephalitis (BSE) or the new variant of Creutzfeld Jakob disease (vCJK).

Example 2: Synthesis of compound 10

N-Ethyldiisopropylamine (7.10 g, 55 mmol) was added dropwise at 0°C to a stirred mixture of 3-aminoacetophenone (3.4 g, 25 mmol), 4- (feAt- butoxycarbonylamino) butyric acid (5.0 g, 24.6 mmol), 1-hydroxybenzotriazole hydrate (3.72 g, 24.3 mmol), 1- [3- (dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (5.27 g, 27.5 mmol) and dichloromethane (75 ml), the mixture was stirred at ambient temperature for 18 hours, then it was washed with water (3 x 100 ml) and saturated aqueous sodium chloride solution (100 ml) and dried (MgS04). The solvent was removed in vacuo to give a pale brown oil which solidified slowly at ambient temperature. The solid was triturated with hexane (100 ml) and the resulting solid was collected by filtration and dried in vacuo. This solid was purified by column chromatography over silica using dichloromethane, followed by a 3: 1 mixture of hexane and ethyl acetate, followed by a 1: 3 mixture of hexane and ethyl acetate as tuants. Appropriate fractions were combined, and the solvents were removed in vacuo to give N- (3-acetylphenyl)-4- (tert- butoxycarbonylamino) butyramide (2.91 g) as an off-white solid, m. pt. 119-121 °C.

N- (3-Acetylphenyl)-4- (tert-butoxycarbonylamino) butyramide (2.39 g, 7.5 mmol) was added in portions at ambient temperature under nitrogen to a stirred solution of trifluoroacetic acid (25 ml) in dichloromethane (25 ml), the mixture was stirred at

ambient temperature for 1 hour, then the solvents were removed in vacuo to leave the amine as an orange oil which was used without further purification. A mixture of the orange oil, N-ethyidiisopropylamine (4.78 g, 37 mmol) and dichloromethane (30 mi) was stirred at 0 °C for 15 minutes. A mixture of 4-acetylbenzoic acid (1.21 g, 7.4 mmol), 1-hydroxybenzotriazole hydrate (2.0 g, 13 mmol), 1- [3- (dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (2.83 g, 14.8 mmol) and dichloromethane (30 mi) was stirred at 0 °C for 10 minutes, then it was added via cannula to the solution of the amine. The mixture was stirred at ambient temperature for 18 hours then it was poured into water (150 ml). The resulting solid was collected by filtration, washed with water (30 ml) and dried in vacuo.

The dichloromethane layer from the filtrate was separated, washed with water (30 ml) and dried (MgS04). The solvent was removed in vacuo and the residue was suspended in dichloromethane (50 ml). Hexane (50 ml) was added and the resulting solid was collected by filtration, dried in vacuo and combined with the first crop of solid to give sacetyl-N-[3-(3-acetylphenylcarbamoyl) propyl] benzamide (2.4 g) as an off-white solid, m. pt. 166.5-167. 5 °C ; 90 MHz H-nmr (dgDMSO) 5 (ppm): 1.9 (m, 2H) (-CH2CH2CH2-), 2.4 (m, 2H) (-CH2CO-), 2.55 (s, 3H) (CH3), 2.6 (s, 3H) (CH3), 3.4 (m, 2H) (-CH2NH-), 7.3-8. 2 (m, 8H) (8 x ArH), 8.7 (br t, 1 H) (-NHCH2- ), 10.1 (s, 1 H) (-NHCO-).

A stirred mixture of 4-acetyl-N- [3- (3-acetylphenylcarbamoyl) propyl] benzamide (0.25 g, 0.68 mmol), aminoguanidine hydrochloride (0.189 g, 1.71 mmol) and 90% aqueous ethanol (25 mi) was heated under reflux for 100 hours. Further aminoguanidine hydrochloride (0.076 g, 0.69 mmol) was added, and heating under reflux was continued for 24 hours. The mixture was allowed to cool to ambient temperature, the solvents were removed in vacuo, and the residue was crystallised from ethanol to give 4-acetyl-N- [3- (3- acetylphenylcarbamoyl) propy, ] benzamide bis-(guanylhydrazone) dihydrochloride 3.5 hydrate (0.289 g) as a white solid, m. pt. 205-210 °C (decomposes); 500 MHz 1H-nmr (d6DMSO) 6 (ppm): 1.88 (m, 2H) (-CH2CH2CH2-), 2.33 (s, 3M (CH3), 2.39 (s, 3H) (CH3), 2.42 (t, 2H) (-CH2NH-), 3.33-3. 36 (m, ~ 9-1 OH) (H20 obscuring -CH2CO-), 7.33 (t, 1) (ArM), 7.5-7. 8 (br, 8H) (4 x NH2-guanidine salts), 7.64 (d, J 8 Hz, 1 H) (ArH), 7.70 (d, J 7.95 Hz, 1 H) (ArH), 7. 92 (d, J 8.5 Hz, 2H) (2 x ArH), 8.01 (s, 1 H) (ArH), 8.05 (d, J 8. 45 Hz, 2H) (2 x ArH), 8.70 (br t, 1H) (-NHCH2-), 10.16 (s, 1 H) (-NHCO-), 11.31 (br s, 2H) (2 x guanidine NH) ; C23H30N1002. 2 HCI. 3.5 H20.

0.05 EtOH requires C: 44.98, H: 6.42, N: 22. 71%-Found C: 45. 39/45. 32, H: 6. 39/6. 42, N: 22. 55/22. 37%.

Example 3: Synthesis of compound 11 Me Me 0 NH2 CICO (CH2) ICOC' 0 N0Me0 p Me O Pyddine/CH2cl2 0Me Me 0 N I O H Me Me H H H Me H NS HN N NHNH2 I [ I/O Me/N N HO ETOH/HO/HCIN, N, _. , N Me0 HNN In H 6. 7 H20 Me

Sebacoyl chloride (1.2 g, 5 mmol) was added dropwise at ambient temperature under nitrogen to a stirred solution of 3, 5-diacetylaniline (1.77 g, 10 mmol) and pyridine (2.37 g, 30 mmol) in dichloromethane (25 ml), then the mixture was stirred at ambient temperature for 18 hours. The resulting solid was collected by filtration, washed with water (30 ml) and dried in vacuo to give N, N'bis-(3, 5- diacetylphenyl) sebacamide (2.33 g) as a white solid, m. pt. 196-198 °C ; 250 MHz 1H-nmr (d6DMSO) 8 (ppm): 1.3 (m, 8H) (4 x-CH2CH2CH2-), 1.65 (m, 4H) (2 x -COCH2CH2-), 2.32 (t, 4H) (2 x-COCH2-), 2.60 (s, 12H) (4 x CH3), 8.15 (s, 2H) (2 x ArH), 8.40 (s, 4H) (4 x ArH), 10.27 (s, 2H) (2 x-NHCO-).

A stirred mixture of NN-bis- (3, 5-diacetylphenyl) sebacamide (0.26 g, 0.5 mmol), 2- hydrazinopyrimidine (0.33 g, 3 mmol), concentrated hydrochloric acid (1 drop) and 90% aqueous ethanol (30 ml) was heated under reflux for 1 hour then allowed to cool to ambient temperature. The resulting solid was collected by filtration and dried in vacuo. An attempt was made to crystallise the solid from methanol (50 ml) but it was not fully soluble. Water (10 ml) was added, but the solid still did not fully dissolve. The mixture was cooled in ice-water and the resulting solid was collected by filtration and dried in vacuo at 35 °C to give N, N'bis-(3, 5- diacetylphenyl) sebacamide tefrakis- [ (2-pyrimidyl) hydrazone] pentahydrate (0.4 g) as an off-white solid. On standing, the solid absorbed further water to become the 6.7 hydrate, m. pt. 186-192 °C ; 300 MHz 1H-nmr (d6DMSO) 6 (ppm): 1.34 (m,

8H) (4 x-CH2CH2CH2-), 1.63 (m, 4H) (2 x-COCH2CH2-), 2.27-2. 35 (m, 16H) (4 x CH3 + 2 x-COCH2-), 6.87 (t, 4H) (4 x ArH), 7.80 (s, 2H) (2 x ArH), 8.04 (d, 4H) (4 x ArH), 8.49 (d, 8H) (8 x ArH), 10.03 (s, 6H) (2 x-NHCO-+ 4 x-NH-pyrimidine) ; C4eHs2Ni802. 6.7 H20 requires C: 54.72, H: 6.53, N : 24.97%-Found C: 54.95/55. 10, H: 6.44/6. 49, N: 24.63/24. 70%.

Example 4: Synthesis of compound 12 A stirred mixture of N, N'-bis- (3, 5-diacetylphenyl) sebacamide (0.52 g, 1 mmol ; prepared in a manner similar to that described above), 2-hydrazino-4, 5- dihydroimidazole hydrobromide (1.63 g, 9 mmol), 2M hydrochloric acid (0.5 ml) and 90% aqueous ethanol (70 ml) was heated under reflux for 1 hour then the resulting solid was collected by filtration from the hot mixture and dried in vacuo.

The product was crystallised from 50% aqueous ethanol and dried in vacuo at 35 oc to give N, N'-bis-(3, 5-diacetylphenyl) sebacamide tetrakis- [ (4, 5-dihydroimidazol- 2-yl) hydrazone] tetrahydrobromide 4.5 hydrate (0.73 g) as a white solid, m. pt. 255- 260 °C (decomposes); 300 MHz H-nmr (deDMSO) 8 (ppm): 1.32 (m, 8M (4 x- CH2CH2CH2-), 1.61 (m, 4H) (2 x-COCH2CH2-), 2.3-2. 42 (m, 16H) (4 x CH3 + 2 x- COCH2CH2-), 3.76 (br s, 16H) (8 x dihydroimidazole-CH2-), 7.99 (s, 2A/) (2 x ArH), 8.17 (s, 4H) (4 x ArH), 8.2-8. 8 (br, 8H) (4 x NH2+-dihydroimidazole salts), 10.14 (s, 2H) (-NHCO-), 11.43 (br s, 4H) (4 x-NH-N) ; C42H60N1802. 4 HBr. 4.5 H20. 0.03 EtOH requires C: 40.25, H: 5. 88, N: 20. 09%-Found C: 40.54, H: 5.98, N: 19.70%.

Example 5: Synthesis of compound 13 Me H i) Oxalyl chloride I DMF 0 N H02C (CH2) CCO2Et mezzo NHB O O ii) ,/Pyridine Me Mye H H H2NNNHZ. H2C03 H2N\/NN N NH y I NH 0 HBr/DMF N Me 0 I H2N y NH 2 HBr OEt OEt NH Me H H i) NAOH I ETOH H20 HN N, N N ii) HCI NH 9 4 N Me 0 1 H2NNH 2 HCI uOH OH NH

Oxalyl chloride (1.33 g, 10.5 mmol) was added dropwise at ambient temperature to a stirred solution of ethyl hydrogen sebacate (2.3 g, 10 mmol) and dimethylformamide (2 drops) in dichloromethane (25 ml), the mixture was stirred at ambient temperature for 1 hour, then it was cooled to 0 °C. 3, 5-Diacetylaniline (1.77 g, 10 mmol) followed by pyridine (1.98 g, 25 mmol) were added in portions at 2-12 °C, then the mixture was stirred at ambient temperature for 18 hours and poured into water (100 ml). The organic layer was separated, washed with 2M hydrochloric acid (10 mi) and dried (MgS04). The solvent was removed in vacuo to leave ethyl 9- (3, 5-diacetylphenylcarbamoyl) nonanoate (3.16 g) as a white solid, m. pt. 77.8-80. 4 °C ; 90 MHz H-nmr (deOMSO) 5 (ppm): 1.15 (t, 3fol) (-OCH2CH3), 1.2-1. 8 (m, 12H) (6 x-CH2CH2CH2-), 2.3 (t, 4H) (2 x-CH2CO-), 2.65 (s, 6H) (2 x- COCH3), 4.1 (q, 2H) (-OCH2CH3), 8. 1 (m, 1H) (ArH), 8. 4 (d, 2H) (2 x ArH), 10.25 (s, 1H)(-NHCO-).

A stirred mixture of ethyl 9- (3, 5-diacetylphenylcarbamoyl) nonanoate (0.78 g, 2 mmol), aminoguanidine bicarbonate (0.816 g, 6 mmol) and dimethylformamide (8 ml) was warmed to 60 °C and 48% hydrobromic acid (2.4 ml) was added dropwise. The mixture was stirred at 70 °C for 2 minutes, then it was cooled in ice and water (10 ml) was added. The mixture was allowed to stand at 4 °C for 18 hours then the resulting solid was collected by filtration, washed with water (5 ml) and dried in vacuo to give ethyl 9- (3, 5-diacetylphenylcarbamoyl) nonanoate bis- (guanylhydrazone) dihydrobromide (0.961 g) as a white solid, m. pt. 99.1-104. 3 °C ; 250 MHz 1H-nmr (d6DMSO) 8 (ppm): 1.17 (t, 3H) (-OCH2CH3), 1.2-1. 35 (m, 8H) (4 x -CH2CH2CH2-), 1.45-1. 67 (m, 4H) (2 x-CH2CH2CO-), 2.15-2. 4 (m, 1 OH) (2 x -CH2CO-+ 2 x-C (=N) CH3), 4.05 (q, 2H) (-OCH2CH3), 7.5-7. 8 (br, 8H) (4 x NH2- guanidine salts), 8.05 (s, 1 H) (ArH), 8.15 (s, 2H) (2 x ArH), 10.1 (s, 1 H) (-NHCO-), 10.7 (br, 2H) (2 x guanidine NH).

Ethyl 9- (3, 5-diacetylphenylcarbamoyl) nonanoate bis- (guanylhydrazone) dihydrobromide (0. 4 g, 0.6 mmol) was dissolved in the minimum volume of industrial methylated spirit, and a solution of sodium hydroxide (0.121 g, 3 mmol) in the minimum volume of water was added. The mixture was stirred at ambient temperature for 18 hours, then water (5 ml) and dichloromethane (5 ml) were added. The mixture was stirred for 10 minutes, then the aqueous phase was separated and acidified to pH 3 by the addition of 2M hydrochloric acid. The resulting solid was collected by filtration and dried in vacuo to give 9- (3, 5- diacetylphenylcarbamoyl) nonanoic acid bis- (guanylhydrazone) dihydrochloride trihydrate (0.211 g), m. pt. 168-169. 2 °C ; 250 MHz'H-nmr (d6DMSO) 8 (ppm): 1.2- 1.35 (m, 8H) (4 x-CH2CH2CH2-), 1.43-1. 67 (m, 4H) (2 x-CH2CH2CO-), 2.19 (t, 2H) (-CH2CO-), 2.3-2. 43 (m, 8H) (-CH2CO- + 2 x-C (=N) CH3), 7.7-7. 95 (br, 8H) (4 x NH2-guanidine salts), 8.05 (s, 1H) (ArH), 8.15 (s, 2H) (2 x ArH), 10.2 (s, 1H) (-NHCO-), 11.25 (s, 2H) (2 x guanidine NH),-11. 5-12.5 (very br,-1/) (-C02H) ; C22H35NgO3. 2 HCI. 3 H20 requires C: 44.00, H: 7.21, N: 20.99%-Found C: 43. 87/43. 78, H: 6.79/6. 91, N: 20. 72/20. 63%.

Example 6: Synthesis of compound 14

A solution of sodium hydroxide (0.032 g, 0.8 mmol) in the minimum volume of water was added to a solution of ethyl 9- (3, 5-diacetylphenylcarbamoyl)-nonanoate (0. 195 g, 0.5 mmol ; prepared in a manner similar to that described above) in the minimum volume of ethanol, and the mixture was stirred at ambient temperature for 16 hours. Water (5 ml) was added and the mixture was acidified to pH 3 by the addition of 2M hydrochloric acid. The resulting solid was collected by filtration and dissolved in ethyl acetate (10 ml). The solution was dried (MgSO4) and the solvent was removed in vacuo to give 9- (3, 5-diacetylphenylcarbamoyl) nonanoic acid (0.14 g) as a white solid, m. pt. 128-130 °C ; 250 MHz 1H-nmr (d6DMSO) 6 (ppm) : 1. 25 (m, 8H) (4 x-CH2CH2CH2-), 1.5 (m, 2M (-COCH2CH2-), 1.65 (m, 2H) (-COCH2CH2-), 2.2 (t, 2H) (-COCH2CH2-), 2.35 (m, 2H) (-COCH2CH2-), 2.65 (s, 6H) (2 x CH3), 8.1 (s, 1H) (ArH), 8. 45 (s, 2H) (2 x ArH), 10.3 (s, 1H) (-NHCO-), 11.95 (br s, 1H) (-C02H).

A mixture of 9- (3, 5-diacetylphenylcarbamoyl) nonanoic acid (2.254 g, 6.24 mmol ; prepared in a manner similar to that described above), 1-hydroxybenzotriazole hydrate (1. 685 g, 12.47 mmol), 1- [3- (dimethylamino) propyl]-3-ethyicarbodiimide hydrochloride (2.391 g, 12.47 mmol) and dichloromethane (10 mi) was stirred at 0

°C for 10 minutes. N-Ethyldiisopropylamine (1.61 g, 12.46 mmol) was added dropwise at ambient temperature to a vigorously stirred mixture of 38% aqueous ammonia solution (0.314 ml, 6.24 mmol) and dichloromethane (10 ml), the mixture was cooled to 0 °C and stirred at that temperature for 10 minutes, then it was added dropwise via syringe to the stirred 9- (3, 5-diacetylphenylcarbamoyl) nonanoic acid solution. The mixture was stirred at ambient temperature under nitrogen for 16 hours, then the resulting solid was collected by filtration and dried in vacuo.

Nmr of the crude product indicated the presence of starting material, so the solid was stirred in 2M aqueous sodium hydroxide solution (10 ml) for 10 minutes. The resulting solid was collected by filtration, washed with water (5 ml), dried in vacuo and crystallised from ethanol to give N- (3, 5-diacetylphenyl) sebacamide (1.17 g) as a white solid, m. pt. 183-189 °C ; 250 MHz H-nmr (deDMSO) S (ppm): 1.25 (m, 8H) (4 x-CH2CH2CH2-), 1.5 (m, 2M (-COCH2CH2-), 1.65 (m, 2H) (-COCH2CH2-), 2.05 (t, 2M (-COCH2CH2-), 2.4 (t, 2H) (-COCH2CH2-), 2.7 (s, 6H) (2 x CH3), 6.7 (br s, 1 H) (-CONH2), 7.3 (br s, 1 H) (-CONH2), 8.15 (s, 1H) (ArH), 8.45 (s, 2H) (2 x ArH), 10.3 (s, 1 H) (-NHCO-).

A stirred mixture of N- (3, 5-diacetylphenyl) sebacamide (0.293 g, 0. 81 mmol), aminoguanidine bicarbonate (0.332 g, 2.44 mmol) and dimethylformamide (2 ml) was warmed to 60 °C and 48% hydrobromic acid (0.97 ml) was added dropwise.

A soon as a clear solution was obtained, the mixture was cooled in ice and ice- cold water (10 ml) was added. The mixture was stored at 4 °C for 16 hours, then the resulting solid was collected by filtration, washed with water (2 x 2 ml) and dried in vacuo at 35 °C for 16 hours to give N- (3, 5-diacetylphenyl) sebacamide bis- (guanylhydrazone) dihydrobromide hydrate (0.328 g) as a white solid, m. pt. 120- 130 °C (decomposes); 300 MHz H-nmr (dgDMSO) 8 (ppm): 1.27 (m, 8H) (4 x- CH2CH2CH2-), 1. 47 (m, 2H) (-COCH2CH2-), 1.60 (m, 2H) (-COCH2CH2-), 2.02 (t, 2H) (-COCH2CH2-), 2.3-2. 4 (m, 8H) (2 x CH3 +-COCH2CH2-), 6.63 (br s, 1H) (- CONH2), 7.2 (br s, 1H) (-CONH2), 7.67 (br s, 8H) (4 x NH2-guanidine salts), 8.03 (s, 1H) (ArH), 8.14 (s, 2H) (2 x ArH), 10.08 (s, 1H) (-NHCO-), 10.68 (s, 2H) (2 x guanidine NH) ; C22H36N10O2. 2 HBr. 2 H20 requires C: 39.41, H: 6. 31, N: 20. 89% - Found C: 39.68/39. 40, H: 6.32/6. 17, N: 20. 59/20. 51%.

Example 7: Synthesis of compound 15

Diphenyl phosphoryl azide (4.67 g, 17 mmol) was added to a stirred solution of ethyl hydrogen sebacate (3.73 g, 16.2 mmol) and triethylamine (1.72 g, 17 mmol) in toluene (35 m !), the mixture was stirred at 80 °C for 2 hours, then it was cooled to 40 °C. tert-Butanol (10 ml) was added, the mixture was heated under reflux for 18 hours, then the solvents were removed in vacuo. The residue was dissolved in ether (200 ml), the solution was filtered through a short column of silica, and the product was eluted with ether (500 ml). The ether solutions were combined and the solvent was removed in vacuo. The column filtration was repeated using ether (1200 ml) and the solvent was removed in vacuo to give ethyl 9- (tert- butoxycarbonylamino) nonanoate (4.67 g) as a yellow oil which was used without further purification.

A solution of potassium hydroxide (2 g) in water (10 ml) was added to a stirred solution of ethyl 9- (tert-butoxycarbonylamino) nonanoate (4. 67 g, 15. 5 mmol) in ethanol (30 ml), the mixture was stirred at 50 °C for 4 hours, then the solvent was removed in vacuo. The residue was dissolved in water (50 ml), the solution was cooled in ice, and it was acidified to pH 4 by the addition of 2M hydrochloric acid.

The resulting solid was collected by filtration then it was dissolved in dichloromethane (50 ml). The solution was washed with water (2 x 20 ml), dried (MgS04) and the solvent was removed in vacuo. The residue was cooled in ice, then it was triturated with hexane (50 ml). The resulting solid was collected by filtration and dried in vacuo to give 9- (tert-butoxycarbonylamino) nonanoic acid (3.31 g) as a pale yellow solid, m. pt. 53-55 °C.

N-Ethyldiisopropylamine (1.6 g, 12.4 mmol) was added dropwise at ambient temperature to a stirred solution of 3, 5-diacetylaniline (1.1 g, 6.2 mmol) in dichloromethane (10 ml), then the mixture was cooled to 0 °C and stirred at that temperature for 10 minutes. A mixture of 9- (tert-butoxycarbonylamino) nonanoic acid (1.7 g, 6.2 mmol), 1-hydroxybenzotriazole hydrate (2.1 g, 15.5 mmol), 1- [3- (dimethylamino) propyq-3-ethylcarbodiimide hydrochloride (3 g, 15.6 mmol) and dichloromethane (40 mi) was stirred at ambient temperature for 10 minutes and at 0 °C for 15 minutes, then it was added dropwise via syringe to the stirred diacetylaniline solution. The mixture was stirred at 0 °C for 10 minutes and at ambient temperature for 24 hours, then it was poured into water (200 ml). The organic layer was separated, further product was extracted from the aqueous layer using dichloromethane (100 ml), the combined organic solutions were washed with 2M hydrochloric acid (50 ml), then they were dried (MgS04) and the solvents were removed in vacuo. The residue was purified by column chromatography over silica using a 1: 1 mixture of ethyl acetate and hexane as eluant. Appropriate fractions were combined and the solvents were removed in vacuo. The residue was triturated with hexane (100 ml) and the resulting solid was collected by filtration and dried in vacuo to give N- (3, 5-diacetylphenyl)-9- (tert butoxycarbonylamino) nonanamide (1. 69 g) as a white solid ; 250 MHz 1H-nmr (d6DMSO) 8 (ppm) : 1.15-1. 4 (m, 10H) (4 x-CH2CH2CH2-+-COCH2CH2-), 1.45 (s, 9H) (3 x-OCCH3), 1. 6 (m, 2H) (-NHCH2CH2-), 2.3 (t, 2/-/) (-COCH2CH2-), 2.65 (s, 6M (2 x-COCH3), 2.85 (m, 2M (-NHCH2CH2-), 6.75 (br t, 1H) (-CH2NH-), 8.15 (s, 1 H) (ArH), 8.4 (s, 2H) (2 x ArH), 10. 3 (s, 1 H) (-NHCO-).

Trifluoroacetic acid (15 ml) was added dropwise at ambient temperature under nitrogen to a stirred solution of N- (3, 5-diacetylphenyl)-9- (tert-

butoxycarbonylamino) nonanamide (1.08 g, 2.5 mmol) in dichloromethane (30 ml), the mixture was stirred at ambient temperature for 30 minutes, then the solvent and other volatile materials were removed in vacuo to give 9-amino-N- (3, 5- diacetylphenyl) nonanamide (0.83 g) as an orange oil which was used without further purification.

N-Ethyidiisopropylamine (1. 61 g, 12.5 mmol) was added dropwise at ambient temperature to a stirred solution of 9-amino-N- (3, 5-diacetylphenyl) nonanamide (0.83 g, 2.5 mmol) in dichloromethane (30 ml), then the mixture was cooled to 0 °C and stirred at that temperature for 10 minutes. A mixture of 3-acetybenzoic acid (0.41 g, 2.5 mmol), 1-hydroxybenzotriazole hydrate (0.67 g, 5 mmol), 1- [3- (dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (0.96 g, 5 mmol) and dichloromethane (25 ml) was stirred at ambient temperature for 10 minutes and at 0 °C for 15 minutes, then it was added dropwise via syringe to the stirred 9-amino- N- (3, 5-diacetylphenyl) nonanamide solution. The mixture was stirred at 0 °C for 10 minutes and at ambient temperature for 18 hours, then it was poured into water (100 ml). The organic layer was separated, further product was extracted from the aqueous layer using dichloromethane (100 ml), the combined organic solutions were washed with water (100 ml), then they were dried (MgS04) and the solvents were removed in vacuo. The residue was triturated with cold dichloromethane (10 mf) followed by hexane (30 ml) and the resulting solid was collected by filtration and dried in vacuo. The product was crystallised from dichloromethane to give 3- acetyl-N- [8- (3, 5-diacetylphenylcarbamoyl)-octyl] benzamide (0.85 g) as a white solid, m. pt. 85-87 °C ; 250 MHz H-nmr (dgDMSO) 5 (ppm): 1.15 (m, 8H) (4 x- CH2CH2CH2-), 1.3-1. 5 (m, 4H) (-COCH2CH2- +-NHCH2CH2-), 2.15 (t, 2H) (- COCH2CH2-), 2.45 (s, 9H) (3 x CH3), 3.15 (m, 2/-/) (-NHCH2CH2-), 7.45 (t, 1 H) (ArH), 7.9 (m, 3H) (3 x ArH), 8.25 (2 x s, 3H) (3 x ArH), 8.5 (br t, 1H) (-CH2NH-), 10.1 (s, 11-1) (-NHCO-).

A stirred mixture of 3-acetyl-N- [8- (3, 5-diacetylphenylcarbamoyl) octyl] benzamide (0.25 g, 0.52 mmol), aminoguanidine bicarbonate (0.28 g, 2.06 mmol) and methanol (2 ml) was heated to 50 °C, 48% hydrobromic acid (0.5 ml) was added, the mixture was stirred at 50 °C for 2 minutes, then it was cooled in ice and diluted with ice-water (20 ml). The mixture was allowed to stand at 4 °C for 18 hours, then the resulting solid was collected by filtration and dried in vacuo at 35 °C for 24 hours to give 3-acetyl-N- [8- (3, 5-diacetylphenylcarbamoyl)-octyl] benzamide fris- (guanylhydrazone) trihydrobromide tetrahydrate (0.409 g) as a white solid, m. pt.

190-192 °C (decomposes); 300MHz 1H-nmr (d6DMSO) S (ppm): 1.32 (m, 8H) (4 x

-CH2CH2CH2-), 1.48-1.65 (m, 4H)(-COCH2CH2- + -NHCH2CH2-), 2.3-2.4 (m, 8H)(2 x CH3 + -COCH2CH2-), 3.27 (m, 2H)(-NHCH2-), 7.51 (t, 1H)(ArH), 7.68 (br s, 12H) (6 x NH2-guanidine salts), 7.89 (d, 1H) (ArH), 8.03 (s, 1H) (ArH), 8.14 (s, 1 H) (ArH), 8.16 (s, 2H) (2 x ArH), 8.26 (s, 1 H) (ArH), 8.55 (brt, 1H) (-CH2NH-), 10.10 (s, 1H) (-NHCO-), 10.67 (s, 1H)(guanidine NH), 10.69 (s, 2H)(2 x guanidine NH); C31H46N1402. 3 HBr. 4 H20 requires C: 38.72, H: 5.98, N: 20.39%-Found C: 39. 22/39.22, H: 5. 81/5. 81, N: 19.90/19. 90%.

Example 8: Synthesis of compound 16 N-Ethyldiisopropylamine (1.61 g, 12.5 mmol) was added dropwise at ambient temperature to a stirred solution of 9-amino-N- (3, 5-diacetylphenyl) nonanamide (0.83 g, 2.5 mmol ; prepared in a manner similar to that described above) in dichloromethane (30 ml), then the mixture was cooled to 0 °C and stirred at that

temperature for 10 minutes. A mixture of 4-acetybenzoic acid (0.41 g, 2.5 mmol), 1-hydroxybenzotriazole hydrate (0.67 g, 5 mmol), 1- [3- (dimethylamino) propyl]-3- ethylcarbodiimide hydrochloride (0.96 g, 5 mmol) and dichloromethane (25 ml) was stirred at ambient temperature for 10 minutes and at 0 °C for 15 minutes, then it was added dropwise via syringe to the stirred 9-amino-N- (3, 5- diacetylphenyl) nonanamide solution. The mixture was stirred at 0 °C for 10 minutes and at ambient temperature for 18 hours, then the resulting solid was collected by filtration and dried in vacuo. The filtrate was diluted with water (100 ml) and the resulting solid was collected by filtration and dried in vacuo. The two crops of solid were combined and suspended in dichloromethane (30 ml). The mixture was heated under reflux for 5 minutes, filtered while hot, cooled in ice and diluted with hexane (30 ml). The resulting solid was collected by filtration and dried in vacuo to give 4-acetyl-N- [8- (3, 5-diacetylphenyl- carbamoyl) octyl] benzamide (1.097 g) as a white solid, m. pt. 180-183 °C ; 250 MHz <BR> <BR> ¹H-nmr (d6DMSO) # (ppm) : 1.15 (m, 8H)(4 x -CH2CH2CH2-), 1.3-1.5 (m, 4H)(- COCH2CH2-+-NHCH2CH2-), 2.15 (t, 2H) (-COCH2CH2-), 2.45 (2 x s, 9H)(3 x CH3), 3.05 (m, 2H) (-NHCH2CH2-), 7.75 (dd, 4H) (4 x ArH), 7.95 (s, 1M) (ArM), 8.25 (s, 2H) (2 x ArH), 8.45 (t, 1 M (-CH2NH-), 10.1 (s, 1 H) (-NHCO-).

A stirred mixture of 4-acetyl-N- [8- (3, 5-diacetylphenylcarbamoyi) octyl] benzamide (0.175 g, 0.37 mmol), aminoguanidine bicarbonate (0.199 g, 1.46 mmol) and methanol (1 mi) was heated to 50 °C, 48% hydrobromic acid (0.7 ml) was added, the mixture was stirred at 50 °C for 1 minute, then it was cooled in ice and diluted with ice-water (20 ml). The mixture was allowed to stand at 4 °C for 18 hours, then the resulting solid was collected by filtration and dried in vacuo at 35 °C for 24 hours to give 4-acetyl-N- [8- (3, 5-diacetylphenylcarbamoyl) octyl]-benzamide tris- (guanylhydrazone) trihydrobromide dihydrate (0.409 g) as a white solid, m. pt. 235- 245 °C (decomposes); 300MHz 1H-nmr (d6DMSO) 6 (ppm): 1.32 (m, 8/-/) (4 x- CH2CH2CH2-), 1. 48-1. 65 (m, 4H) (-COCH2CH2- +-NHCH2CH2-), 2. 3-2. 4 (m, 8H) (2 x CH3 +-COCH2CH2-), 3.25 (m, 21-1) (-NHCH2CH2-), 7.67 (br s, 12H) (6 x NH2- guanidine salts), 7.97 (dd, 4H)(4 x ArH), 8.04 (s, 1H)(ArH), 8.15 (d, 2H) (2 x ArH), 8.53 (t, 1H) (NH), 10.10 (s, 1H) (-NHCO-), 10.66 (s, 1/-/) (guanidine NH), 10.68 (s, 2H) (2 x guanidine NH) ; C31H46N1402. 3 HBr. 2 H20 requires C: 40.23, H: 5.77, N: 21. 19%-Found C: 40.11/40. 06, H: 5. 75/5. 76, N: 21.02/21. 04%.

Example 9: Synthesis of compound 17 i) Oxalyl chloride/DMF i) NaOH/H20/EtOH HO2CICH2) 8C02Et >> H2NCo (CH2) 8CO2Et + r Me Me H i) Oxalyl chloride/DMF o4N HO 2C (CH2) BCONH2 Mye/ NHZ O ii) o NH,/Pyridine 0 Me CN OMe" H H H O Me Mye Vi2N"r H2CO3 H2N) N<NtX NU N i o HBR DMF N Me H2N y NH CN T NH 2 HBr. 1 H20. 0. 04 DMF Oxalyl chloride (1.33 g, 10.5 mmol) was added dropwise at 20-25 °C to a stirred solution of ethyl hydrogen sebacate (2.3 g, 10 mmol) and dimethylformamide (1 drop) in dichloromethane (5 ml), the mixture was stirred at ambient temperature for 1 hour, then the solvent was removed in vacuo. The residue was added dropwise via syringe to stirred, ice-cold 0.880 ammonia solution (10 mi), the mixture was stirred at ambient temperature under nitrogen for 2 hours, then the resulting solid was collected by filtration, washed with water (10 ml) and dried in vacuo to give 9-ethoxycarbonyinonanamide (1.84 g) as a white solid, m. pt. 70- 71. 5 OC ; 250 MHz'H-nmr (d6DMSO) 8 (ppm): 1.15 (t, 3H) (-OCH2CH3), 1.25 (m, 8H) (4 x-CH2CH2CH2-), 1.4-1. 6 (m, 4H) (2 x-COCH2CH2-), 2.0 (t, 2H) (-COCH2CH2- ), 2.25 (t, 2H) (-COCH2CH2-), 4.0 (q, 2H) (-OCH2CH3), 6.65 (br s, 1H) (-CONH2), 7.2 (brs, 1H) (-CONH2).

A solution of sodium hydroxide (0.42 g, 10.5 mmol) in the minimum volume of water was added to a stirred solution of 9-ethoxycarbonyinonanamide (1.5 g, 6.54 mmol) in the minimum volume of ethanol, the mixture was stirred at ambient temperature for 6 hours, then it was diluted with water (5 mi) and acidified to pH 3 by the addition of 2M hydrochloric acid. The resulting solid was collected by filtration, washed with water (10 ml) and dried in vacuo to give 9-

carbamoylnonanoic acid (1.176 g) as a white solid, m. pt. 124.2-127°C; 250 MHz<BR> ¹H-nmr (d6DMSO) # (ppm) : 1.25 (m, 8H) (4 x -CH2CH2CH2-), 1.4-1.6 (m, 4H)(2 x -COCH2CH2-), 2.0 (t, 2H) (-COCH2CH2-), 2.15 (t, 2H) (-COCH2CH2-), 6.65 (br s, 1 H) (-CONH2), 7.2 (br s, 1 H) (-CONH2), 11.95 (s, 1 H) (-C02H).

Oxalyl chloride (0.533 g, 4.2 mmol) was added dropwise at 20-28 °C to a stirred suspension of 9-carbamoylnonanoic acid (0.402 g, 2 mmol) and dimethylformamide (2 drops) in dichloromethane (5 ml), the mixture was stirred at ambient temperature for 2 hours, then it was cooled to 0 °C. 3, 5-Diacetylaniline (0.354 g, 2 mmoi) followed by pyridine (0.4 ml) were added, the mixture was stirred at ambient temperature for 18 hours, then it was poured into 2M hydrochloric acid (25 ml). The aqueous layer was separated and further product was extracted from it using dichloromethane (2 x 5 ml). The dichloromethane solutions were combined, washed with water (2 x 10 ml) and dried (MgS04). The solvent was removed and the residue was crystallised from ethanol to give N- (3, 5- diacetylphenyl)-9-cyanononanamide (0.303 g) as a white solid, m. pt. 130-134 °C ; <BR> <BR> 250 MHz ¹H-nmr (d6DMSO) # (ppm) : 1.3 (m, 8H)(4 x -CH2CH2CH2-), 1.5-1.7 (m, 4H) (2 x-COCH2CH2-), 2.35 (t, 2H) (-COCH2CH2-), 2.55 (t, 2H) (-COCH2CH2-), 2.65 (s, 6H) (2 x CH3), 8.15 (s, 1) (Ar), 8.45 (s, 2H) (2 x ArH), 10.3 (s, 1/) (-NCO-).

A stirred mixture of N- (3, 5-diacetylphenyl)-9-cyanononanamide (0.303 g, 0.89 mmol), aminoguanidine bicarbonate (0.361 g, 2.65 mmol) and dimethylformamide (3 ml) was heated to 60 °C, 48% hydrobromic acid (1 ml) was added dropwise and the mixture was cooled in ice. Water (10 ml) was added and the mixture was allowed to stand at 4 °C for 18 hours. The resulting solid was collected by filtration and dried in vacuo at 35 °C for 24 hours to give N-(3,5-diacetylphenyl)-9- cyanononanamide bis-(guanylhydrazone) dihydrobromide hydrate (0.373 g) as a <BR> <BR> white solid, m. pt. 170-190 °C; 300 MHz ¹H-nmr (d6DMSO) # (ppm) : 1.25-1.4 (m, 8H) (4 x-CH2CH2CH2-), 1.48-1. 65 (m, 4/-/) (2 x-COCH2CH2-), 2.3-2. 4 (m, 8M (2 x CH3 +-COCH2CH2-), 2.45 (t- partially obscured by DMSO peak, 2H)(-CH2CN), 7.70 (br s, 8H)(4 x NH2 - guanidine salts), 8.03 (s, 1H)(ArH), 8.18 (s, 2H)(2 x ArH), 10.13 (s, 1H)(-NHCO-), 10.73 (s, 2H)(2 x guanidine NH), C22H34N10O. 2 HBr. 1 H2O. 0.04 DMF requires C: 41.68, H: 6.05, N: 22.06%Fund C: 41.48/41.40, H: 6.06/6.04, N: 21.97/21.98%.