NOVEL COMPOUNDS USEFUL IN PAIN MANAGEMENT

Abstract: Compounds of general formula (I) wherein A is (a) or (b); Z is (CH2)m or a carbonyl group are disclosed and claimed in the present application, as well as their pharmaceutically acceptable salts, pharmaceutical compositions comprising the novel compounds and their use in therapy, in particular in the management of pain. Also intermediates to the compounds of formula (I) are claimed.

Description: NOVEL COMPOUNDS USEFUL IN PAIN MANAGEMENT Field of the invention The present invention is related to novel compounds, to a process for their preparation, intermediates, their use and pharmaceutical compositions comprising the novel compounds. The novel compounds are useful in therapy, and in particular for the treatment of pain. Background and prior art The δ receptor has been identified as having a role in many bodily functions such as circulatory and pain systems. Ligands for the δ receptor may therefore find potential use as analgesics, and/or as antihypertensive agents. Ligands for the δ receptor have also been shown to possess immunomodulatory activities. The identification of at least three different populations of opioid receptors (μ, δ and K) is now well established and all three are apparent in both central and peripheral nervous systems of many species including man. Analgesia has been observed in various animal models when one or more of these receptors has been activated. With few exceptions, currently available selective opioid δ ligands are peptidic in nature and are unsuitable for administration by systemic routes. Some non-peptidic δ antagonists have been available for some time (see Takemori and Portoghese, 1992, Ann. Rev. Pharmacol. Tox., 32: 239-269. for review). These compounds, e.g. naltrindole, suffer from rather poor (i.e., < 10-fold) selectivity for the δ receptor vs. μ receptor binding and exhibit no analgesic activity, a fact which underscores the need for the development of highly selective non-peptidic δ ligands. Thus, the problem underlying the present invention was to find new analgesics having improved analgesic effects, but also with an improved side-effect profile over current μ agonists and potential oral efficacy. Analgesics that have been identified and are existing in the prior art have many disadvantages in that they suffer from poor pharmacokinetics and are not analgesic when administered by systemic routes. Also, it has been documented that preferred compounds, described within the prior art, show significant convulsive effects when administered systemically. The problem mentioned above has now been solved by developing novel 1 ,4-substituted cyclohexyl compounds, as will be described below. Outline of the invention The novel compounds according to the present invention are defined by the formula I wherein A is / R2 N — CH \ \ 3 R 3 or R 3 7 3 wherein R and R are as defined below; Z is (CH2)m or a carbonyl group; m and n are each and independently an integer of from 0-3, and one or more of the hydrogens in such an alkylene-chain may optionally be substituted by anyone of Cj - Cg alkyl, Cj - C6 alkoxy, or hydroxy; or one or more of the methylene groups may optionally be substituted by a heteroatom such as O, N or S; m and n may not both be 0; Q is selected from any of CH3; wherein 4 5 6 R , R and R is each and independently selected from any of (i) C6-Cιo aryl; or (ii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below; (iii) hydrogen; (iv) a straight or branched alkyl, C2-C6 alkenyl or C2-C6 alkynyl; (v) C1-C3 alkoxy; (vi) saturated or unsaturated C3 - C 1 0 cycloalkyl, optionally and independently substituted by one or more aryl groups or heteroaryl groups having from 5 to 10 atoms with the heteroatom(s) being selected from any of S, N and O and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; (vii) -[(CU2)q-aryl] where q is an integer of from 1-3, and the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined below; (viii) -[(CH2) r -heteroaryl] where r is an integer of from 1-3, the heteroaryl having from 5 to 10 atoms with heteroatoms(s) being selected from any of S, N, and O, optionally and independently substituted by 1 or 2 substituents Y as defined below; (ix) -[CH2-O-aryl] where the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined below; (X) '(CH 2 )— H * N ' Aryl where q is an integer of from 1-3, and the aryl is as defined below, optionally substituted by 1 or 2 substituents Y, where each Y is as defined below; R .1 i •s selected from anyone of (i) a straight or branched alkyl, C2-C6 alkenyl or C2-C6 alkynyl. where each alkyl, alkenyl or alkynyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (ii) C3-C7 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more of C \ - C(, alkyl, Ci - C6 alkoxy, hydroxy; or substituted by one or more aryl(s), or heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; (iii) hydrogen, halogen or C1-C6 alkoxy; (iv) C6-C 10 aryl; (v) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; (vi) 9, 10-dihydro-9, 10-ethanoantracenyl; (vii) -[(CH2)q-aryl] where q is an integer of from 1-3 and the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined below; (viii) -[(CH2) r -heteroaryl] where r is an integer of from 1-3, the heteroaryl having from 5 to 10 atoms and the heteroatoms(s) being selected from any of S, N, and O, and wherein the heteroatom(s) may optionally and independently be substituted by 1 or 2 substituents Y, where each Y is as defined below; (ix) -[(CH2)q-aryl-O-(CH2) r -aryl] where q and r is each and independently an integer of from 1-3; (x) -(CH2)q-[C3-C6 cycloalkyl] where q is from 1-2, optionally substituted by 1 or 2 substituents Y and wherein Y is as defined below; 2 R is selected from any of (i) hydrogen; (ii) a straight or branched Ci-Cζ alkyl, C2-Cg alkenyl or C - ^ alkynyl, where each alkyl, alkenyl or alkynyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (iii) C(, - C ιo arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; (iv) heteoaryl-(C5 - Cio alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below; (v) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally susbtituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below; (vi) C6-C10 aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; (vii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; 3 R is selected from anyone of (i) hydrogen; (ii) a straight or branched alkyl, C2-C6 alkenyl or C2- alkynyl, where each alkyl, alkenyl or alkynyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (iii) C6 - CJO arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;, (iv) heteoaryl-(C5 - CJO alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below: (v) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below; wherein R , R , R , R and R is each and independently selected from (a) hydrogen; (b) a straight or branched Cj-Cό alkyl, C2-C6 alkenyl or C2-C6 alkynyl, where each alkyl, alkenyl or alkynyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (c) CO - C10 arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; (d) heteoaryl-(C5 - o alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below; (e) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally susbtituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below; (f) C6-C10 aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; or 2 3 R and R may optionally form a heterocyclic ring; Y is each and independently selected from any of hydrogen, CH3; — (CH2) p ιCF3; halogen; C1-C3 alkoxy; hydroxy; -NO 2 ; -OCF3; — CONR^; — COOR a ; — COR a ; — (CH 2 ) p 2NR a R b ; — <CH 2 )p3CH3 , (CH 2 ) p4 SOR a R b ; — (CH 2 ) p 5SO 2 R a ; — (CH 2 ) p 6SO 2 NR a ; C 4 -C 8 (alkyl-cycloalkyl) wherein alkyl is -C2 alkyl and cycloalkyl is C3-C6 cycloalkyl; 1 or 2 heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O; and oxides such as N-oxides or sulfoxides; and wherein a b R and R is each and independently selected from hydrogen, a branched or straight Cj-Cg alkyl, Cj-C6 alkenyl, C3-C8 cycloalkyl; and wherein pi, p2, p3, p4, p5 and p6 is each and independently 0, 1 or 2. Within the scope of the invention are also pharmaceutically acceptable salts of the compounds of the formula (I), as well as isomers, hydrates, isoforms and prodrugs thereof. Preferred compounds according to the invention are compounds of the formula (I) wherein A is κ R2 / R ' N — CH \ \ . R 3 0, R " 2 3 wherein R and R are as defined below; Z is (CH2)m ° r a carbonyl group; m and n are each and independently an integer of from 1-3; Q is selected from any of CH3; wherein 4 5 6 R , R and R is each and independently selected from any of (i) C 6 -C 10 aryl; or (ii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above; (iii) a straight or branched Ci-Cό alkyl or C2-C6 alkenyl; (iv) C1-C3 alkoxy; (v) saturated or unsaturated C3 - C cycloalkyl, optionally and independently substituted by one or more aryl groups or heteroaryl groups having from 5 to 10 atoms with the heteroatom(s) being selected from any of S, N and O and wherein the aryl, heteroaryl and cycloalkyl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above; (vi) -[(CH2)q-aryl] where q is an integer of from 1-3, and the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined above; (vii) -[(CH2) r -heteroaryl] where r is an integer of from 1-3, the heteroaryl having from 5 to 10 atoms with heteroatoms(s) being selected from any of S, N, and O, optionally and independently substituted by 1 or 2 substituents Y as defined above; (viii) -[CHb-O-aryl] where the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined above; (ix) • N- (C - H Aryl where q is an integer of from 1-2, and the aryl is as defined below, optionally substituted by 1 or 2 substituents Y, where each Y is as defined above; 1 . R is selected from anyone of (i) a straight or branched alkyl or C2-C6 alkenyl, where each alkyl and alkenyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (ii) C3-C7 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more of Ci - C(, alkyl, Cj - C6 alkoxy, hydroxy; or substituted by one or more aryl(s), or heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above; (iii) hydrogen, halogen or C \ -C(, alkoxy; (iv) C 6 -C 10 aryl; (v) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O: wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above; (vi) 9,10-dihydro-9,10-ethanoantracenyl; (vii) -[(CH2)q-aryl] where q is an integer of from 1-3 and the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined above; (viii) -[(CH2) r -heteroaryl] where r is an integer of from 1-3, the heteroaryl having from 5 to 10 atoms and the heteroatoms(s) being selected from any of S, N, and O, and wherein the heteroatom(s) may optionally and independently be substituted by 1 or 2 substituents Y, where each Y is as defined above; (ix) -[(CH2)q-aryl-O-(CH2) r -aryl] where q and r is each and independently an integer of from 1-3; (x) -(CH2)q-[C3-C6 cycloalkyl] where q is from 1-2, optionally substituted by 1 or 2 substituents Y and wherein Y is as defined above; 7 R~ is selected from any of (i) hydrogen; (ii) a straight or branched Cj-Cg alkyl or C2-Cg alkenyl, where each alkyl and alkenyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (iii) C - Cio arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any ofS, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above; (iv) heteoaryl-(C5 - C\Q alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above; (v) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally susbtituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above; (vi) Cg-Cio aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above; (vii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above; 3 R is selected from anyone of (i) hydrogen; (ii) a straight or branched Cj-Cg alkyl or C2-C6 alkenyl, where each alkyl and alkenyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (iii) C - C 1 0 arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above; (iv) heteoaryi-(C5 - C \ alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above; (v) C3-C6 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above; (Vi) wherein 7 8 9 10 11 R , R , R , R and R is each and independently selected from (a) hydrogen; (b) a straight or branched Cj-Cό alkyl or C2-C6 alkenyl, where each alkyl and alkenyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (c) C - C \Q arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above; (d) heteoaryl-(C5 - CJO alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above; (e) C3-C 1 0 cycloalkyl, optionally comprising one or more unsaturations and optionally susbtituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above; (f) C6-C 10 aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above. Particularly preferred compounds according to the invention are compounds of the formula (I) wherein A is / R2 N — CH \ \ 3 R 3 or R 3 7 3 wherein R and R are as defined below; Z is (CH2) m or a carbonyl group; m and n are each and independently 1 or 2; O / C X ,4^ Q is R ^ \ or R ' - wherein 4 R is selected from (i) phenyl; (ii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the phenyl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above; (iii) cyclohexyl; (iv) Cι-C 6 alkyl; (v) C1-C3 alkoxy; R is (i) -[(CH2)q-aryl] where q is an integer of from 1-3 and the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined above; or (ii) C3-C7 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more of Ci - C(, alkyl, Cj - Co alkoxy, hydroxy; or substituted by one or more aryl(s), or heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above; (iii) -(CH2)-cyclohexyl; 2 R is hydrogen; R 3 is wherein R , R , R , R and R are as defined above. 2 3 Examples of heterocyclic ring systems which may be formed by R and R together include but are not limited to azeridine, pyrrolidine, piperidine, azepine, azocine, their hydrogenated or dehydrogenated derivatives, their aminoderivatives and other aza- heterocycle moieties and their derivatives, such as dihydroimidazoles, di-, tetra- and hexahydropyrimidines and the like. By "halogen" we mean chloro. fluoro, bromo and iodo. By "aryl" we mean an aromatic ring having 6 or 10 carbon atoms, such as phenyl and naphthyl. By "heteroaryl" we mean an aromatic ring in which one or more of the from 5-10 atoms in the ring are elements other than carbon, such as N, S and O. By "isomers" we mean compounds of the formula (I), which differ by the position of their functional group and/or orientation. By "orientation" we mean stereoisomers, diastereoisomers, regioisomers and enantiomers. By "isoforms" we mean compounds of the formula I which differ in the relative physical arrangement of molecules by crystal lattice, such that isoforms refer to various crystalline compounds and amorphous compounds. By "prodrug" we mean pharmacologically acceptable derivatives, e.g. esters and amides, such that the resulting biotransformation product of the derivative is an active form of the drug. The reference by Goodman and Gilmans, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs, p. 13-15, describing prodrugs generally, is hereby incoφorated by reference. The novel compounds of the present invention are useful in therapy, especially for the treatment of various pain conditions such as chronic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive. Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumour agents and anti viral agents. Compounds of the invention are useful in disease states where degeneration or dysfunction of opioid receptors is present or implicated in that paradigm. This may involve the use of isotopically labelled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET). Compounds of the invention are useful for the treatment of diarrhoea, depression, urinary incontinence, various mental illnesses, cough, lung oedema, various gastro-intestinal disorders, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension. Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (eg. Amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotica, anxiolytics, neuromuscular blockers and opioids. The compounds of the present invention in isotopically labelled form are useful as a diagnostic agent. Also within the scope of the invention is the use of any of the compounds according to the formula (I) above, for the manufacture of a medicament for the treatment of any of the conditions discussed above. A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula (I) above, is administered to a patient in need of such treatment. The best mode of performing the invention known at present, is to use the compounds according to Example 9 (compound 14), Example 14 (compound 30) and Example 53 (compound 120). The numbering of the compounds is in accordance with the numbering in the Schemes presented in the following. Methods of preparation Compounds of the formula I, as described above, may be obtained by following the procedures described below. Preparation of l,4-cis,trans-cvclohexane derived compounds SCHEME 1 (III) (VI) The compounds of general formula (VI) may be prepared by following the procedure described in Scheme I above. Commercially available cis/trans-mixtures of 1 ,4-bis-aminomethyl cyclohexane is converted to mono-(diBoc)guanidinomethyl derivative, using a protected guanylating reagent such as l-H-pyrazole-l-(N,N-bis(tert-butoxycarbonyl)carboxamidine in an organic solvent such as THF. The secondary amine (compound III) can be generated using a reductive amination step where compound III is reacted with an aldehyde (compound II) such as C i -C alkylaldehyde or phenylaldehyde in the presence of an acid such as acetic acid or ZnCb in a protic solvent such as methanol or ethanol in the presence of a reducing agent such as sodiumcyanoborohydride. Compounds of the general formula (V) may be obtained by performing an acylating reaction where compound III is mixed with an acid chloride (compound IV) or other appropriate acylating agent such as acid anhydride in a solvent such as methylene chloride and in the presence of a tertiary amine as base, such as triethylamine. Finally, compounds of the general formula (VI) may be obtained by cleavage of the Boc protecting groups with an acid such as aqueous hydrochloric acid, or by using organic acid such as trifluoroacetic acid in a solvent such as methylene chloride. 1 4 In the formulas (III), (IV), (V) and (VI) in Scheme I above, R and R are as defined in formula I of claim 1. SCHEME II (IX) (X) Alternatively, compounds of the general formula (X) may be obtained as described in Scheme II above. Cis,trans-4-(aminomethyl)-cyclohexane carbonitrile is reacted with an aldehyde in the presence of a reducing agent such as sodium cyanoborohydride in a protic solvent such as methanol, and in the presence of an acid such as acetic acid or alternatively a Lewis acid such as zinc chloride. Compounds of the general formula (VIII) may be prepared by acylating the remaining secondary amines of compound (VII) using an acylating reagent such as benzoyl chloride in an organic solvent such as methylene chloride in the presence of a base such as triethylamine. The primary amine of the general formula (IX) may be obtained by reducing the nitrile group in compound (VIII) using hydrogen in the presence of a catalyst such as 10 % Pd on carbon in an organic solvent such as ethanol. Compounds of the general formula (X) may be prepared by guanylation, amidination or alkylation in an organic solvent such as methanol and DMF in the presence of an organic base such as triethylamine. 1 4 In the formulas (VII), (VIII), (IX) and (X) in Scheme II above, R and R are as defined in formula I above. Preparation of 1.4-cis-cvclohexane derived compounds SCHEME III Bn 2 NH (XII) (Xlll) (XIV) (XV) (XVI) The 1 ,4-cis-cyclohexane derived compounds of the general formula (XVI) may be obtained by following the reaction sequence in Scheme III above. The cis- 1 ,4-cyclohexane dicarboxylic acid anhydride is prepared according to H.K. Halt (J. Org. Chem. 2027, 1963). The anhydride is then reacted with dibenzylamine to generate the corresponding cis-acid amide. Compounds of the general formula XII may be obtained by reacting the acid functionality with a primary amine of formula XI in the presence of a tertiary amine base such as diisopropylethylamine in an organic solvent such as DMF. Both carbonyl groups are then reduced to generate compounds of the general formula (XIII). The use of a reducing reagent such as BH3-THF in an organic solvent such as THF effectively reduces both amides. Compounds of the general formula (XIV) may be obtained by using an acylating reagent such as benzoyl chloride in an organic solvent such as methylene chloride in the presence of a base such as triethylamine. Compounds of the general formula (XV) may be obtained by cleavage of the benzyl groups using a reduction reaction such as hydrogenation. The hydrogenation is performed in the presence of a catalyst such as 10 % Pd on carbon in a solvent such as acetic acid and using a pressure of 50 psi. Compounds of the general formula (XVI) may be obtained by reacting the primary amine of the formula (XV) with a guanylating reagent such as l-H-pyrazole-l-(N,N-bis(tert- butoxycarbonyl))carboxamidine, or with an amidinating reagent or by alkylation, in a solvent such as THF or DMF. In the formulas (IV), (XI), (XII), (XIII), (XIV), (XV), and (XVI), in Scheme IH above, 1 2 3 4 R , R , R and R are as defined in formula I above. Preparation of trans-guanidinomethyl cyclohexane derived compounds SCHEME IV O^^NHR 1 (XVII) (XIX) (XX) (XXI) (XXII) The trans-guanidinomethyl cyclohexane derived compounds of the general formula (XXII) may be obtained as shown in Scheme IV above. Commercially available trans-4-aminomethyl cyclohexane carboxylic acid is protected using either di-tert-butyl dicarbonate or benzoyl chloride, followed by amidation using a primary amine of the formula (XI) in an organic solvent such as methylene chloride in the presence o coupling reagent such as BOPC1 and a tertiary amine base such as triethylamine, providing compounds of the general formula (XVII). Cleavage of the Boc- protecting groups may be effected using an organic acid such as trifluoroacetic acid in an organic solvent such as methylene chloride, providing compounds of the formula (XVIII). Compounds of the formula (XIX) may be obtained by using a reduction procedure consisting of using a hydride source such as a Borane complex in an organic solvent such as THF. Compounds of the formula (XX) may be obtained by reacting the primary amine in (XIX) with a guanylating reagent such as l-H-pyrazole-l-(N,N-bis(tert- butoxycarbonyl)carboxamidine in an organic solvent such as THF. Acylation of the remaining secondary amine in XX with an acylating reagent IV such as benzoyl chloride in an organic solvent such as dioxane or methylene chloride in the presence of a base such as triethylamine, providing compounds of the general formula (XXI). A deprotection step of (XXI) with an acid such as trifluoroacetic acid or an aqueous solution of hydrochloric acid, provides compounds of the general formula (XXII). 1 4 In Scheme IV above, R and R are as defined in formula I above. EXAMPLES The invention will now be described in more detail by way of the following general procedures and specific examples, which should not in any way be regarded as limiting the invention. EXAMPLE 1 Preparation of l-f(N-ben2θyl)-N-(l-methyl-l-phenyl-ethyl)l-aminomethyl- 4-guanidinomethylcvclohexane hydrochloride (compound 6) Compound 6 of Example 1 was prepared by following the synthetic route described in Scheme 1 below. (5) Example 1 Compound (6) Preparation of l-(diBoc)-guanidinomethyl-4-aminomethyl cyclohexane Part A 1-H-pyrazole-l-carboxamidine was prepared according to Bernatowicz et.ai, J. Org. Chem. 1992, 57, pp.2497-2502, and protected with di-tert-butyl dicarbonate to give l-H-pyrazole-l-(N.N-6/ ' s(tert-butoxycarbonyl)carboxamidine (compound 1) according to Drake et.al, Synth. 1994. pp.579-582. Part B Ste l Preparation of l-(diBoc)-guanidinomethyl-4-aminomethyl cyclohexane (compound 3) To a solution of l ,4-/3z -aminomethyl-cyclohexane (compound 2) (20 g, 0.14 mol) in THF (200 mL) was added a solution of l-H-Pyrazole-l-(N,N- >zs(tert- butoxycarbonyl)carboxamidine (compound 1) ( 22.0 g, 0.07 mol) in THF (100 mL). The solution was stirred at room temperature for 3 hrs. The solvent was removed under reduced pressure to give a syrupy residue which was taken up in ethyl acetate and washed with water until neutral pH. The organic layer was washed with brine, dried over MgSO4 and concentrated. The product (compound 3) was purified by column chromatography on silica gel using a mixture of methylene chloride:methanol as the eluent to afford 11.6 g ( 43 % yield) of l-(diBoc)-guanidinomethyl-4-aminomethyl cyclohexane, i.e. compound 3. IH NMR (CDCI3) δ 3.26 (d of t, 2H), 2.52 (d of d, 2H), 1.82-0.97 (m, 28H, with singlet at 1.5). Step 2 Preparation of 4-N-(diBoc)guanidinomethyl-l-N-(l-methyl-l-phenylethyl)- aminomethylcvclohexane (compound 4) To a solution of l-(diBoc)-guanidinomethyl-4-aminomethyl cyclohexane (compound 3) (1 eq) in methanol containing 1% (v/v) of glacial acetic acid (alternatively, ZnCb can be used) was added 2-methyl-phenylacetaldehyde (1 eq), followed by NaBH3CN (3-4 eq). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water, basified with aqueous NaHCO3 solution and extracted with methylene chloride. The organic layer was washed with brine, dried over MgSO4 and concentrated. The product (compound 4) was chromatographed on silica gel using a mixture of hexane:ethyl acetate as the eluent. Step 3 Preparation of 4-N-(diBoc)-guanidinomethyl-l-(N-benzoyl)-N-(l-methyl-l- phenylethvD-aminomethylcvclohexane (compound 5) To a solution of compound 4 prepared in step 2 (1 eq) in dioxane or methylene chloride, was added triethylamine (1.5-2.0 eq), followed by benzoyl chloride (1 eq). The reaction mixture was stirred at room temperature for 3 h, then basified with IN K2CO3 solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, concentrated and chromatographed on silica gel or purified by preparative TLC using a mixture of hexane-ethyl acetate as the eluent. Step 4 Preparation of l-(N-benzoyl)-N-(l-methyl-l-pheπylethyl)-aminomethyl-4- guanidinomethyl cvclohexane (compound 6) The diBoc-guanidino compound (compound 5) was dissolved in 4N HCl in dioxane or 50% trifluoroacetic acid in methylene chloride and stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in water and lyophylized. The product (compound 6) can also (when appropriate) be purified by reversed-phase HPLC using acetonitrile-water as the eluent. Step 5 Preparation of l-(N-benzoyl)-N-(l-methyl-l-phenylethyl)-aminomethyl-4- guanidinomethyl cyclohexane hydrochloride (compound 6 x HCl) To a mixture of the base compound 6 prepared in Step 4 (2 mmol) in methylene chloride (10 ml) and methanol (10 ml) was added a solution of HCl (1 M) in ether (8ml, 8 mmol). The reaction mixture was allowed to stir at room temperature for 2 h. The volatile was removed under vacuum and the resulting solid dried under vacuum to give the corresponding hydrochloride salt. MS(APCI): 407.06 (M + H) Examples 2-11 Examples 2 to 11 (compounds 7 to 16) were prepared as described for compound 6 of Example 1, using the reagents in the respective Examples as described in Table 1 below. Example 12 Preparation of cis/trans-l-Aminomethyl-4-rN-2,2-diphenylmethyl)-N- benzoyllaminomethyl-cvclohexane (compound 21) The title compound 21 was prepared by following the synthetic route described in Scheme 2 below. Example 12 Compound 21 Step l Preparation of rø,frgws-4-N-(2,2-diphenylethyl)aminomethyl-cvclohexane carbonitrile (compound 19) To a methanolic solution (20 mL) of cz ' .s, rn s-4-(aπιinomethyl)-cyclohexane carbonitrile (compound 17) (0.69 g, 5 mmol) and diphenylacetaldehyde (compound 18) (0.981, 5 mmol) was added zinc chloride (0.681 g, 5 mmol), and solid sodium cyanoborohydride (0.32 g, 5 mmol). The mixture was stirred overnight under nitrogen. It was diluted with aqueous sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed with brine, dried over MgSO4 and concentrated. The product (compound 19) was purified by silica gel chromatography: Yield: 1.24 g. MS: 319.03(M+H). Step 2 Preparation of c/5..'rα«y-4-fN-(2.2-diphenylethyl)-N-benzoyllaminomethyl- cvclohexane carbonitrile (compound 20) To a solution of cz ?rø>7s-4-N-(2,2-diphenylethyl)aminomethy}-cyclohexane carbonitrile (compound 19) prepared in step 1 (0.60 g, 1.89 mmol) in methylene chloride was added triethylamine (0.35 mL) and benzoyl chloride (0.241 mL, 2.07 mmol). The mixture was stirred at r.t. for 3 h., and washed with 5% aq. HCl, saturated sodium bicarbonate, dried over magnesium sulfate and concentrated. The product (compound 20) was purified by silica gel chromatography. giving 0.65 g. Step 3 Preparation of c/s,.rflras-l-Amipomethyl-4-[N-(2,2-diphenylethyl)-N- benzoyllaminomethyl-cvclohexane (compound 21) A solution of cw.rra«5'-4-[N-(2,2-diphenylethyl)-N-benzoyl]aminomethyl-cyclohexane carbonitrile (compound 20) prepared in the previous step 2 (0.483 g, 1.14 mmol), was dissolved in a mixture of ethanol (25 mL) and CHCI3 (0.6 mL) and hydrogenated overnight at 50 psi in the presence of 10% Pd/C catalyst (0.10 g). The mixture was filtered through Celite. The filtrate was concentrated and the product (compound 21) was purified by silica gel chromatography, using a mixture of methanol/methylene chloride/ammonium hydroxide as the eluent. *H NMR (CDC ) δ 7.65-6.90 (m, 15H), 4.60 (t, IH), 4.15 (d, 2H), 3.98 (broad s, IH), 3.37 (broad s, IH), 2.95- 0.45 ( m, 14H). MS(APCI): 427.06 (M+H). Example 13 Preparation of ct ' s,frflns-l-Aminomethyl-4-rN-(2,2-diphenylethyl-N- benzoyllacetamidinomethyl cyclohexane (compound 22) The title compound 22 was prepared by following the synthetic routes described in Scheme 3 below. Scheme 3 (21 ) Example 13 Compound 22 To a solution of compound 21 (450 mg, 1.05 mmol) in DMF (10 ml) at room temperature was successively added triethylamine (735 μl, 5.28 mmol) and methylacetimidate x HCl (580 mg, 5.28 mmol). The solution was stirred at the same temperature over night, thereafter the solvent was reduced under reduced pressure. The residue was dissolved in dichloromethane, washed with a saturated aqueous sodium chloride solution and extracted several times with dichloromethane. Removal of the solvent from dried organic layers (MgSO 4 ) afforded an oil which was further purified by MPLC with reverse phase silica gel using a solvent gradient (20 - 45 % CH3CN/H2O) to give a white crystalline product. The pure compound was washed with an aqueous sodium hydroxide solution (I M) and extracted several times with dischloromethane. The combined layers were dried over MgSO4, filtered and concentrated to give the methyl amidine (compound 22) (421 mg, 86 %) as a white powder. !H NMR (MeOD-d4) δ 7.50-6.90 (m, 15H), 4.60 (broad t, IH), 4.25-3.95 (m, 3H), 3.47(broad s, IH), 3.30- 2.72 ( m, 6H), 2.18 (s, 3H), 1.98-0.45 (m, H). MS(APCI): 468.10 (M+H). EXAMPLE 14 Preparation of cis-ri-N-(diphenylethvI)-N-benzovIlaminomethyl-4-N- guanidinomethyl cyclohexane (compound 30) The title compound 30 was prepared by following the synthetic routes described in Scheme 4 below. Scheme 4 (29) Example 14 Compound 30 Step l Preparation of ci -4-(N.N-dibenzyl)carboxamido) cyclohexane carboxylic acid (compound 25) The anhydride was prepared according to literature procedure [H.K. Hall, J. Org. Chem., 2027 (1963)]. A mixture of c/5-l,4-cyclohexane dicarboxylic acid (compound 23) (7.0 g, 40.65 mmol) and acetic anhydride (23 g) was heated at reflux for 5 h. Excess acetic anhydride and other volatiles were removed in vacuo under reduced pressure to give an oily residue as compound 24. To this crude anhydride (compound 24) was added neat dibenzylamine (8.68 g. 44 mmol) slowly. A viscous solution formed which was diluted with methylene chloride and the solution was stirred overnight. The mixture was then washed with 10% HCl solution, water, brine and then dried over magnesium sulfate. After concentration, the product (compound 25) was purified by silica gel column chromatrography, using a mixture of methanol/methylene chloride as the eluent. MS (APCI): 350.28(M-H). Step 2 Preparation of cw-l-N-(diphenylethyl)-4-(N.N-dibenzyl) cyclohexane dicarboxamide (compound 26) To an ice-cooled DMF solution (15 mL) of cw-4-(N.N-dibenzyl)carboxamido) cyclohexane carboxylic acid (compound 25) prepared in the previous step 1 (1.76 g, 5 mmol), was added 2.2-diphenylethylamine ( 1.03 g, 5 mmol), diisopropylethylamine (2.2 mL, 12.5 mmol), and BOP reagent (2.2 g, 5 mmol). The reaction mixture was stirred overnight. It was diluted with ethyl acetate, and washed with 10% HCl, aqueous sodium bicarbonate solution, brine, dried over magnesium sulfate and concentrated. The product (compound 26) was purified by silica gel chromatography, using a mixture of methanol/methylene chloride as the eluent. Yield: 1.30 g. MS(APCI): 531.26 (M+H). Step 3 Preparation of c«-[l-N-(diphenylethyl)-4-(N,N-dibenzyl)l-bis-aminomethyl cyclohexane (compound 27) A mixture of cw-l-N-(diphenylethyl)-4-(N,N-dibenzyl) cyclohexane dicarboxamide (compound 26) prepared in the previous step 2 (1.2 g, 2.26 mmol), and a IM borane.TΗF complex (14 mL) was heated at reflux overnight. After cooling to r.t., a 3.3M solution of HCl in methanol (3.6 mL) was added to the reaction mixture and heated at reflux for 2 h. The mixture was then concentrated, diluted with ethyl acetate and washed with aqueous sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to give 1.08 g of product (compound 27). MS(APCI): 503.31 (M+H). Step 4 Preparation of cis -f l-N-(diphenylethvD-N-benzoyll-4-(N.N-dibenzyl)l-bis- aminomethyl cyclohexane (compound 28) A methylene chloride solution of cz ' 5 , -[l-N-(diphenylethyl)-4-(N,N-dibenzyl)]-6/5- aminomethyl cyclohexane (compound 27) prepared in the previous step 3 (0.82 g, 1.63 mmol), was acylated with benzoyl chloride (0.21 mL. 1.79 mmol) in the presence of triethylamine (0.454 mL, 3.26 mmol). After 4 h. at r.t., the mixture was washed with sodium bicarbonate solution, brine, dried over magnesium sulfate and concentrated. The product (compound 28) was purified by silica gel chromatography, using a mixture of ethyl acetate/hexane as the eluent. Yield: 0.609 g. MS(APCI): 607.36 (M+H). Step 5 Preparation of cis-\ l-N-(diphenylethyl)-N-benzoyll-4-6/s-aminomethyl cyclohexane (compound 29) A solution of cis-[ 1 -N-(diphenylethyl)-N-benzoyl]-4-(N,N-dibenzyl)]-iw-aminomethyl cyclohexane (compound 28) prepared in the previous step 4 (0.77 g, mmol), in glacial acetic acid (25 mL) was hydrogenated at 55 psi in the presence of 10% Pd/C catalyst (0.9 g) for 3 days. The mixture was filtered. The filtrate was concentrated and the product (compound 29) was purified by silica gel chromatography. MS(APCI4: 427.24 (M+H). Step 6 Preparation of c«-[l-N-(diphenylethyl)-N-benzovI]aminomethyl-4-N- guanidinomethyl cyclohexane (compound 30) The above product diamine (0.154 g, 0.36 mmol) was dissolved in THF and 1-H-pyrazole- l-(N,N-έ/s(tert-butoxycarbonyl)carboxarrudine (0.13 g) was added. The mixture was stirred at r.t. for 2-3 h and then concentrated. The product was purified by silica gel chromatography using ethyl acetate/hexane as the eluent. -[l-N-(diphenylethyl)-N-benzoyl]aminomethyl-4-N-(diBoc)guanidinomethyl- cyclohexane (0.16 g, mmol) was mixed with 50% TFA/CH2CI2 and stirred at r.t. for 2.5 h. The mixture was concentrated. The residue was dissolved in water and lyophilized to give a powder. MS (APCI): 469.24 (M+H). EXAMPLE 15 Preparation of frfl«s-1 N-benzoyl-N-(2 -diphenylethyl)aminomethyl-4- guanidinomethyl cvclohexanel (compound 37) The title compound 37 was prepared by following the synthetic routes described in Scheme 5 below. Scheme 5 (XXIII) (XXIV) Examples 15-33 Compounds 37-55 Step l Preparation of ftϊ?«s-4-N-(Boc)aminomethyl cyclohexane carboxylic acid (compound 32) To an aqueous solution (500 mL) of sodium hydroxide (68 g, 1.7 mol) cooled in an ice bath was added /røws-4-aminomethyl cyclohexane carboxylic acid (compound 31) (150 g, 0.95 mol). The solution was diluted to 1 liter with acetonitrile. Di-/erf-butyl dicarbonate (229 g, l.Zeq) was added portionwise and the mixture was stirred overnight. The acetonitrile was removed by rotary evaporation and the remaining aqueous mixture was extracted with ethyl acetate. The aqueous layer was acidified to pH 3 with NaHSO4, then was extracted with ethyl acetate. The pooled organic extracts were dried over MgSO and concentrated to give 224. g of product (compound 32) (0.87 mol, 91%). Step 2 Preparation of frα« -4-aminomethyl cvclohexane-l-(N-2.2-diphenylethyl) carboxamide (compound 33) rrα« -4-N-(Boc)aminomethyl cyclohexane carboxylic acid (compound 32) (37 g, .147 mol) was dissolved in methylene chloride (250 mL) and treated with 2,2-diphenylethylamine (29 g, 0.147 mol), benzotriazol-1-yloxy- fns(dimethylamino)phosphonium hexafluorophosphate (BOP reagent ) (65.1 g, .147 mol), then basified with triethylamine (37.2. g, 0.367 mol, 2.5 eq). After stirring overnight the reaction mixture was washed with water, 10% Na2CO3, and 10% NaHSO4, dried over MgSO4 and concentrated to give 76 g of product (compound 33). The product (compound 33) was dissolved in methylene chloride (200 mL) and treated with trifluoroacetic acid (200 mL). After stirring for 30 minutes, solvent and excess reagent were removed by rotary evaporation. Water (400 mL) was added and the mixture extracted with ethyl acetate. The aqueous layer was then treated with base to pH 12 and chilled. The precipitated free amine product (compound 34) was collected by filtration and dried: 36.2 g (0.108 mol). MS (APCI): 354 (M+H) Step 3 Preparation of fr< ι 5-4-aminomethyl-l-N-(2. > 2-diphenylethyl)aminomethyl cyclohexane (compound 35) A mixture of the carboxamide (compound 34) ( 15. g,~ 44.6 mmol) and 1 M solution of borane.TΗF complex ( 180 mL) was refluxed overnight. After cooling a solution of HCl in methanol ( 180 mmol) was added, and the mixture was heated at reflux for 2 h. Excess reagent and solvent were removed under reduced pressure. The residue was dissolved in CH2CI2 and washed with 1 N NH4OH, brine, dried over MgSO4 and concentrated to give 11.1 g of product (compound 35). Step 4 Preparation of .ra«,s-4-N-(diBoc)guanidinomethyl-l-rN-(2.2- diphenylethvDaminomethyl cyclohexane (compound 36) A mixture of the diamine (compound 35) (10. g, 31 mmol) and l-H-Pyrazole-l-(N,N- έ/s(tert-butoxycarbonyl)carboxamidine ( 9.6 g, 31 mmol) in THF (100 mL) was stirred at r.t. for 3-5 h. The reaction mixture was concentrated and the product was purified by silica gel chromatography to afford 15 g. of product (compound 36). l U NMR (CDCI3) δ 8.18 (broad s. IH), 7.44 (s, IH), 7.43-7.03 (m. 10H), 4.04 (t, IH), 3.09 (m. 4H), 2.31 (d, 2H), 1.62-1.49 (m, 6H), 1.34 (s, 18 H), 0.77-0.71 (m. 4H). MS (APCI): 565.36 (M + H), 465.31, 365.20. Step 5 Preparation of fra«s-4-N-(diBoc)guanidinomethyl-l-N-rN-benzoyl-N-2.2- 2 diphenylethvDaminomethyl cyclohexane (compound XXIII where R = phenyl) To a solution of secondary amine (compound 36) (1 eq) in dioxane or methylene chloride, was added triethylamine (1.5-2.0 eq), followed by benzoyl chloride (1 eq). The reaction mixture was stirred at room temperature for 3 h, then basified with 1 N K2CO3 solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, concentrated and chromatographed on silica gel or purified by preparative TLC using a mixture of hexane-ethyl acetate as the eluent. Step 6 Preparation of fra/.s-MN-benzoyl-N-(2,2-diphenylethyl)aminomethyl1-4- guanidinomethyl cyclohexane (compound XXIV where R = phenyl) The diBoc-guanidino compound (compound XXIII) was dissolved in 4 N HCl in dioxane or 50 % trifluoroacetic acid in methylene chloride, and stirred at room temperature for 2 h. The solvent was removed under reduced presure. The residue was dissolved in water and 2 lyophilized. The product (compound XXIV where R =phenyl) may also be purified by reversed-phase HPLC using acetonitrile-water as the eluent. Examples 16-33 The compounds of Examples 16-23 (compounds 38-55) were prepared as described for compound 37 of Example 15, using the reagents in the respective Examples as described in Table 2 below. ON Examples 34-35 The compounds 60 and 61 of Examples 34 and 35 were prepared by following the synthetic procedure described in Scheme 6 below. Scheme 6 .Example 34 Compound 61 Example 35 Example 34 Preparation of trans-l-r(N-Benzoyl-N-(2,2-diphenylethyl)l-aminomethyll-4-(N- benzvD-aminomethyl cyclohexane (compound 60) Step 1 Preparation of .'ra/is-4,N,N-(Dibenzvi)-aminomethyl cyclohexane carboxylic acid (compound 56) To a suspension of (40.0 g, 254 mmol) of tn y-4-(Aminomethyl)cyclohexanecarboxylic (compound 31) acid, in 1.5 L of methanol was added benzaldehyde (60 ml, 590 mmol) followed by sodium cyanoborohydride (16g, 254 mmol). The pH was then adjusted to approx. 5 with glacial acetic acid. The reaction was allowed to stir for 48 hrs, during which the pH is monitored and adjusted to 5 as needed, after which the reaction volume was then decreased and the pH adjusted to 9 with 1 N NaOH. The reaction was then extracted repeatedly with diethyl ether. The organic layers were combined, washed with brine, dried over Na SO 4 , filtered and concentrated. The resulting product solidifies on standing and was recrystallized from methanol giving 32 g of impur product (compound 56) which was , used without further purification in the next step. The monobenzyl was isolated as a white solid which formed during the extraction and was collected by filtration. (8.2g) Monobenzyl H NMR: (D 2 O) δ (ppm): 7.40-7.20 (5H, m, Ar), 4.06 (CH 2 Ar, 5H, s), 2.75 (2H, d, J=7.2, NCH 2 ), 1.95-1.85 (IH, m), 1.75-1.72 (2H, m), 1.64-1.62 (2H, m), 1.56-1.51 (lH, m), 1.22-1.11 (2H, m), 0.91-0.81 (2H, m). 13 C NMR: (D 2 O, DSS) δ (ppm): 31.43 (CH 2 ), 31.88 (CH 2 ), 36.81 (CH), 48.95 (CH), 54.01 (NCH 2 ), 55.35 (NCH 2 ), 131.94 (CH), 132.37 (CH), 132.60 (CH), 133.30 (C), 188.43 (C=O). Step 2 Preparation of rr ns-4-N,N-(Dibenzyl)-aminomethyl cyclohexane-l-(N- 2.2-diphenylethyl) carboxamide (57) To a solution of (compound 56) prepared in the previous step 1 (5,3 g, 15,72 mmol), in dry THF (75 ml) at -25 °C, was added triethylamine (2.63 ml, 18.87 mmol) followed by isobutylchloroformate (2.45 ml, 18.87 mmol). The reaction mixture was stirred 30 min at 25 °C. A white pricipitate was formed during the reaction. The 2,2-diphenylethylamine (4.65 g, 23.58 mmol) was added. The reaction mixture was warmed up to r.t., stirred for 3h30 and quenched with saturated aqueous NH4CI solution, and extracted with CH 2 C1 2 . The organic layer was dried over anhydrous MgSO4 and concentrated to give a crude product (compound 57), which was further purified by silica gel column chromatography using CH 2 C1 2 to give a white powder which was used directly to the next step. H NMR: (CDCI3, TMS) δ (ppm): 7.47-7.19 (20H, m Ar), 5.30 (IH, m, NH), 4.17-4.14 (IH. m, CH), 3.88-3.80 (2H, m, CH 2 N), 3.49 (4H, s, CH 2 Ph), 2.16-2.14 (2H, m, CH 2 N), 1.91-1.43 (6H, m), 1.33-1.28 (2H, m). 0.69-0.64 (2H, m). Step 3 Preparation of fra«s-4-N,N-(Dibenzyl)-aminomethyl-l-(N-2,2-diphenylethyl) aminomethyl cvclohexane(compound 58) To a solution of crude product (compound 57) (6.19 g, 11.9 mmol) in dry THF (150 ml) at r.t was added LAH (6.83 g, 180 mmol). The mixture was heated at reflux 80 °C overnight. The mixture was then cooled down at r.t. quenched with MeOH at 0 °C until no hydrogen formation evolved and 1 N HCl was added to dissolve the precipitate formed. The gray mixture was extracted with CH 2 C1 . The organic layer was dried over anhydrous Na 2 SU4 and concentrated to give the crude product which was further purified by MPLC using CH 2 Cl 2 MeOH (97:3) to provide the titled compound (compound 58) (4.15 g, 67%) as a white powder. H NMR: (CDCI3, TMS) δ (ppm): 7.35-7.18 (20H, m, Ar), 4.19(1H, t, CH), 3.49 (4H, s, CH 2 Ph), 3.19 (2H, d, CH 2 N), 2.45 (2H, d, CH 2 N), 2.16 (2H, d, CH 2 N), 1.87-1.84 (2H, m), 1.65-1.62 (2H, m), 1.52 (2H, m), 1.27 (IH, s, br, NH), 0.90-0.64 (4H, m). Step 4 Preparation of /ra« -4-N,N-(Dibenzyl)-aminomethyl-l-(N-2,2-diphenylethyl) aminomethyl cyclohexane benzamide (compound 59) To a solution of (compound 58) prepared in the previous step 3 (4.1 g, 8.17 mmol), in dry CH 2 C1 2 at r.t., was added triethylamine (2.27 ml, 16.34 mmol) and benzoyl chloride (1.19 ml, 9.8 mmol). The reaction mixture was stirred 1 h at r.t. then the solvent was removed under reduced pressure. The resulting crude product (compound 59) was further purified by silica gel column chromatography using hexane-AcOEt (9: 1-1:1) to give (4.14 g, 84 %) of title product as a white powder. *H NMR: (CDCI3, TMS) δ (ppm): 7.34-7.20 (22H, m, Ar), 7.20-6.98 (3H, m, Ar), 4.59- 4.4.55 (IH, m, CH), 4.13-3.94 (2H, m, CH 2 N), 3.51-3.33 (4H, m, CH 2 Ph), 2.78-2.76 (2H, , m, CH 2 N), 2.19-2.13 (2H, m, CH 2 N), 1.92-1.25 (6H, m), 0.90.51 (4H, m). Step 5 Preparation of /ra t5-4-N-(Benzyl)-aminomethyl-l-(N-2,2-diphenylethyl) aminomethyl cyclohexane benzamide (compound 60) To a solution of (compound 59) prepared in the previous step 4 (870mg, 1.44 mmol), in AcOH (10ml) and MeOH (10 ml), was added palladium on activated carbon 10 % (187 mg). The mixture was stirred overnight at r.t. with 60 psi of hydrogen. The mixture was then filtered over celite pad and the solvent was removed under reduced pressure. The resulting mixture was dissolved in CH 2 C1 2 and extracted with saturated aqueous NaHCO3 solution. The organic layer was dried over anhydrous MgSO4 and concentrated to give the crude product (compound 60) which was further purified by silica gel chromatography using CH Cl 2 -MeOH (9: 1) to provide the desired product as a clear oil (631 mg, 85 %). *H NMR: (CDCI3, TMS) δ (ppm): 7.43-7.23 (17H, m, Ar), 6.96-6.94 (3H, m, Ar), 4.60-4.55 (IH, m, CH), 4.20-3.95 (2H, m, CH 2 N), 3.79 (2H, s, br, CH 2 Ph), 3.20 (IH, s, br CH 2 N), 2.85-2.79 (IH, m, CH 2 N), 2.59-2.53 (2H, m, CH 2 N), 1.90-1.20 (5H, m),1.30 (IH, s, br), 1.10-0.90 (2H, m), 0.65-0.50 (2H, m). Example 35 Preparation of /ra/i5-4-Aminomethyl-l-(N-2^2-diphenylethyl)-aminomethyl cyclohexane benzamide (compound 61) The compound 60 (3.2 g, 6.25 mmol) was dissolved in AcOH (20 ml) and MeOH (20 ml) and Palladium on activated carbon (10 %) (546 mg) was added to the solution. The mixture was stirred overnight with 60 psi of hydrogen, then 4h at 70 °C. The mixture was then cooled down and filtered over celite pad and the solvent removed under reduced pressure. The crude product was dissolved in CH 2 C1 and the organic phase washed with saturated aqueous NaHCO3 solution. The organic layer was dried over anhydrous MgSO4 and concentrated to give the pure desired product (compound 61) (2.6 g, 98 %). X H NMR: (CDCI3, TMS) δ (ppm): 7.35-7.22 (12H, m, Ar), 7.00-6.98 (3H, m, Ar), 4.60-4.58 (IH, m, CH), 4.16-4.14 (IH, m, CH 2 N), 3.97 (IH, s, br, CH 2 N), 3.36 (IH, s, br CH 2 N), 2.82-2.80 (IH, m, CH 2 N), 2.49 (2H, m, CH 2 N), 1.81-1.53 (7H, m),1.09 (IH, m), 0.83-0.80 (2H, m), 0.59-0.55 (2H, m). Example 36 Preparation of /ra«s-l-fN-(/ran.s-2-phenyl cvclopropyD-N-benzoyll-aminomethyl -4- guanidinomethyl cyclohexane (compound 67) Compound 67 of this Example was prepared by following the synthetic route described in Scheme 7 below. 1.TFA 2. BH 3 .THF (63) (64) (65) (66) Step l Preparation of frgfis-4-N-(Boc)-aminomethyl cvclohexane-l-(fra«jf-2-phenyl cyclopropyl) carboxamide (compound 63) The compound 63 was prepared according to the general protocol for amide bond formation: To an ice-cooled DMF solution (15 mL) of trα«s-2-phenylcyclopropylamine hydrochloride (compound 62) (0.848 g, 5 mmol) was added DIEA (3.071 mL, 17.5 mmol), /r< s-4-N-(Boc)aminomethyl cyclohexane carboxylic acid (compound 32) (1.285 g, 5 mmol), and BOP reagent (2.21 g, 5 mmol). The reaction mixture was stirred at r.t. overnight and worked up according to the general protocol. Step 2 Preparation of fra/ιs-4-aminomethyl -l-N-(frans-2-phenyl cvclopropyD-aminomethyl cyclohexane (compound 64) trα«j , -4-N-(Boc)-aminomethyl cyclohexane- 1 -(fn s-2-phenyl cyclopropyl )carboxamide (compound 63) prepared in the previous step 1 (1.1 g, mmol) in 50%TFA/CH2θ2 was stirred at r.t. for 1.5 h and then concentrated. The crude product was diluted with methylene chloride and neutralized with K2CO3 solution. The organic layer containing the carboxamide was dried over MgSO4 and concentrated to a solid residue: MS(APCI): 273.1 (M+H). The carboxamide (0.200 g. 0.7 mmol) was suspended in THF (3 mL). A I M solution of borane.THF complex (6 mL) was added and the reaction mixture was refluxed overnight. After cooling to r.t. a 1.77 M solution of HCl in methanol (3.3 mL) was added, and the mixture was heated at reflux for 2 h. Excess reagent and solvent were removed under reduced pressure. The residue was dissolved in CH2CI2 and washed with 1 N NaOH, brine, dried over MgSO4 and concentrated: 0.184 g. MS(APCI): 259.1 (M+H) Step 3 Preparation of fra/ιs-4-N-(diBoc)-guanidinomethyl -l-N-(fraw -2-phenyl cyclopropyl)- aminomethyl cyclohexane (compound 65) The crude diamine (compound 64) (0.18 g) was reacted with an equimolar 1-H-pyrazole- l-(N,N-όw(tert-butoxycarbonyl)-carboxamidine in THF following the protocol described in the General Procedure. The product was purified by silica gel chromatography: 0.059 MS(APCI): 501.2 (M+H), 401.2, 301.2 Step 4 Preparation of fra/ι,s-4-N-(diBoc)-guanidinomethyl -l-ιN-(fra/ts-2-phenyl cvclopropyD-N-benzoyll -aminomethyl cyclohexane (compound 66) Benzoylation was carried out according to the protocol described in the General Procedure. The product was purified by preparative TLC using a mixture of ethyl acetate/hexane as the eluent: 0.026 g. MS(APCI): 605.1 (M+H), 505.2, 405.1 Step 5 Preparation of fra«5-l-[N-(fra« -2-phenyl cvclopropyD-N-benzoyllaminomethyl -4- guanidinomethyl cyclohexane (compound 67) The deprotection was carried out according to the protocol described in the General Procedure. Solvent and excess reagent were removed under reduced pressure. The residue was dissolved in a mixture of acetonitrile/water and lyophilized to give the product as a powder: MS (APCI): 405.2 (M+H) Example 37 The compound 75 of Example 37 was prepared by following the synthetic procedure described in Scheme 8 below. Scheme 8 Stepl Preparation of 9,10-Dihvdro-9,10-ethanoanthracene-l 1-carboxylic acid (compound 69) Diethyl 9,10-Dihydro-9,10-ethanoanthracene-l 1,1 1-dicarboxylic acid (2.05 g, 5.85 mmol) was dissolved in a 95% ethanolic aqueous solution. KOH pellets (0.794 g) were added and the mixture was refluxed overnight. The reaction mixture was extracted with diethyl ether. The ether extracts were concentrated to give a solid residue (compound 69) which was fractionated on a silica gel column to give the product (0.84 g): 1H NMR (CDC1 3 ) δ 7.05-7.40 (m, 8H), 4.67 (m, IH), 4.32 (m. IH), 2.90 (m, IH), 1.96- 2.18 (m, 2H). MS(APCI) -Q1MS: 249.0 (M-H). Step 2 Preparation of 9,10-Dihvdro-9,10-ethanoanthracene-ll-amine (compound 70) A round bottom flask was charged with 9,10-Dihydro-9,10-ethanoanthracene-l 1- carboxylic acid (0.635 g, 2.54 mmol), benzene (10 mL), triethylamine (0.356 mL), and diphenylphosphoryl azide (0.718 g). The solution was heated at 90 C for 1 h. t-Butanol ' (0.222 g) was added to the reaction mixture and it was refluxed overnight. The reaction mixture was then concentrated, redissolved in ethyl acetate, washed with sodium bicarbonate, brine, dried over Mg SO4 and concentrated. Brief exposure to 50%TFA/CH2θ2, followed by neutralization with potassium carbonate solution gave the amine: 1H NMR (CDCb) δ 7.20 (m, 8H), 4.38 (br s, IH), 4.26 (br s, IH), 3.75 (m, IH), 2.32 (m, IH), 1.55 (m, IH), 1.50 (s, 2H). MS(APCI): 222.1 (M+H) Step 3 Preparation of fra«y-4-N-(Boc)-aminomethyl cvc.ohexane-l-N-(9.10-dihvdro-9,10- ethanoanthracen-ll-vD-carboxamide (compound 71) This compound was prepared according to the General Procedure described for amide formation: To an ice-cooled DMF solution (5 mL) of 9,10-Dihydro-9,10- ethanoanthracene-11 -amine (0.221 g, 1 mmol) was added DIEA (0.479 mL, 2.75 mmol), r< y-4-N-(Boc)aminomethyl cyclohexane carboxylic acid (0.282 g, 1.1 mmol), and BOP reagent (0.487 g, 1.1 mmol). The reaction mixture was stirred at r.t. overnight and worked up according to the general protocol. Crude yield: 0.418 g. The product was purified by silica gel chromatography. Step 4 Preparation of fraws-4-aminomethyl -l-N-(9,10-dihvdro-9.10-ethanoanthracen-ll- vDaminomethyl cyclohexane (compound 72) /ra 75-4-N-(Boc)-aminomethyl cyclohexane-l-N-(9,10-dihydro-9,10-ethanoanthracen-l 1- yl)carboxamide (0.28 g, 0.61 mmol) in 50%TFA/CH2Cl2 was stirred at r.t. for 1.5 h and then concentrated. The crude product was diluted with methylene chloride and neutralized with K2CO3 solution. The organic layer was dried over MgSO4 and concentrated to a solid residue: 1H NMR (CDCb) δ 7.20 (m, 8H), 4.84 (br d, IH), 4.36 (m, 2H), 4.28 (br s, IH), 2.50 (d, 2H), 2.35 (m, IH), 1.8 (m, 5H), 1.2-1.5 (m, 4H), 0.85 (m, 2H). MS(APCI): 361.1 (M+H) ■ The carboxamide (0.22 g, .61 mmol) was dissolved in THF (3 mL). A 1 M solution of borane.THF complex (2.5 mL) was added and the reaction mixture was refluxed overnight. After cooling a 1.77 M solution of HCl in methanol ( 1.4 mL) was added, and the mixture was heated at reflux for 2 h. Excess reagent and solvent were removed under reduced pressure. The residue was dissolved in CH2CI2 and washed with 1 N NaOH, brine, dried over MgSO4 and conconetrated: 0.165 g. MS(APCI): 347.2 (M+H) Step5 Preparation of fra i -4-N-(diBoc)-guanidinomethyl -l-N-(9,10-dihvdro-9,10- ethanoanthracen-ll-vD-aminomethyl cyclohexane (compound 73) The crude diamine (0.16 g, 0.46mmol) was reacted with an equimolar 1-H-pyrazole-l- (N,N-όw(tert-butoxycarbonyl)-carboxamidine in THF. The product was purified by silica gel chromatography: 0.290 g. MS(APCI): 589.2(M+H), 489.2, 389.1 Step 6 Preparation of l'ra/i5-4-N-(diBoc)-guanidinomethyl -l-[N-(9 Q-dihydro-9.10- ethanoanthracen-ll-yl)-N-benzoyllaminomethyl cyclohexane (compound 74) Benzoylation was carried out according to the protocol described in the General Procedure. The product was purified by preparative TLC using a mixture of ethyl acetate/hexane as the eluent: 0.174 g o.- MS(APCI): 693.2 (M+H), 593.1, 493.1 Step 7 Preparation of fra«s-l-fN-benzovI-N-(9,10-dihvdro-9,10-ethanoanthracen-ll- yl)l aminomethyl -4-guanidinomethyl cyclohexane (compound 75) The deprotection was carried out according to the protocol described in the General Procedure. Solvent and excess reagent were removed under reduced pressure. The residue was dissolved in a mixture of acetonitrile/water and lyophilized to give the product as a powder: MS (APCI): 493.15 (M+H) General Procedures for the preparation of substituted diphenylethyl derived compounds: Substituted diaryl acetaldehyde may be prepared according to the following reaction Scheme 9, that is, by a Wittig reaction on the corresponding diaryl ketone to form an enol ether which was then hydrolyzed to the aldehyde by acid treatment. Scheme V (XXIII) (XXIV) (XXV) The substituted diaryl acetaldehyde was then reacted with rαw-4-aminomethyl cyclohexane carboxamide under reductive amination conditions to form the secondary amine. The carboxamide was then reduced by borane to the primary amine which was guanylated. The secondary amine was then acylated, and finally the protecting group was removed by acid treatment to release the free guanidine. The reaction sequence is depicted in Scheme 9 below: Examples 39-47 Compounds 79-88 Step l Preparation of /ra/ι.s-l-carboxamide-4-aminomethyl cyclohexane (compound 78) Scheme 10 (76) (77) (78) To an ice-cooled THF solution (300 mL) containing m rcs'- 1-N-Cbz-aminomethyl- cyclohexane-4-carboxylic acid (29.1 g, 0.1 mol) was added N-methylmorpholine (11 mL, 0.1 mol) and isobutyi chloroformate (13 mL, 0.1 mol). After 4 minutes, a 30% solution of ammonium hydroxide (30mL, 0.53 mol) was added. The reaction mixture was agitated while the reaction was allowed to warm to r.t. in one hour. The reaction mixture was duluted with ethyl acetate and the precipitated product was collected by filtration. The solid residue was washed with aq. sodium bicarbonate, water, and dried, 25-1 g (98%). l U NMR (DMSO-d6) δ 7.12 (m, 5H), 7.0 (t, IH), 6.9 (br s, IH), 6.35 (br s, IH), 4.77 (s, 2H), 2.65 (t, 2H), 1.75 (m, IH), ), 1.5 (m, 4H), 1.0 (m, 3H), 0.6 (m, 2H). MS(APCI): 291.05 (M+H). The Cbz-protected /n s-1-N-Cbz-aminomethyl cyclohexane-4-carboxamide (25.1 g, 98 mmol) was dissolved in a mixture of methanol (200 mL) and DMF (40 mL). The solution was hydrogenolyzed at 50 psi in the presence of a 10% Pd/C catalyst (3.5 g). The reaction mixture was filtered through a pad of Celite. The filtrate was evaporated to give a solid, 15.2 g. l H NMR (DMSO-d6) δ 7.15 (s, IH), 6.6 (s, IH), 4.3 (br s, 2H), 2.35 (d, 2H), 1.9 (m, IH), 1.7 (m, 4H), 1.25 (m, 3H), 0.8 (m, 2H). MS(APCI): 157.05 (M+H). Step 2 Enol ether formation (general formula XXIV) To a suspension of the methoxymethyl triphenylphosphine chloride (2 eq) in anhydrous THF was added potassium tert-butoxide ( 2 eq) (alternatively sodium hydride can be used). To this solution was added a THF solution containing diaryl ketone (1 eq) of the general formula XXHI. The reaction mixture was stirred under nitrogen or argon overnight, at r.t. or warmed to 70° C if necessary. Water was added, and the reaction mixture was diluted with ethyl acetate and aq. sodium bicarbonate. The organic layer was washed with brine, dried over MgSO4 and concentrated. The product was purified by silica gel chromatography using a mixture of ethyl acetate and hexane as the eluent. Step 3 ' Conversion of enol ether to aldehyde (general formula XXV) The enol ether of the general formula XXIV( 1 eq) and p-toluenesulfonic acid monohydrate (5 eq) (aq. HCl may be used) was dissolved in THF. The mixture was heated at reflux for up to 16 h. and then was diluted with diethyl ether, washed with water, aq. sodium bicarbonate, brine, dried over MgSO4 and concentrated. The product aldehyde of the general formula XXV may be purified by silica gel chromatography. Step 4 Preparation of secondary amines by reductive amination To a solution of trans-l -aminomethyl cyclohexane-4-carboxamide (compound 78)(1 eq) in methanol containing 1% (v/v) of glacial acetic acid (alternatively, ZnCl2 can be used) was added aldehyde (1 eq), followed by NaBH3CN (3-4 eq). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water, basified with aqueous NaHCO3 solution and extracted with methylene chloride. The organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was chromatographed on silica gel using a mixture of methylene chloride/methanol as the eluent. Step 5 Reduction of carboxamide The carboxamide product ( 1 eq) from above was dissolved in minimum amount of THF. To this solution was added a IM solution of BH3.THF complex (3-5 molar excess) and the reaction mixture was heated at reflux overnight. After cooling to r.t., a methanolic hydrochloric acid solution (3-5 molar excess) was added to the reaction mixture and the mixture was refluxed for 2-4 h. It was then concentrated, diluted with methylene chloride and washed with N NaOH, brine, dried over MgSO4 and concentrated. Step 6 Guanylation The above product diamine (1 eq) was dissolved in THF and l-H-pyrazole-l-(N,N-6w(tert- butoxycarbonyl)carboxamidine ( 1 eq) was added. The mixture was stirred at r.t. for 2-3 h and then concentrated. The product was purified by silica gel chromatography using ethyl acetate/hexane or methylene chloride/methanol as the eluent. Step 7 Acylation To a solution of secondary amine ( 1 eq) in dioxane or methylene chloride was added triethylamine (1.5-2.0 eq), followed by the acid chloride (1 eq). The reaction mixture was stirred at room temperature for 3 h-overnight, then basified with IN K2CO3 solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, concentrated and chromatographed on silica gel or purified by preparative TLC using a mixture of hexane-ethyl acetate as the eluent. Step 8 Deprotection of diBoc-guanidino compounds The diBoc-guanidino compound was dissolved in 4N HCl in dioxane or 50% trifluoroacetic acid in methylene chloride and stirred at room temperature for 2 h to overnight. The solvent was removed under reduced pressure. The residue was dissolved in water and lyophylized. The product can also (when appropriate) be purified by reversed-phase HPLC using acetonitrile-water as the eluent. Example 38 Preparation of fra i -l-f(N-Benzoyl) -N-(2.2 t -Di(p-Tolyl)ethyl)1-aminomethyl- 4-guanidinomethyl cyclohexane hydrochloride (compound 79) Compound 79 Following the procedure described in the general procedures for the preparation of substituted diphenylethyl derived compounds step 2, but using 4,4-dimethylbenzophenone as the dialkyl ketone followed by step 3 to 8, the title compound 79 was achieved. 1H NMR (MeOD-d 4 ) δ 7.35 (m, 4H), 7.3 (d, 2H), 7.15 (d, 2H), 7.05 (m, 4H), 6.90 (d, IH), 4.55 (t, IH), 4.15 (d, 2H), 3.05 (dd, 2H), 2.85 (d, 2H), 2.6 (s, 6H), 1.9 - 1.75 (m, 4H), 1.0 ( m, 4H), 0.6 (m, 2H). MS(APCI):497.53 Examples 39-45 By following the same synthetic procedure as described for the preparation of compound 79 of Example 38, the compounds indicated in Table 3 below were prepared. Table 3 σv Table 3 (Contd.) Table 3 (Contd.) Table 3 (Contd.) Example 46 Preparation of Trans-l-rN-(benzoyl)-N-(2-phenyl-2-phenylethyl)l-aminomethyl- 4-guanidinomethyl cyclohexane hydrochloride (compound 97) The compound 97 of this Example, was prepared by following the synthetic route described in Scheme 11 below. Scheme 11 Example 46 Step l Preparation of 2-Phenyl benzaldehyde (compound 88) To a solution of compound 87 (10.6 g, 57.6 mmol) in methylene chloride (250 mL) was added manganese dioxide (63.16 g), and anhydrous magnesium sulfate (15 g). The mixture was stirred at r.t. for 16 h. The black suspension was filtered and washed with 4 100 mL of methylene chloride, concentrated in vacuo to give an almost colorless and highly refractive liquid (compound 88) (9.81 g): DNPH active, single spot on TLC (R f 0.39 in 4/1 hexane:ethyl acetate). Step 2 Preparation of 2-Phenyl nitrostyrene (compound 89) Compound 89 was synthesized in a similar fashion as reported for nitrostyrene (Organic Syntheses, Coll. Vol. I. 2nd ed., John Wiley & Sons, 1941, p.413): In a 1 litre round bottom flask placed in an ice bath and containing a solution of the aldehyde (compound 88) (9.81 g, 53.8 mmol) and nitromethane (3.3 g, 54.0 mmol) in methanol (25 mL) was added dropwise in 10 minutes a solution of 2.27 g NaOH in 3 mL of water. A viscous and almost colorless clear solution formed. This reaction mixture was stirred in the cold bath for 4.5 h. Then the light brownish clear solution was added dropwise to 20 mL of well stirred hydrochloric acid solution (1.5:l/water:conc. HCl) in 15 minutes. A bright yellowish brown oil formed. After about half of the reaction mixture was added, additional cone. HCl (10 mL) was added to the acidic solution and addition of the nitronate was continued. A thick brown oil formed. The mixture was stirred at r.t. for 1.5 h, then was extracted with methylene chloride 3 times. The organic extracts were combined, dried over magnesium sulfate and concentrated. The crude was chromatographed on silica gel column and eluted with a mixture of 20: 1 hexane:ethylacetate. The nitroolefin product (compound 89) was recrystallized from diethyl ether-hexane: 4.8 g of lemon yellow needles. Step 3 Preparation of 2-Phenyl-2-phenethylamine (compound 90) Compound 90 was synthesized in a similar fashion as reported in the literature (A. Kubo et al, Synthesis, 824 (1987)): In a 500 mL round bottom flask was placed LAH (2.5 g, 65.88 mmol) and dry THF (100 mL). To the stirred LAH suspension was added dropwise a solution of the nitroolefin (compound 89) (3.9 g, 17.33 mmol) in THF (10 mL) in 20 minutes. An exothermic reaction occurred. The reaction mixture was stirred for 15 minutes at r.t., then was heated to just boil for 10 minutes, and then was stirred at r.t. for 48 h. It was then cooled to 0°C and decomposed with 30% NaOH, diluted with hexane (20 mL), diethyl ether (100 mL) and allowed to warm to r.t. The mixture was dried with potassium carbonate, filtered, and concentrated to an oil. MS (APCI): 198. (M+H). Step 4 Preparation of Trans-l-(2-Phenyl-2-phenethyl)-4-N-Boc-4-aminomethvI cyclohexane carboxamide (compound 91) To an ice-cooled DMF solution (5 mL) of trαns-N-Boc-4-aminomethyl cyclohexane carboxylate (0.257 g, 1 mmol) was added 2-phenyl phenethylamine (compound 90) (0.197 g, 1 mmol), diisopropylethylamine (0.435 mL, 2.5 mmol) and BOP reagent (0.442 g, 1 mmol) successively. The reaction mixture was stirred overnight at r.t. It was then diluted with ethyl acetate and washed with water, 1 % HCl, sodium bicarbonate solution, brine and dried over magnesium sulfate and then concentrated. The product (compound 91) was purified on a silica gel column (eluting solvent : methylene chloride to 3% methanol in methylene chloride): 0.35 g. MS(APCI): 437.2 (M+H). Step 5 Preparation of Trans-(2-Phenyl-2-phenethyl)-4-aminomethyl cyclohexane carboxamide (compound 92) Compound 91 (0.34 g, 0.78 mmol) was dissolved in 50% trifluoroacetic acid in methylene chloride (5 mL) and stirred at r.t. for 2 h. The reaction mixture was concentrated and then redissolved in methylene chloride, basified with 30% ammonium hydroxide. The organic layer was washed with brine, dried over magnesium sulfate and then concentrated to a syrupy residue (compound 92): MS (APCI) 336.90 (M+H). Step 6 Preparation of fra i5-l-N-(2-phenyl-2-phenethyl)-aminomethyl-4-aminomethyl cyclohexane (compound 93) Compound 92 (0.191 g, .57 mmol) was dissolved in dry THF (2 mL). To this solution was added a 1 M solution of borane.THF complex (1.7 mL) and the reaction mixture was heated at reflux for 16 h under nitrogen. After cooling to r.t., a 3.3 M solution of HCl in methanol (0.7 mL) was added to the reaction mixture and the mixture was refluxed for 2 h. After cooling to r.t., the reaction mixture was concentrated and then basified with IN NaOH. The product was extracted with methylene chloride. The organic extractes were dried over magnesium sulfate and concentrated to give (compound 93): MS (APCI) 323.16 (M+H). Step 7 Preparation of frα«s-l-N-(2-phenyl-2-phenethvD-aminomethyl-4-N-(diBoc)- guanidinomethyl cyclohexane (compound 95) The diamine (compound 93) (0.18 g, .56 mmol) was dissolved in THF (5 mL). To this solution was added diBOC-guanylpyrazole (compound 94) (0.174 g, 0.56 mmol). The mixture was stirred at r.t. overnight, then was concentrated. The product (compound 95) was purified by silica gel chromatography (eluting solvent: methylene chloride to 3 % methanol in methylene chloride): 0.121 g. 1H NMR (CDCI 3 ) δ 8.2 (br t, IH), 7.05-7.3 (m, 10H), 3.08 (br t, 2H), 2.65 (t, 2H), 2.5 (t, 2H), 2.15 (d, 2H), 1.45-1.7 (m, 4H), 1.39 (s, 18H), 0.6-1.19 (m, 6H). MS (APCI): 565.37 (M+H). Step 8 Preparation of Trans -l-fN-benzoyl-N-(2-phenyl-2-phenylethyl)l-aminomethyl-4-N- (diBoc)-guanidinomethyl cyclohexane (compound 96) The acylation was carried out according to the General procedure for acylation of secondary amine: Compound 95 (0.121 g, 0.214 mmol) was dissolved in methylene chloride (3 mL). To this solution was added triethylamine (0.060 mL, 0.429 mmol) and benzoyl chloride (0.028 mL, 0.24 mmol). The mixture was stirred at r.t. for 2 h. The product (compound 96) was purified by prep TLC (2mm thickness, solvent: l:3/ethyl acetate: hexane): .118 g (83%). Step 9 Preparation of rra«5-l-fN-(benzoyl)-N-(2-phenyl-2-phepylethyl)l-aminomethyl- 4-guanidinomethyl cyclohexane hydrochloride (compound 97) " The title compound 97 (0.112 g, 0.167 mmol) was deprotected according to General procedure for deprotection of diBoc-guanidino compounds. The product (compound 97) was dissolved in an aqueous solution and lyophilized. H NMR (DMSO-d6) δ 7.52-6.75 (m, 17H), 3.9 (m, 3H), 2.55-3.12 (m, 5H), 0.2-1.8 (m, 10H). MS (APCI): 469.31 (M+H). Example 47 Preparatiop of trans-[N-(benzoyl)-N-2-(2-hydroxyphenyl)ethyll-aminomethyl- 4-guanidinomethyl cyclohexane hydrochloride (compound 107) The compound of this Example was prepared by following the synthetic procedure described in Scheme 12 below. Step 1 Preparation of 2-Benzyloxy-2- phenethylamine (compound 99) 2-benzyloxyphenylacetonitrile (compound 98) (15 g, 67.2 mmol) was dissolved dry THF (20 mL). To this solution was added a 1.0 M solution of borane THF complex (200 mL). The reaction mixture was refluxed overnight, then cooled to r.t. A 3M solution of HCl in methanol.(67 mL) was added and the mixture was refluxed again for 3 h. After cooling, the reaction was basified with Na 2 CO 3 , extracted with methylene chloride, dried and concentrated to give compound 99. MS:227.93 (M+H) Step 2 Preparation of Trans-2-[(2-benzyloxyphenyl)ethyll-N-Boc-4-aminomethyl cyclohexane carboxamide (compound 101) Compound 99 (16 g )was dissolved in THF and cooled in an ice bath, trans -4-N-(Boc) aminomethyl cyclohexane- 1-carboxylate (compound 100) (18.1 g) was added, followed by the additions of diisopropylethylamine (20 g), and BOP reagent (31 g). The reaction mixture was stirred at r.t. for 3 days. THF was removed and the reaction mixture was diluted with water and EtOAc. The organic layer was dried over magnesium sulfate and concentrated.The brown residue (compound 101)was repeatedly washed with ether until it was light yellow. MS: 466.93 Step 3 Preparation of Trans-2-r(2-benzyloxyphenyl)ethvn-N-4-aminomethyl cyclohexane carboxamide (compound 102) Compound 101 was deprotected by stirring in a 50% TFA CH 2 C1 2 solution for 3 hours. Solvent and excess reagent were evaporated and the residue was redissolved in EtOAc and basified with K CO 3 . At pH 9, white solid (compound 102) precipitated and was collected and washed with EtOAc and dried. MS: 367.2 Step 4 Preparation of Trans-l-N-r2-(benzyloxyphenyl)ethyll-aminomethyl-4-aminomethyl cyclohexane (compound 103) Compound 102 (10 g) was dissolved in dry THF (10 mL) and a IM solution of borane/THF complex (81 mL) was added.The reaction mixture was refluxed overnight, then cooled and a 2.8M solution of HCl in methanol (30 mL) was added.The mixture was refluxed again for 3 hours. After cooling to r.t., the reaction was basified with Na 2 CO 3 , extracted with methylene chloride, dried and concentrated. 7.6 g of product (compound 103) were obtained. MS: 352.92 Step 5 Preparatiop of /rfl/i5-l-N-r(2-Benzyloxyphenyl)ethyll-aminomethyl-4- (diBoc)guanidinomethyl cyclohexane (compound 104) Compound 103 (7.6 g) was reacted with diBoc-guanylpyrazole (compound 94) (6.7 g) in THF according to the conditions described in the general procedure to give the product (compound 104) (6.0 g). MS: 595.23 Step 6 Preparatiop of Trans-l-rN-(benzoyl)-N-(2-benzyloχyphenyl)ethyll-aminomethyl-4- (diBoc)guanidinomethyl cyclohexane (compound 105) Compound 104 (6.0 g) was acylated with benzoyl chloride (1.68 g) according to the General procedure for acylation of secondary amine. The acylated product (compound 105) was purified by silica gel chromatography: 6.2 g. 1H NMR (CDC1 3 ) δ 7.35 (m, 10H), 6.9 (broad, 4H), 5.70 (broad, IH), 4.85 (s, 2H), 3.50 (t, 2H), 3.35(d, 2H), 3.15 (broad, 2H), 2.75(broad, 2H), 1.8 (m, 6H), 1.55 (s, 18H), 0.9 (m,4H). MS: 699.38 Step 7 Preparation of frgns-l-[N-(benzoyl)-N-2-benzyloxyphenyl)ethyll-aminomethyl-4- (diBoc)guanidinomethyl cyclohexane (compound 106) Compound 105 (6.2 g) was dissolved in 5 ml of EtOAc and then diluted to 100 mL with methanol. 10% Pd on carbon catalyst (1 g) was added and the reaction was hydrogenolyzed (60 psi) in a Parr apparatus overnight. The reaction mixture was filtered through Celite and the filtrate was concentrated to give product (compound 106) (5 g). 1H NMR (CDCb) δ 8.7 (broad, IH), 8.3 (t, IH), 7.5 (m, 5H), 7.25 (dd, IH), 7.15 (d, IH), 7.0 (d, 2H), 6.75 (dd, IH), 3.60 (t, 2H), 3.25 (m, 4H), 3.0 (dd, 2H), 1.8 (m, 6H), 1.55 (s, 18H), 0.9 (m, 2H). 1.65 (m, 2H). MS: 609.38 Step 8 Preparation of fra ιs-l-fN-(benzoyl)-N-2-(2-hydroxyphenyl)ethyll-aminomethyl- 4-guanidinomethyl cyclohexane Hydrochloride (compound 107) Compound 106 was deprotected according to the General procedure for deprotection of diBoc-guanidino compounds to give the free guanidino compound 107 . ' 1H NMR (MeOD-d 4 ) d 7.40 (m, 4H), 7.05 (m,2H), 6.8 (d, 2H), 6.6 (m, 2H), 3.5 (m, 2H), 3.0 (m, 4H), 2.75 (t, 2H), 1.9 - 0.75 (broad m, 10H). MS(APCI): 409.27 Examples 48-51 The compounds 108-111 of Examples 48-51 were prepared by following the synthetic route described in Scheme 13 below. Example 49 & 51 Compouαds 109 & 111 X = 4-chloro X = 2-OCF, These compounds were synthesized by alkylating the appropriate primary amines by N-methyl chloroacetanilide to give the secondary amines. The secondary amines were then condensed with either /rø«.s-4-N-(diBoc)-guanidinomethyl cyclohexane- 1 -carboxylic acid or /ra«.s4-N-(Boc)-aminomethyl cyclohexane- 1 -carboxylic acid to form a new amide bond via BOP reagent as described in General Procedure for amide bond formation. Finally the amine protecting group (Boc) was removed by acid treatment as described in General Procedure to provide the desired products. Step l To a cooled suspension of tr< y-4-aminomethyl cyclohexane- 1 -carboxylic acid (25 g, 0.159 mol) in dry methanol (200 mL) was added thionyl chloride (17.4 mL, 0.238 mol) dropwise. After standing overnight, the solvent and excess reagent were evaporated. The hydrochloride salt was partitioned between diethyl ether and saturated potassium carbonate. The ether layer was dried over magnesium sulfate and evaporated to a colorless oil. Step 2 ' Preparation of Methyl /rα«5-4-N-(diBoc)-guanidinomethyl cyclohexane-1-carboxylate trans-Methyl 4-aminomethyl cyclohexane- 1 -carboxylic acid (8.61 g, 50.29 mmol) was dissolved in THF (80 mL) and a solution of l-H-pyrazole-l-(N,N-&w(tert- butoxycarbonyl)carboxamidine (15.59 g, 50.29 mmol) in THF was added. After stirring at r.t. for 3 h, solvent was evaporated. The residue was redissolved in diethyl ether, washed with water, dil. HCl solution, saturated sodium bicarbonate, brine, dried over magnesium sulfate and evaporated to a solid, 19.6 g (94%). Step 3 Preparation of fra/ιs-4-N-(diBoc)-guanidinomethvl cyclohexane-l-carboxylic acid To a solution of methyl tn y-4-N-(diBoc)-guanidinomethyl cyclohexane-l-carboxylic acid (19.5 g, 47.2 mmol) in dry THF (200 mL) was added potassium trimethylsilanolate (12.1 g, 94.4 mmol). The mixture was stirred at r.t. overnight. It was diluted with ethyl acetate/water. The organic layer was dried over magnesium sulfate and evaporated to give a solid residue. Step 4 Preparation of N-methyl chloroacetanilide To a solution of N-methylaniline (1.5 eq) in dichloromethane at 0 °C was added a solution of chloroacetylchloride (1 eq) in dichloromethane dropwise. The reaction was stirred at room temperature for 20 minutes before it was diluted with dichloromethane and washed with 1 N HCl (2x), saturated aqueous NaHCU 3 (2x), brine, and dried over MgSO 4 . Upon filtration and evaporation of the solvent, the product was obtained as a yellow solid. MS (APCI) : 183.95. Step 5 Amination of N-methyl chloroacetanilide A solution of the N-methyl chloroacetanilide (1 eq), triethylamine (2 eq), and a primary amine ( 1 eq) in dichloromethane was stirred at room temperature overnight. The reaction was diluted with dichloromethane and extracted with an aqueous solution of NaHCO3, brine, and dried over MgSO4. The sample was concentrated and purified by silica gel flash column chromatography using ethyl acetate/hexane. Specific examples are provided below: *H-NMR (CDC1 3 ): 7.4 (m, 2H), 7.2 (m, 3H), 7.1 (m, 2H), 3.6 (s, 2H), 3.4 (s, 3H), and 3.1 (s, 2H). The compounds 108, 109, 110 and 111 of Examples 48-51 were prepared as described above. The results are presented in Table 4 below. Example 52 Preparation of /ra iy-l-lN-(2.2-diphenylethyl)-N-(p-chlorophenoxyacetyl)l aminomethyl-4-guanidinomethyl cyclohexane hydrochloride (compound 112) (112) The acylation was carried out according to the General procedure for acylation of secondary amines: rrαns-4-N-(diBoc)guanidinomethyl-l-N-(2,2- diphenylethyl) aminomethyl cyclohexane (0.20 g, 0.35 mmol) was reacted with 4- chlorophenoxyacetyl chloride (61.5 mg, 0.3 mmol). The acylated product was purified by silica gel chromatography using a mixture of hexane-ethyl acetate as the eluent. MS: 733.4 (M+H) . The above compound was deprotected according to General procedure for deprotection of diBoc-guanidino compounds to give the free guanidino-compound 112 as the hydrochloride salt MS: 533.4 (M+H). Example 53 Preparation of frans-l-N-(cvcloheχylmethyl)-N-(benzoyl)-aminomethyl-4- guanidinomethyl cyclohexane hydrochloride (compound 120) Scheme 14 (i) Preparation of trans-4 N,N-(Dibenzyl)-aminomethyl cyclohexane carboxylic acid (compound 113) To a suspension of (40.0 g, 254.4 mmol) of trans-4-(aminomethyl)cyclohexanecarboxylic acid, in 1.5 L of methanol was added benzaldehyde (60 ml, 590.8 mmol) followed by sodium cyanoborohydride (16g, 254.6 mmol). The pH was then adjusted to approx. 5 with glacial acetic acid. The reaction was allowed to stir for 48 hrs, during which the pH is monitored and adjusted to 5 as needed, after which the reaction volume was then decreased and the pH adjusted to 9 with 1 N NaOH. The reaction was then extracted repeatedly with diethyl ether. The organic layers were combined, washed with brine, dried over NaiSO.,, filtered and concentrated. Product solidifies on standing and was recrystallized from methanol giving 32 g of impure product which was used without further purification in the next step The monobenzyl was isolated as a white solid, which formed during the extraction and was collected by filtration. (8.2g) Monobenzyl *H NMR: (400 MHz, D 2 O) δ: (2H, m, 0.81-0.91), (2H, m, 1.11-1.22), (IH, m, 1.51-1.56), (2H, m, 1.62, 1.64) (2H, m. 1.72-1.75), (IH, m, 1.87-1.95), (NCH 2 , 2H, d, J - = 7.2 ), (CH 2 Ar, 5H, s) 1 3 C NMR: (100, D 2 O, DSS) δ 31.43 (CH 2 ), 31.88 (CH 2 ), 36.81(CH), 48.95 (CH), 54.01 (NCH 2 ), 55.35 (NCH 2 ), 131.94 (CH), 132.37 (CH), 132.60 (CH), 133.30 (C), 188.43 (C=O) (ii) Preparation of /rfl«s-l-N-(Cvclohexylmethyl)-4-N,N-(dibenzvD- aminomethylcvclohexane carboxamide (compound 114) To a solution of the acid (compound 113) (8.11 g, 24.07 mmol, 1 eq) in THF (150 mL) at -25 °C was added Et 3 N (4.02 ml, 28.88 mmol, ml 1.2 eq) followed by chloroformate (3.75 ml, 28.88 mmol, 1.2 eq) Aloud to react for 30 mins then added cyclohexanemethylamine (4.7 ml, 36.11 mmol, 1.5 eq). Strirred over night, added saturated NHLCl, extracted 3 X with ethyl acetate, dried over MgSO 4 . Purified by MPLC, 5 % MeOH/CH 2 Cl 2 . Yielded 10.4 g, 100% (iii) Preparation of fran,s-l-N-(Cvclohexylmethyl)-aminomethyl-4-N,N-(dibenzyl) aminomethyl cyclohexane (compound 115) To a solution of amide (compound 114) in THF 100 mL was added BH 3 THF IM (71.9 mL, 71.9 mmol, 3 eq). The reaction was heated at reflux for 12 hrs. 80 °C. Then cooled down to RT. A solution of 1 N HCl was added slowly and the mixture was heated at reflux for 3 hrs. The mixture was extracted 4 times with CH2C12. washed with NaHCO 3 then dried over MgSO 4 . Purified by MPLC. Yielded 7.37 g, 74 %. (iv) Preparation of fraw,y-N-ff4-[fbis(phenylmethyl)aminolmethvH cvclohexyl1methyll-N-(cvclohexylmethyl)-benzamide. (compound 116) To a solution of (compound 115) (740 mg, 1.77 mmol, 1 eq) in CH 2 C1 2 (10ml) was added Et 3 N (0.492 ml, 3.54 mmol, 2 eq) followed by benzoyl chloride (0.322 ml, 2.66 mmol, 1.5 eq). The reaction was allowed to stir over night. Saturated NH4CI was added and the „ reaction was extracted 3 times with CH 2 C1 2 . The combined organic layers were dried over MgSO , filtered and concentrated. The product was purified by silica gel flash chromatography using hexanes:ethyl acetate; 4:1. Yielded 675 mg, 73 % (v) Preparation of trans, N-f[4-(aminomethyl)cyclohexyllmethyll-N- (cvclohexylmethyl)-benzamide (Compound 117) To a solution of (compound 116) (675 mg, 1.29 mmol) in acetic acid (100 ml) was added Pd/C 10 % 70 mg. This was placed on a Parr apparatus under H 2 at 50 PSI and 70 °C overnight. Reaction was filtered through celite and concentrated. The extract was washed with NaHCO 3 then extracted 3 times with CH 2 C1 2 . Purification was done by silica gel flash chromatography. CH 2 Cl 2 :MeOH:8:2. Yielded 386 mg of a clear oil, 88 %. (vi) Preparatiop of /ra/i5-l-N-(cvclohexylmethyl)-N-(benzoyl)-aminomethyl-4-(di-t- butyl carbonyloxy)-guanidinomethyl cyclohexane (compound 118) To a solution of (compound 117) (140 mg, 0.55 mmol, 1 eq) in THF 3 mL at RT was added 133 mg, 0.61 mmol. 1.1 eq) The reaction was stirred for 48 hrs then concentrated un reduced pressure. Purified by flash chromatography on silica gel with 8:2 hex/Ethyl Acetate. Yielded 251 mg, 77 yield. (vii) Preparation of /rα«s-l-N-(cvclohexylmethyl)-N-(benzoyl)-aminomethyl-4- guanidinomethyl cyclohexane trifluoroacetate (compound 119) To a solution of (compound 117) (250 mg) in CH 2 C1 2 (5 mL) at RT wad added dropwise TFA. The mixture was allowed to stir 3 hrs then the reaction was concentrated. The product was washed with NaOH then extracted 3 times with CH 2 C1 2 . The combined organic layers were dried over MgSO , filtered then concentrated. Yielded 163 mg, 100% (viii) Preparation of frans-l-N-(cvclohexylmethyl)-N-(benzoyl)-aminomethyl-4- guanidinomethyl cvclohexane hydrochloride (compound 120) To a solution of (compound 118) (163mg) in CH 2 Cl 2 /Et 2 O (2ml/2ml) was added 1 N HCl in Et 2 O (1 mL). The mixture was allowed to stir at RT for 2 Hrs. It was then concentrated and purified by MPLC 20 % to 50 % CH 3 CN/H 2 O. Yielded 117 mg of a white powder, 66 %. (400 MHz, CDC13, TMS, Free amine, equilibrium):7.37 (s, 3H, C=CH), 7.31 (s, 2H, C=CH), 3.40 (s broad, 2H, CH2N), 3.10 (d, 2H, CH2N), 2.90 and, 2.82 (d and d, 2H, CH2N), 1.81-1.48 (m, 13H, CH2, NH), 1.26-0.80 (m, 10H, CH, CH2), 0.61-0.58 (m, 2H. CH2). C23H36N4O X 1.3 HCl, X 0.1 H2O, X 0.4 C4H10O Found: C 63.75% H 8.84%, N 11.95% Calc.:C 63.76%, H 9.03%, N 12.09%, 05.18%, Cl 9.95%. Pharmaceutical compositions The novel compounds according to the present invention may be administered orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints. A preferred route of administration is orally, intravenously or intramuscularly. The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level as the most appropriate for a particular patient. For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify. Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low- melting wax, cocoa butter, and the like. Pharmaceutically acceptable salts are acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glucaptate, gluconate, glutamate. glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate mesylate, methylbromide, methylnitrate, methylsulfate. mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, triethiodide, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminium, calcium, lithium, magnesium, potassium, sodium, and zinc. Preferred pharmaceutically acceptable salts are the hydrochlorides, trifluoroacetates and bitartrates. The term composition is intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Liquid from compositions include solutions, suspensions, and emulsions. Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art. Preferably the pharmaceutical compositions is in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms. BIOLOGICAL EVALUATION A ΓN VΓTRQ MODEL Cell culture Human 293S cells expressing cloned human μ, δ, and K receptors and neomycin resistance were grown in suspension at 37°C and 5% CO, in shaker flasks containing calcium-free DMEM10% FBS, 5% BCS, 0.1% Pluronic F-68, and 600 μg/ml geneticin. Membrane preparation Cells were pelleted and resuspended in lysis buffer (50 mM Tris, pH 7.0, 2.5 mM EDTA, with PMSF added just prior to use to 0.1 mM from a 0.1 M stock in ethanol), incubated on ice for 15 min, then homogenized with a polytron for 30 sec. The suspension was spun at lOOOg (max) for 10 min at 4°C. The supernatant was saved on ice and the pellets resuspended and spun as before. The supernatants from both spins were combined and spun at 46,000 g(max) for 30 min. The pellets were resuspended in cold Tris buffer (50 mM Tris/Cl, pH 7.0) and spun again. The final pellets were resuspended in membrane buffer ( 50 mM Tris, 0.32 M sucrose, pH 7.0). Aliquots (1 ml) in polypropylene tubes were frozen in dry ice/ethanol and stored at -70°C until use. The protein concentrations were determined by a modified Lowry assay with SDS. Binding assays Membranes were thawed at 37°C, cooled on ice, passed 3 times through a 25-gauge needle, and diluted into binding buffer (50 mM Tris, 3 mM MgCl,, 1 mg/ml BSA (Sigma A-7888), pH 7.4, which was stored at 4°C after filtration through a 0.22 m filter, and to which had been freshly added 5 μg/ml aprotinin, 10 μM bestatin, 10 μM diprotin A, no DTT). Aliquots of 100 μl (for μg protein, see Table 1) were added to iced 12x75 mm polypropylene tubes containing 100 μl of the appropriate radioligand (see Table 1) and 100 μl of test peptides at various concentrations. Total (TB) and nonspecific (NS) binding were determined in the absence and presence of 10 μM naloxone respectively. The tubes were vortexed and incubated at 25°C for 60-75 min, after which time the contents are rapidly vacuum-filtered and washed with about 12 ml tube iced wash buffer (50 mM Tris, pH 7.0, 3 mM MgCl,) through GF/B filters (Whatman) presoaked for at least 2h in 0.1% polyethyleneimine. The radioactivity (dpm) retained on the filters was measured with a beta counter after soaking the filters for at least 12h in minivials containing 6-7 ml scintillation fluid. If the assay is set up in 96-place deep well plates, the filtration is over 96-place PEI-soaked unifilters, which were washed with 3 x 1 ml wash buffer, and dried in an oven at 55°C for 2h. The filter plates were counted in a TopCount (Packard) after adding 50 μl MS-20 scintillation fluid/well. Data analysis The specific binding (SB) was calculated as TB-NS, and the SB in the presence of various test peptides was expressed as percentage of control SB. Values of IC 50 and Hill coefficient (n H ) for ligands in displacing specifically bound radioligand were calculated from logit plots or curve fitting programs such as Ligand, GraphPad Prism, SigmaPlot, or ReceptorFit. Values of K ; were calculated from the Cheng-Prussoff equation. Mean ± S.E.M. values of IC 50 , K and n H were reported for ligands tested in at least three displacement curves. Receptor saturation experiments Radioligand K values were determined by performing the binding assays on cell membranes with the appropriate radioligands at concentrations ranging from 0.2 to 5 times the estimated Kδ(up to 10 times if amounts of radioligand required are feasable). The specific radioligand binding was expressed as pmole/mg membrane protein. Values of Kg and B maχ from individual experiments were obtained from nonlinear fits of specifically bound (B) vs. nM free (F) radioligand from individual according to a one-site model. B) BIOLOGICAL MODEL (IN VIVO MODEL) FREUND'S COMPLETE ADJUVANT (FCA), AND SCIATIC NERVE CUFF INDUCED MECHANO-ALLODYNIA IN RAT Animals Male Sprague-Dawley rats (Charles River, St-Constant, Canada) weighing 175-200g at the time of surgery were used. They were housed in groups of three in rooms thermostatically maintained at 20° C with a 12:12 hr light/dark cycle, and with free access to food and water. After arrival, the animals were allowed to acclimatize for at least 2 days before surgery. The experiments were approved by the appropriate Medical Ethical Committee for animal studies. EXPERIMENTAL PROCEDURE FREUND'S COMPLETE ADJUVANT The rats were first anesthetized in a Halothane chamber after which lOμl of FCA was injected s.c. into the dorsal region of the left foot, between the second and third external digits. The animals were then allowed to recover from anesthesia under observation in their home cage. SCIATIC NERVE CUFF The animals were prepared according to the method described by Mosconi and Kruger (1996). Rats were anesthetized with a mixture of Ketamine / Xylazine i.p. (2ml/kg) and placed on their right side and an incision made over, and along the axis of, the lateral aspect of the left femur. The muscles of the upper quadriceps were teased apart to reveal the sciatic nerve on which a plastic cuff (PE-60 tubing, 2mm long) was placed around. The wound was then closed in two layers with 3-0 vicryl and silk sutures. DETERMINATION OF MECHANO-ALLODYNIA USING VON FREY TESTING Testing was performed between 08:00 and 16:00h using the method described by Chaplan et al. (1994). Rats were placed in Plexiglas cages on top of a wire mesh bottom which allowed access to the paw, and were left to habituate for 10-15 min. The area tested was the mid-plantar left hind paw, avoiding the less sensitive foot pads. The paw was touched with a series of 8 Von Frey hairs with logarithmically incremental stiffness (0.41, 0.69, 1.20, 2.04, 3.63, 5.50, 8.51, and 15.14 grams; Stoelting, 111, USA). The von Frey hair was applied from underneath the mesh floor perpendicular to the plantar surface with sufficient force to cause a slight buckling against the paw, and held for approximately 6-8 seconds. A positive response was noted if the paw was sharply withdrawn. Flinching immediately upon removal of the hair was also considered a positive response. Ambulation was considered an ambiguous response, and in such cases the stimulus was repeated. TESTING PROTOCOL The animals were tested on postoperative day 1 for the FCA-treated group and on postoperative day 7 for the Sciatic Nerve Cuff group. The 50% withdrawal threshold was determined using the up-down method of Dixon (1980). Testing was started with the 2.04 g hair, in the middle of the series. Stimuli were always presented in a consecutive way, whether ascending or descending. In the absence of a paw withdrawal response to the initially selected hair, a stronger stimulus was presented; in the event of paw withdrawal, the next weaker stimulus was chosen. Optimal threshold calculation by this method requires 6 responses in the immediate vicinity of the 50% threshold, and counting of these 6 responses began when the first change in response occurred, e.g. the threshold was first crossed. In cases where thresholds fell outside the range of stimuli, values of 15.14 (normal sensitivity) or 0.41 (maximally allodynic) were respectively assigned. The resulting pattern of positive and negative responses was tabulated using the convention, X = no withdrawal; O = withdrawal, and the 50% withdrawal threshold was interpolated using the formula: 50% g threshold = 10 (Xf + kδ) / 10,000 where Xf = value of the last von Frey hair used (log units); k = tabular value (from Chaplan et al. (1994)) for the pattern of positive / negative responses; and δ = mean difference between stimuli (log units). Here δ = 0.224. Von Frey thresholds were converted to percent of maximum possible effect (% MPE), according to Chaplan et al. 1994. The following equation was used to compute % MPE: % MPE = Drug treated threshold (g) - allodvnia threshold (g X 100 Control threshold (g) - allodynia threshold (g) ADMINISTRATION OF TEST SUBSTANCE Rats were injected (subcutaneously, intraperitoneally, or orally) with a test substance prior to von Frey testing, the time between administration of test compound and the von Frey test varied depending upon the nature of the test compound.

Claims: CLAIMS 1. A compound according to formula I (CH 2 ) n - wherein A is R 2 FT / / -N -CH \ \ R 3 or R J ? 3 wherein R~ and R are as defined below; Z is (CH2) m or a carbonyl group; m and n are each and independently an integer of from 0-3, and one or more of the hydrogens in such an alkylene-chain may optionally be substituted by anyone of C] - C alkyl, Ci - C alkoxy, or hydroxy; or one or more of the methylene groups may optionally be substituted by a heteroatom such as O, N or S; m and n may not both be 0; Q is selected from any of CH3; O O I! II O I I < > ,f \ ' R A R ^ or R 6 ^ \ wherein 4 5 6 R , R and R is each and independently selected from any of (i) C6-Cιo aryl; or (ii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below; (iii) hydrogen; (iv) a straight or branched alkyl, C2-C6 alkenyl or C2-C6 alkynyl; (v) C1-C3 alkoxy; (vi) saturated or unsaturated C3 - C10 cycloalkyl, optionally and independently substituted by one or more aryl groups or heteroaryl groups having from 5 to 10 atoms with the heteroatom(s) being selected from any of S, N and O and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; (vii) -[(CH2)q-aryl] where q is an integer of from 1-3, and the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined below; (viii) -[(CH2) r -heteroaryl] where r is an integer of from 1-3, the heteroaryl having from 5 to 10 atoms with heteroatoms(s) being selected from any of S, N, and O, optionally and independently substituted by 1 or 2 substituents Y as defined below; (ix) -[CH2-O-aryl] where the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined below; (x) ■ N- (C - H Aryl where q is an integer of from 1-3, and the aryl is as defined below, optionally substituted by 1 or 2 substituents Y, where each Y is as defined below; R .1 i.s selected from anyone of (i) a straight or branched alkyl, C2-C6 alkenyl or C2-C6 alkynyl, where each alkyl, alkenyl or alkynyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (ii) C3-C7 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more of - C6 alkyl, C \ - Cg alkoxy, hydroxy; or substituted by one or more aryl(s), or heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; (iii) hydrogen, halogen or C \ -C(, alkoxy; (iv) C 6 -C 10 aryl; (v) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; (vi) 9, 10-dihydro-9,10-ethanoantracenyl; (vii) -[(CH2)q-aryl] where q is an integer of from 1-3 and the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined below; (viii) -[(CH2) r -heteroaryl] where r is an integer of from 1-3, the heteroaryl having from 5 to 10 atoms and the heteroatoms(s) being selected from any of S, N, and O, and wherein the heteroatom(s) may optionally and independently be substituted by 1 or 2 substituents Y, where each Y is as defined below; , (ix) -[(CH2)q-aryl-O-(CH2) r -aryl] where q and r is each and independently an integer of from 1-3; (x) -(CH2)q-[C3-C6 cycloalkyl] where q is from 1-2, optionally substituted by 1 or 2 substituents Y and wherein Y is as defined below; 2 R is selected from any of (i) hydrogen; (ii) a straight or branched -C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, where each alkyl, alkenyl or alkynyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (iii) C - C 10 arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; (iv) heteoaryl-(C5 - C JO alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below; (v) C3-C 1 0 cycloalkyl, optionally comprising one or more unsaturations and optionally susbtituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below; (vi) C6-C 1 0 aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; (vii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; 3 R is selected from anyone of (i) hydrogen; (ii) a straight or branched Cj-Cg alkyl, C2-C6 alkenyl or C2-C6 alkynyl, where each alkyl, alkenyl or alkynyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (iii) CO - Cjo arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; (iv) heteoaryl-(C5 - C \ o alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below; (v) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below; wherein 7 8 9 10 1 1 R , R , R , R and R is each and independently selected from (a) hydrogen; (b) a straight or branched -Cδ alkyl, C2-C6 alkenyl or C2-C6 alkynyl, where each alkyl, alkenyl or alkynyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (c) Cζ - arylalkyl. wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; (d) heteoaryl-(C5 - alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below; (e) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally susbtituted by one or more heteroaryl(s) where the heterβaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below; (f) aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below; or 2 3 R and R may optionally form a heterocyclic ring; Y is each and independently selected from any of hydrogen, CH3; — (CH2) p ιCF3; halogen; C 1 -C3 alkoxy; hydroxy; -NO 2 ; -OCF3; — CONR 5 ; — COOR a ; — COR a ; — (CH 2 )p2NR a R b ; — (CH 2 ) p 3CH 3ι (CH 2 )p 4 SOR a R ; — (CH 2 )p5SO 2 R a ; — (CH 2 ) p 6SO 2 NR a ; C 4 -C 8 (alkyl-cycloalkyl) wherein alkyl is Cι-C alkyl and cycloalkyl is C3-C6 cycloalkyl; and 1 or 2 heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O; and oxides such as N-oxides or sulfoxides; and wherein a b R and R is each and independently selected from hydrogen, a branched or straight Cj-Cό alkyl, -Cό alkenyl, C3-C8 cycloalkyl; and wherein pi, p2, p3, p4, p5 and p6 is each and independently 0, 1 or 2; as well as pharmaceutically acceptable salts, isomers, hydrates, isoforms and prodrugs thereof. 2. A compound according to formula I of claim 1 , wherein m and n are each and independently an integer of from 1-3; Q is selected from any of CH3; o o II Q * s *0 ,4/- = p^ C \ r .66// \ and R \ wherein 4 6 R and R is each and independently selected from any of (i) C 6 -C 10 aryl; or (ii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined in claim 1 ; (iii) a straight or branched Cj-Cg alkyl or C2-C6 alkenyl; (iv) C1-C3 alkoxy; (v) saturated or unsaturated C3 - Cg cycloalkyl, optionally and independently substituted by one or more aryl groups or heteroaryl groups having from 5 to 10 atoms with the heteroatom(s) being selected from any of S, N and O and wherein the aryl, heteroaryl and cycloalkyl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1 ; (vi) -[(CH2)q-aryl] where q is an integer of from 1-3, and the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1; (vii) -[(CH2) r -heteroaryl] where r is an integer of from 1-3, the heteroaryl having from 5 to 10 atoms with heteroatoms(s) being selected from any of S, N, and O, optionally and independently substituted by 1 or 2 substituents Y as defined in claim 1; (viii) -[CH2-O-aryl] where the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1 ; (ix) '(CH 2 )— H ' N ' Aryl where q is an integer of from 1-2, and the aryl is as defined below, optionally substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1 ; R .1 i.s selected from anyone of (i) a straight or branched Cj-Cό alkyl or C2-C6 alkenyl, where each alkyl and alkenyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (ii) C3-C7 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more of C \ - C(, alkyl, C \ - Cg alkoxy, hydroxy; or substituted by one or more aryl(s), or heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1; (iii) hydrogen, halogen or alkoxy; (iv) C 6 -Cιo aryl; (v) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1 ; (vi) 9,10-dihydro-9,10-ethanoantracenyl; (vii) -[(CH2)q-aryl] where q is an integer of from 1-3 and the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1 ; (viii) -[(CH2) r -heteroaryl] where r is an integer of from 1-3, the heteroaryl having from 5 to 10 atoms and the heteroatoms(s) being selected from any of S, N, and O, and wherein the heteroatom(s) may optionally and independently be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1 ; (ix) -[(CH2)q-aryl-O-(CH2) r -aryl] where q and r is each and independently an integer of from 1-3; (x) -(CH2)q-[C3-C6 cycloalkyl] where q is from 1-2, optionally substituted by 1 or 2 substituents Y and wherein Y is as defined in claim 1 ; 7 R " is selected from any of (i) hydrogen; (ii) a straight or branched alkyl or C2-C6 alkenyl, where each alkyl and alkenyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (iii) C - C10 arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1 ; (iv) heteoaryl-(C5 - o alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined in claim 1 ; (v) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally susbtituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined in claim 1 ; (vi) C6-C10 aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1 ; (vii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1; 3 R is selected from anyone of (i) hydrogen; (ii) a straight or branched C \ -C(, alkyl or C2-C6 alkenyl, where each alkyl and alkenyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (iii) CO - C10 arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1 ; (iv) heteoaryl-(C5 - C\Q alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined in claim 1 ; (v) C3-C6 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined in claim 1; (vi) wherein 7 8 9 10 11 R , R , R , R and R is each and independently selected from (a) hydrogen; (b) a straight or branched alkyl or C2-C6 alkenyl, where each alkyl and alkenyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (c) C - C[Q arylalkyl, wherein the aryl may optionally be substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1 ; (d) heteoaryl-(C5 - o alkyl), where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O, and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined in claim 1 ; (e) C3-C10 cycloalkyl, optionally comprising one or more unsaturations and optionally susbtituted by one or more heteroaryl(s) where the heteroaryl has from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independenϊly be substituted by 1 or 2 substituents Y where each Y is as defined in claim 1 ; (f) aryl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1. 3. A compound according to claim 2, wherein 2 R is hydrogen; R 3 is wherein R , R , R , R and R are as defined in claim 2. m and n are each and independently 1 or 2; O O II 4^ \ -\ R Q is or wherein 4 R is selected from (i) phenyl; (ii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the phenyl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1 ; (iii) cyclohexyl; (iv) Cι-C 6 alkyl; (v) C1-C3 alkoxy; R is (i) -[(CH2) q -aryl] where q is an integer of from 1-3 and the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1 ; or (ii) C3-C7 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more of C \ - Cβ alkyl, Ci - C alkoxy, hydroxy; or substituted by one or more aryl(s), or heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1; (iii) -(CH2)-cyclohexyl; . A compound according to claim 1, which compound is anyone selected from 155 5. A compound according to claim 4, which compound is anyone selected from 6. A compound according to any of the preceding claims, in form of its hydrochloride, sulfate, tartrate or citrate salts. A compound according to any of claims 1-6 for use in therapy. 8. A compound according to claim 7, wherein the therapy is pain management. 9. A compound according to claim 7, wherein the therapy is directed towards 5 gastrointestinal disorders. 10. A compound according to claim 7, wherein the therapy is directed towards spinal injuries. o 11. A compound according to claim 7, wherein the therapy is directed to disorders of the sympathetic nervous system. 12. Use of a compound according to formula I of claim 1 for the manufacture of a medicament for use in the treatment of pain. 5 13. Use of a compound according to formula I of claim 1 for the manufacture of a medicament for use in the treatment of gastrointestinal disorders. 14. Use of a compound according to formula I of claim 1 for the manufacture of ao medicament for use in the treatment of spinal injuries. 15. A compound according to any of claims 1-11, further characterised in that it is isotopically labelled. 5 16. Use of a compound according to claim 15 as a diagnostic agent. 17. An isotopically labelled compound of the formula I of claim 1. 18. A diagnostic agent comprising a compound of the formula I of claim 1. 0 19. A pharmaceutical composition comprising a compound of the formula I according to claim 1 as an active ingredient, together with a pharmacologically and pharmaceutically acceptable carrier. 20. A process for the preparation of a compound of the formula I according to claim 1 , whereby A) (i) a cis/trans-mixture of 1,4-bis-aminomethyl cyclohexane is converted into a mono- (diBoc)guanidinomethyl derivative, which in turn is reacted with an aldehyde of the formula R CHO, providing a secondary amine of the formula (IH) (ii) the compound of the formula (HT) is reacted with an acylating reagent of the formula 44 RR CCOOCCll aanndd tthheerreeaafftteerr ddeepprroott*ected, providing a cis/trans-guanidinomethyl cyclohexane compound of the formula (VI) B) (i) cis,trans-4-(aminomethyl)-cyclohexane carbonitrile is reacted with an aldehyde of the 1 4 ffoorrmmuullaa RR CCHHOO,, wwhhiicchh tthheerreeaafftteerr iiss rreeaacctteedd with an acylating reagent R COCl, providing a compound of the formula (VIE) (ii) the nitrile group of the compound of the formula (VOT) is reduced and thereafter guanylated, amidinated or alkylated, providing a compound of the formula (X) cis-l,4-cyclohexane dicarboxylic acid anhydride is converted to the cis-acid amide, which thereafter is reacted with a primary amine, wherafter the carbonyl groups are reduced, providing a compound of formula (Xm) which in turn is acylated, reduced, and finally amidinated, alkylated or guanylated, providing a cis-compound of the formula (XVI) D) trans-4-aminomethyl cyclohexane is protected, thereafter amidated and deprotected, providing a compound of the formula (XVHT) (XVIII) O^R 1 which in turn is reduced, protected, acylated, and finally deprotected, providing a compound of the formula (XXH) wherein 1 7 3 4 R , R~, R and R in each step are as defined for formula I of claim 1. 21. A compound of the formula (IH) wherein R is selected from anyone of (i) a straight or branched C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, where each alkyl, alkenyl or alkynyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (ii) C3-C7 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more of C \ - Cg alkyl, Cj - Cζ alkoxy, hydroxy; or substituted by one or more aryl(s), or heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1 ; (iii) halogen or alkoxy; (iv) C 6 -Cιo aryl; (v) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1 ; (vi) 9,10-dihydro-9,10-ethanoantracenyl; (vii) -[(CH2)q-aryl] where q is an integer of from 1-3 and the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1 ; (viii) -[(CH2) r -heteroaryl] where r is an integer of from 1-3, the heteroaryl having from 5 to 10 atoms and the heteroatoms(s) being selected from any of S, N, and O, and wherein the heteroatom(s) may optionally and independently be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1 ; (ix) -[(CH2)q-aryl-O-(CH2) r -aryl] where q and r is each and independently an integer of from 1-3. 22. A compound of the formula (VII) wherein R is selected from anyone of (i) a straight or branched Cj-Cό alkyl, C2-C6 alkenyl or C2-C6 alkynyl, where each alkyl, alkenyl or alkynyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (ii) C3-C7 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more of Cj - CO alkyl, Cj - Cβ alkoxy, hydroxy; or substituted by one or more aryl(s), or heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1; (iii) hydrogen, halogen or Cj-Cg alkoxy; (iv) C 6 -Cιo aryl; (v) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1 ; (vi) 9,10-dihydro-9,10-ethanoantracenyl; (vii) -[(CH2)q-aryl] where q ia an integer of from 1-3 and the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1; (viii) -[(OHbVheteroaryl] where r is an integer of from 1-3. the heteroaryl having from 5 to 10 atoms and the heteroatoms(s) being selected from any of S, N, and O, and wherein the heteroatom(s) may optionally and independently be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1 ; (ix) -[(CH2)q-aryl-O-(CH2) r -aryl] where q and r is each and independently an integer of from 1-3. 23. A compound of the formula (IX) wherein R. is selected from anyone of (i) a straight or branched C Cό alkyl, C2-C6 alkenyl or ^- ^ alkynyl, where each alkyl, alkenyl or alkynyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (ii) C3-C7 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more of C \ - C alkyl, C - C6 alkoxy, hydroxy; or substituted by one or more aryl(s), or heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1 ; (iii) hydrogen, halogen or alkoxy; (iv) C 6 -C 10 aryl; (v) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1 ; (vi) 9, 10-dihydro-9, 10-ethanoantracenyl; (vii) -[(CH2)q-aryl] where q ia an integer of from 1-3 and the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1; (viii) -[(CH2) r -heteroaryl] where r is an integer of from 1-3, the heteroaryl having from 5 to 10 atoms and the heteroatoms(s) being selected from any of S, N, and O, and wherein the heteroatom(s) may optionally and independently be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1; (ix) -[(CH2)q-aryl-O-(CH2) r -aryl] where q and r is each and independently an integer of from 1-3; and 4 R is selected from anyone of ' (i) C 6 -C 10 aryl; or (ii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined in claim 1 ; (iii) hydrogen; (iv) a straight or branched Ci-Cό alkyl, C2-C6 alkenyl or C2-C6 alkynyl; (v) C1-C3 alkoxy; (vi) saturated or unsaturated C3 - CJQ cycloalkyl, optionally and independently substituted by one or more aryl(s) or heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1 ; (vii) -[(CH2)q-aryl] where q is an integer of from 1-3, and the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1; (viii) -[(CH2) r -heteroaryl] where r is an integer of from 1-3, the heteroaryl having from 5 to 10 atoms and the heteroatoms(s) being selected from any of S, N, and O, and wherein the heteroatom(s) may optionally and independently be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1 ; (ix) -[CH2-O-aryl] where the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1; (x) -(CH 2 ) ' N ' Aryl where q is an integer of from 1-3, and the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1. 24. A compound according to formula (XITJ) wherein R is selected from anyone of (i) a straight or branched Cj -Cβ alkyl, C2-C6 alkenyl or C2-C6 alkynyl, where each alkyl, alkenyl or alkynyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (ii) C3-C7 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more of Cj - C^ alkyl, C \ - C alkoxy, hydroxy; or substituted by one or more aryl(s), or heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1; (iii) hydrogen, halogen or C Cό alkoxy; (iv) C6-Ci 0 aryl; (v) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1 ; (vi) 9, 10-dihydro-9, 10-ethanoantracenyl; (vii) -[(CH2)q-aryl] where q ia an integer of from 1-3 and the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1; (viii) -[(CH2) r -heteroaryl] where r is an integer of from 1-3, the heteroaryl having from 5 to 10 atoms and the heteroatoms(s) being selected from any of S, N, and O, and wherein the heteroatom(s) may optionally and independently be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1; (ix) -[(CH2)q-aryl-O-(CH2) r -aryl] where q and r is each and independently an integer of from 1-3. 25. A compound according to formula (XV) wherein R is selected from anyone of (i) a straight or branched Cj-Cό alkyl, C2-C6 alkenyl or C2-C6 alkynyl, where each alkyl, alkenyl or alkynyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (ii) C3-C7 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more of C \ - Cβ alkyl, Cj - Cβ alkoxy, hydroxy; or substituted by one or more aryl(s), or heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1 ; (iii) hydrogen, halogen or alkoxy; (iv) C6-Cι 0 aryl; (v) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined inclaim 1 ; (vi) 9, 10-dihydro-9, 10-ethanoantracenyl; (vii) -[(CH2)q-aryl] where q ia an integer of from 1-3 and the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1; (viii) -[(CH2) r -heteroaryl] where r is an integer of from 1-3, the heteroaryl having from 5 to 10 atoms and the heteroatoms(s) being selected from any of S, N, and O, and wherein the heteroatom(s) may optionally and independently be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1 ; (ix) -[(CH2)q-aryl-O-(CH2) r -aryl] where q and r is each and independently an integer of from 1-3; and 4 R is selected from anyone of (i) C6-C 10 aryl; or (ii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined in claim 1; (iii) hydrogen; (iv) a straight or branched Cj-Cδ alkyl, C2-C6 alkenyl or C2-C6 alkynyl; (v) -C3 alkoxy; (vi) saturated or unsaturated C3 - CJO cycloalkyl, optionally and independently substituted by one or more aryl(s) or heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1 ; (vii) -[(CH2)q-aryl] where q is an integer of from 1-3, and the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1 ; (viii) -[(CH2) r -heteroaryl] where r is an integer of from 1-3, the heteroaryl having from 5 to 10 atoms and the heteroatoms(s) being selected from any of S, N, and O, and wherein the heteroatom(s) may optionally and independently be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1 ; (ix) -[CH2-O-aryl] where the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1 ; (x) -(CH 2 ) * N ' Aryl where q is an integer of from 1-3, and the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1. 26. A compound of the formula (XIX) wherein R is selected from anyone of (i) a straight or branched C i -Cβ alkyl, C2-C6 alkenyl or C2-C6 alkynyl, where each alkyl, alkenyl or alkynyl may optionally be substituted by one or more aromatic or heteroaromatic substituents; (ii) C3-C7 cycloalkyl, optionally comprising one or more unsaturations and optionally substituted by one or more of C \ - CO alkyl, C \ - Cβ alkoxy, hydroxy; or substituted by one or more aryl(s), or heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1; (iii) hydrogen, halogen or -CO alkoxy; (iv) C 6 -C 10 aryl; (v) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined in claim 1 ; (vi) 9,10-dihydro-9,10-ethanoantracenyl; (vii) -[(CH2)q-aryl] where q ia an integer of from 1-3 and the aryl may optionally be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1 ; (viii) -[(CH2) r -heteroaryl] where r is an integer of from 1-3, the heteroaryl having from 5 to 10 atoms and the heteroatoms(s) being selected from any of S, N, and O, and wherein the heteroatom(s) may optionally and independently be substituted by 1 or 2 substituents Y, where each Y is as defined in claim 1 ; (ix) -[(CH2)q-aryl-O-(CH2) r -aryl] where q and r is each and independently an integer of from 1-3. 27. A method for the treatment of pain, whereby an effective amount of a compound of the formula I according to claim 1 is administered to a subject in need of pain management. 28. A method for the treatment of gastrointestinal disorders, whereby an effective amount of a compound of the formula I according to claim 1 , is administered to a subject suffering from said gastrointestinal disorder. 29. A method for the treatment of spinal injuries, whereby an effective amount of a compound of the formula I according to claim 1, is administered to a subject suffering from said spinal injury.

Inventors: DELORME DANIEL, GREGOR VLAD, ROBERTS EDWARD, SUN ERIC, DELORME, DANIEL, GREGOR, VLAD, ROBERTS, EDWARD, SUN, ERIC
Applicants: ASTRA AB, ASTRA PHARMA INC, DELORME DANIEL, GREGOR VLAD, ROBERTS EDWARD, SUN ERIC, ASTRA AKTIEBOLAG, ASTRA PHARMA INC., DELORME, DANIEL, GREGOR, VLAD, ROBERTS, EDWARD, SUN, ERIC
Application year: 1999
Main classification: C07C279
IPC codes: C07C211, C07C233, C07C237, C07C257, C07C279