LV12459B - Novel compounds and compositions for treating diseases associated with tryptase activity - Google Patents

Abstract

The present invention relates to novel compounds which are tryptase inhibitors; the pharmaceutically acceptable salts and N ¡oxides thereof; their uses as therapeutic agents and the methods of their making.

Description

LV 12459 -l-

NOVEL COMPOUNDS AND COMPOSITTONS FOR TREATING DĪSEASES ASSOCIATED

WITH TRYPTASE ACHVITY 3 This application claims the benefit of U.S. Provisional Application No. 60/023,139, filed

July 30, 1996.

Field of the Invention: 6 This invention relates to novel methods and compositions for treating diseases associaied with tryptase activity by administration of novel tryptase inhibitors.

Description of the Field: 9 Tryptase, the predominant protease secreted from human mast celis, is thought to be involved in neuropeptide processing and tissue inflammation. Tryptase concentrations are elevated in the bloodstream for several hours foIIowing anaphylaxis (Schvvartz et al. (19S7) 12 N. Eng. J. Med 316:1622-1626), are increased in nasal and lung lavage fluid from atopic subjects foliowing specific antigen challenge (Castells et al. (19S8) J. Āllerg. Clin. Immunol 141:563-568) and are elevated in lung lavage fluid of atopic asthmatics after endobronchial 15 allergen challenge. Smokers often have striking elevations of bronchoalveolar lavage fluid tryptase Ievels, a finding thal provides some support for the hypothesis that release of proteinase from activated mast celis could contribute to lung destruction in smoker’s emphysema. 18 (Celenteron et al. (1988) Chest 94:119-123). In addition, tryptase has been shovra to be a potent mitogen for fibroblasts, suggesting that it is involved in pulmonary fibrosis and interstitial lung disease (Ross et al. (1991)7. Clin. Invest. 88:493-499). 21 Asthma is recognized as an inflammatory disorder (Hood et al. (1984)

In: Benjamin-Cummings, ed. lmmunology 2nd ed.) and frequently is characterized by Progressive development of hyper responsiveness of the trachea and bronchi to both 24 immunospecific allergens and generalized Chemical or physical stimuli. The disease involves multiple biochemical mediators in both its acute and chronic stages. The hyper responsiveness of asthmatic bronchiolar tissue is beiieved to be the result of chronic inflaminatory reactions, which 27 iiritate and damage the epithelium Iining the airway wall and promote pathological thickening of the underlying tissue. Bronchiai biopsies in patients with only mild asthma have features of inflammation in the airway wall.

Allergic responses to inhaled allergens can initiate the inflammatory sequence. For example, allergens can activate mast celis and basophils, which are present in the epithelium and underlying smooth muscle tissue by binding IgE located on the celi surface. Activated mast celis release a number of preformed or primary Chemical mediators (e.g., histamine) ofthe inflammatory response and generate numerous other secondary mediators of inflammation (e.g., superoxide, lipid derived mediators, etc.) in silu. In addition, several large molecules (e.g., proteoglycans, tryptase, chymase, etc.) are released by degranulation of mast celis.

The release of these preformed mediators from mast celis probably accounts for the early bronchiolar constriction in the asthmatic reaction to air bome allergens. The early phase of the asthmatic reaction peaks approximately fifteen minūtes after cxposure to allergen and is generally followed by recovery over the ensuing one to two hours. Twenty five to thirty five percent ofthe patient population experience a further decline in respiratory function which -v* maximizes six to twelve hours after exposure. This late reaction phase is accompanied by a marked increase in the number of inflammatory celis (e.g., eosinophils, neutrophils, lymphocytes, etc.) infiltrating the bronchiolar tissue. The infiltrating celis are attracted to the site by release of mast celi derived chemotactic aģents and then become activated during the late reaction phase. The late asthmatic response is believed to be a secondary inflammatory reaction mediated in part by the secretory activity of granuIocytes.

Tryptase is implicated in the degradation of vasodilating and bronchorelaxing neuropeptides (Caughey el al. (1988) J.Pharmacol. Exp. Ther. 244:133-137; Franconi et al. (1988) J. Pharmacoi Exp. Ther. 248:947-951; and Tam et al. (1990) Am. J. Respir. Celi Mol. Biol. 3:27-32) and modulation of bronchiai responsiveness to histamine (Sekizavva et al. (1989) J. Clin. Invest. 83:175-179). These findings suggest that tryptase may increase bronchoconstriction in asthma by destroying bronchodilating peptides. Tryptase cleaves fibrinogen α-chains and high molecular weight kinninogen, which suggests that tryptase plays a role with heparin as a local anticoagulant. Tryptase activates prostromelysin (pro-MMP-3) and procollagenase (pro-MMP-1) via MMP-3, vvhich suggests that tryptase is involved in tissue inflammation and remodeling and joint destruction in rheumatoid arthritis. Further, -3- LV 12459

administration of tryptase inhibitor protects against development of the late and airway hyper responsive phases in allergen challenged sheep (Clark et ai (1995) Ām. J. Respir. Crit. Care 3 MedL 152:2076-2083) and inhibits the immediate cutaneous response to intradermal injection of allergen in ailergic sheep (Molinari et al. (1995) Amer. Physiol. Soc. 79(6):1966-1970). Ali of the above-described findings clearly indicate the applicability of tryptase inhibitors as therapeutic 6 aģents in treating asthma and other disorders associated with inflaimnation of the respiratory tracL

The disclosures of these and other documents referred to throughout this application are 9 incoīporated herein by reference.

SUMMARY OF THE INVENTION

This application relates to a compound of Formula I: 12 ^.χ^χ^-Χΐ /X5 r2-x9-x8-x7-x6^

I in which: X5 is (C3.14)cycloalkylene, hetero(C3_M)cycloalkylene, (C6.ļ4)arylene or 15 hetero(Cj.M)arylene; X4 and X6 are independently (C<>_2)alkylene; X' and X9 are independently a covalent bond, -C(O)-, -C(0)0-, -OC(O)-, -C(0)N(R3)-, 18 -N(R3)C(0)-, -S(0)2N(R3)-, -N(R3)S(0)2-, -0C(0)N(R3)-, -N(R3)C(0)0-, -N(R3)C(0)N(R3)- or -0C(0)0-, wherein each R3 is independently hydrogen, (C,.3)alkyl or (Cj_*)cycloalkyl, with the proviso that X1 and X9 are not both covalent bonds; 21 XJ and X7 are independently -C(O)-, -C(0)0-, -OC(O)-, -C(0)N(R3)-, -N(R3)C(0)-, -S(0)2N(R3)-, -N(R3)S(0)2-, -0C(0)N(R3)-, -N(R3)C(0)0-, -N(R3)C(0)N(R3)- or -0C(0)0-, wherein R3 is as defined above; -4- X2 and X* are independently (Cux)alkylene, hetero(C,_j)alkylene, -Xl0-Xu- or -X"-X10-, v/herein X10 is (C(M)alkylene or hetero(C3.4)alkylene and X" is (Cj.s)cycIoalkyIenc or hetero(C3.j)cycloaIkylcne; R1 is R4-X12- or Rs-Xn-, wherein: R4 is amino, amidino, guanidino, l-iminoethyl or methylamino, X12 is (C«^)alkylene, hetero(C4.4)alkylene, heterooxo(C4Jalkylene, oxo(C4.6)alkylene or -XM-XI5-X'4-, wherein X,J is (Cj.4)cycIoalkylene, hetero(Cj^)aryIene, hetero(Cj^)cycloalkyIene or phenylene, XM is (CnM)alkylene and X'4 is (Cnl6)alkylene, whcrein the suin of nl4 and nl6 is 0, l, 2, 3 or 4, R5 is a group selected from azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl imida2oI-l-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazoIin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-l-yi, 4-methyiimidazol-l-yl, 5-methylimidazoi-I-y[, l-methylpiperid-3-yl, l-methy!piperid-4-yl, piperid-3-yl, pipcrid-4-yl, pipcrazin-l-yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrroiidin-3-yl, l,4,5,6-tetrahydropyrimidin-2-yl, l,4,5,6-tetrahydropyrimidin-4-yl and l,4,5,6~tetrahydropyrimidin-5-yl and any carbocyciic ketone or thioketone derivative thereof, v/hich group is optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (C,.j)alkyl, (C3.|4)cycloalkyl, (C^Oatļd, (C6.l4)aryl(CM)alkyl, (C|.j)aikanoyl, (C,.,)alkyloxy, (Cs.l4)aryloxy, (C3.l4)cycloalkyIoxy, (Cw)alkyloxy, (C,.j)alkylthio, (Cj.u)cycloalkylthio, (C6.14)arylthio and -NR6R7, wherein R4 and R7 are independently selected from hydrogen, (C,.j)alkyl, (C,.,)aIkanoyl, (Cj.,4)cycloalkyl or (Ce.|4)aryl and

XlJ is (C0^)alkylene, hetero(Cw)alkylene, heterooxo(Cw)alkylene, oxo(C2^)alkylene or -X,7-X'*-X19-, wherein X1* is as deftned above for XIS, X'7 is (Cnl7)alkylene andX19 is(Cni9)alkylene, wherein the sum of nl7 and nl9 is 0, l or 2; and R2 is R*-XM- or R’-Χ21-, wherein: R* is amino, l-iminoethyl or methylamino, X-° is (C4^)alkyiene, hetero(C4.4)a!kylene, hecerooxo(C4^)alkylene, oxo(C4^)aIkylene or -X22*X23-X24-, wherein X23 is as defined above for Xts, X~ is (C^2)aikylene and X24 is (Cn24)aikylene, \vherein the sum of n22 and n24 is 0, 1, 2, 3 or 4, -5- LV 12459 with the proviso that when R* is amino then X20is not (C4^)alkylene or oxa(C4^)alkylene and n22 is not 1,2,3 or 4, 3 R9 is as defined above for R5 and X21 is (CoJalkylene, hetero(C24)aIkylene, heterooxo(C3 Jalkylene, oxo(C2^)alkyiene or -Χ^-Χ^-Χ27-, wherein X26 is as defined above for X15, X25 is 6 (Cn25)alkylene and X27 is (Cn27)alkylene, vvherein the sum of n25 and n27 is 0,1 or 2; wherein each alkylene, cycIoalkylene, heteroalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene, as defined above, are optionally substituted with one or more 9 radicals selected from halo, hydroxy, mercapto, (C,.8)alkyl, (C3.I4)cycloalkyl, (C^Jaiļd, (C6_14)aryl(C|-4)aIkyl, (C,.*)alkanoyl, (C,.8)alkyloxy, (C6.M)aryloxy, (C3.M)cycloalkyloxy, (CM)alkyloxy, (C1.s)alkylthio, (C3.14)cycloalkylthio, (C6.,4)arylthio and -NR6R7, wherein 12 R6 and R7 are as defined above; with the proviso that covalent bonds do not occur between heteroatoms contained vvithin R1, X2, X4, X6, X* and R2 and any heteroatoms contained with X3, X5, X7 and X9; and 15 the phaimaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. A second aspect of this application relates to a compound of Formula I: ^>5 r2-x9-x*-x7-x6^

I in which: X4-X5-X6 together are (C2.|,)alkylene or hetero(C3.I2)alkylene; 21 X* and X9 are independently a covalent bond, -C(O)-, -0(0)0-, -OC(O)-, -C(0)N(R3)-, -N(R3)C(0)-, -S(0)2N(R3>, -N(R3)S(0)2-, -0C(0)N(R3)-, -N(R3)C(0)0-, -N(R3)C(0)N(R3)- or -00(0)0-, wherein each R3 is independently hydrogen, (C,_3)alkyl or (C3.8)cycloaIkyl, with the 24 proviso that X1 and X9 are not both covalent bonds; X3 and X7 are independent!y -C(O)-, -0(0)0-, -OC(O)-, -C(0)N(R3)-, -N(R3)C(0)-, -6- -S(0),N(R5h -N(R3)S(OV, -0C(0)N(R3)-, -N(R3)C(0)0-, -N(R3)C(0)N(R3)- or -0C(0)0-, whercin R3 is as defined above; X2 and X* are independentiy (C,.4)alkylene, hetero(C,.j)aIkylene, -Xl0-X!1- or -Xn-X10-, wherein X10 is (C<u)allcylene or hetero(Cw)aIkyiene and X11 is (Cj.,)cyc[oaikyIene or hetero(C3.t)cycloalkylene; R1 is R4-X12- or R3^13*, v/herein: R4 is amino, amidino, guanidino, l-iminoethyl or methylamino, X12 is (C4^)alkylene, hetero(C^)alkylene, heterooxo(C4^)alkylene1 oxo(C4^)alkylene or -Χ14-Χ'3-Χιβ-, wherein X13 is (Cw)cycloalkylene, hetero(Cj4S)arylene, hetero(C3^)cycloa]kylene or phenylene, Xu is (CM4)alkylene and Xl& is (C„|6)aikylene, wherein the sum of nl4 and π 16 is 0, 1, 2, 3 or 4, R3 is a group seiected from azetidin-3-yl, benzoimida2oI-4-y[, benzoimidazol-5-yl imidazol-l-yl, imidazol-2-yl, imidazoi^^l, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-l-yll 4-methyiimidazol-l-yl, 5-methylimidazol-l-yl, l-methyipiperid-3-yl, l-methylpiperid-4-yl, piperid-3-yl, piperid-4-yl, piperazin-I-yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrroIidin-3-yi, 1.4.5.6- tetrahydropyrimid'm-2>yl, l,4,5,6-tetrahydropyrimidin-4-yl and 1.4.5.6- tctrahydropyrimidin-5>yl and any carbocyciic ketone or thioketone derivative thereof, which group is optional!y substituted with one or more radicais seiected from halo, hydroxy, mercapto, (C|.t)alkyl, (Cj_l4)cycloalkyl, (Cs.,«)aryl, (C4.|4)aryl(C1_4)alkyl, (C,.*)aIkanoyI, (C,.,)aIkyIoxy, (C4.M)aryloxy, (C3.14)cycloalkyloxy, (CM)aIkyloxy, (C,.I)alkylthio, (Cj.M)cycloalkylthio, (C6.,4)arylthio and -NR6R7, wherein R6 and R7 are independently seiected from hydrogen, (Ct.,)alkyl, (C,.j)aikanoyl, (Cj.,4)cycloaIkyl or (CS-u)aryl ^ X13 is (Co^)aIkylene, hetero(C^)alkylene, heterooxo(Cw)alkylene, oxo(C^)alkylene or -Χ^-Χ^Χ19-, wherein X'* is as defmed above for X13, X’7 is (C,,(7)alkylene and Xl9.is(C„i9)alkylene, wherein the sum of nl7 and nl9 is 0, 1 or 2; and R2 is R‘-X20- or R9-X21-, wherein: R1 is as defmed above for R\ X20 is (C4.4)alkylene, hetero(C4.4)alkylene, heterooxo(C4.4)alkylene, -7- LV 12459 oxo(C4^)aIkyiene or -Χ^-Χ^-Χ24-, wherein X23 is as defined above for X'5, X22is (C^alkjdene and X24 is (C^alkjdene, wherein the sum of n22 and n24 is 0,1,2,3 or 4, 3 R9 is as defined above for R5 and X21 is (C(w)alkylene, hetero(C2^)alkylene, heterooxo(Cw)aIkylene, oxo(C2^)aIkylene or -X25-X26-X27-, wherein X26 is as defined above for X15, X23 is 6 (C^alkjdene and X27 is (C^alkļdene, wherein the sum of n25 and n27 is 0,1 or 2; wherein each alkylene, cycloaikyiene, heteroalkylene, heterocycloalkylene, phenyiene, arylene and heteroaiylene, as defined above, are optionally substituted with one or more 9 radicals selected from halo, hydroxy, mercapto, (CM)aIkyl, (C3.14)cycloalkyl, (C6.14)aryl, (C6.]4)aiyl(Cw)alkyl, (C,.s)alkanoyl, (Cu)alkyioxy, (C6.14)aryioxy, (C3.14)cycloalkyloxy, (CM)alkyloxy, (C|.j)aIkylthio, (C3.l4)cycioalkylthio, (C6.,4)arylthio and -NR6R7, wherein 12 R6 and R7 are as defined above; with the proviso that covalent bonds do not occur between heteroatoms contained within R1, X2, X4, X6, X* and R2 and any heteroatoms contained with X3, X5, X7 and X9; and 15 the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. A third aspect of this invention is a pharmaceutical composition which contains a 18 compound of Formula I, or a phaimaceutically acceptable salt, N-oxide or prodrug derivative thereof in admixture with one or more suitable excipients. A fourth aspect of this invention is a method of treating a disease in an animal in which 21 tiyptase activity contributes to the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of Formula I or a pharmaceutically acceptable salt, N-oxide or prodrug derivative thereof.

24 A fifth aspect of this invention is the processes for preparing compounds of Formula I and the pharmaceutically acceptable salts, //-oxides, prodrug derivatives and protected derivatives thereof as set forth in "Detailed Description of the Invention".

27 DETAILED DESCRIPTION OF THE INVENTION

Definitions: -8-

Unless othervvise stated, the follovving terms used in the specification and claims have the meanings given below: “Alkanojd” means the radical -C(0)R, v/herein R !s alky! as defmed below, having overall the number of carbon atoms indicated (e.g., (C,_j)alkanoyl includes the radicals formyl, acetyl, propionyl, butyryl, isobutyryl, crotonoy[, isocrotonyl, etc.). uAlkyl”, as in alkyl, arylalkyl, a!kyloxy, aIkylthio, means a straight or branched, saturated or unsaturated hydrocarbon radical having the number of carbon atoms indicated (e.g., (CM)alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, /er/-butyl, vinyl, allyt, l-propenyl, isopropenyl, l-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, l-propynyl, 2-propynyl, etc.). “Alkylene” means a straight, saturated or unsaturated hydrocarbon divalent radical having the number of carbon atoms indicated (e.g., (Co.4)alkylene includes methylene (-CH2-), ethylene (-(CHj)2-), vinylene (-CH:CH-), ethynylene (-C: Cr), 2-propylene (-CH:CH-CH2-), l-propylene (-CH2*CH:CH-), tetramethylene (-(CH2)4-), pentamethylene (-(CH:)S-) and hexamethylene (-(CH2)4-), etc.). The term (C0)alkylene is meant to represent a covalent bond. “Alkyloxy” means the radical -OR, wherein R is alkyl as defmed above, having the number of carbon atoms indicated (e.g., (C,.,)alkyloxy includes the radicals methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, etc.). “AlkyIthio” means the radical -SR, wherein R is alkyl as defmed above, having the number of carbon atoms indicated (e.g., (C,.*)alkyIthio includes the radicals methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, etc.). "Animal" includes humāns, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, etc.) and non-mammals (e.g., birds, etc.). “Aryl”, as in aryl, arylalkyl, aryloxy and arylthio, means an aromatic monocyclic or polycycIic hydrocarbon radical containing the number of carbon atoms indicated, vvherein the carbon atom with the free valence is a member of an aromatic ring. and any carbocylic ketone or thioketone derivative thereof (e.g., (C^a^l includes phenyl, naphthyl, anthracenyl, phenanthrenyl, 1,2,3,4-tetrahydronaphth-5-yl, 1 -οχο-1,2-dihydronaphth-6-yl, l -thioxo-1,2-dihydronaphth-7-yl, etc.). “Arylene” means an aromatic monocyciic or polycyclic hydrocarbon divalent radical -9- LV 12459 containing the number of carbon atoms indicated, wherein the carbon atoms with the free valence are members of an aromatic ring, and any carbocylic ketone or thioketone derivative tbereof (e.g., (Cj.ļ^a^lene includes l,4-phenylene, l,3-phenylene, l,4-naphthylene, 2,6-naphthylene, 1.4- anthracenylene, 2,6-antbracenylene, l,6-phenanthrenylene, 1.2.3.4- tetrahydro-5,8-naphthylene, l-oxo-l,2-dihydro-5,7-naphthylene, 1 -thioxo-l ,2-dihydro-5,8-naphthylene, etc.). “Aryloxy” means the radical -OR, wherein R is aiyl, as defined above, having the number of carbon atoms indicated (e.g., (C6.14)aryloxy includes the radicals phenoxy, naphthyloxy, anthracenyloxy, etc.). “Aiylthio” means the radical -SR, wherein R is aryl, as defined above, having the number of carbon atoms indicated (e.g., (C6.M)arylthio includes the radicals phenylthio, naphthylthio, anthracenylthio, etc.). “CycloaIkyl”, as in cycloalkyl and cycloalkyloxy, means a saturated or unsaturated, monocyclic or polycyclic hydrocarbon radical containing the number of carbon atoms indicated, wherein the carbon atom with the free valence is a member of a non-aromatic ring, and any caibocyclic ketone and thioketone derivative thereof (e.g., (C3.,4)cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cycIohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, 1,2,3,4-tetrahydronaphth-1 -y 1, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, etc.). “Cycloalkylene” means a saturated or unsaturated, monocyclic or polycyclic hydrocarbon divalent radical containing the number of carbon atoms indicated, wherein the carbon atoms with the free valence are members of a non-aromatic ring, and any carbocyclic ketone and thioketone derivative thereof (e.g., (C3^)cycloalkylene includes l,2-cycIopropylene, I,2-cyclobutylene, 1.3- cyclobutylene, l,2-cyclopentylene, l,3-cyclopentylene, l,4-cyclopentylene, 1.4- cyclohexylene, 3-cyclohexen-l,2-ylene, 2,5-cyclohexadien-l,4-ylene, 1.4- bicyclo[2.2.2]octylene, l,2,3,4-tetrahydro-l,4-naphthylene, 5-oxo-l,3-cyclohexylene, 2.5- dioxo-l,4-cyclohexylene, 5-thioxo-l,4-cyclohexylene, etc.). “Cycloalkyloxy” means the radical -OR, wherein R is cycloalkyl, as defined above, having the number of carbon atoms indicated (e.g., (C3_l4)cycloalkyloxy includes the radicals cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc.). -10- “Cycloalkylthio” means the radical -OR, vvherein R is cycIoalkyl, as defined above, having the number of carbon atoms indicated (e.g., (Cj.M)cycloalkylthio includes the radicals cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexyIthio, etc.). "Deprotecting"Tefers to removing any protective groups present after the selective reaction has been carried out. "Disease" specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition which may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the "side effects" of such therapy. “Halo” means fluoro, chloro, bromo or iodo. “HeteroaIkylene” means alkylene, as defined above, vvherein 1 to 5 of the carbon atoms indicated is replaced by a heteroatom chosen from N, 0 or S (e.g., azaalkylene, oxaalkylene and thiaalkylene, respectively), with the proviso that the oxygen, nitrogen and sulfur atoms contained therein do not form bonds with other heteroatoms. For example, hetero(C2.,2)alkylene is meant to encompass aza(C3)alkylene which includes 3-azatrimethylene (-NHCH2CH2-), » 2- azatrimethylene (-CH2’NH'CH2-), etc.; o>-a2a(C2.j)aIkylene which includes 2-azaethylene (-NH-CHi-), 3-azatrimethylene, 4-azatetramethylene (-NH-CH2*CH2*CH2-) and 5-azapentamethylene (-NH-CH2-CH2-CH2'CH2-); oxa(C2)alkylene which includes as 3- oxatrimethylene (-OCH2-CH2-), 2-oxatrimethylene (-CH2*OCH2-), etc.; oxa(Cj)aIkylene such as 3-oxapentamethylene (-CH2-CH2O*CH2-CH2-), etc.; thia(C2)alkylene which includes 3-thiatrimethylene (-S-CH2-CH2-), 2-thiatrimethylene (-CH2-S-CH2-), etc.; o-thia(C2.4)aIkylene ’ which includes 2-thiaethylene (-NH-CH2-), 3-thiatrimethylene and 4-thiatetramethylene (-S-CH2-CH2'CH2-); diaza(Cs)aikylene which includes 2,5-diazahexamethylene (-CH2-NH-CH2*CH2*NH-CH2-); azaoxa(C4)alkylene which includes 2,-oxa-5-azahexamethylene (-CH2-0-CH2-CH2-NH-CHj-); and the Iike. “Heteroarylene" means arylene, as defined above, vvherein l to 5 of the carbon atoms indicated are replaced by a heteroatom chosen from N, 0 or S (e.g., hetero(C3.4)aryiene includes furylene, thienylene, pyrrolylene, imidazolylene, pyridylene, etc.). “Heterocycloalkylene” means cycloalkylene, as defined above, vvherein l to 5 ofthe carbon atoms indicated are replaced by a heteroatom chosen from N, 0, or S (e.g., hetero(Cj.u)cycloaIkylene includes 2,4-pyrroUdinylene, 2,4-pyrrolinylene, -11- LV 12459 2.4- imidazoIinyIene, 2,4-imidazolinylene, 3,5-pyrazoIinylene, l,4-piperidylene, 1.4- piperazinylene, 2,5-quinuclidinylene, 2,5-morphoIinylene, 1.3-isoindolinylene, etc.). “Heterooxoalkylene” means alkylene, as defined above, wherein one of the number of carbon atoms indicated is replaced by a heteroatom chosen from N, 0 or S and a carbon atom adjacent to the heteroatom is replaced by a carbonyl group (C=0), e.g., azaoxoalky!ene, oxaoxoalkylene and thiaoxoalkylene, respectively, with the proviso that the oxygen, nitrogen and sulfur atoms contained therein do not form bonds with other heteroatoms. For exampie, heterooxo(C4^)alkylene is meant to encompass azaoxo(C3)alkylene which includes 2- aza-3-oxotrimethylene (-C(0)*NH*CH2-), 3-aza-2-oxotrimethylene (-NH*C(0)-CH2-), etc.; oxaoxo(C3)aikyiene which includes 2-oxa-3-oxotrimethylene (-C(0)O’CH2-), 3- oxa-2-oxotrimethylene (-OC(0)*CH2-), etc.; and thiaoxo(C3)alkylene which includes 2- thia-3-oxotrimethylene (-C*(0)‘S*CH2-), 3-thia-2-oxotrimethylene (-S-C(0)*CH2-), etc. "Leaving group" has the meaning conventionaIIy associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under alkylating conditions, and includes, halogen, hydroxy, alkylsulfonloxy (e.g., mesyloxy, ethanesulfonyIoxy, etc.), arylsulfonyloxy (e.g., benzenesulfonyloxy and tosyioxy, thienyloxy), dihalophosphinoyloxy, tetrahalophosphaoxy, and the like. "Optional" or “optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not For example, the phrase "optionally substituted with one or more radicals" means that the group referred to may or may not be substituted in order to fall within the scope of the invention. "Pharmaceutically acceptable N-Oxide" means compound in which nitrogens are in an oxidized State (i.e., 0-N) which are pharmaceutically acceptable, as defined below, and which possess the desired phannacological activity. The JV-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art “Oxoalkylene” means alkylene, as defined above, vvherein one of the number of carbon atoms indicated is replaced by a carbonyl group (C=0), e.g., oxo(C3)alkylene includes 3- oxotrimethylene (-C(0)*CH2-CH2-), etc.. “Pathology” of a disease means the essential nature, causes and development of the -12- disease as well as the structural and functional changes that result from the disease processes. "Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor othenvise undesirabie and inciudes that which is acceptable for veterinary use as well as human pharmaceutical use. "Pharmaceutically acceptable salts" means salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid and the Iike; or with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, p-chlorobenzene-sulfonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glyco!ic acid, hexanoic acid, heptanoic acid, o-(4-hydroxybenzoyI)benzoic acid, 2-hydroxyethanesulfonic acid, hydroxynaphthoic acid, lāctic acid, lauryl sulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyibicyclo[2.2.2]oct-2-ene-l-carboxylic acid, 4,4'-methylenebis(3-hydroxy-2-ene-l-carboxylic acid), muconic acid, 2-naphthalenesulfonic acid, oxaIic acid, 3-phenylpropionic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiary butylacetic acid, /Moluenesulfonic acid, trimethylacetic acid and the like.

Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. Acceptable organic bases include diethanolamine, ethanolamine, iV-methylglucamine, triethanolamine, tromethamine and the like. “Phenylene” means the divalent aromatic radical -C6H4- and inciudes 1,4-pnenylene, 1,3-phenylene and the like. "Pharmaceutically acceptable prodrug derivatives" means derivatives of compounds of Formula 1 vvhich are pharmaceutically acceptable, as defined above, and which are converted irt vivo to the corresponding non-derivatized form of a compound of Formula I. Such prodrugs include compounds of Formula I vvhich have /V-acylated piperidyl (i.e., N(P)CSH,-), N-acylated azaalkylene (e.g., -N(P)-CHyCH2-), /V-acylated amino (i.e., -NH:(P)), /V-acylated amidino -13- LV 12459 (i.e.,-C(NP)-NHP, -C(NH)-NHP or -C(NP>NH2), W-acylated guanidino (i.e., -NHC(NP)-NHP, -ΝΗ*0(ΝΗ)·ΝΗΡ or -NH*C(NP)-NH2) groups, in which P is a group selected from -C(0)R10, 3 wherein R'° can be (C,.|0)alkyloxy or cfr-2-(C,_,0)alkanoyloxyphenylvinyl, 3-(C,.,o)alkanoyloxybutyryl, Rn-X2*-, wherein R“ is carboxy and X2* is (C,.|0)alkylene or -C(0)O*CH(Rl2)*0-C(0)R13, wherein R12 is hydrogen, (CM0)alkyl or (C3.I0)cycloalkyl and R13 is 6 (C].,0)alkyl. "Protective group" has the meaning conventionally associated with it in synthetic organic chemistry, i.e., a group which selectively blocks one reactive site in a multifunctional compound 9 such that a Chemical reaction can be cairied out selectively at another unprotected reactive site and which can be readily removed after the seiective reaction is completed. "Protecting aģent" means an aģent which will react with a multifunctional compound and 12 create a protective group at a reactive site. "Protected derivatives" in reference to a compound or a group means a derivative of compound or group in which a reactive site or sites are blocked with protective groups. 15 Protected derivatives of compounds of Formula I are in themselves active as tryptase inhibitors and are useful in the preparation of other compounds of Formula I. Suitable protecting groups for reactive nitrogen atoms include /erf-butoxycarbonyl, benzyloxycarbonyl and any other 18 suitable amino protective groups (e.g., see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981). “Symptomatology” of a disease means any morbid phenomenon or departure from the 21 normai in structure, function or sensation experienced by the patient and indicative of the disease, their production and the indications they fumish. "Therapeutically effective amount" means that amount which, when administered to an 24 animal for treating a disease, is suffrcient to effect such treatment for the disease. "Treating" or "treatment" of a disease includes preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display 27 symptoms of the disease, inhibiting the disease (i.e., arresting its development) or reiieving the disease (i.e., causing regression of the disease).

The term “q.s." means adding a quantity sufficient to achieve a stated function, e.g., to 30 bring a solution to the desired volume (i.e., 100%). -14-

The compounds of Formula I and the intermediates and starting materiāls used in their preparation are named in accordance IUPAC rules of nomenclature in which the characteristic 3 groups have decreasing priority for citation as the principle group as follows: acids, esters, amides and amidines. Furthermore, for the purposes of this Application, when referring to a divalent radical by vvritten description the order of the number prefixes signifies the orientation 6 of its attachment. Similarly, when referring to a divalent radical by formula the way in which the formula is presented signifies the orientation of attachment. For example, a compound of Formula I in which R1 is 4-amidinobenzyl, X1 and X9 each are -NHC(O)-, X2 is 9 l,4-piperazinylene, X7 is -C(0)0-, X* is 4,l-piperidylene and R2 is R9-X21, wherein R9 is piperid-4-yl and X21 is 3-azatrimethylene, is illustrated by the following formula:

12 NH

which compound is named: cis-1,5-cycloocty lene 4-(4-amidinobenzylcarbamoy l)-1 -piperazinecarboxy late 15 4-(2-piperid-4-ylaminoethylcarbamoyl)-I-piperidinecarboxylate when X3 and X7 each are -C(0)0-, X3 and X6 each are a covaient bond, X5 is cis- 1,5-cyclooctylene and P is hydrogen; 3- {4-[2-( l - {c/i-5-[4-(4-amidinobenzylcarbamoy l)piperazin-1 -ylcarbonyloxy]cycloocty loxy- 18 carbonyl}piperid-4-ylcarbonylamino)ethylamino]piperid-l-yicarbonyl} propionic acid when XJ and X7 each are -C(0)0-, X4 and Xs each are a covaient bond, X5 is cis-1,5-cyclooctylene and P is 3-carboxypropionyl; 21 4-[4-(4-amidinobenzylcarbamoyl)piperazin-1 -ylcarbonyl]benzyl 4- (2-piperid-4-ylaminoethylcarbamoyl)-l-piperadinecarboxylate when X3 is -C(O)-, X7 is -C(0)0-, X* is a covaient bond, X6 is methviene, X5 is phenylene and P is hydrogen; -15- LV 12459 l,4-tetramethylene 4-amidinobenzylcarbamoyl-l-piperazinecarboxylate when X3 and X7 are each is -C(0)0- and X4-X5-X6 is l,4-tetramethylene (i.e., -CH2-CH2-CH2-CH2-); and 3 Ai’-4-amidinobenzyl-4-{ 5-[4-(2-piperid-4-ylaminoethylcarbamoyl)piperid-1 -ylcarbony 1] valery 1} -l-piperazmecarboxamide whenX3 and X7 are each is -C(0)- and X4-X5-X6 is l,4-tetramethylene (i.e., -CH2-CH2-CH2-CH2·). 6 Presently Preferred Embodiments:

While the broadest defmition of this invention is set forth in the Summary of the Invention, certain compounds of Formula I are preferred. For example, preferred compounds of 9 Formula I are those in which X5 is cis-1,5-cyclooctylene and X4 and X6 each are a covalent bond, X4-X5-X6 together are (C4_*)alkylene or X5 is l,4-phenylene and X4 and X6 are (Co_,)'alkylene X1 and X9 are independen£ly a covalent bond, -C(O)-, -NHC(O)-, -C(0)NH-, -N(CH3)C(0)- or 12 -S(0)2NH-, with the proviso that X1 and X9 are not both covalent bonds; X3 and X7 are independently -C(O)- or -C(0)0-; X2 and X* are independently -Xl0-X"-, vvherein X10 is a covalent bond or methylene and Xfi is 4,l-piperidylene or l,4-piperazinylene; R1 is R4-X'2- or 15 R5-X13-, vvherein R4 is amidino, guanidino or methylamino, X12 is -X14-XIS-X16-, wherein XIS is 1.4- phenylene or l,4-piperidylene, X14 is (Cnl4)alkylene and X16 is (C„16)alkylene, wherein the sum of nl4 and nl6 is 0,1 or 2, R5 is piperid-4-yl and X13 is (C2.3)alkylene; and R3 is R8-X20- or 18 R9-X21-, vvherein R8 is amino, amidino, guanidino, methylamino or l-iminoethyl, X20 is -Χ^-Χ^-Χ24-, whereinX23 is frany-l,4-cyclohexylene, l,4-phenylene, 4,l-pyridylene, 1.4- piperidylene, X22 is (Cn22)alkylene andX24 is (Cn24)alkylene, wherein the sum of n22 and n24 21 is 1 or 2, R9 is benzoimida2ol-5-yl, imidazol-l-yl, imidazol-4-yl, 2-imidazolin-2-yl, 4-methylimidazoI-l-yl, 5-methylimidazol-l-yl, l-methyipiperid-4-yi, piperid-4-yl, piperazin-l-yl, pyrid-3-yl, pyrid-4-yl, l,4,5,6-tetrahydropyrimidin-5-yI or 24 l,4,5,6-tetrahydro-2-dioxopyrimidin-5-yl and X21 is (C,.6)alkylene, Q-aza(C2.5)alkylene, 3-oxotrimethylene, o-thia(C2J,)alkylene, 3-oxo-2-azatrimethylene, 3-aza-2-oxotrimethylene or -X2i-X26-X27-, vvhereinX26 is l,4-phenylene, X23 is (Cn23)alkylene andX27 is (C^al^lene, 27 wherein the sum of n25 and n27 is 0 or 1; and the pharmaceutically acceptable salts, jV-oxides, prodrug derivatives and protected derivatives thereof.

More preferred compounds of Formula I are those in vvhich X5 is cii-l,5-cyclooctylene -16- and X4 and X6 each are a covalent bond or X4-X3-Xs together are (CM)aIkylene; X1 and X’ are independently a covalent bond -C(0)-, -NHC(O)-, -C(0)NH- or -S(0)2NH-, with the proviso that X’ and X9 are not both covalent bonds; X3 and X7 are independently -C(0)- or -C(0)0-; X2 and X* are independently -X10-XM-, wherein X10 is a covalent bond or methyiene and X11 is 4,l-piperidylene or l,4-piperazinylene; R‘ is R4-X12-, wherein R4 is amidino or guanidino and X12 is -X14-Xl3-X16-, wherein X13 is 1,4-phenylene or l,4-piperidylene, X14 is (CnM)alkylene and X16 is (Cnl6)alkylene, wherein the sum of nl4 and nl6 is 0, 1 or 2; and R2 is R!-X20- or R9-X21-, whcrein R‘ is amino or methylamino, X2a is -X22-Xu-X74-, wherein X22 is trans-1,4-cyclohexylene or l,4-phenylene, X22 is (Cn2:)alkylene and X16 is (Cn2<)alkylene, wherein the sum of n22 and n24 is l or2, R9 is imidazol-l-yl, imidazol-4-yI, 4-methylimidazol-l-yl, 5-methylimidazol-l-yl, piperid-4-yl or pyrid-4-yl and X21 is (C|.5)alkylene or 3-a2atrimethylene; and the pharmaceutically acceptable salts, jV-oxides, prodrug derivatives and protected derivatives thereof.

Particularly preferred compounds of Formula l are those in which X3 is cis- l,5-cyclooctylene and X4 and X6 each are a covalent bond; X1 and X9 are independent!y -C(O)- or -NHC(O)-; XJ and X7 each are -C(0)0-; X2 and X* are independcntly -X,0-X"-, v/herein X10 is a covalent bond and X" is l,4-piperazinyiene; R1 is R4-X12-, wherein R4 is amidino or guanidino and X12 is -Xl4-Xl3-X14-, wherein X13 is l ,4-phenylene, X'4 is a covalent bond and X14 is methylene; and R2 is R*-X20- or R’-Χ21-, wherein R1 is amino, X20 is -X22-X22'X24-, wherein X22 is rrans-l,4-cyclohexylene·, X22is a covalent bond and X24 is methylene, R9 is piperid-4-yl and X21 is ethylene or trimethylene; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.

Particularly preferred compounds of Formula 1 are those in which X4-X5-Xs together are (C4.,)alkylene; X' and X9 are independently -C(O)- or -NHC(O)-; X3 and X7 are independently -C(O)- or -C(0)0*; X2 and X* each are -X,0-X"-, wherein X10 is a covalent bond and X11 is l ,4-piperazinylene; R1 is R4-X12-, wherein R4 is amidino or guanidino and X12 is -Xl4-X,3-X'6-, wherein X13 is 1,4-phenylene, X'4 is a covalent bond and X16 is methylene; and R2 is R1^20-, wherein R* is amidino or guanidino and X20 is -X22-X22-X24-, vvherein X22 is l,4-phenylene, X“is a covalent bond and X24 is methylene; and the pharmaceutically acceptable salts, /V-oxides, prodrug derivatives and protected derivatives thereof. -17- LV 12459

Most preferred compounds of Fonnula I are the following: 4-guanidinobenzyl 4- { 7-[4-(4-guanidinoben7y lcarbamoy I)piperazin-1 -y Icarbony I] -3 heptanoyI} -1 -piperazinecarboxamide; 4-guanidinobenzyl 4*{ 8-[4-(4-guanidinobenzylcarbamoyl)piperazin-l -ylcarbonyljoctanoyl}-6 l-piperazinecarboxamide; 4-guanidinobenzyl 4- {9-[4-(4-guanidinobenzy lcarbamoyl)piperazin~ 1 -ylcarbony 1]-nonanoyl}-1 -piperazinecarboxamide; 9 4-amidmobenzyl 4-{7-[4-(4-amidinobenzylcarbamoyl)pipera2in-l-ylcarbonyl]heptanoyl}-1 -piperazinecarboxainide; 12 cis-1,5-cyclooctylene 4-(4-amidinobenzylcarbamoyl)-l -piperazinecarboxylate 4-(2-piperid-4-yIethylcarbamoyl)-l-pipera2inecarboxylate; 1,5-pentamethylene di[4-(4-guanidinobenzylcarbamoyl)-l-pipera23necarboxylate]; 15 cis-1,5-cycIooctylene 4-(4-amidinobenzyIcarbamoyI)-1 -piperazinecarboxyIate 4-(4-piperid-4-yIbutyiyl)-1 -piperazmecarboxylate; cis-l,5-cyclooctylene /7-am,-4-(4-aininocyclohexylmethylcarbamoyI)-18 1 -piperazinecarboxylate 4-(4-guanidinobenzylcarbamoy I)-1 *piperazmecarboxylate; cis-1,5-cycIooctyiene 4-(4-amidinophenylacetyI)-1 -piperazinecarboxylate 4-(4-piperid-4-y lbutyry 1)-1 -piperazinecarboxylate; 21 l,4-tetramethylene di[4-(4-guamdmobenzylcarbamoyl)-l-piperazinecarboxylate]; cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoyl)-1 -piperazinecarboxylate; 24 4-guanidinobenzyl 4- {6-[4-(4-guanidinobenzy lcarbamoyl)piperazin-1 -y lcarbony 1] hexanoyl} -1 -piperazinecarboxamide; 27 cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate 4-(4-piperid-4-yIbutyry I)-1 -piperazinecarboxy Iate; cis-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-1 -piperazinecarboxylate 30 4-(2-piperid-4-ylethylcarbamoyl)-1 -piperazinecarboxylaie;

Claims (11)

A compound of formula (I): R 1 -X 1 -X 2 -X 3 -X * ^ / χ 5 R 2 -X 9 -X 8 -X 7 -X 6 -X wherein: X 5 is C 0-12 alkylene, hetero-C 3 -I2alkylene, C3-14cycloalkylene, hetero-C3-14cycloalkylene, C6-14arylene or hetero-C5-Cuarylene; X and X, independently of one another, are Co-2 alkylene; X 1 and X 9, independently of one another, are a covalent bond, -CO-, -COO-, -O-CO-, -CONR 3 -, -NR 3 CO-, -SO 2 NR 3 -, -NR 3 SO 2 -, -OCONR 3 -, -NR 3 COO - , -NR3CONR3- or -OCOO-, wherein R3 is independently hydrogen, C1-3alkyl, or C3-4cycloalkyl, provided that X1 and X9 are not simultaneously a covalent bond; X3 and X7 independently of one another are -CO-, -COO-, -O-CO-, -CONR3-, -NR3CO-, -SO2NR3-, -NR3SO2-, -OCONR3-, -NR3COO-, -NR3CONR3 -or -OCOO-, where the meanings of R3 are already mentioned; X2 and X8, independently of one another, are C1-4alkylene, hetero-C1-8alkylene, -X10-X11- or -X11-X10-, where X10 is C0-4alkylene or hetero-C1-4alkylene, X11 is 4.1 -piperidinylene; R 1 is R 4 -X 12 - or R 5 -X 13 - wherein: R 4 is amino, amidine, guanidine, 1-iminoethyl or methylamino; X 12 is C 4 -C 4 alkylene, hetero-C 4 -C 6 alkylene, heterooxy-C 4 -C 6 alkylene, oxo-C 4 -C 6 alkylene or -X 14 -X 15 -X 16 -, where X 15 is C 5 -C 6 -alkoxyalkylene, hetero-C 5 -C 6 arylene, hetero-C 3 cycloalkylene or phenylene, X 14 is C 1-6 alkylene and X 16 is C 1-6 alkylene, wherein the sum of n 14 and n 16 is 0.1, 2, 3 or 4; R5 is selected from the group consisting of azetidin-3-yl, benzimidazol-4-yl, benzimidazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-methylpiperidin-3-yl, 1-methylpiperidine -4-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-5 -Igroup, pyrrolidin-3-yl, 1,4,5,6-tetrahydropyrimidin-2-yl, 1,4,5,6-tetrahydropyrimidin-4-yl, 1,4,5,6-tetrahydropyrimidin-5-yl as well as the carbocyclic oxo or thioxo derivatives of said groups, said groups being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, mercapto, C 1-7 -alkyl, C 3-14 -cycloalkyl, C 6 -aryl, C 6 -C 14 -aryl. C 1-4 alkyl, C 1-4 alkanoyl, C 6-14 aryloxy, C 3-14 cycloalkyloxy a group, C 1-4 alkoxy, C 1-4 alkylthio, C 3-14 cycloalkylthio, C 6arylthio and -NR 6 R 7 wherein R 6 and R 7 are independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkanoyl, C 3 C 1-4 cycloalkyl and C 6 -aryl; X 13 is C 0 -C 6 alkylene, hetero-C 1 -C 4 alkylene, hetero-oxo-C 3 -C 6 alkyl-ene, oxo-C 2 -C 6 alkylene, or X 17 -X 18 -X 19 - in which X 18 is the same as X 15, X 7 is C 1 -C 7 alkylene and X 19 is C 1-9 alkenyl, wherein the sum of n 17 and n 19 is 0.1 or 2; r2 and r8-X20. or R 9 -X 21 - where: R 8 is amino, 1-iminoethyl or methylamino, X 20 is C 4 -C 6 alkylene, hetero-C 4 -C 6 alkylene, heteroxy-C 4 -C 6 alkylene, oxo-C 1 -C 4 alkylene or X 22 -X 23 -X 24 - wherein X 23 has the same meanings as X 15, X 20 is C 1-4 alkylene and X 24 is C n 24 alkylene, wherein the sum of n 22 and n 24 is 0, 1, 2, 3 or 4, provided that when R 8 is amino, X 20 is not C 1-4. alkylene or oxa-C 1-4 alkylene and n 22 is not 1, 2, 3 or 4; R9 has the meanings already given in R5; X 21 is C 0 -C 4 alkylene, hetero-C 2 -C 4 alkylene, hetero-oxo-C 3 -C 4 alkylene, oxo-C 2 -C 4 alkylene or X-X 26 -X 27 -, where X 26 is the same as X 15, X 25 is C 25 alkylene and X 27 is C 27 alkylene, wherein any of the above alkylene groups, cycloalkylene groups, heterocycloalkylene groups, phenylene groups, arylene groups and heteroarylene groups is optionally substituted with one or more substituents selected from the group consisting of halogen, -C3-hydroxy, C 1-4 aryl, C 6-14 aryl-C 1-4 alkyl, C 1-4 alkanoyl, C 1-4 alkoxy, C 6-14 cycloalkyloxy, C 1-4 alkoxy, C 1-4 alkylthio, C 3-14 cycloalkylthio, C 6-10aryl, has the same meanings as given above, provided that the heteroatoms of R1, X1, X2, X6, X8, R1 and the heteroatoms of X3, X5, X7 and X are not covalent bonds and pharmaceutically acceptable salts thereof, N -ox di, prodrug derivatives and protecting groups. A compound according to claim 1 wherein: 2 1,4-phenylene and X 2 and X 6 are both C 0 alkylene; 3 X5. is cis-1,5-cyclooctylene and X2 and X6 are both covalent bonds or X5 is X4 and X6 independently of one another are C0-6alkylene; X1 and X9 independently of one another are a covalent bond, -CO-, -NHCO-, -CONH-, -N (CH3) CO- or -SO2NH- X1 and X7 independently of one another are -CO- or -COO-; X 2 and X 8, independently of one another, are -X 10 -X 11 -, wherein X 10 is a covalent bond or methylene, X 11 is 4,1-piperidinylene; R1 is R4-X12- or R5-X13-, wherein: R4 is amidino, guanidine or methylamino; X 12 is -X 14 -X 15 -X 16 - where X 15 is 1,4-phenylene or 1,4-piperidinyl-ene, X 14 is C 1-4 alkylene and X'6 is C 1-6 alkylene where n 14 and n 16 are 0, 1 or 2 ; R5 is piperidin-4-yl; X 13 is C 2-3 alkylene; R2 is R8-X20- or R9-X21-, where: R8 is amino, methylamino or 1-iminoethyl, X20 is X22-X -X24-, where X23 is trans-1,4-cyclohexylene, 1,4-phenylene, 4,1-pyridinylene, 1,4-piperidinylene, X 22 is C n 22 alkylene and X 24 is C 1-4 alkylene, wherein the sum of n 22 and n 24 is 1 or 2; R 9 is benzimidazol-5-yl, imidazol-1-yl, imidazol-4-yl, 2-imidazolin-2-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-methylpiperidin- 4-yl, piperidin-4-yl, piperazin-1-yl, pyridin-3-yl, pyridin-4-yl, 1,4,5,6-tetrahydropyrimidin-5-yl or 1,4,5,6- tetrahydro-2-dioxo-pyrimidin-5-yl; X 21 is C 1-4 alkylene or (o-aza-C 2 -alkylene, 2-aza-3-oxotrimethylene, 3-aza-2-oxotrimethylene, 3-oxotrimethylene, cD-thia-C 2-4 alkylene or -X 25 -). X26-X27-, wherein X26 is 1,4-phenylene, X25 is C1-C25 alkylene and X27 is -C1-4 alkylene, wherein the sum of n25 and n27 is 0 or 1, and pharmaceutically acceptable salts, N-oxides, prodrugs thereof and A compound according to claim 2 wherein: X5 is cis-1,5-cyclooctylene and X4 and X6 are both covalent bonds, X1 and X9 are independently a covalent bond, -CO-, -NHCO -, -CONH-, -N (CH3) CO- or -SO2NH-X3 and X7, independently of one another, are -CO- or -COO-; R1 is R4-X12-, wherein: R4 is an amidine or guanidine; R2 is Re-X20- or R9-X * - where: R8 is amino or methylamino, X23 is trans-1,4-cyclohexylene, 1,4-phenylene, R9 is imidazol-1-yl, imidazol-4-yl , 4-methylimidazoH-yl, 5-methylimidazol-1-yl, piperidine -4-yl, pyridin-4-yl, X 21 is C 1-6 -alkylene or 3-aza-trimethylene, and pharmaceutically acceptable salts, N-oxides, prodrugs and protecting groups thereof. 4 A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in association with a pharmaceutically acceptable diluent. 5. The compound of formula (I) κ'-χ'-χ2-χ3-χν / χ5R2-x9-x8-x7-x610 X5 is C 0-12 alkylene, hetero-C 3-12 alkylene, C 3-14 cycloalkylene, hetero-C 3 C14-14cycloalkylene, C6-14arylene or hetero-C5-14arylene; X and X6, independently of one another, are Co-2 alkylene; X 1 and X 9, independently of one another, are a covalent bond, -CO-, -COO-, -O-CO-, -CONR 3 -, -NR 3 CO-, -SO 2 NR 3 -, -NR 3 SO 2 -, -OCONR 3 -, -NR 3 COO - , -NR3CONR3- or -OCOO-, wherein R3 is independently hydrogen, C1-3alkyl or C3cycloalkyl; X3 and X7 independently of one another are -CO-, -COO-, -O-CO-, -CONR3-, -NR3CO-, -SO2NR3-, -NR3SO2-, -OCONR3-, -NR3COO-, -NR3CONR3 -or -OCOO-, where the meanings of R3 are already mentioned; X2 and X8, independently of one another, are C1-4 alkylene, hetero-C1-4 alkylene, -X10-X11- or -X11-X10-, wherein X10 is C0-4 alkylene or hetero-C3-4 alkylene, X11 is 4.1 -piperidinylene; R 1 is R 4 -X 12 - or R 5 -X 13 - wherein: R 4 is amino, amidine, guanidine, 1-iminoethyl or methylamino; X 12 is C 1 -C 6 alkylene, hetero-C 4 -C 4 alkylene, heteroxy-C 1 -C 4 alkylene-group, oxo-C 4 -C 4 alkylene or -X 14 -X 15 -X 16 -, wherein X 15 is C 3 -C 6 cycloalkylene, hetero-C 5 -aryylene, hetero-C 3 -6Cycloalkylene or phenylene, X 14 is C 1-4 alkylene and X 16 is C 1-4 alkylene, wherein the sum of n 14 and n 16 is 0.1, 2, 3 or 4; R5 is selected from the group consisting of azetidin-3-yl, benzimidazol-4-yl, benzimidazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-methylpiperidin-3-yl, 1-methylpiperidin-4-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrrolidine, 3-yl, 1,4,5,6-tetrahydropyrimidin-2-yl, 1,4,5,6-tetrahydropyrimidin-4-yl, 1,4,5,6-tetrahydropyrimidin-5-yl, and the aforementioned group carbocyclic oxo or thioxo derivatives, said groups being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, mercapto, C 1-4 alkyl, C 3-14 cycloalkyl, C 6 -aryl-C 6 -aryl-C 1 C 1-4 alkyl, C 1-4 alkanoyl, C 6 -aryloxy, C 3-6 cyclo oalkyloxy, C 1-4 alkoxy, C 1-4 alkylthio, C 3-14 cycloalkylthio, C 6arylthio and -NReR 12 wherein R 6 and R 7 are independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkyl, C 1-4 cycloalkyl and C 6-14 aryl; X 13 is C 0 -C 6 alkylene, hetero-C 2 -C 6 alkylene, heteroxy-C 3 -C 6 alkylene, oxo-C 2 -C 6 alkylene, or X 17 -X 18 -X 19-where X 19 is as defined above for X 15, X 1 is C 1 -C 7 alkylene and X 19 is C 1-9 alkenyl, wherein the sum of n 17 and n 19 is 0, 1 or 2; R2 is R-X20- or R3-X21-, wherein: Ra is amino, 1-iminoethyl or methylamino, X20 is C4-alkylene, hetero-C4-4 alkylene, heteroxy-C4-6 alkylene, oxo-C4-4 alkyl; alkylene or X22-X23-X24-, where X23 is as defined above for X15, X22 is Cn22alkylene and X24 is Cn24alkylene, wherein the sum of n22 and n24 is 0, 1, 2, 3 or 4, provided that when R 4 is amino, X 20 is not C 1-4 alkylene or oxa-C 1-4 alkylene and n 22 is not 1,2,3 or 4; R3 has the meanings already indicated in R5; X 21 is C 0 -C 2 alkylene, hetero-C 2 alkylene, heterooxy-C 3 -C 6 alkylene, oxo-C 2 -C 6 alkylene or X-X 26 -X 27 - where X 26 is the same as X 15, X 25 is Cn 25 alkylene and X 27 is Cn 27 alkylene. the sum of n25 and n27 is 0.1 or 2, wherein any of the above alkylene, cycloalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene groups is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy and hydroxy; alkyl, C5-udcloalkyl, C6-14 aryl, C 6 -aryl-C 1-4 alkyl, C 1-4 alkanoyl, C 1-4 alkoxy, C 6 -aryloxy, C 3-14 cycloalkyloxy, C 1-4 alkoxy, C 1-4 alkylthio, C 5-10 cycloalkyl arylthio and -NR6R2 wherein R6 and R2 have the meanings given above, provided that there is no covalent bond between the heteroatoms of R1, X2, X4, X6, X4, R2 and the heteroatoms of X3, X5, X2 and X3 as well as its pharmacist the use of a pharmaceutically acceptable salt, N-oxide, prodrug or protecting derivative for the manufacture of a medicament for the treatment of animal diseases in which pathology and / or symptomatology is related to tryptase activity. The use according to claim 5, wherein said disease is of the group: asthma, allergic rhinitis, rheumatoid spondylitis, osteoarthritis, gout, rheumatoid arthritis, various types of arthritic conditions, urticaria, angioedema, eczema dermatitis, anaphylaxis, hyperproliferative, inflammation of the intestine, conjunctivitis of the eyes and spring, and inflammatory conditions of the skin. The use according to claim 6, wherein said disease is asthma. 3 a pharmaceutically acceptable aerosol-forming carrier suitable for inhalation. The use according to claim 7, wherein the compound is administered in combination with step 6 The use according to claim 8, wherein the therapeutically effective amount of the compound is administered in combination with a β-adrenoreceptor agonist, methylxanthine, chromoglycate or corticosteroid. The use according to claim 9, wherein the β-adrenoreceptor agonist is selected from the group consisting of albuterol, terbutaline, phenoterol and prenaline; methylxanthine is selected from the group: caffeine, theophylline, aminophylline and theobromine; the chromoglycate is selected from the group consisting of chromoline and nedocromil; corticosteroid taken from the series: beclomethasone, triamcinolone, flunisolide and dexamethasone. The use according to claim 6, wherein said disease is rheumatoid atrophy or conjunctivitis. The use of claim 11, wherein the compound is co-administered with a pharmaceutically acceptable aerosol-forming carrier suitable for application to the skin. A compound of formula (I): K 1 -X 1 -X 2 -X 3 -X * x 5 -R 2 -X 9 -X 8 -X 7 -X 6 I wherein: X 4 -X 5 -X® together are C 2-12 alkylene or hetero-C 3 .12 alkylene; X 1 and X 9, independently of one another, are a covalent bond, -CO-, -COO-, -O-CO-, -CONR 3 -, -NR 3 CO-, -SO 2 NR 3 -, -NR 3 SO 2 -, -OCONR 3 -, -NR 3 COO - , -NR3CONR3- or -OCOO-, wherein R3 is independently hydrogen, C1-3alkyl, or C3-8cycloalkyl, provided that X1 and X9 are not at the same time a covalent bond; X3 and X7 independently of one another are -CO-, -COO-, -O-CO-, -CONR3-, -NR3CO-, -SO2NR3-, -NR3SO2-, -OCONR3-, -NR3COO-, -NR3CONR3 -or -OCOO-, where the meanings of R3 are already mentioned; X 2 and X 8, independently of one another, are C 1-6 alkylene, hetero-C 1-6 alkylene, -X 10 -X 11 - or -X 11 -X 10 -, where X 10 is Co-talcylene or hetero-C 3-4 alkylene, X 11 is 4.1 -piperidinyl group; R 1 is R 4 -X 12 - or R 5 -X 13 - wherein: R 4 is amino, amidine, guanidine, 1-iminoethyl or methylamino; X 12 is C 1-4 alkylene, hetero-C 1-4 alkylene, heterooxy-C 1-4 alkylene, oxo-C 1-4 alkylene or -X 14 -X 15 -X 16 -, wherein X 15 is C 3-6 cycloalkylene, hetero-C 5 -aryylene, hetero-C 3 -6cycloalkylene or phenylene, X 14 is C 1-6 alkylene and X 16 is C 1-6 alkylene, wherein the sum of n 14 and n 16 is 0.1, 2, 3 or 4; . R5 is selected from the group consisting of azetidin-3-yl, benzimidazol-4-yl, benzimidazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-4-yl; 2-yl, 2-imidazolin-3-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-methylpiperidin-3-yl, 1-methylpiperidin- 4-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl ilyl, pyrrolidin-3-yl, 1,4,5,6-tetrahydropyrimidin-2-yl, 1,4,5,6-tetrahydropyrimidin-4-yl, 1,4,5,6-tetrahydropyrimidin-5-yl, as well as carbocyclic oxo or thioxo derivatives of said groups, said groups being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, mercapto, C 1-4 alkyl, C 3-14 cycloalkyl, C 6 -aryl, C 6 -aryl-C 1 C 1-4 alkyl, C 1-4 alkanoyl, C 6 -aryloxy, C 5 -cycloalkyl kloxy, C 1-4 alkoxy, C 1-4 alkylthio, C 3-14 cycloalkylthio, C 6-14 arthio and -NR 8 R 7 where R 6 and R 7 are independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkanoyl, C14-Cycloalkyl and C 6 -aryl; X 13 is C 0 -C 6 alkylene, hetero-C 2 -C 6 alkylene, heterooxy-C 3 -C 6 alkylene, oxo-C 1 -C 4 alkylene, or -X 17 -X 18 -X 19 - where X 19 has the same meaning as X 15, X 17 is C 1 -C 7 alkylene and X 19 is C 1-9 alkylene, wherein the sum of n 17 and n 19 is 0, 1 or 2; R2 is R8-X20- or R9-X21-, wherein: R8 has the meanings given above for R4; X 20 is C 1-4 alkylene, hetero-C 1-4 alkylene, heterooxy-C 1-4 alkylene, oxo-C 1-4 alkylene or -X 22 -X 23 -X 24 - wherein X 23 is the same as X 15, X 22 is C 1-4 alkylene and X 24 is C 1-24 alkylene. wherein the sum of n22 and n24 is 0,1, 2, 3 or 4; R9 has the meanings already given in R5; X 21 is C 0 -C 6 alkylene, 'hetero-C 2 -C 6 alkylene, heteroxy-C 3 -C 6 alkylene, oxo-C 1 -C 4 alkylene or -X-X 28 -X 27 -, wherein X 28 has the same meaning as X 15, X 25 is Cn 25 alkylene and X 27 is Cn 27 alkylene; wherein the sum of n25 and n27 is 0.1 or 2, wherein any of the above alkylene, cycloalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene groups is optionally substituted with one or more of the substituents: halo, hydroxy, hydroxy, C 1-6 alkyl, C 3-14 cycloalkyl, C 6-10 aryl, C 6-14 aryl-C 1-4 alkanoyl, C 1-4 alkoxy, C 6 -aryloxy, C 5 -cycloalkyloxy, C 1-4 alkoxy, C 1-6 alkylthio, -NR8R7 wherein R8 and R7 have the meanings given above, provided that there is no covalent bond between the heteroatoms of R1, X2, X4, X8, X8, R2 and the heteroatoms of X3, X5, X7 and X, as also its far pharmaceutically acceptable salts, N-oxides, prodrugs and protecting groups. 14. The compound of claim 13, wherein: X4-X5-X6 are each C2-10 alkylene or hetero-C3-10 alkylene; X 1 and X 9, independently of one another, are a covalent bond, -CO-, -NHCO-, -CONH-, -N (CH 3) CO- or -SO 2 NH-; X 8 and X 7, independently of one another, are -CO-, -COO-; X2 and X8, independently of one another, are -X10-X11- or -X11-X10-, wherein X10 is a covalent bond or methylene and X11 is 4,1-piperidinylene; R1 is R4-X12- or R5-X13-, wherein: R4 X12 R5 X13 R2 1,4- is amidine, guanidine or methylamino; is -Χ14-Χ1 * -Χιβ-, where X15 is a 1,4-phenylene piperidinylene group, X14 is a C 1-7 alkylene group and a C 1-6 alkylene group, wherein the sum of n 14 and n 16 is 0, 1 or 2; and piperidin-4-yl; is C 2-3 alkylene; is R8-X20- or R9-X21-, wherein: R8 is amino, amidine, guanidine, methylamino or 1-iminoethyl; X 20 is -NH 4 -CH 2 -CH 2 - where X 23 is trans-1,4-cyclohexylene, 1,4-phenylene, 4,1-pyridinylene, 1,4-piperidinylene, X 22 is Cn 22 alkylene and X 24 is C n 24 alkylene, at wherein the sum of n22 and n24 is 1 or 2; R 9 is benzimidazol-5-yl, imidazol-1-yl, imidazol-4-yl, 2-imidazolin-2-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-methylpiperidin- 4-yl, piperidin-4-yl, piperazin-1-yl, pyridin-3-yl, pyridin-4-yl, 1,4,5,6-tetrahydropyrimidin-5-yl or 1,4,5,6- tetrahydro-2-dioxo-pyrimidin-5-yl; X 21 is C 1-4 alkylene or < a-aza-C2.5 alkylene, 2-aza-3-oxotri-methylene, 3-aza-2-oxotrimethylene, 3-oxotrimethylene, a) -thia-C 2-4 alkylene or - X2S-X26-X27-, wherein X26 is 1,4-phenylene, X25 is C1-4alkylene and X27 is Cn27alkylene, the sum of n25 and n27 being 0 or 1, and pharmaceutically acceptable salts, N-oxides, prodrugs thereof and protecting groups containing derivatives. 15. The compound of claim 14, wherein: 'X4-X5-X6 are all together C4-salkylene or hetero-C4-10-olfkylene; X 1 and X 9, independently of one another, are a covalent bond, -CO-, -NHCO-, -CONH-, or -SO 2 NH-; X 3 and X 7 are independently -CO-, -COO-; R1 is R4-X12 where: R4 is amidine or guanidine; r2 is r8-x2 ° or R9-xyl-, wherein: R8 is amino, amidine, guanidine or methylamino; X 23 is trans-1,4-cyclohexylene or 1,4-phenylene; R 9 is imidazol-1-yl, imidazol-4-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, piperidin-4-yl, pyridin-4-yl; X 21 is C 1 -C 6 -alkylene or 3-aza-trimethylene, and its pharmaceutically acceptable salts, N-oxides, prodrugs and protecting groups. 9 EN 12459 A process for the preparation of a compound of formula (I) X5 r2-X9-X8-X7-X6-I wherein: X5 is C0-12 alkylene, hetero-C3-12 alkylene, C3-14 cycloalkylene, hetero-C5-cycloalkylene, C6-14 arylene or heteroaryl. -C 8 -arylene-4 9a group: X and X ° independently of one another are C 0-4 alkylene; X 1 and X 9, independently of one another, are a covalent bond, -CO-, -COO-, -O-CO-, -CONR 3 -, -NR 3 CO-, -SO 2 NR 3 -, -NR 3 SO 2 -, -OCONR 3 -, -NR 3 COO - , -NR3CONR3- or -OCOO-, wherein R3 is independently hydrogen, C1-3alkyl, or C3.8Cycloalkyl, provided that X1 and X9 are both not simultaneously a covalent bond; X3 and X7 independently of one another are -CO-, -COO-, -O-CO-, -CONR3-, -NR3CO-, -SO2NR3-, -NR3SO2-, -OCONR3-, -NR3COO-, -NR3CONR3 -or -OCOO-, where the meanings of R3 are already mentioned; X 2 and X 8, independently of one another, are C 1-4 alkylene, hetero-C 1-4 alkylene, -X 10 -X 11 - or -X 11 -X 10 -, wherein X 10 is C 0-4 alkylene or hetero-C 3-6 alkylene, X 11 is 4.1 -piperidinylene; R 1 is R 4 -X 12 - or R 5 -X 13 - wherein: R 4 is amino, amidine, guanidine, 1-iminoethyl or methylamino; X 12 is C 4 -C 6 alkylene, hetero-C 4 -C 6 alkylene, heteroxy-C 4 -C 6 alkylene, oxo-C 4 -C 6 alkylene or -X 14 -X 15 -X 16 - wherein X 15 is C 3 -C 6 cycloalkylene, hetero-C 5 -C 6 arylene, hetero-C 3 cycloalkylene or phenylene, X 14 is C 1-7 alkylene and X 16 is C 1-6 alkylene, wherein the sum of n 14 and n 16 is 0, 1, 2, 3 or 4; R5 is selected from the group consisting of azetidin-3-yl, benzimidazol-4-yl, benzimidazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-methylpiperidin-3-yl, 1-methylpiperidin-4-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrrolidine, 3-yl, 1,4,5,6-tetrahydropyrimidin-2-yl, 1,4,5,6-tetrahydropyrimidin-4-yl, 1,4,5,6-tetrahydropyrimidin-5-yl, and the aforementioned group carbocyclic oxo or thioxo derivatives, said groups being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, mercapto, C 1-6 alkyl, C 8 -cycloalkyl * C 6 -aryl, C 6 -aryl-C 1-4 alkyl, C 1 -C 10 , C 6 -aryloxy, C 3-14 cycloalkyloxy particularly C 1-4 alkoxy, C 1-4 alkylthio, C 3-6 cycloalkylthio, C 6-14 arthio and -NR 6 R 7 wherein R 6 and R 7 are independently selected from hydrogen, C 1-8 alkyl, C 1-8 alkanoyl, C 3-8 C 14 -cycloalkyl and C 6 -C 10 alkyl; X 13 is C 0 -C 6 alkylene, hetero-C 2 -C 6 alkylene, heterooxy-C 3 -C 4 alkylene, oxo-C 2 -C 4 alkylene, or X 17 -X 18 -X 19-where X 18 is as defined above for X 15, X 17 is C 1 -C 7 alkylene, and X 19 is C -groups wherein the sum of n17 and n19 is 0, 1 or 2; R2 is R-X20- or R9-X21-, where: R8 is amino, 1-iminoethyl or methylamino, X20 is C4-6 alkylene, hetero-C4-6 alkylene, heteroxy-C4-4 alkylene, oxo-C4-4 alkylene or X22- X23-X24-, where X23 is as defined above for X15, X22 is C1-4 alkylene and X24 is Cn24 alkylene, wherein the sum of n22 and n24 is 0, 1, 2, 3 or 4, provided that when R8 is amino, X 20 is not C 4-6 alkyl-ene or oxa-C 4-6 alkylene and n 22 is not 1, 2, 3 or 4; R9 has the meanings already given in R5; X 21 is C 0 -C 6 alkylene, hetero-C 2 -C 4 alkylene, heteropoxy-C 3 -C 4 alkylene, oxo-C 2 -C 4 alkylene or X-X 26 -X 27 - where X 26 is the same as X 15, X 25 is Cn 25 alkylene, and X 27 is Cn 27 alkylene. any of the above alkylene groups, cycloalkylene groups, heterocycloalkylene groups, phenylene groups, arylene groups and heteroarylene groups is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, mercapto, C 1-3 alkyl, C 1-3 alkyl, C 1-3 alkyl, -aryl-C1-4alkyl, C1-4alkanoyl, C1-4alkoxy, C5-14aryloxy, C3-4cycloalkyloxy, C1-4alkoxy, C1-4alkylthio, C3-14cycloalkylthio, C6arylthio, and -NR6R7 are wherein provided that the heteroatoms of R 1, X 2, X 4, X 6, X 8, R 2 and the hetero atoms of X 3, X 5, X 7 and X are not covalent bonds, and pharmaceutically acceptable salts, N-oxides thereof, for the preparation of a medicament containing a prodrug or protecting group comprising: (a) reacting a compound of formula (1) xs Y8-X7-X6 ^ 1 or a protected derivative thereof with a compound of the formula R2-Y9-CO-L or a protected derivative thereof; a derivative in which L, respectively, is a leaving group, Y 9 is a bond, -O- or -NR 3 -, Y 8 is piperidin-4-yl or HNR 3 -C 1-8 alkyl, R 1, R 2, R 3, X 1, X 2, X 3, X 4 , X5, X6 and X7 have the meanings given in the brief description of the invention, if necessary followed by the cleavage of protecting groups to provide a compound of formula (I) wherein X8 is 1,4-piperidinylene and X9 is -CO-, -O-CO - or -NR3CO-; or X 8 is C 1-4 alkylene and X 9 is -CONR 3 -, -O-CONR 3 - or -NR 3 CONR 3 -; (b) reacting a compound of formula (1) or a protected derivative thereof with an isocyanate R2-NCO or a protected derivative thereof, if necessary followed by cleavage of a protecting group, to form a compound of formula (I) wherein X8 is 1,4-piperidinylene; -NHCO-; or X 8 is C 1-4 alkylene and X 9 is -NHCONR 3 -; (b) reacting a compound of formula (2) Υ ^ χ ^ χ4. > R2-X9-X8-X7-X6 ^ 2, or a protected derivative thereof, with a compound R1-Y1-CO-L, or a protected derivative thereof wherein L is a leaving group, Y1 is a bond, -O- or -NR3, respectively -, Y 2 is piperidin-4-yl or HNR 3 -C 1-8 alkyl, the meanings of R 1, R 2, R 3, X 3, X 4, X 5, X 6, X 7, X 8 and X 9 are as defined in the brief description of the invention a compound of Formula I wherein X 5 is 1,4-piperidinylene and X 1 is -CO-, -O-CO- or -NR 3 CO-; or X 2 is C 1-6 alkylene and X 1 is -CONR 3 -, -O-CONR 3 - or -NR 3 CONR 3 -; (d) reacting a compound of formula (2) or a protected derivative thereof with an isocyanate R1-NCO or a protected derivative thereof, optionally followed by cleavage of protecting groups to provide a compound of formula (I) wherein X2 is 1,4-piperidinylene and X1 is -NHCO-; or X 2 is C 1 -C 1 -alkylene and X 1 is -NHCONR 3 -; (e) reacting a compound of formula (3) Y2-x3-xV / χ5 Y8-X7OC3 or a protected derivative thereof with 2 or more moles of a compound R1-Y1-CO-L or a protected derivative thereof wherein L is Y1 is a bond, -O- or -NR3-, Y2 and Y8 independently of one another are piperidin-4-yl or RNR1-6C1alkyl, R1, R3, X3, X4, X5, X6 and X7 the meanings are as defined in the brief description of the invention, optionally followed by the cleavage of protecting groups to provide a compound of formula (I) wherein R 1 is R 2, X 2 and / or X 8 is 1,4-piperidinylene, X 9 is -CO-, -O- CO or -NR 3 CO-; and / or X 2 and / or X 8 is C 1-4 alkylene, X 1 is -CONR 3 -, -O-CONR 3 - or -NR 3 CONR 3 -, X 9 is -CONR 3 -, -O-CONR 3 - or -NR 3 CONR 3 -; (f) reacting a compound of formula (3) or a protected derivative thereof with two or more moles of R-NCO isocyanate or a protected 12 derivative thereof, optionally followed by cleavage of the compound of formula (I) wherein R1 is R2 ; X2 is 1,4-piperidinylene and X1 is -NHCO-; or X 2 is C 1-8 alkylene and X 1 is -NHCONR 3 -; (g) the action of an amine of formula R 1 -NR 3 H or a protected derivative thereof with the compound (4) LC (0 > y..xW / χ 5 r 2 -x 9 -x 8 -x 7 -x 6 4) or a protected derivative thereof, wherein is a leaving group, Y 1 is a bond, -O- or -NR 3 -, R 1, R 2, R 3, X 2, X 3, X 4, X 5, X 6, X 7, X 8 and X 9 have the meanings given in the brief description of the invention to give a compound of formula (I) wherein X1 is -NR3CO-, -NR3COO- or -NR3CONR3- (h) reacting a compound of formula R1-X1-Y2 or a protected derivative thereof with a compound of formula (5) 3. LC (0) ) -Y-X 1 / X 5 R 2 -X 9 -X * -X 7 -X 6 5 or a protected derivative thereof wherein L is a leaving group, Y 3 is a bond, -O- or -NR 3 -, Y 2 is piperidine-4, respectively. -I or HNR 3 -C 1-8 alkyl, R 1, R 2, R 3, X 1, X 2, X 3, X 4, X 5, X 6, X 7, X 8 and X 9 have the meanings given in the brief description of the invention, optionally followed by cleavage of protecting groups (I) wherein X2 is 1,4-piperidinylene and X3 is -CO-, -COO- or -CONR3-; or X 2 is C 1-6 alkylene and X 3 is -NR 3 CO-, -NR 3 COO - or -NR 3 CONR 3 -; (i) 2 or more moles of a compound of formula R 1 -X 1 -Y 2 or a protected derivative thereof, with a compound of formula (6) LC (O) -Y 3 -X 4x > 5 LC (O) Y 7 -X 6 6 wherein, respectively, L Y3 and Y7 are independently a bond, -O- or -NR3-, Y2 is piperidin-4-yl, HNR3-C1-8 alkyl or HNR3-hetero-C1-8 alkyl, R1, X1, X4, X5 and X6 have the meanings given in the brief description of the invention, where appropriate followed by cleavage of the protecting groups to provide a compound of formula I wherein X2 and X8abi are 1,4-piperidinylene and X3 and X7 are each independently -CO -, -COO- or -CONR3-; or X8 are both C 1-8 alkylene or hetero-C 1-7 alkylene and X 3 and X 2 are each independently -NR 3 CO-, -NR 3 COO - or -NR R COON R 3 -; (j) if necessary, treating the compound of formula (I) wherein R4 is amino with cyanamide to provide a compound of formula (I) wherein R4 is guanidine; (k) further converting the compound of formula (I) into a pharmaceutically acceptable salt, where appropriate; (l) if necessary, further converting the salt form of the compound of formula (I) into the salt form; (m) if necessary, further converting the non-oxidized form of the compound of formula (I) into a pharmaceutically acceptable N-oxide form; (n) if necessary, further converting the N-oxide form of the compound of formula (I) into the non-oxidized form; (o) where appropriate, further converting the compound of formula (I) from the free form into a derivative which is a pharmaceutically acceptable precursor; (p) converting, if necessary, the precursor of the compound of formula (I) into the free form of the compound.