LV12291B - Novel compounds and compositions for treating diseases associated with tryptase activity - Google Patents

Novel compounds and compositions for treating diseases associated with tryptase activity Download PDF

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LV12291B
LV12291B LVP-99-27A LV990027A LV12291B LV 12291 B LV12291 B LV 12291B LV 990027 A LV990027 A LV 990027A LV 12291 B LV12291 B LV 12291B
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compound
alkylene
hetero
formula
independently
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LV12291A (en
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Jeffrey Mark DENER
Elaine Yee-Lin KUO
Ken Duane Rice
Vivian Rucywen Wang
Wendy Beth YOUNG
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Arris Pharmaceutical Corporation
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Priority to LVP-00-31A priority Critical patent/LV12459B/en
Priority to LVP-00-30A priority patent/LV12458B/en
Publication of LV12291B publication Critical patent/LV12291B/en

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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    • C07D233/06—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
    • C07D233/08—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms
    • C07D233/12—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms with alkyl radicals, containing more than four carbon atoms, directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D233/14—Radicals substituted by oxygen atoms

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Abstract

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

Description

-1- LV 12291
NOVEL COMPOUNDS AND COMPOSmONS FORTREATING DISEASES ASSOCIATED
WITH TRYPTASE ACTIVITY 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 associated 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 foliowing anaphylaxis (Schwartz et al. (1987) 12 N. Eng. J. Med. 316:1622-1626), are increased in nasai and lung iavage fluid from atopic subjects following specific antigen challenge (Castells et al. (1988) J. Allerg. Clin. Immunol. 141:563-568) and are elevated in lung Iavage fluid of atopic asthmatics after endobronchial 15 allergen challenge. Smokers often have striking elevations of bronchoalveolar Iavage fluid tryptase Ievels, a fmding that 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, trvptase has been shown to be a potent mitogen for fibroblasts, suggesting that it is involved in pulmonary fibrosis and interstitial lung disease (Ross et al. (1991) J. Clin. Invest. 88:493-499). 21 Asthma is recognized as an inflammatory disorder (Hood et al. (1984)
In: Benjamin-Cummings, ed. Immunology 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 hvper responsiveness of asthmatic bronchiolar tissue is believed to be the result of chronic inflaxnmatory reactions, which 27 irritate and damage the epithelium lining the airway wall and promote pathological thickening of -2- the underlying tissue. Bronchial biopsies in patients with oniy 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) of the inflammatory response and generate numerous other secondary mediators of inflammation (e.g., superoxide, lipid derived mediators, etc.) in situ. 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 exposure to allergen and is generally followed by recovery over the ensuing one to two hours. Twenty five to thirty five percent of the patient population experience a further decline in respiratory function which maximizes six to trwe!ve 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 secondar/ inflammatory reaction mediated in part by the secretory activity of granulocytes.
Tryptase is implicated in the degradation of vasodilating and bronchorelaxing neuropeptides (Caughey et al. (1988) J.Pharmacol. Exp. Ther. 244:133-137; Franconi et al. (1988)7. Pharmacol. Exp. Ther. 248:947-951; and Tam et ai (1990) Am. J. Respir. Celi Mol. Biol. 3:27-32) and modulation of bronchial responsiveness to histamine (Sekizawa 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 iocal anticoagulant. Tryptase activates prostromelysin (pro-MMP-3) and procollagenase (pro-MMP-1) via MMP-3, which suggests that tryptase is involved in tissue inflammation and remodeling and joint destruction in rheumatoid arthritis. Further, -3- LV 12291 administration of tryptase inhibitor protects against development of the late and airway hyper responsive phases in allergen challenged sheep (Clark et al. (1995) Am. J. Respir. Crit. Care 3 Med. 152: 2076-2083) and inhibits the immediate cutaneous response to intradermal injection of allergen in allergic 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 inflammation of the respiratory tract.
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 ιι'-χ'-χ^χ^χ4 R2-X9-X8-X7-X6' in which: X5 is (C3.i4)cycloalkylene, hetero(C3.I4)cycloalkylene, (C6.!4)arylene or 15 hetero(C5.,4)arylene; X4 and X6 are independently (Co_2)alkylene; X1 and X9 are independently a covalent bond, -C(O)-, -C(0)0-, -OC(O)-, -C(0)N(RJ)-> 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 (C3.s)cycloalkyl, with the proviso that X1 and X9 are not both covalent bonds; 21 X3 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 defmed above; -4- X2 and Xs are independently (C|.j)alkylene, hetero(C,.j)alky!ene, -X'°-Xu- or -X"-X10-, vvherein X10 is (Co_,)alkylene or hetero(C3.4)alkylene and X1' is (C3.j)cycloalkyIene or hecero(Cj.5)cycloalkylene; R1 is R4-X12- or R5-X13-, wherein: R4 is amino, amidino, guanidino, l-iminoethyl or methylamino, X12 is (C4^)alkylene, hetero(C4.4)aIkylene, heterooxo(C4.4)alkyiene, oxo(C4.6)alkylene or -XI4-XI5-X16-, wherein X15 is (C3_6)cycloalkylene, hetero(Cj^)arylene, he[ero(C3.6)cyc!oa!kyIene or phenylene, X14 is (CnJ4)aIkyIene and XIS is (Cnia)alkylene, vvherein the sum ofn!4 and nl6 is 0, l, 2,3 or 4,
Rs is a group selected from azetidin-3-yl, benzoimidazoi-4-yI, benzoimidazol-5-yl imidazo[-l-yi, imidazol-2-yi, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazoIin-3-yl, 2-methy limidazol-1 -yl, 4-methylimidazol-1 -y!, 5-methylimidazol-l-yl, I-methylpiperid-3-yl, l-methylpiperid-4-yl, piperid-3-yi, piperid-4-yl, piperazin-l-yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yi, pyrimidin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1.4.5.6- tetrahydropyrimidin-2-yl, l,4J5T6-tetrahydropyrimidin-4-yl and 1.4.5.6- tetrahydropyrimidin-5-yl and any carbocyclic ketone or thioketone derivative thereof, which group is optional!y substituted with one or more radicals selected from halo, hydroxy, mercapto, (C,.i)alkyl, (C3.14)cycloalkyl, (C6_1A)aryl, (C6.14)aryl(C,_l)alkyl, (C,.s)alkanoyl, (CM)alkyloxy, (Ca.M)aryloxy, (C3.l4)cyc!oaikyloxy, (CM)aikyIoxy, (CUJ)aIkylthio, (C3.I4)cycioa!kyithio, (C4.l4)aryIthio and -NR6R7, vvherein R6 and R7 are independently selected from hydrogen, (C,.g)aikyl, (C,.i)alkanoyl, (C3.N)cycioalkyl or (C4.|4)aryl and X13 is (C0.4)alkylene, hetero(Cw)alkylene, heterooxo(C3Jalkylene, oxo(C2.6)alkylene or -Χ^-Χ^-Χ'9-, vvherein Xu is as defmed above for X15, X17 is (Cnl7)alkylene andX19 is(Cni9)aikytene, vvherein the sum of nl7 and nl9 is 0, 1 or 2; and R2 is R‘-X2Q- or R9-X21-, vvherein: R1 is amino, l-iminoethyi or methylamino, X:a is (C4^)alkylene, hetero(C4.4)alkylene, heterooxo(C4^)alkylene, oxo(C4.6)aIkylene or -X22-X23-X24-, vvherein X23 is as defmed above for X15, X~ is (C^-Oal'^lene and X24 is (C„24)alkyiene, vvherein the sum of n22 and n24 is 0, 1, 2, 3 or 4, -5- LV 12291 with the proviso that when Rs is amino then X20is not (C4.6)alkylene or oxa(C4.6)aIkylene and n22 is not 1, 2, 3 or 4, 3 R9 is as defined above for R5 and X21 is (CQ^)aIkyiene, hetero(C^)alkylene, heterooxo(C3.6)alkylene, oxo(C2_6)alkylene or -X25-X26-X27-, wherein X26 is as defined above for X15, X25 is 6 (C„25)alkylene and X27 is (Cn27)alkyiene, vvherein the sum of n25 and n27 is 0,1 or 2; wherein each alkyiene, cycioalkylene, heteroa!kylene, heterocycloaIkyIene, pnenylene, arylene and heteroarylene, as defined above, are optionally substituted with one or more 9 radicals selected from haio, hydroxy, mercapto, (C,.g)alkyl, (C3.I4)cycloalkyl, (C6.14)aryl, (C6.i4)aiyl(Cw)aIkyi, (C,.g)alkanoyl, (C,.g)alkyloxy, (C6.,4)aryloxy, (C3_14)cycloalkyloxy, (CM)alkyloxy, (C1.g)aIkylthio, (C3.l4)cycloaIkylthio, (C4.14)aryithio 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, X8 and R2 and any heteroatoms contained with X3, X5, X7 and X9; and 15 the pharmaceutically acceptable salts, jV-oxides, prodrug derivatives and protected derivatives thereof. A second aspect of this application relates to a compound of Formula I: 18 r’-x‘-x2-x3-x1 R2-X9-X8-X7-X6 ^
I in which: X4-X5-X6 together are (C2.|2)alkyiene or hetero(C3.t2)alkylene; 21 X1 and X9 are independently a covalent bond, -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 each R3 is independently hydrogen, (C,.3)alkyl or (C3.g)cycloalkyl, with the 24 proviso that X1 and X9 are not both covalent bonds; X3 and X7 are independent!y -C(O)-, -C(0)0-, -OC(O)-, -C(0)N(R3)-, -N(R3)C(0)-, -6- -S(0)2N(R3)-, -N(R3)S(0)r, -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; X2 and X1 are independently (CM)alkylene, hetero(C,.j)alkylene, -Xl0-X“- or -Xll-X'°-, wherein X10 is (CV*)alkylene or hetero(C3_,)alkylene and X11 is (Cj_j)cycloaikylene or hetero(C3.,)cycloalkylene; R1 is R4-X12- or R3^13-, wherein: R4 is amino, amidino, guanidino, l-iminoethyl or methyIamino, X11 is (C4.4)alkylene, hetero(C^)alkylene, heterooxo(C4.4)alkylene, oxo(C4^)aIkylene or -Xl4-X13-X16-, wherein X13 is (C3^)cycloalkylene, hetero(C5.4)arylene, hetero(C3^)cycloaikyiene or phenylene, X14 is (Cnļ4)alkyiene and X14 is (Cnl4)alkylene, \vherein the sum of nl4 and nl6 is 0, 1, 2, 3 or 4, R3 is a group selected from azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl imidazol-l-yl, imidazol-2-yl, imidazoi-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-1 -yl, 4-methylimidazol-1 -yl, 5-methy limidazol-1 -yl, l-methylpiperid-3-yI, l-methylpiperid-4-yI, piperid-3-yl, piperid-4-yI, piperazin-I-yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-4-yl, pynmidin-5-yl, pyrro(idin-3-yl, 1.4.5.6- tetrahydropyrimid'm-2-yl, l,4,5,6-tetrahydropyrimidin-4-yl and 1.4.5.6- tetrahydropyrimidin-5-yl and any carbocyclic ketone or thioketone derivative thereof, which group is optionally substituted with one or more radicais selected from halo, hydroxy, mercapto, (C|_4)alkyl, (Cj.M)cycloalkyl, (C4.H)aryl, (C6.H)aryl(C,.4)alkyl, (C,.s)alkanoyl, (C,_,)alkyloxy, (C4.H)aryloxy, (C3.|4)cycioalkyloxy, (CM)aIkyloxy, (CM)alkylthio, (C3.M)cycloalkylthio, (C4.M)arylthio and -NR6R7, \vherein R6 and R7 are independently selected from hydrogen, (C,.,)alkyl, (C,.J)alkanoyl, (C3.M)cycloaIkyl or (C4.,4)aryl and X13 is (Co-i)aIkylene, hetero(C,^)a!kylene, heterooxo(C3.4)alkylene, oxo(C24S)a[kylene or -X17-XIS-X19-, wnerein X's is as defined above for X13, X’7 is (Cn,7)alkylene and X19 is(Cni9)alkylene, wherein the sum of nl7 and nl9 is 0, 1 or 2; and R2 is R3^20- or R9-X21-, wherein: R1 is as defined above for R\ X20 is (C4.4)alkylene, hetero(C4.4)alkyIene, heterooxo(C4.6)alkylene -7- LV 12291 oxo(C4^)aIkyIene or -ΧΏ-Χ23-Χ24-, wherein X23 is as defined above for X15, X22is (C„22)alkylene and X24 is (C„24)alkylene, 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 (Co_6)aIkylene, hetero(CM)alkyiene, heterooxo(C3_6)aIkylene, oxo(C2^)alkylene or -X25-X26-X27-, wherein X26 is as defined above for X15, X25 is 6 (C„25)alkylene and X27 is (C^alkļdene, wherein the sum of n25 and n27 is 0,1 or 2; wherein each alkylene, cycloalkylene, heteroalkylene, heterocycloa!kylene, phenylene, arylene and heteroarylene, as defined above, are optionally substituted with one or more 9 radicals selected from halo, hydroxy, mercapto, (C|.g)alkyl, (C3.!4)cycIoalkyl, (C6.I4)aryl, (C6.!4)aryl(CM)alkyl, (C,.s)alkanoyl, (C,.s)aIkyIoxy, (C6.14)aryloxy, (C3.l4)cycloalkyloxy, (Ci.4)alkyioxy, (C,.8)alkylthio, (Cj_|4)cycIoalkylthio, (C6.,4)arylthio and -NR6R7, wherein 12 R6 and R7 are as defined above; with the proviso that covalent bonds do not occur beriveen heteroatoms contained within R', X2, X4, X6, X8 and R2 and any heteroatoms contained with X3, Xs, X7 and X9; and 15 the pharmaceutically acceptable salts, jV-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 pharmaceutically 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 tryptase activity contributes to the pathoIogy 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, JV-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 otherwise stated, the following terms used in the specification and claims have the meanings given below: “Alkanoyl” means the radical -C(0)R, wherein R is alkyl as defined below, having overall the number of carbon atoms indicated (e.g., (C,.g)alkanoyl includes the radicals formyl, acetyl, propionyl, butyryl, isobutyryl, crotonoyl, isocrotonyl, etc.). “Alkyl”, as in alkyl, arylalkyl, aIkyloxy, alkylthio, means a straight or branched, saturated or unsaturated hydrocarbon radical having the number of carbon atoms indicated (e.g., (C,.s)alkyl includes methyl, ethyl, propyl, isopropyl, butyl, ^ec-butyl, isobutyl, /er/-butyl, vinyl, allyl, l-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylaIIyl, ethynyl, l-propynyl, 2-propynyl, etc.). “Alkylene” means a straight, saturated or unsaturated hydrocarbon divaient radical having the number of carbon atoms indicated (e.g., (C0^)alkylene includes methylene (-CH2-), ethylene (-(CH2)2-), vinylene (-CH:CH-), ethynylene (-C; C-), 2-propylene (CHiCH-CH,-), l-propylene (-CH,-CH:CH-), tetramethylene (-(CH2)4-), pentamethylene (-(CH2)5-) and hexamethylene (-(CH2)6-), etc.). The term (C0)alkyiene is meant to represent a covalent bond. “Alkyloxy” means the radical -OR, wherein R is alkyl as defined above, having the number of carbon atoms indicated (e.g., (C,.j)alkyloxy includes the radicals methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, etc.). “Alkylthio” means the radical -SR, wherein R is atky! as defined above, having the number of carbon atoms indicated (e.g., (C,.*)alkylthio 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, aryla!kyl, aryloxy and arylthio, means an aromatic monocyclic or polycyclic hydrocarbon radical containing the number of carbon atoms indicated, vvherein the carbon atom vvith the free valence is a member of an aromatic ring. and any carbocylic ketone or thioketone derivative thereof (e.g., (C6.M)aryl includes phenyl, naphthyl, anthracenyl, p’nenanthrenyl, 1,2,3,4-tetrahydronaphth-5-yl, 1 -οχο-1,2-dihydronaphth-6-yl, 1 -thioxo-1,2-dihydronaphth-7-yl, etc.). “Arylene" means an aromatic monocyclic or polycyclic hydrocarbon divaient radical -9- LV 12291 containing the number of carbon atoms indicated, vvherein the carbon atoms with the free valence are members of an aromatic ring, and any carbocyIic ketone or thioketone derivative thereof 3 (e.g., (C6.l4)arylene includes 1,4-phenylene, l,3-phenylene, 1,4-naphthylene, 2,6-naphthylene, 1.4- anthracenylene, 2,6-anthracenylene, l,6-phenanthrenylene, 1.2.3.4- tetrahydro-5,8-naphthylene, 1 -oxo-l ,2-dihydro-5,7-naphthylene, 6 l-thioxo-l,2-dihydro-5,8-naphthylene, etc.). “Aryloxy” means the radical -OR, wherein R is aryl, as defined above, having the number of carbon atoms indicated (e.g., (C6.14)aryloxy includes the radicals phenoxy, naphthyloxy, 9 anthracenyloxy, etc.). “Arylthio” means the radical -SR, wherein R is aryl, as defined above, having the number of carbon atoms indicated (e.g., (C^^a^lthio includes the radicals phenylthio, naphthylthio, 12 anthracenylthio, etc.). “Cycloalkyl”, as in cycloalkyl and cycloalkyloxy, means a saturated or unsaturated, monocyclic or polycyclic hydrocarbon radical containing the number of carbon atoms indicated, 15 vvherein the carbon atom with the free valence is a member of a non-aromatic ring, and any carbocyclic ketone and thioketone derivative thereof (e.g., (C3.,4)cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, 18 bicyclo[2.2.2]octyl, 1,2,3,4-tetrahydronaphth-l-yl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, etc.). “Cycloalkylene” means a saturated or unsaturated, monocyclic or polycyclic hydrocarbon 21 divalent radical containing the number of carbon atoms indicated, vvherein the carbon atoms with the free valence are members of a non-aromatic ring, and any carbocyclic ketone and thioketone derivative thereof (e.g., (C3.6)cycloalkylene includes 1,2-cyclopropylene, l,2-cyclobutylene, 24 l,3-cyclobutylene, l,2-cyclopentylene, l,3-cyclopentylene, l,4-cyclopentylene, 1.4- cyclohexylene, 3-cyclohexen-1,2-ylene, 2,5-cyclohexadien-1,4-ylene, 1.4- bicyclo[2.2.2]octylene, 1,2,3,4-tetrahydro-l ,4-naphthylene, 5-oxo-1,3-cyclohexylene, 27 2,5-dioxo-1,4-cyclohexylene, 5-thioxo-1,4-cyclohexylene, etc.). “Cycloalkyloxy” means the radical -OR, vvherein R is cycloalkyl, as defined above, having the number of carbon atoms indicated (e.g., (C3_14)cycloalkyloxy includes the radicals 30 cyclopropoxy, cyciobutoxy, 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"-refers 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 vvhich 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. “Heteroalkylene” means alkylene, as defmed above, vvherein l 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(C3.|2)alkylene is meant to encompass aza(C3)alkylene which includes 3-azatrimethylene (-NHCH2CH2-), 2- azatrimethylene (-CH2*NH-CH2-), etc.; co-aza(C2.3)aIkylene vvhich includes 2-azaethylene (-NH-CH,-), 3-azatrimethylene, 4-azatetramethylene (-NH-CH2-CH2*CH2-) and 5-azapentamethylene (-NH-CH2-CH2-CH2-CH2-); oxa(C3)alkylene vvhich includes as 3- oxatrimethylene (-OCH2-CH2-), 2-oxatrimethylene (-CH2-OCH2-), etc.; oxa(C5)alkylene such as 3-oxapentamethylene (-CH2*CH2O-CH2-CH2-), etc.; thia(Cj)aIkylene vvhich includes 3-thiatrimethylene (-S*CH2-CH2-), 2-thiatrimethylene (-CH2-S-CHr), etc.; ω-thia(C2.4)alkylene vvhich includes 2-thiaethylene (-NH-CH2-), 3-thiatrimethylene and 4-thiatetramethylene (-S-CH2-CH2-CH2-); diaza(C6)aikylene vvhich includes 2,5-diazahexamethylene (-CH2'NH-CH2-CH2*NH*CH2-); azaoxa(C6)alkylene vvhich includes 2,-oxa-5-azahexamethylene (-CH2-0-CH2-CH,-NH-CHr); and the like. “Heteroarylene” means arylene, as defmed above, vvherein l to 5 ofthe carbon atoms indicated are replaced by a heteroatom chosen from N, 0 or S (e.g., hetero(C5.6)arylene includes furylene, thienylene, pyrrolylene, imidazolylene, pyridylene, etc.). “Heterocycloalkylene” means cycloaIkylene, as defmed 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.u)cycloalkylene includes 2,4-pyrrolidinylene, 2,4-pyrrolinylene, -11- LV 12291 2.4- imidazolinylene, 2,4-imidazolinylene, 3,5-pyrazoIinylene, 1,4-piperidylene, 1.4- piperazinylene, 2,5-quinuclidinylene, 2,5-morpholinylene, 1.3-isoindolinyIene, etc.). “HeterooxoaIkylene” 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., azaoxoalkylene, oxaoxoalkyIene and thiaoxoalkylene, respectively, with the proviso that the oxygen, nitrogen and sulfur atoms contained therein do not form bonds with other heteroatoms. For example, heterooxo(C4.6)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)aIkylene 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-oxotrimethyIene (-S-C(0)-CH2-), etc. "Leaving group" has the meaning conventionally 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, ethanesulfonyloxy, etc.), arylsulfonyloxy (e.g., benzenesulfonyloxy and tosyloxy, 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 iV-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 pharmacological activity. The N-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, wherein 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 stmctural and functional changes that result from the dissase processes. "Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use. "Pharmaceutically acceptable salts" means salts v/hich 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 like; 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, glycolic acid, hexanoic acid, heptanoic acid, o-(4-hydroxybenzoyl)benzoic acid, 2-hydroxyethanesulfonic acid, hydroxynaphthoic acid, lāctic acid, lauryl sulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbicycIo[2.2.2]oct-2-ene-l-carboxylic acid, 4,4,-methylenebis(3-hydroxy-2-ene-l-carboxyiic acid), muconic acid, 2-naphthalenesulfonic acid, oxalic acid, 3-phenyipropionic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiary butylacetic acid, p-toluenesulfonic acid, trimethylacetic acid and the like.
PharmaceuticaIIy 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, echanolamine, /V-metl^lglucamine, triethanolamine, tromethamine and the like. “Phenylene’’ means the divalent aromatic radical -C6Hj- and includes 1,4-phenylene, l ,3-phenylene and the like. "Pharmaceutically acceptable prodrug derivatives" means derivatives of compounds of Formula I which are pharmaceutically acceptable, as defined above, and which are converted in vivo to the corresponding non-derivatized form of a compound of Formula I. Such prodrugs include compounds of Formula I vvhich have A-acylated piperidyl (i.e., N(P)C5H9-), //-acylated azaalkvlene (e.g., -N(P)-CH:-CHr), /V-acylated amino (i.e., -NH;(P)), /V-acylated amidino -13- LV 12291 (i.e.,-C(NP)*NHP, -C(NH>NHP or -C(NP)*NH2), N-acylated guanidino (i.e, -NHC(NP)-NHP, -NH-C(NH)-NHP or -NH-C(NP)-NH2) groups, in which P is a group selected from -C(0)R10, wherein R10 can be (C,.10)alkyloxy or c/i-2-(C,.]0)alkanoyloxyphenylvmyl, 3-(C,.10)alkanoyloxybutyryl, R“-X28-, wherein R“ is carboxy andX28 is (C,.10)alkylene or -C(0)O*CH(Rl2)-0-C(0)R13, wherein R12 is hydrogen, (CM0)alkyl or (C3.10)cycloalkyl and R13 is (C,.10)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 such that a Chemical reaction can be carried 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 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.
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 suitable amino protective groups (e.g., see T.W. Greene, Protective Groups irt Organic Synthesis, John Wiley & Sons, Inc. 1981). “Symptomatology” of a disease means any morbid phenomenon or departure from the 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 animal for treating a disease, is sufficient 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 symptoms of the disease, inhibiting the disease (i.e., arresting its development) or relieving 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 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 written 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 vvhich 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-X2', wherein R9 is piperid-4-yl and X2' is 3-azatrimethylene, is illustrated by the following formula:
12 NH
which compound is named: c/.r-1,5-cyclooctylene 4-(4-amidinobenzylcarbamoy 1)-1 -piperazinecarboxylate 15 4-(2-piperid-4-ylaminoethyicarbamoyl)-l-piperidinecarboxylate when X3 and X7 each are -C(0)0-, X4 and X5 each are a covalent bond, X3 is czr-l,5-cyclooctylene and P is hydrogen; 3- {4-[2-(l-{c/r-5-[4-{4-amidinobenzylcarbamoyl)piperazin-l-ylcarbonyloxy]cyclooctyloxy-13 carbonyl}piperid-4-ylcarbonylamino)ethyiamino]piperid-l-ylcarbonyl}propionic acid when X3 and X7 each are -C(0)0-, X4 and Xs each are a covalent bond, X3 is cis-l,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(O)Ο-, X' is a covalent bond, X6 is methvlene, X3 is phenylene and P is hydrogen; -15- LV 12291 1.4- tetramethylene 4-amidinobenzylcarbamoyl-l-piperazinecarboxylate when X3 and X7 are each is -C(0)0- and X4-X5-Xfi is 1,4-tetramethylene (i.e., -CH2-CH2-CH2-CH2-); and 3 Ar-4-amidinobenzyl-4-{5-[4-(2-piperid-4-ylaminoethylcarbamoyl)piperid-l-ylcarbonyl]valeryl}-l-piperazinecarboxamide when X3 and X7 are each is -C(0)- and X4-X3-X6 is l,4-tetramethylene (i.e., -CH2-CH2-CH2-CHr). 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 czj-I ,5-cyclooctylene and X4 and X6 each are a covalent bond, X4-Xs-X6 together are (C4_3)alkylene or X5 is l,4-phenylene and X4 and X6 are (C0_i}aikylene X! and X9 are independently 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 Xs are independently -XI0-Xn-, wherein X'° is a covalent bond or methylene and X11 is 4,l-piperidylene or l,4-piperazinylene; R1 is R4-X12- or 15 Rs-X’3-, wherein R4 is amidino, guanidino or methylamino, X12 is -Xl4-X15-X16-, wherein X13 is 1.4- phenylene or l,4-piperidylene, X14 is (Cnļ4)alkylene and X16 is (C„|6)alkylene, whereinthe sum of nl4 and ηΐβ is 0, 1 or 2, R3 is piperid-4-yl and X13 is (C2.3)alkylene; and R2 is Rs-X20- or 18 R9-X2'-, wherein Rs is amino, amidino, guanidino, methylamino or 1-iminoethyl, X20 is -Χ^-Χ^-Χ24-, wherein X23 is trans-1,4-cyclohexylene, l,4-phenylene, 4,l-pyridylene, 1.4- piperidylene, X22 is (C^a^lene andX24 is (Cn24)alkylene, wherein the sum of n22 and n24 21 is 1 or 2, R9 is benzoimidazol-5-yl, imidazol-l-yl, imidazol-4-yl, 2-imidazolin-2-yl, 4-methylimidazol-l-yl, 5-methyiimidazol-l-yl, l-methyipiperid-4-yl, piperid-4-yl, piperazin-l-yi, pyrid-3-yl, pyrid-4-yl, l,4,5,6-tetrahydropyrimidin-5-yl or 24 l,4,5,6-tetrahydro-2-dioxopyrimidin-5-yl and X21 is (C,.6)alkylene, a>-aza(C2.j)alkyiene, 3-oxotrimethylene, a>-thia(C2.4)alkylene, 3-oxo-2-azatrimethylene, 3-aza-2-oxotrimethylene or -Χ^-Χ^-Χ27-, wherein X26 is l,4-phenylene, X23 is (Cn2J)alkylene andX27 is (Cn27)alkylene, 27 wherein the sum of n25 and n27 is 0 or 1; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
More preferred compounds of Formula I are those in which X3 is cis- l,5-cyclooctylene -16- and X4 and X6 each are a covalent bond or X4-X3-X6 together are (C4.s)alkylene; X1 and X9 are independently a covalent bond -C(O)-, -NHC(O)-, -C(0)NH- or -S(0)2NH-, with the proviso that 3 X1 and X9 are not both covalent bonds; X3 and X7 are independently -C(O)- or -C(0)0-; X2 and Xs are independently -X'°-Xn-, wherein X10 is a covalent bond or methylene and X" is 4,l-piperidylene or l,4-piperazinylene; R1 is R4-X12-, wherein R4 is amidino or guanidino and X12 6 is -Xl4-Xl3-X16-, wherein X13 is 1,4-phenylene or l ,4-piperidylene, X14 is (Cnl4)alkylene and X16 is (Cnl6)alkylene, wherein the sum of nl4 and nl6 is 0, 1 or 2; and RJ is R‘-X20- or R9-X2'-, wherein R! is amino or methylamino, X2U is -X22-X23-X24-, vvherein X23 is trans-] ,4-cyclohexylene or 9 l,4-phenylene, X22 is (Cn22)alkylene and X16 is (C,,24)alkylene, wherein the sum of n22 and n24 is 1 or2, R9 is imidazol-l-yl, imidazol-4-yl, 4-methylimidazol-l-yl, 5-methylimidazol-l-yl, piperid-4-yl or pyrid-4-yl and X1’ is (C|.5)alkylene or 3-azatrimethylene; and the 12 pharmaceutically acceptable salts, yV-oxides, prodrug derivatives and protected derivatives thereof.
Particularly preferred compounds of Formula I are those in vvhich X3 is 15 crj-l,5-cyclooctylene and X4 and X6 each are a covalent bond; X' and X9 are independently -C(O)- or -NHC(O)-; X3 and X7 each are -C(0)0-; X2 and Xs are independently -Xl0-X"-, wherein X10 is a covalent bond and X11 is l,4-piperazinylene; R1 is R4-X12-, wherein R4 is 18 amidino or guanidino and X'2 is -Χ|4-Χι5-Χιδ-, wherein X,s is 1,4-phenylene, X’4 is a covalent bond and X16 is methylene; and R2 is Rs-X20- or R9-X21-, wherein Rs is amino, X20 is -X22-X23-X24-, vvherein X23 is fram,-l,4-cyc!ohexy!ene, X22is a covalent bond and X24 is 21 methylene, R9 is piperid-4-yl and X21 is ethy!sne or trimethy!ene; and the pharmaceutically acceptable salts, jV-oxides, prodrug derivatives and protected derivatives thereof.
Particularly preferred compounds of Formula I are those in vvhich X4-X3-X6 together are 24 (C4.5)alkylene; X1 and X9 are independently -C(0)- or -NHC(O)-; X3 and X7 are independentlv -C(O)- or -C(0)0-; X2 and X* each are -XIQ-XU-, vvherein X10 is a covalent bond and X11 is l,4-piperazinylene; R1 is R4-X12-, vvherein R4 is amidino or guanidino and X12 is -X|4-X'3-X14-, 27 vvherein X13 is 1,4-phenylene, X'4 is a covalent bond and X16 is methylene; and R2 is Rs-X20-, vvherein R* is amidino or guanidino and X20 is -X22-X23-X24-, vvherein X23 is 1,4-phenylene, X22is a covalent bond and X24 is methylene; and the pharmaceutically acceptable salts, N-oxides, 30 prodrug derivatives and protected derivatives thereof. -17- LV 12291
Most preferred compounds of Formula I are the foliovving: 4-guanidinobenzyl 4- {7-[4-(4-guanidinobenzylcarbamoy l)piperazin-1 -ylcarbonyl]-3 heptanoy 1} -1 -piperazinecarboxamide; 4-guanidinobenzyl 4- {8- [4-(4-guanidinobenzy Icarbamoyl)piperazin-1 -y lcarbony l]octanoy 1} -6 l-piperazinecarboxamide; 4-guanidinobenzyl 4- {9-[4-(4-guanidinobenzylcarbamoyl)piperazin-1 -ylcarbonyl]-nonanoyl} -1 -piperazinecarboxamide; 9 4-amidinobenzyl 4-{7-[4-{4-amidinobenzylcarbamoyl)piperazin-l-ylcarbonyl]heptanoyl}-1 -piperazinecarboxamide; 12 cis-1,5-cyclooctylene 4-(4-amidinobenzylcarbamoyl)-1 -piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoyl)-1 -piperazinecarboxylate; 1,5-pentamethylene di[4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate]; 15 cis-1,5-cyclooctyIene 4-(4-amidinobenzylcarbamoyl)-l -piperazinecarboxylate 4-(4-piperid-4-ylbutyryl)-1 -piperazinecarboxylate; cz's-1,5-cyclooctylene iram-4-(4-aminocyclohexylmethylcarbamoyl)-18 1 -piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyI)-1 -piperazinecarboxylate; cis-1,5 -cycIooctylene 4-(4-amidinophenylacetyl)-1 -piperazinecarboxylate 4-(4-piperid-4-ylbutyryl)-1 -piperazinecarboxylate; 21 1,4-tetramethylene di[4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate]; cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoyl)-l-piperazinecarboxylate; 24 4-guanidinobenzyl 4-{6-[4-(4-guanidinobenzylcarbamoyl)piperazin-l-ylcarbonyl]hexanoyl}-1 -piperazinecaxboxamide; 27 cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoy 1)-1 -piperazinecarboxylate 4-(4-piperid-4-ylbutyry I)-1 -piperazinecarboxy late; cis-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-l -piperazinecarboxylate 30 4-(2-piperid-4-ylethylcarbamoyl)-1 -piperazinecarboxylate; -18- cM--l,5-cyclooctyiene 4-(4-guanidinophenylacetyl)-l-piperazinecarboxylate 4-(4-piperid-4-ylbutyryl)-l-pipera2inecarboxylate; 3. 4-guanidinobenzyl 4- {5-[4-(4-guanidinobehzylcarbamoyl)piperazin-1 -ylcarbony 1] valeryl }-1 -piperazinecarboxamide; 6 3-oxa-l,5-pentamethylene di[4-(4-guanidinophenylacetyI)piperazin-l-ylcarbonylļ; and cis-1,5-cycloocty lene 4-(4-amidinophenylacetyI)-1 -piperazinecarboxyIate 4-(2-piperid-4-ylethylcarbamoy!)-l-piperazinecarboxylate; and the pharmaceutically acceptable 9 salts, N-oxides, prodrug derivatives and protected derivatives thereof.
Pharmacology and Utility:
The compounds of this invention are tryptase inhibitors. As such the compounds of 12 Formula I are useful for treating diseases, particularly immunomediated inflammatory diseases in which tryptase activity contributes to the pathology and/or symptomatology of the disease. For example, immunomediated inflammatory diseases in which tryptase activity contributes to its 15 pathology and/or symptomatology include asthma, allergic rhinitis, rheumatoid spodylitis, osteoarthritis, gouty arthritis, rheumatoid arthritis, arthritic conditions in general, urticaria, angioedema, eczematous dermatitis, anaphyiaxis, hyper proliferative skin disease, peptic ulcers, 13 inflammatory bowel disease, ocular and vemal conjunctivitis, inflammatory skin conditions, and the like.
Suitable in vitro assays for measuring tryptase activity and the inhibition thereof by 21 compounds are known (e.g., see Sturzebecher et ai. (1992) Biol. Chem. Hoppe-Seyler 373:1025-1030). Typically, the assay will measures tryptase induced hydrolysis of peptide base substrate. For further details of an in vitro assay for measuring tryptase activity see Example 33, 24 infra.
Suitable in vivo models of inflammation are known to those of ordinary skitl in the art. For example, in vivo models for asthma are known (e.g., see Larsen (1991) Experimental Models 27 of Reversible Airway Obstruction. In: West et ai, eds. The Lung: Scientific Foundations Raven Press, New York). For further details of an in vitro modei of asthma see Example 2, infra. Further, in vivo models of inflammatory skin conditions (Walsh ei ai (1995) Br. J Pharmacol. LV 12291 -19- 114: 1343-1350; and Armstrong et al. (1995) Prostaglandins 49: 205-224), arthritic conditions (Peacock et al. (1995) Celi Immunol. 160:178-184; andHouri et al. (1995) Curr. Opin. 3 Rheumatol. 7: 201-205) and gastrointestinal diseases (Anthony et al. (1995) Int. J. Exp. Pathol. 76: 215-224.; and Carter et al. (1995) Dig. Dis.Sci. 40: 192-197) are known. For further details of an in vivo assay for measuring asthmatic responses see Example 34, infra. -20-
Administration and Pharmaceutical Compositions:
In general, compounds of Formula I v/ill be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another therapeutic aģent. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. For example, therapeutica!!y effective amounts of a compound of Formula I for the treatment of asthma may range from 0.1 micrograms per kilogram body vveight (pg/kg) per day to 1 milligram per kilogram body weight (mg/kg) per day, typically 1 pg/kg/day to 0.1 mg/kg/day. Therefore, a therapeutically effective amount for a 80 kg asthmatic human patient may range from 10 pg/day to 10 mg/day, typically 0.1 mg/day to 10 mg/day.
Therapeutic aģents that may be usefiii for administration in combination with compounds of Formula I in treating asthma include β-adrenergic agonists (e.g., albuterol, terbutaline, formoterol, fenoterol, prenaline and the like), methylxanthines (e.g., caffeine, theophylIine, aminophylline, theobromine and the like), cromoglycates (e.g., cromolyn, nedocromil, and the like) and corticosteroids (e.g., beclomethasome, triamcinolone, flurisolide, dexamethasone and the like). In general, one of ordinary skill in the art, acting in reliance upon personai knovvledge and the disciosure of this application, vvill be abie to ascertain a tnerapeutically effective amount of a compound of Formula I for treating a given inflammatory disease.
The compounds of Formula I can be administered as pharmaceutical compositions by one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous). Compositions can take the form of tablets, pilis, capsules, semisolids, powders, sustained release formulations, Solutions, suspensions, elixirs, aerosols, or any other appropriate composition and are comprised of, in general, a compound of Formula I in combination with at Ieast one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration. and do not adversely affect the therapeutic benefit of the active ingredient. Such excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, -21- LV 12291 gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid and semisolid excipients 3 may be selected from water, ethanol, glycerol, propylene glvcol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.). Preferred liquid carriers, particularly for injectable Solutions, include water, 6 saline, aqueous dextrose and glycols.
Compressed gases may be used to disperse the active ingredient in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, nitrous oxide, etc. Other suitable 9 pharmaceutical carriers and their formulations are described in A.R. Alfonso Remington’s Pharmaceutical Sciences 1985, 17th ed. Easton, Pa.: Mack Publishing Company.
The amount of a compound of Formula I in the composition may vary widely depending 12 upon the type of formulation, size of a unit dosage, kind of excipients and other factors known to those of skill in the art of pharmaceutical Sciences. In general, a composition of a compound of Formula I for treating asthma will comprise from 0.0l%w to 10%w, preferably 0.3%w to l%w, 15 of active ingredient with the remainder being the excipient or excipients. Preferably the pharmaceutical composition is administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically 18 required. Representative pharmaceutical formulations containing a compound of Formula I are described in Example 34.
Chemistry: 21 The compounds of the invention are comprised of five distinct subunits (i.e., R'-, -X2-, -X4-X5-X6-, -X8- and R2-) which subunits are connected via carbonyl, formyloxy, amide, sulfonamide, carbamate or urea linkages (i.e., -C(O)-, -C(0)0-, -OC(O)-, -C(0)N(R3)-, 24 -N(R3)C(0)-, -S(0),N(R3K -N(R3)S(0)r, -0C(0)N(R3)-, -N(R3)C(0)0-, -N(R3)C(0)N(R3)- or -OC(O)O-). Methods for forming such linking groups are known and suitable reaģents are readily available (e.g., see, March, Advanced Organic Chemistry, 4th Ed. (Wiley 1992); Larock, 27 Comprehensive Organic Transformations (VCH 1989); and Fumiss et ai., Vogel 's Textbook of Practical Organic Chemistry, 5th Ed.. (Longman 1989).
The subunits comprising the compounds of Formula I can be assembled individually or as -22- larger combinations of subunits. The following reaction schemes are representative methods for preparing compounds of Formula I. It is understood that the compounds of Formula I can be 3 prepared by other anaiogous procedures.
Compounds of Formula I in which X1 is l,4-piperazinylene or 1,4-piperidylene and X9 is -C(O)-, -OC(O)- or -N(R3)C(0)- or in which X! is (C,.4)alkylene and X9 is -C(0)N(R3)-, 6 -0C(0)N(R3)- or -N(R3)C(0)N(R3)- can be prepared by reacting a compound of Formula 1: \ ιι'-χ'-χ^-χ4 Y8-X7-X6 · or a protected derivative thereof, with a compound of the formula R2-Y9-C(0)L, or a protected 9 derivative thereof, wherein L is a leaving group, Υ9 is a bond, -0- or -N(R3)-, Y8 is piperazin-l-yl, piperid-4-yl or HN(R3)-(C,.a)aikyl, respectively, and each R1, R2, R3, X1, X2, X3, X4, X5, X4 and X7 are as defined in the Summary of the Invention, and then deprotecting when 12 necessary. Altematively, compounds of Formula I in which X8 is l,4-piperazinylene or 1,4-piperidylene and X9 is -NHC(O)- or in which X* is (C,.a)alkylene and X9 is -NHC(0)N(R3)-can be prepared by reacting an appropriate compound of Formula 1, or a protected derivative 15 thereof, with an isocyanate of the formula R2-NC(0), or a protected derivative thereof, and then deprotecting when necessaiy (for further details see Example 8, infra.).
In an anaiogous fashion, compounds of Formula I in which X2 is l ,4-piperazinylene or 18 l,4-piperidylene and X1 is -C(0)-, -0C(0)- or -N(R3)C(0)- or in which X2 is (C,.a)alkylene and X1 is -C(0)N(R3)-, -0C(0)N(R3)- or -N(R3)C(0)N(R3)- can be prepared by reacting a compound of Formula 2: 21 Y2-X3-X\ r2-x9-x8-x7-x6 2 -23- LV 12291 or a protected derivative thereof, with a compound of the formula Rl-Y'-C(0)L, or a protected derivative thereof, wherein L is a leaving group, Υ1 is a bond, -O- or -N(R3)-, Y2 is 3 piperazin-l-yl, piperid-4-yl or HN(R3)-(C,.8)alkyl, respectively, and each R1, R2, R3, X3, X4, X5, X6, X7, X8 and X9 are as defined in the Summary of the Invention, and then deprotecting when necessary. Altematively, compounds of Formula I in which X2 is l,4-piperazinylene or 6 1,4-piperidylene and X1 is -NHC(O)- or in which X2 is (C,.g)alkylene and X1 is -NHC(0)N(R3)- can be prepared by reacting a compound of Formula 2, or a protected derivative thereof, with an isocyanate of the formula R'-NC(O), or a protected derivative thereof, and then deprotecting 9 when necessary (for further details see Example 14(b), inffa.).
Compounds of Formula I in which R1 equals R2; X2 and/or X* is l,4-piperazinylene or l,4-piperidylene; X1 is -C(O)-, -OC(O)- or -N(R3)C(0)-; and X9 is -C(O)-, -OC(O)- or 12 -N(R3)C(0)- and/or in which X2 and/or X8 is (C,.g)alkylene; X1 is -C(0)N(R3)-, -0C(0)N(R3)- or -N(R3)C(0)N(R3)-; and X9 -C(0)N(R3)-, -0C(0)N(R3)- or -N(R3)C(0)N(R3)- can be prepared by reacting a compound of Formula 3: 15 Y2-X3-X4- X5 Y8-X7-X6 3 or a protected derivative thereof, with 2 or more molar equivalents of a compound of the formula R'-Y'-C(0)L, or a protected derivative thereof, vvherein L is a leaving group, Υ1 is a bond, -0- or 18 -N(R3)-, Y2 and Y8 are independently piperazin-l-yl, piperid-4-yl or HN(R3)-(C|.g)alkyl and each R1, R3, X3, X4, X5, X6 and X7 are as defined in the Summary of the Invention, and then deprotecting when necessary. Altemativeiy, compounds of Formula I in which R1 equals R2; X2 21 and/or X8 is 1,4-piperazinylene or l,4-piperidylene; X1 is -NHC(O)- and/or X9 is -NHC(O)-and/or in which X2 and/or X8 is (C,.g)alkylene and X1 is -NHC(0)N(R3)- and/or X9 is -NHC(0)N(R3)- can be prepared by reacting a compound of Formula 3, or a protected derivative 24 thereof, with two or more molar equivalents of an isocyanate of the formula R'-NC(O), or a protected derivative thereof, and then deprotecting when necessary (for further details see -24-
Examp!e 10, infra.).
Compounds of Formula I in vvhich X1 is -N(R3)C(0)*, -N(R3)C(0)0- or 3 -N(R3)C(0)N(R3)- can be prepared by reacting an amine of the formula R'-N(R3)H, or a protected derivative thereof, with a compound of Formula 4:
lc(0)-y'-x2-x3-xV r2-x9-x*-x7-x6^ 4 6 or a protected derivative, wherein L is a leaving group, Υ1 is a bond, -0- or -N(R3)- and each R1, R2, R3, X3, X3, X4, X5, X6, X7, X® and X9 are as defined in the Summarv of the Invention (for further details see Examp!e 20, infra.). 9 Compounds of Formula I in which X2 is l,4-piperaziny!ene or 4,l-piperidylene and X3 is -C(O)-, -C(0)0- or -C(0)N(R3)- or in which X2 is (C,.i>lkylene and X3 is -N(R3)C(0)-, -N(R3)C(0)0- or -N(R3)C(0)N(R3)- can be prepared by reacting a compound of the 12 formula R'-Χ'-Υ2, or a protected derivative thereof, with a compound of Formula 5: LC(0)-Y3-X4v. R2-X9-X*-X7-X6 5 or a protected derivative thereof, wherein L is a leaving group, Y3 is a bond, -O- or -N(R3)-, Υ2 is 15 piperazin-l-yl, piperid-4-yl or HN(R3)-(C,.i)alkyl, respectively, and each R1, R2, R3, X', X2, X3, X4, X5, X6, X7, X* and X9 are as defmed in the Summary of the Invention (for further details see Example 31, infra.). 1 8 Compounds of Formula I in vvhich X2 and X5 each are 1,4-piperazinylene or 4,l-piperidylene and X3 and X7 are independently -C(O)-, -C(0)0- or -C(0)N(R3)- or in which X2 and X3each are (C,.5)alkylene or hetero(C|.j)alkylene and X: and X7 are indspendently -25- LV 12291 -N(R3)C(0)-, -N(R3)C(0)0- or -N(R3)C(0)N(R3)- can be prepared by reacting two or more molar equivalents of a compound of the formula R'-Χ'-Υ2, or a protected derivative thereof, with 3 a compound of Formula 6:
LC(0)-Y3-xV ">5 LC(0)Y7-X6 6 or a protected derivative thereof, wherein L is a Ieaving group, YJ and Y7 are independently a 6 bond, -O- or -N(R3)-, Y2 is piperazin-l-yl, piperid-4-yl, HN(R3)-(C,.g)aikyl or HN(R3)-hetero(C1.ī)alkyl, respectively, and each R1, X1, X4, X5 and X6 are as defined in the Summary of the Invention (for further details see Example 32, infra.). 9 The acylation reactions described above can be carried out by reacting together an activated ester (e.g., an acid chloride derivative) and an appropriate nucleophile in the presence of a suitable organic base (e.g., A^-diisopropylethylamine (DIEA), iV-methylmorphoIine, etc. 12 preferably DIEA) and suitable solvent (e.g., A,A-dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane, etc.) at 20 to 30°C, typically at approximately 23°C, for several minūtes to 24 hours. Altematively, the acylation can be effected by reacting together an 15 appropriate carboxylic acid and nucleophile in the presence of a suitable coupling reaģent (e.g., l-(3-dimethylaminopropyl)-3-ethylcarbodiimide, etc.) and a suitable solvent (e.g., DMF, etc.) at 20 to 30°C, typically at approximately 23 °C, for several hours to several days. The reactions 18 described above for the preparation of compounds of Formula I and the conditions for effecting the reactions are illustrative and one of ordinary skill in the art will recognize that other reaction conditions can be applied and different starting materiāls can be used to prepare the compounds 21 of the invention.
Deprotection can be effected by any means which removes the protective group and gives the desired product in reasonable yield. A detailed description of the techniques applicable to the 24 creation of protective groups and their removai can be found in T.W. Greene, Protective Groups irt Organic Synthesis, John Wiley & Sons, Inc. 1981. -26-
Generally, the starting materiāls useful in preparing the compounds of Formula I and the intermediates useful in preparing the compounds of Formula I are commercially available or can 3 be readily prepared by those of ordinary skill in the art. For example, intermediates useful in preparing the compounds of Formula I are conveniently prepared by the acylation reactions described above. When necessary suitable protection chemistry is employed to direct the 6 reaction to the desired reactive site when multiple reactive sites are present in the starting materiāls. A convenient starting material for preparing compounds of Formulai in which X3 and X7 9 each are -C(0)0- is a compound of Formula 7: ΙΧΙΟΙ-Ο-Χ4. X5 LC(0)-0-X6 7 in vvhich each X4, X5 and X6 are as defined in the Summary of the Invention. For example, 12 compounds of Formula 6 in which L is chloro can be prepared by reacting a corresponding diol (e.g., cis-l,5-cyclooctanediol, trans-l,4-cyclohexylendimethanol, l,4-phenylenedimethanol, etc.) with triphosgene (for further details see Example 5, infra.). 15 Intermediates useful in preparing compounds of Formula I in vvhich such intermediate contains a amidino group can be prepared by treating a corresponding nitrile with hydrogen chloride in ethanol and then reacting with ammonia. 18 Additional Processes for Preparing Compounds of Formula I:
Compounds of Formula I in which R4 is guanidino can be prepared by reacting a corresponding compound of Formula I in v/hich R4 is amino with cyanamide. The reaction is 21 carried out by treating the amine v/ith hydrogen chloride and then reacting neat with an excess of cyanamide at approximately 65°C for abouttwo hours (for further details see £xample 15, infra.). 24 Compounds of Formula I may be prepared as pharmaceutically acceptable acid addition -27- LV 12291 salts by reacting the firee base forms of a compound of Formula I with a pharmaceutically acceptable inorganic or organic acid. Altematively, the pharmaceutically acceptable base addition salts of compounds of Formula I may be prepared by reacting the free acid forms of compounds of Formula I with pharmaceutically acceptable inorganic or organic bases. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compounds of Formula I are set forth in the definitions section of this application. Altematively, the salt forms of the compounds of Formula I may be prepared using salts of the starting materiāls or intermediates.
The free acid or free base forms of the compounds of Formula I can be prepared from the corresponding base addition salt or acid addition salt form. For example, compounds of Formula I in an acid addition salt form may be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). Compounds of Formula I in a base addition salt form may be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc).
The 7V-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art. For example, lV-oxides can be prepared by treating an unoxidized form of the compound of Formula I with an oxidizing aģent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, /neia-chloroperoxybenzoic acid, etc.) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as methylene chioride) at approximately 0°C. Altematively, the Ar-oxides of the compounds of Formula I can be prepared from the jV-oxide of an appropriate starting material.
Compounds of Formula I in unoxidized form can be prepared from jV-oxides of compounds of Formula I by treating with a reducing aģent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, etc.) at 0 to 80 °C.
Prodrug derivatives of the compounds of Formula I can be prepared by methods knovm to those of ordinary skill in the art (e.g., for further details see Saulnier et a/.(1994), Bioorgartic and Medicīnai Chemistry Letters. 4:1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of Formula I with a suitable carbamylating aģent (e.g., l,l-acyloxyalkylcarbonochloridate,para-nitrophenyl carbonate, etc.). -28-
Protected derivatives of the compounds of Formula I can be made by means knovvn to those of ordinary skill in the art. A detailed description of the techniques applicable to the 3 creation of protective groups and their removal can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley 8c Sons, Inc. 1981.
In summary, an aspect of this invention is a process for preparing compounds of 6 Formula I, which process comprises: (a) reacting a compound of Formula 1: ιι'-χ'-χΑχΑχ4 Y8-X7-X6 1 9 or a protected derivative thereof, vvith a compound of the formula R2-Y9-C(0)L, or a protected derivative thereof, wherein L is a leaving group, Υ9 is a bond, -0- or -N(R3)-, Y8 is piperazin-l-yl, piperid-4-yl or HN(R3)-(CM)alkyl, respectively, and each R', R2, R3, X', X2, X3, 12 X\ Xs, X6 and X7 are as defmed in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formulai, in which Xs is 1,4-pipera2inylene or 1.4- piperidylene and X9 is -C(0)-, -0C(0)- or -N(R3)C(0)- or in which Xs is (C,.s)alkylene and 15 X9 is -C(0)N(R3)-, -0C(0)N(R3)- or -N(R3)C(0)N(R3·)-; (b) reacting a compound of Formula 1, or a protected derivative thereof, vvith an isocyanate of the formula R2-NC(0), or a protected derivative thereof, and then deprotecting when 18 necessary, to give a compound of Formula I in vvhich X! is 1,4-piperazinylene or 1.4- piperidylene and X9 is -NHC(O)- or in vvhich Xs is (C,.g)alkylene and X9 is -NHC(0)N(R3)- (c) reacting a compound of Formula 2: 21 Y2-X3-X\ ^X5 r2-x9-x8-x7-x6 ? -29- LV 12291 or a protected derivative thereof, with a compound of the formula RI-Y'-C(0)L, or a protected derivātive thereof, wherein L is a leaving group, Υ1 is a bond, -O- or -N(R3)-, Y2 is 3 piperazin-l-yl, piperid-4-yl or HN(R3)-(C|.g)alkyl, respectively, and each R1, R2, R3, X3, X4, X5, X6, X7, X8 and X9 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I in which X2 is 1,4-piperazinylene or 6 l,4-piperidylene and X1 is -C(O)-, -OC(O)- or -N(R3)C(0)- or in which X2is (C1.g)alkylene and X1 is -C(0)N(R3)-, -0C(0)N(R3)- or -N(R3)C(0)N(R3)-; (d) reacting a compound of Formula 2, or a protected derivative thereof, with an isocyanate 9 of the formula R'-NC(O), or a protected derivative thereof, and then deprotecting when necessary, to give a compound of Formula I in which X2 is l,4-piperazinylene or l,4-piperidylene and X1 is -NHC(O)- or in which X2is (C,_g)alkylene and X1 is -NHC(0)N(R3)-; 12 (e) reacting a compound of Formula 3: Υ^Χ3-*4· Y*-X7-X6' or a protected derivative thereof, with 2 or more molar equivalents of a compound of the formula 15 R1-Y'-C(0)L, or a protected derivative thereof, wherein L is a leaving group, Yl is a bond, -O- or -N(R3)-, Y2 and Y8 are independently piperazin-l-yl, piperid-4-yl or HN(R3)-(C,.g)alkyl and each R1, R3, X3, X4, X5, X6 and X7 are as defined in the Summary of the Invention, and then 18 deprotecting when necessary, to give a compound of Formula I in vvhich R‘ equals R2; X2 and/or X* is l,4-piperazinylene or l,4-piperidylene; X1 is -C(O)-, -OC(O)- or -N(R3)C(0)-; and X9 is -C(O)-, -OC(O)- or -N(R3)C(0)- and/or in vvhich X2 and/or X8 is (C|.g)alkylene; X! is 21 -C(0)N(R3)-, -0C(0)N(R3)- or -N(R3)C(0)N(R3)-; and X9 -C(0)N(R3)-, -0C(0)N(R3)- or -N(R3)C(0)N(R3)-; (f) reacting a compound of Formula 3, or a protected derivative thereof, with two or more 24 molar equivalents of an isocyanate of the formula R'-NC(O), or a protected derivative thereof, and then deprotecting when necessary, to give a compound of Formula I in vvhich R1 equals R2; -30- X2 and/or Xi is l,4-piperazinylene or l,4-piperidylene; X1 is -NHC(O)- and/or X9 is -NHC(O)-and/or in which X2 and/or X‘ is (C,.g)alkylene and X1 is -NHC(0)N(R3)- and/or X9 is 3 -NHC(0)N(R3)-; (g) reacting an amine of the formula R'-N(R3)H, or a protected derivative thereof, with a compound Formula 4:
6 LC(0)-Y'-X2-X3-xY r2-x9-x*-x7-x6^ 4 or a protected derivative thereof, wherein L is a leaving gToup, Yl is a bond, -O- or -N(R3)- and each R1, R2, R3, X2, X3, X4, X5, X6, X7, X* and X9 are as defined in the Summary of the Invention, 9 and then deprotecting when necessary, to give a compound of Formula I in vvhich X’ is -N(R3)C(0)-, -N(R3)C(0)0- or -N(R3)C(0)N(R3)-; (h) reacting a compound of the formula R'-Χ'-Υ1, or a protected derivative thereof, with a 12 compound of Formula 5: ΙΧίΟ^-Χ4. X5 R2-X9-X3-X7-X6 or a protected derivative thereof, vvherein L is a leaving group, Y3 is a bond, -0- or -N(R3)-, Y2 is 15 piperazin-l-yl, piperid-4-yl or HN(R3)-(C,.j)alkyl, respectively, and each R1, R2, R3, X1, X2, X3, X4, X5, X4, X7, Xs and X9 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I in vvhich X2 is I,4-piperazinylene or 18 4,l-piperidylene and X3 is -C(O)-, -C(0)0- or -C(0)N(R3)- or in vvhich X2 is (C,.g)alkylene and X3 is -N(R3)C(0)-, -N(R3)C(0)0- or -N(R3)C(0)N(R3)-; (i) reacting 2 or more molar equivalents of compound of the formula R'-Χ’-Υ2, or a -31- LV 12291 protected derivative thereof, with a compound of Formula 6: LC(0)-Y3-X4n. LC(0)Y7-X6 6 3 or a protected derivative thereof, wherein L is a leaving group, Y3 and Y7 are independently a bond, -0- or -N(R3)-, Y2 is piperazin-l-yl, piperid-4-yl, HN(R3)-(C,.8)aIkyl or HN(R3)-hetero(C|.s)alkyl and each R1, X1, X4, X5 and X6 are as defmed in the Summary of the 6 Invention, and then deprotecting when necessary, to give a compound of Formula I in which X2 and X8 each are 1,4-piperazinylene or 4,l-piperidyiene and X3 and X7are independently -C(0)-, -C(0)0- or -C(0)N(R3)- or in which X2 and X8 each are (C,.8)alkylene or hetero(C!.g)alkylene 9 and X3 and X2 are independently -N(R3)C(0)-, -N(R3)C(0)0- or -N(R3)C(0)N(R3)-, respectively; (j) optionally reacting a compound of Formula I in which R4 is amino with cyanamide to give a compound of Formula I in which R4 is guanidino; 12 (k) optionally further converting a compound of Formula I into a pharmaceuticallv acceptable salt; (1) optionaIly further converting a salt form of a compound of Formula I to non-salt form; 15 (m) optionally further converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable jV-oxide; (n) optionally further an jV-oxide form of a compound of Formula I its unoxidized form; 18 (o) optionally further converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and (p) optionally further converting a prodrug derivative of a compound of Formula I to its 21 non-derivatized form.
In any of the above processes, a reference to Formula I refers to such Formula vvherein each R\ R2, R\ X!, X2, X3, X4, X5, X6, X7 X8 and X9 are as defmed in their broadest definitions 24 set forth in the Summary of the Invention, with the processes applying particularly well to the presently preferred embodiments. -32-
Examples: EXAMPLE l 3 /err-Butyl 4-aminobenzylcarbamate hydrochloride 4-Aminobenzylamine (50.34 g, 0.412 mol) in dichloromethane (200 mL) was placsd in a one liter 3 neck round bottom flask fitted with a mechanical stirring apparatus and the solution 6 was cooled to 0°C. di-/ert-Butyl dicarbonate (89.9 g, 0.412 mol.) in dichloromethane (200 mL) was added dropwise to the solution over 30 minūtes and the resulting suspension was stirred 2 hours at 0°C giving a nearly homogeneous solution. The dichloromethane solution 9 subsequently was washed with aqueous sodium hydroxide (1.0 M, 500 mL) and then water (500 mL). The organic layer was dried (MgS04), fīltered and concentrated in vacuo giving a ye!low oil. The oil was taken into ethyl ether : methanol (2: l, 225 mL) and the solution was 12 cooled to 0°C, acidified with hydrogen chloride in dioxane (4.0 M, 115 mL, 0.412 mol.) and combined with ethyl ether (200 mL) giving a thick pale ye!low precipitate. The precipitate was collected by filtration and washed vvith additional ethyl ether (500 mL). Drying in vacuo gavē 15 ferf-buty! 4-aminobenzylcarbamate hydrochloride (100.23 g, 0.387 mol, 94% yield) as a pale yellow solid; Ή-NMR (300MHz, DMSO-d6): 10.40-10.20 (br s, 3H), 7.40 (tr, 1H), 7.30 (s, 4H), 4.10 (d,2H), 1.40 (s, 9H). 18 EXAMPLE 2 tert-Butyl 4-guanidinobenzylcarbamate
Cyanamide (100 g, 2.4 mol) was placed in a 500 mL round bottom flask and heated to 21 between 60 and 65°C until the material comp!etely melted and then rert-butyl 4-aminobenzylcarbamate hydrochloride (25.3 g, 97.8 mmol.), prepared as in Example 1, was added directly to the liquid cyanamide giving a yellow solution. The solution was stirred 2 hours 24 at betv/een 60 and 65 °C and then water (100 mL) was added. The aqueous mixture was cooled to room temperature and washed vvith ethyl ether (1 L). The organic phase was back extracted with water (2x. 100 mL) and the combined aoueous lavers were washed with ethvl ether (500 -33- LV 12291 mL), cooled in an ice water bath and then basified with aqueous sodium hydroxide (10 M, 100 mL) giving an insoluble oil which sIowly crystallized. The crystals were collected by 3 filtration washed with water. Drying irt vacuo gavē tert-butyl 4-guanidinobenzylcarbamate (18.3 g, 69.24 mmol, 70.8% yield) as a colorless crystalline solid; Ή-NMR (300MHz, DMSO-dJ: 9.70 (s, 1H), 7.42 (tr, 1H), 7.40 (s, 4H), 7.25 (d, 2H), 7.15 (d, 2H), 4.10 (d, 2H), 1.40 6 (s, 9H). EXAMPLE 3 ieri-Butyl 4-chlorocarbonyl-l -piperazinecarboxylate 9 Triphosgene (25 g, 84.2 mmol) was taken into dichloromethane (200 mL) and the resulting solution cooled to 0°C. A mixture of ier/-butyl 1 -piperazinecarboxylate (40 g, 214.8 mmol) and pyridine (35 mL, 432.7 mmol) in dichloromethane (100 mL) then was added 12 dropwise to the triphosgene solution and the reaction mixture was allowed to warm to room temperature over 30 minūtes. The mixture was quenched with aqueous hydrochloric acid (0.1N, 200 mL) and the aqueous phase was washed with dichloromethane (50 mL). The combined 15 organic layers were dried (MgS04) and filtered. Concentrating in vacuo gavē tert-butyl 4-chlorocarbonyl-l-piperazinecarboxylate (45.6 g, 71.6 mmol, 85% yield) as a yellow solid; 'H-NMR (300MHz, CDC13): 3.70 (m, 2H), 3.60 (m, 2H), 3.50 (m, 4H), 1.50 (s, 9H). 18 EXAMPLE 4 /eri-Butyl 4-(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate trifluoroacetate ierr-Butyl 4-guanidinobenzylcarbamate (41.77 g, 0.158 mol.), prepared as in Example 2, 21 was treated with trifluoroacetic acid (TFA) (100 mL) for 30 minūtes at room temperature. The resulting nearly colorless liquid was concentrated in vacuo at 45 °C and the residue was triturated with ethyl ether (3x, 400 mL) and dried in vacuo to a colorless foam. The residue was dissolved 24 in methanol (200 mL) and then DIEA (55 mL, 0.32 mol, amount based on estimated excess TFA present) was added to the solution. The mixture was cooled to 0°C and then tert-butyl 4-chlorocarbonyl-l-piperazinecarboxylate (39.3 g, 0.158 mol.), prepared as in Example 3, in -34- dichloromethane (120 mL) was added. An additional amount of DIEA (30 mL) was added and the reaction mixture was alIowed to warm to room teraperature, stirred 12 hours and concentrated 3 in vacuo giving an orange oil. The oil was combined with water (200 mL) giving a thick precipitate. Recrystallization of the precipitate from acetonitrile and ether gavē ter/-butyl 4-(4-guanidinobenzylcarbamoyl)-l-piperazinecarboxylatetrifluoroacetate (62.0 g, 0.126 mol, 6 80% yield) as a pale yellow solid; Ή-NMR (300MHz, DMSO-d4): 10.15 (s, 1H), 9.10 (br s, 2H), 7.65 (s, 4H), 7.40 (tr, 1H), 7.25 (dd AB, 4H), 4.25 (d, 2H), 3.55 (m, 4H), 3.10 (s, 4H); Electrospray LRMS: Calculated for Ci3H20N6O: ΜΗ*: 277.4; MH,*2/2: 139.2, 9 Found: MH*: 277.4; MH2+1/2: 139.3. -35- LV 12291 EXAMPLE 5 cis-1,5-Cyclooctylene di(chloroformate) 3 ds-l,5-Cyclooctanediol (20.2 g, 0.14 mol.) was taken into acstonitrile (250 mL) and potassium carbonate (41.4 g, 0.3 mol.) was added to the mixture giving a suspension. The suspension was cooled to 0°C under a nitrogen atmosphere and then phosgene (1.9M in toluene, 6 220 mL, 0.42 mol.) was added dropwise over one hour. The suspension was wanned to room temperature and stirred 12 hours and then ether (1 L) was added. The suspension was filtered free of insoluble salts and concentrated. Recrystallization of the residue fforn hexane gavē 9 cis-1,5-cyclooctylene di(chloroformate) as a colorless crystalline solid. Further purification can be effected with silica gel flash chromatography using hexane:ethyl ether (10:1) as eluent; ‘H-NMR (300MHz, CDC13): 5.00-4.85 (m, 2H), 2.20-1.60 (m, 12H). 12 EXAMPLE 6 cis-1,5-Cyclooctylene chloroformate 4-tert-butoxycarbonyl-1 -piperazinecarboxylate cz5-1,5-Cyclooctylene di(chloroformate) (1.91 g, 7.1 mmol), prepared as in Example 5, in 15 dichloromethane (25 mL) was added dropwise to a mixture of tert-butyl l-piperazinecarboxylate (1.3 g, 7.1 mmol) and DIEA (1.3 mL, 7.1 mmol) in dichloromethane (25 mL). The mixture was stirred 15 minūtes at room temperature and then a workup with 0.1M aqueous hydrochloric acid 18 was performed. The dichloromethane layer was dried (MgS04), filtered and concentrated. Purifying from the residue by silica gel flash chromatography using ethyl ether and hexanes as eluent gavē cis-l,5-cyclooctylene chloroformate 4-ierf-butoxycarbonyl-l-piperazinecarboxylate 21 (660 mg, 1.6 mmol, 22% yield) as a colorless oil; Ή-NMR (300MHz, CDC13): 5.00-4.90 (m, 1H), 4.80-4.70 (m, 1H), 3.40 (s, 8H), 2.05-1.40 (m, 12), 1.40 (s, 9H). -36- ΕΧΑΜΡΙΕ 7 cis-1,5-Cyclooctylene 4-(4-guanidinobenzyIcarbamoy!)-1 -piperazinecarboxylate 3 4-terr-butoxycarbonyl-l -pipera2inecarboxylate terr-Butyl 4-(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate trifluoroacetate (383.7 mg, 1.06 mmol), prepared as in Example 4, was treated with trifluoroacetic acid (1 mL) 6 neat for 10 minūtes at room temperature. The mixture was concentrated in vacuo giving a colorless oil. The oil was then taken into water (15 mL) and the pH of the aqueous solution was adjusted to betv/een 7 and 8 with 5M aqueous sodium hydroxide added dropwise. 9 c/s-l,5-Cyclooctylene chloroformate 4-rer(’-butoxycarbonyl-l-piperazinecarboxylate (444.7 mg, 1.06 mmol), prepared as in Example 6, in THF (10 mL) was added to the aoueous solution and the pH was continually adjusted vvith IM aqueous sodium hydroxide added dropwise until no 12 further change in pH v/as observed. The mixture was concentrated in vacuo removing the bulk of THF and then ethyl ether (5 mL) and 5M aqueous sodium hydroxide (sufficient to adjust the pH to 14) was added giving a thick vvhite suspensioru The suspension was allovved to stand for 15 15 to 30 minūtes at room temperature and then the precipitate was collected by filtering and vvashed vvith water (2x, 15 mL). Drying in vacuo gavē cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1 -pipera2inecarboxylate 4-rar/-butoxycarbonyl-18 1-piperazinecarboxylate (527 mg, 0.82 mmol, 77% yield) as a colorless solid; H-NMR. (300MHz, DMSO-d6): 7.05 (d, 2H), 7.00 (tr, 1H), 6.70 (d, 2H), 5.10 (br, 3H), 4.65 (m, 2H), 4.15 (d, 2H), 3.30 (s, 16H), 1.90-1.40 (m, 12H), 1.40 (s, 9H). 21 EXAMPLE 8 m-l,5-Cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-l-piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoyl)-l-piperazinecarboxylate trifluoroacetate 24 (Compound 1)
The follovving is the preparatīon of a compound of Formula ī in vvhich R1 is 27 4-guanidinobenzyl, R2 is 2-piperid-4-ylethyl, X1 and X9 each are -NHC(O)-, X: and Xs each are 1,4-piperazinvlene, XJ and X7 each are -C(0)0-, X4 and X6 each are a covalent bond and X’ is -37- LV 12291 cis-1,5-cyclooctylene. 3 cis-1,5-CyclooctyIene 4-(4-guanidinobenzylcarbamoyI)-1 -piperazinecarboxylate 4-feri‘-butoxycarbonyl-l-piperazinecarboxylate (818 mg, 1.24 mmol.), prepared as in Example 7, was treated vvith TFA (2 mL) neat for 10 minūtes. The mixture was concentration in vacuo 6 giving a colorless oil. The residue was triturated with ethyl ether (2x, 10 mL) and dried in vacuo giving a colorless foam. The residue was then taken into DMF (2 mL) and then DIEA (700 mL, 4.0 mmol.) and tert-butyl 4-(2-isocyanatoethyl)-l-piperidinecarboxylate (3.2 mL, 0.39 M in 9 DMF, 1.25 mmol.) were added. The mixture was stirred 12 hours and then concentrated in vacuo. The residue was triturated with water (2x, 5 mL) and dried in vacuo giving a yeIlow solid. The solid v/as then treated vvith TFA (2 mL) and the mixture was concentrated in vacuo. 12 The residue was taken into water. Purifying from the aqueous mixture by preparative reverse phase HPLC gavē cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(2-piperid-4-ylethyIcarbamoyl)-l-piperazinecarboxylate as an 15 amorphous colorless solid; Plasma Desorption LRMS: Calculated for C35H55Nio06: ΜΗ1-: 712.9, Found: MH+: 713.2.
Proceeding as in Example 8 and substituting different starting materiāls the folIowing 18 compounds of Formula I were prepared: CZJ--1,5-cyclooctylene 4-(4-aminobenzylcarbamoyl)-1 -piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyl)-l-piperazinecarboxylate (Compound 2); Calculated for 21 C3JHjoN1006: MH+: 707.9, Found: MH+: 707.7; cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate 4-(4-piperidylmethylcarbamoyl)-l-piperazinecarboxylate (Compound 3); Calculated for 24 C^H^NtA: MH+: 698.9, Found: MH+: 699.7; cis-\ ,5-cyclooctylene 4-(rraro’-4-aixiinocyclohexylmethylcarbamoyl)-1 -piperazinecarboxy late 4-(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate 27 (Compound 4); Calculated for C35H55N10O6: MH+: 712.9, Found: MH+: 713.6; cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyI)-1 -piperazinecarboxylate -38- 3- piperid-4-yipropylcarbamoyl-l-piperazinecarboxylate (Compound 5); Calculated for C36HS8Ni0O6: MFT: 727.9 Found: MFT: 727.9; 3 4-[4-(2-piperid-4-ylethylcarbamoyl)piperazin-1 -ylcarbonyl]benzyl 4- (4-guanidinobenzylcarbamoyI)-l-piperazinecarboxylate (Compound 6); Calculated for C34H<8N,0Os: MH+: 677.8 Found: MfT: 677.6; 6 4-[4-(3-piperid-4-ylpropylcarbamoyl)piperazin-1 -ylcarbonyl]benzyl 4-(4-guanidinobenzylcarbamoyl)-l-piperazinecarboxylate (Compound 7); Calculated for C3JH50NI0Os: MFT: 691.9 Found: MFT: 691.5; 9 4-(4-(4-piperid-4-ylbuty Icarbamoyl)piperazin-1 -ylcarbonyl]benzy 1 4-(4-guanidinobenzylcarbamoyl)-l-piperazinecarboxylate (Compound 8); Calculated for C36HS2N10O3: MH*: 705.9 Found: MFT: 705.9;
12 4-[4-(4-guanidinobenzylcarbamoyl)piperazin-1 -ylcarbonyl]benzyI 4-(2-piperid-4-ylethylcarbamoyl)-l-piperazinecarboxylate (Compound 9); Calculated for C34H4SN10O5: MFT: 677.8 Found: MFT: 677.7; 15 4-[4-(4-guanidinobenzylcarbamoyl)p:perazin-1 -ylcarbonyl]benzy l 4-(3-piperid-4-ylpropylcarbamoyl)-l-piperazinecarboxylate (Compound 10); Calculated for C3jH50NI0O5: MFT: 691.9 Found: MFT: 691.3; 18 4-(4-(2-piperid-4-ylethylcarbamoyl)piperazin-1 -ylcarbonylmethy l]benzy l 4-(4-guanidinobenzylcarbamoyl)-l-piperazinecarboxylate (Compound 11); Calculated for C33H50Nl0O5: MFT: 691.9 Found: MFT: 692.1;
21 4-(4-(3-piperid-4-ylpropylcarbamoyl)piperazin-I-yIcarbonylmethyl]benzyI 4-(4-guanidinobenzylcarbamoyI)-l-piperazinecarboxylate (Compound 12); Calculattd for C36HJ2N10O5: MFT: 705.9 Found: MFT: 705.6; 24 c/j-l ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(4-methyiaminomethylbenzylcarbamoyl)-l-piperazinecarboxylate (Compound 13); Calculated for C37H54N,o06: MFT: 735.9 Found: MFT: 735.7; 27 c(j-l,5-cyclooctylene 4-(4-guanidinophenylacetyl)-l-piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoyI)-l-piperazinecarboxylate (Compound 14); Calculated for C35H55N906: MFT: 698.9, Found: MFT: 698.2; 30 cis-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-1 -piperazinecarboxyiate -39- LV 12291 4-(3-piperid-4-ylpropylcarbamoyl)-l-piperazinecarboxylate (Compound 15); Calculated for C36H57N906·· MH+: 712.9, Found: MH+: 712.3; cis-1,5 -cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxy late 4-(4-imidazol-l-ylbutylcarbamoyl)-l-piperazinecarboxylate (Compound 16); Calculated for C35H53N„06: MH+: 724.9, Found: MH+: 724.5; c/j-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyI)-l-piperazinecarboxylate 4-(4-imidazolin-2-ylaminobutylcarbamoyl)-l-piperazmecarboxylate (Compound 17); Calculated for C35H56Ni206: MH+: 741.9, Found: MH+: 741.7; cis-l ,5-cyclooctylene 4-(rmra-4-aminocyclohexylmethylcarbamoyl)-1 -piperazinecarboxylate 4-(4-guanidinoben2ylcarbamoyl)-l -piperazinecarboxylate (Compound 18); Calculated for C35HJ6N|0O6: MH+: 713.9 Found: MH": 714.1; cis-1,5-cyclooctylene 2-( 1 -terf-butryryloxymethoxycarbonylpiperid-4-yl)ethylcarbamoyl-1 -piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate (Compound 19); Calculated for C42H66NI0OI0: MH+: 872.1, Found: MH+: 871.8; cis-1,5 -cy clooctylene 4-(4-guanidinobenzylcarbamoy l)-1 -piperazinecarboxylate 4-[2-(l-methylpiperid-4-yl)ethylcarbamoyl]-l-piperazinecarboxylate (Compound 20); Calculated for C36H58N10O6: MH2272: 364.0, Found: MH2272: 364.3; cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate 4-(3-imidazolin-2-ylaminopropylcarbamoyl)-l -piperazinecarboxylate (Compound 21); Calculated for C34H54N1206: MH+: 727.9, Found: MH+: 728.0; cis-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-1 -piperazinecarboxylate 4-[l-(l-iminoethyI)piperid-4-ylmethylcarbamoyI]-l-piperazinecarboxylate (Compound 22); Calculated for C36H57Nn06: MH7 740.9, Found: MFT: 740.5; cis-1,5-cyclooctylene 4-(4-guanidinobenzoylaminomethy 1)-1 -piperidinecarboxylate 4-(2-piperid-4~ylethylcarbamoyl)-l-piperazinecarboxylate (Compound 23); Calculated for C36H57N906: ΜΗ": 712.9, Found: MH+: 711.6; cis-1,5-cycloocty lene 4-(4-amidinobenzylcarbamoy 1)-1 -piperazinecarboxylate 2-( 1 -methoxycarbonylpiperid-4-yI)ethylcarbamoyl-1 -piperazinecarboxylate (Compound 24); Calculated for C37H57N9Og: MH+: 756.9, Found: MH+: 756.7; and -40- 3- (4-(2-(4-{c/.r-5-[4-(4-ainidinobenzylcarbamoyl)piperazin-l-ylcarbonyloxy]cyclooctyloxy-carbonyl}piperazin-l-ylcarbonylamino)ethyl]piperid-l-ylcarbonyl}propionic acid 3 (Compound 25); Calculated for ^,ΗβοΝ,Ο»: ΜΗ": 799.0, Found: ΜΗ": 798.6.
Procesding as in Example 8 and replacing the isocyanate with an activated ester the following compounds of Formula I were prepared: 6 cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyI)-1 -piperazinecarboxy!ate 4- imidazol-4-ylacetyl-l-piperazinecarboxylate (Compound 26); Calculated for C32H46N1(A: MH": 667.8, Found: MH\· 667.7; 9 cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxyiate 4-(£-3-imidazol-4-ylacryloyl)-l-piperazinecarboxylate (Compound 27); Calculated tor C33H46Nl0O4: MH": 679.9, Found: MH": 679.8; 12 c/i-l,5-cyclooctyiene 4-(4-guanidinobenzylcarbamoyI)-l-piperazinecarboxyiate 4-(3-imidazol-4-ylpropionyl)-l-piperazinecarboxylate (Compound 28); Calculated for CMH4lNl0O6: MHr: 681.8, Found: MH": 681.7; 15 cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate 4-(5-imidazol-l-ylvaleryI)-l-piperazinecarboxylate (Compound 29); Calculated for C33H3:NI0O6: MH": 709.9, Found: MH": 709.5; 18 cis-1,5-cyciooctylene 4-(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate 4-(6-imidazol-l-ylhexanoyl)-l-piperazinecarboxylate (Compound 30); Calculated for C36HS4N10O6: MH": 723.9, Found: MH": 723.4; 21 cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-l-piperazinecarboxylate 4-(4-imidazol-l-ylmethylphenylacetyl)-l-piperazinecarboxylate (Compound 31); Calculated for C39H3,N10O6: MH": 757.9, Found: MH": 757.2; 24 cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoy 1)-1 -piperazinecarboxylate 4-(4-imidazol-l-ylmethylbenzoyl)-l-piperazinecarboxylate (Compound 32); Calculated for CjjH3oNi0Os: MH": 743.9, Found: MH": 743.7; 27 cis-l ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoy 1)-1 -piperazinecarboxylate 4-(3-imidazol-l-ylmethylbenzoyl)-l-piperazinecarboxylate (Compound 33); Calculated for -41- LV 12291 C3«H30N,0O6: MH+: 743.9, Found: MH": 743.6; m-l,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-l-piperazinecarboxylate 3 4-(7-imidazoI-1 -ylheptanoyl)-1 -piperazinecarboxylate (Compound 34); Calculated for C37H56N|0O6: MH+: 737.9, Found: MH+: 737.6; cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoy 1)-1 -piperazinecarboxylate 6 4-[6-(2-methylimidazol-l-yl)hexanoyl]-l-piperazinecarboxylate (Compound 35); Calculated for C37Hj6N10O6: MFT: 737.9, Found: MH+: 737.3; cis-1,5-cyclooctylene 4-(4-guanidinoben2yicarbamoyl)-1 -piperazinecarboxylate 9 4-(4-imidazol-1 -ylphenoxyacetyl)-l-piperazinecarboxylate (Compound 36); Calculated for C3gH50N10O7: MH+: 759.9, Found: MH+: 759.3; cis-\,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate 12 4-[6-(4-methylimidazol-l -yl)hexanoyI]-l-piperazinecarboxylate and cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate 4-[6-(5-methylimidazol-l-yl)hexanoyI]-l-piperazinecarboxylate as a mixture (Compound 37); 15 Calculated for C37H56N10O6: MH+: 737.9, Found: MH+: 738.2; cis-1,5-cyclooctylene 4-(4-guanidinobenzy lcarbamoy 1)-1 -piperazinecarboxylate 4-(4-piperid-4-yIbutyryl)-l-piperazinecarboxylate (Compound 38); Calculated for 18 C36H57N906: ΜΡΓ: 712.9 Found: MH+: 712.4; cis- l,5-cyclooctylene 4-(4-guanidinophenylacetyl)-l-piperazinecarboxylate 4-(4-piperid-4-ylbutyryl)-l-piperazinecarboxylate (Compound 39); Calculated for 21 C36H56Ns06: MH+: 697.9, Found: MH+: 697.5; cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoy 1)-1 -piperazinecarboxylate 4-(2-piperid-4-ylethyl)(methyl)carbamoyl-l-piperazinecarboxylate (Compound 40); Calculated 24 for C36H58N10O6: ΜΗΓ: 727.9, Found: MH*: 727.6; cis-1,5-cycloocty lene 4-(4-guanidinopheny lacety 1)-1 -piperazinecarboxylate 4-(2-piperid-4-ylethyl)(methyl)carbamoyl-l-piperazinecarboxylate (Compound 41); Calculated 27 for C36H57N906: MH+: 712.9, Found: MH+: 712.7; cis-1,5-cy cloocty lene 4-(4-guanidinobenzylcarbamoy I)-1 -piperazinecarboxy late 4-(2-piperid-4-ylethoxycarbonyl)-l-piperazinecarboxylate (Compound 42); Calculated for 30 C33H33N907: MH+: 714.9, Found: MH*: 714.5; -42- cis-\,5-cycIooctyIene 4-(4-guanidinobenzylcarbamoyl)-l-piperazinecarboxy!ate 4-(4-imidazol-l-ylphenylacetyl)-l-piperazinecarboxylate (Compound 43); Calculated for C3«H50Nl0Os: MH*: 743.9, Found: MH*: 743.6; cis-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-1 -piperazinecarboxylate 4-(6-imidazol-l-ylhexanoyl)-l-piperazinecarDOxyIate (Compound 44); Calculated for C36HS3N906: MH+: 708.9, Found: MH*: 708.3; cis-1,5-cyclooctyiene 4-(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate 4-(3-pyrid-4-ylthiopropionyl)-l-piperazinecarboxylate (Compound 45); Calculated for C3sH49N906: MH*: 724.9, Found: MH*: 724.4; c/.?-l,5-cyclooctylene 4-(4-guanidinobenzylcarbonyl)-l-piperazinecarboxylate 4-pyrid-4-ylthioacetyl-l-piperazinecarboxylate (Compound 46); Calculated for C34H47N906: MH*: 710.9, Found: MH*: 710.8; c/i-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-l -piperazinecarboxylate 4-(3-pyrid-4-ylthiopropionyI)-l-piperazinecarboxylate (Compound 47); Calculated for C3SH4SNA: MH*: 709.9, Found: MH*: 709.3; cz>l,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-l-piperazinecarboxylate 4-(6-imidazol-4-ylhexanoyl)-l-piperazinecarboxylate (Compound 48); Calculated for C36H54N,0O6: MH*: 723.9, Found: MH*: 723.5; cis-1,5-cyclooctylene 4-(benzoimidazol-6-ylcarbony!)-1 -piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyl)-l-piperazinecarboxylate (Compound 49); Calculated for CjjH47N|0O6: MH*: 703.8, Found: MH*: 703.4; cis-1,5-cyclooctylene 4-(4-amidinobenzylcarbamoy 1)-1 -piperazinecarboxylate 4-(6-imidazol-l-ylhexanoyI)-l-piperazinecarboxylate (Compound 50); Calculated for C36H53N906: MH*: 708.9, Found: MH*: 708.6; c/j,-l,5-cyclooctylene 4-(4-amidinobenzoylaminomethyl)-l-piperidinecarboxylate 4-(6-imidazol-4-yIhexanoyl)-l-piperazinecarboxylate (Compound 51); Calculated for C37H54NsOs: MH*: 707.9, Found: MH*: 707.5; cis-1,5-cyclooctylene 4-(4-guanidinophenylacety I)-1 -piperazinecarboxylate 4-(6-imidazol-4-ylhexanoyl)-l-piperazinecarboxylate (Compound 52); Calculated for C35Hi:Nl0Oa: MH*: 708.9 Found: MH*: 708.4; -43- LV 12291 cis-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-l -piperazinecarboxylate 4-pyrid-4-yicarbamoyIacetyl-l-piperazinecarboxylate (Compound 53); Calcuiated for 3 C35H47N907: MH+: 706.8, Found: MH7 706.3; cis-\,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxyIate 4-(3-pyrid-4-ylaminopropionyl)-l-piperazinecarboxylate (Compound 54); Calcuiated for 6 C35H50N10O6: MH+: 707.9, Found: MH7 707.3; cis-1,5-cyclooctylene 4-(4-guanidinobenzyIcarbamoyI)-1 -pipera2dnecarboxylate 3- [pyrid-4-yl(re7-butoxycarbonyl)amino]propionyl-1 -piperazinecarboxyiate (Compound 55); 9 Calcuiated for C4&H58N10O8: MH2272:404.5, Found: MH,272: 404.2; cis-1,5 -cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate 4- (3-piperazin-l-ylcarbonylpropionyl)-l-piperazinecarboxylate (Compound 56); Calcuiated for 12 C35H54N10O7: MH7 727.9, Found: MH7 727.5; cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate 4-piperid-l-ylcarbonylaminoacetyl-l-piperazinecarboxylate (Compound 57); Calcuiated for 15 C35H54N10O7: MH7 727.9, Found: MH7 727.5; cis-1,5-cycIooctylene 4-(4-guanidinobenzy lcarbamoyI)-1 -piperazinecarboxylate 4-(5-imidazol-4-yIvaleryl)-l-piperazinecarboxylate (Compound 58); Calcuiated for 18 C35H52N,0O6: MH+: 708.9, Found: MH7 709.4; c/j-l,5-cyclooctylene 4-(4-amidinobenzoylaminomethyl)-l-piperidinecarboxylate 4-(3-piperazin-l-ylcarbonylpropionyI)-l-piperazinecarboxylate (Compound 59); Calcuiated for 21 C36H54N807: MH7 711.9, Found: MH7 711.4; cis-1,5-cycIooctylene 4-(4-amidinobenzoylaminomethyI)-l-piperidinecarboxylate 4-piperid-4-ylcarbonylaminoacetyl-1 -piperazinecarboxyiate (Compound 60); Calcuiated for 24 C36H54N807: MH7 711.9, Found: MH7 711.4; cw-l ,5-cyclooctylene 4-[3-(2-aminopyrimidin-5-yl)propionyl]-l -piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyl)-l-piperazinecarboxylate (Compound 61); Calcuiated for 27 C34H49Nn06: MH+: 708.8, Found: MH7 708.4; cis-1,5-cyclooctylene 4-[3-(6-aminopyrid-3-yI)propionyl]-l-piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate (Compound 62); Calcuiated for 30 C35H50NI0O6: MH7 707.8, Found: MH7 707.4; -44- cis-1,5-cyclooctylene 4-(4-guanidtnobenzylcarbamoyl)-l-piperazinecarboxylate 4-[4-(4-pyrid-4-ylthio)butyryl]-l-piperazinecarboxylate (Compound 63); Calculated for C36H5,N906: MH*: 738.9, Found: MH*: 738.4; cis-1,5-cyclooc'tylene 4-[3-(2-ammo-2,4-dioxo-I,2,3,4-tetrahydropyrimidin-5-yl)propionyl]-l-piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyl)-l-piperazinecarboxyIate (Compound 64); Calculated for C34H48Nl0O8: ΜΗ”: 725.8, Found: MH*: 725.2; cis-1,5-cyclooctylene 4-(4-amidinobenzylcarbamoy 1)-1 -piperazinecarboxy late 4-(4-piperid-4-ylbutyryl)-l-piperazinecarboxylate (Compound 65); Calculated for C36HJ6Ns06: MH*: 697.9, Found: MH*: 697.4; cis-1,5-cyclooctylene 4-(4-amidinobenzoy laminomethyl)-1 -piperidinecarboxylate 4-(4-piperid-4-ylbutyryI)-l-piperazinecarboxylate (Compound 66); Calculated for C37Hj7N706: MH*: 696.9, Found: MH*: 696.4; c/j-l,5-cyclooctylene 4-(l-axnidinopiperid-4-ylacetyl)-l-piperidinecarboxylate 4-(6-imidazol-l-ylhexanoyl)-l-piperazinecarboxylate (Compound 67); Calculated for C3jHS7N906: MH*: 700.9, Found: MH*: 700.5; cw-l,5-cyclooctylene 4-(l-amidino-4-piperidyIacetyI)-l-piperazinecarboxylate 4-(4-piperid-4-ylbutyryl)-l-piperazinecarboxylate (Compound 68); Calculated for CjjH^NA: MH*: 689.9, Found: MH*: 689.4; cis-1,5-cyclooctylene 4-( 1 -amidino-4-piperidylacety 1)-1 -piperazinecarboxylate 4-(6-imidazol-l-ylhexanoyl)-l-piperazinecarboxylate (Compound 69); Calculated for C3iHS7N9Oi:MH*: 700.9, Found: MH*: 700.4; cis-1,5-cyclooctylene 4-(4-amidinobenzylcarbamoy 1)-1 -pipera2inecarboxylate 4-(6-imidazol-4-ylhexanoyl)-l-piperazinecarboxylate (Compound 70); Calculated for C36H3jN906: MH*: 708.9, Found: MH*: 708.4; cis-1,5-cyclooctyiene 4-(4-amidinobeazoylaminomethy 1)-1 -piperidinecarboxylate 4-(6-imidazol-4-ylhexanoyl)-l-piperazinecarboxylate (Compound 71); Calculated for C37H54N805: MH*: 707.9, Found: MH*: 707.4; cis-1,5-cyclooctylene 4-(4-amidinophenylacetyl)~l -piperazinecarboxylate 4-(6-imidazoI-l-ylhexanoyl)-l-piperazinecarboxylate (Compound 72); Calculated for -45- LV 12291 C36H52N806: MH+: 693.9, Found: MH+: 693.4; cis-1,5-cyclooctylene 4-(4-amidinophenylacetyl)-1 -piperazinecarboxylate 3 4-(4-piperid-4-ylbutyiyl)-l-piperazinecarboxylate (Compound 73); Calculated for C36H55N706: MH*: 682.9, Found: MFT: 682.4; cis-l ,5-cyclooctylene 4-(4-amidinophenylacetyI)-l -piperazinecarboxylate 6 4-(6-imidazol-4-yIhexanoyl)-l-piperazinecarboxylate (Compound 74); Calculated for C36H52N806: MH+: 693.9 MH+: 693.4; and cis-1,5-cyclooctylene 4-(4-amidinobenzy lcarbamoyl)-1 -piperazinecarboxylate 9 4-[4-(2-( 1 -teri-butylcarbonyloxymethoxycarbonyl)piperid-4-ylethylcarbamoyl)- l-piperazinecarboxylate (Compound 75); Calculated for C42H65N90|o: MH+: 857.0 Found: MFP: 856.6. -46- EXAMPLE 9 c/j-l,5-cyclooctyiene di(4-/err-butoxycarbonyl-l-piperazinecarboxylate) 3 c;'j-l,5-Cyclooctylene di(chioroformate) (3.69 g, 13.7 mmol.), prepared as in Example 5, and DIEA (7.2 mL, 41 mmol.) were taken into DMF (25 mL) and te/7-butyl l-piperazinecarboxylate (5.1 g, 27.4 mmol.) was added. The mixture was stirred 12 hours at 6 room temperature and then concentrated in vacuo giving a semi-solid residue. The residue vvas partitioned betvveen dichloromethane (50 mL) and water (50 mL) and the dichloromethane layer was washed vvith 0.1N aqueous hydrochloric acid (2x, 25 mL), dried (MgS04) and filtered. 9 Concentrating in vacuo gavē c/r-l,5-cyclooctylene di(4-ferf-butoxycarbonyl- 1- piperazinecarboxylate) as an amorphous solid; ‘H-NMR (300MHz, CDC13): 4.80 (m, 2H), 3.40 (br s, 16H), 2.00-1.40 (m, 12H), 1.40 (s, 18H). 12 EXAMPLE 10 c/5’-l,5-cyclooctylene di[4-(2-piperid-4-ylethyicarbamoyl)-l-piperazinecarboxylate] (Compound 76) 15 The follovving is the preparation of a compound of Formula I in vvhich Rl and R1 each are 2- piperid-4-ylethyl, X1 and X9 each are -NHC(O)-, X: and X® each are l,4-piperazinylene, X3 and X7 each are -C(0)0-, X4 and X6 each are a covalent bond and X5 is cir-l,5-cyclooctylene. 18 c/s-l,5-CyclooctyIene di(4-rert-butoxycarbonyl-l-piperazinecarboxylate) (47.9 mg, 0.088 mmol.), prepared as Example 9, was treated with TFA (l mL) neat for 10 minūtes giving a colorless oil. The mixture was concentrated in vacuo and the residue was triturated with ethyl 21 ether (2x, 5 mL) and repeatedly dried in vacuo giving an amorphous solid. The solid residue was taken into DMF (5 mL) and DIEA (100 mL, 0.5 mmol.) and then rert-butyl 4-(2-isocyanatoethyl)-l-piperidinecarboxyIate (460 mL, 0.39 M in DMF, 0.18 mmol.) was added 24 to the solution. The mixture was stirred 12 hours and concentrated in vacuo. The residue was triturated vvith vvater (2x, 5 mL) and dried in vacuo giving a yellow solid. The solid vvas treated vvith TFA (2 mL) and the mixture vvas concentrated in vacuo. The residue vvas taken into vvater. 27 Purifying from the aqueous mixture by preparative reverse phase HPLC follovved by -47- LV 12291 lyophillization gavē cis-1,5-cyclooctylene di[4-(2-piperid-4-ylethylcarbamoyl)-l-piperazinecarboxylate] as a colorless amorphous solid; Electrospray LRMS: Calculated for 3 C34H60NgO6: MH+: 677.9, Found: MH+: 677.6.
Proceeding as in Example 10 and substituting different starting materiāls cis-1,5-cyciooctylene di[4-(4-methylaminomethylbenzylcarbamoyl)-1 -piperazinecarboxylate] 6 (Compound 77) was prepared; Calculated for C3gH56Ng06: MH+: 721.9, Found: MH+: 721.7.
Proceeding as in Example 10 and repiacing the isocyanate with an activated ester the following compounds of Formula I were prepared: 9 cis-1,5-cyclooctylene di[4-(4-piperid-4-ylbutyryl)-1 -piperazinecarboxylate] (Compound 78); Calculated for C36H62N606: MH+: 675.9, Found: MH+: 675.6; and /?ara-dimethylenephenylene di[4-(4-piperid-4-ylbutyryl)-1 -piperazinecarboxylate] 12 (Compound 79); Calculated for C36H56N606: MH+: 669.9, Found: MH+: 669.4. EXAMPLE 11 fer/-Butyl 4-(3-imidazol-l -ylpropy lcarbamoyl)-1 -piperazinecarboxylate 15 rerr-Butyl 4-chlorocarbonyl-l-piperazinecarboxylate (188 mg, 0.76 mmol.), prepared as in Example 3, was taken into dichloromethane (10 mL) and DIEA (150 mL, 0.86 mmol) was added. l-(3-Aminopropyl)imidazole (100 mL, 0.84 mmol) was added by syringe and the 18 mixture was stirred 12 hours. Dichloromethane (10 mL) was added to the mixture and the organic layer was washed with water (lx, 10 mL), dried (MgS04) and filtered. Concentrating gavē tert-buty! 4-(3-imidazol-l-ylpropylcarbamoyl)-l-piperazinecarboxylate (230 mg, 21 0.68 mmol, 90% yield) as a colorless oil; Ή-NMR (300MHz, DMSO-d6): 7.60 (s, 1H), 7.20 (s, 1H), 6.85 (s, 1H), 6.60 (tr, 1H), 3.95 (tr, 2H), 3.30 (s, 8H), 3.00 (q, 2H), 1.80 (m, 2H), 1.40 (s, 9H). -48- EXAMPLE 12 iert-Butyl 4-aminomethyl-l-ben2enecaxbamate hydrochloride 3 4-Aminobenzylamine (5.56 g, 45.6 mmol.) was taken into water (45 mL) and citric acid (9.63 g, 50 mmol) was added to the solution. Di-/err-butyl dicarbonate (9.94 g, 45.5 mmol) in dioxane (20 mL) was added dropwise to the solution and the mixture was stirred 48 hours at 6 room temperature giving a yellow suspension. The suspension was filtered and the aqueous solution was basified with excess solid sodium carbonate and extracted with ethyl acetate (3x, 35 mL). The combined extracts were washed with saturated aqueous sodium chloride, dried 9 (MgS04), filtered and concentrated in vacuo giving a white solid. The solid was taken into methanol (30 mL), the solution vvas acidified with hydrogen chloride in dioxane (4M, 8.4 mL, 33.6 mmol.) and then ethyl ether (100 mL) was added giving a suspension. The particulate 12 matter was isolated by filtration. Drying in vacuo gavē tert-butyl 4-aminomethyl-l-benzenecarbamate hydrochloride (7.2 g, 27.8 mmol, 61% yield) as a colorless solid; Ή-NMR (300MHz, DMSO-d6): 9.43 (s, 1Η>, 8.20 (br s, 3H), 7.40 (dd AB, 4H), 3.92 (m, 15 2H), 1.50 (s, 9H). EXAMPLE 13 rerf-Butyl 4-isocyanatomethyl-1 -benzenecarbamate: 18 rerf-Butyl 4-aminomethyl-l-benzenecarbamate hydrochioride (3.39 g, 13.1 mmol), prepared as in Example 12, was taken into dichloromethane (120 mL) at 0°C and pyridine (4.3 mL, 53 mmol) and triphosgene (1.3 g, 4.4 mmol) vvas added. The mixture vvas allovved to 21 vvarm to room temperature over 30 minūtes and aqueous hydrochloric acid (0.5N, 100 mL) vvas added. The organic layer vvas dried (MgS04) and filtered. Concentrating gavē rerf-butvl 4-isocyanatomethyl-l-benzenecarbamate (2.7 g, 11 mmol, 84% yield) as a yellow solid; 24 Ή-NMR (300MHz, CDC13): 7.29 (dd AB, 4H), 6.55 (br s, IH), 4.40 (s, 2H), 1.55 (s, 9H). -49- LV 12291 EXAMPLE 14 cis-\ ,5-Cyclooctylene 4-(4-aminobenzylcarbamoyl)-l -piperazinecarboxylate 3 4-(3-imidazol-1 -ylpropylcarbamoyl)-1 -piperazinecarboxylate (Compound 80)
The following is the preparation of a compound of Formula I in vvhich R1 is 6 4-aminobenzyl, R2 is 3-imidazol-l-yipropyl, X1 and X9 each are -NHC(O)-, X2 and X8 each are l,4-piperazinylene, X3 and X7 each are -C(0)0-, X4 and X6 each are a covalent bond and X5 is c/j·-! ,5-cyclooctylene. 9 (a) tert-Buty 14-(3-imidazol-1 -ylpropylcarbamoyl)-1 -piperazinecarboxylate (225 mg, 0.67 mmol), prepared as in Example 11, was treated with TFA (1 mL) neat for 10 minūtes. The mixture was concentrated in vacuo and the residue was taken into dichloromethane (10 mL) and 12 an excess of DIEA (1.0 mL) was added to the solution. czs-1 ,5-Cyclooctylene chloroformate 4-tert-butoxycarbonyl-1 -piperazinecarboxy!ate (279 mg, 0.67 mmol), prepared as in Example 6, in dichloromethane (5 mL) was added to the solution and the mixture was stirred for 1 hour. 15 Additional dichloromethane (10 mL) was added and the organic layer was washed with saturated aqueous sodium bicarbonate (lx, 10 mL), dried (MgS04) and filtered. Concentrating gavē crude c/.y-l,5-cyclooctylene 4-(3-imidazol-l-ylpropylcarbamoyl)-l -piperazinecarboxylate 18 teri-butoxycarbonyl-1 -piperazinecarboxylate adduct as a colorless foam. (b) The adduct prepared in Part (a) was treated with TFA (1 mL) neat for 10 minūtes and then the mixture was concentrated in vacuo. The residue was taken into DMF (10 mL) and an 21 excess of DIEA (1.5 mL) and terr-butyl 4-isocyanatomethyl-l-benzenecarbamate (165 mg, 0.67 mmol.), prepared as in Example 13 were added. The mixture was stirred 12 hours and concentrated in vacuo. The residue was treated with TFA neat and mixture was concentrated 24 in vacuo. The residue was taken into water (15 mL) and the aqueous solution was extracted with ethyl ether (lx, 15 mL). The aqueous layer was basified with 1.0M aqueous sodium hydroxide and then extracted with dichloromethane. The dichloromethane was dried (MgS04) and filtered. 27 Concentrating in vacuo gavē cis-1,5-cyclooctylene 4-(4-aminobenzyIcarbamoyI)- l-piperazinecarboxylate 4-(3-imidazol-l-ylpropylcarbamoyl)-l-piperazinecarboxylate as a colorless foam; ‘H-NMR (300MHz, CDC13): 7.45 (s, 1H), 7.10 (d, 2H), 7.05 (s, 1H), 6.90 (s, -50- 1Η), 6.60 (d, 2H), 4.85-4.70 (m, 4H), 4.30 (d, 2H), 4.00 (tr, 2H), 3.50-3.30 (m, 18H), 2.00 (m, 2H), 1.90-1.50 (m, 12H). 3 Proceeding as in Example 14 and substituting different starting materiāls the following compounds of Formula I were prepared: cis-1,5-cyclooctylene 4-(4-aminobenzylcarbamoyI)-1 -piperazinecarboxylate 6 4-(2-pyrid-4-ylethylcjrbamoyl)-l-piperazinecarboxylate (Compound 81); cis-1,5-cyclooctylene 4-(4-aminobenzylcarbamoyl)-1 -piperazinecarboxylate 4-(3-piperid-4-ylpropyl)-l-piperidinecarboxylate (Compound 82); and 9 cis-\,5-cyclooctylene 4-(4-aminobenzylcarbamoyl)-1 -piperazinecarboxylate 4-(4-piperid-4-ylbutyI)-l-piperidinecarboxylate (Compound 83). EXAMPLE 15 12 cis-1,5-Cyclooctylene 4-(4-guanidinobenzy lcarbamoy 1)-1 -piperazinecarboxylate 4-(3-imidazol-l -ylpropylcarbamoyl)-1 -piperazinecarboxylate (Compound 84) 15 The following is the preparation of a compound of Formula I in which R1 is 4-guanidinobenzyl, R2 is 3-imidazol-l-ylpropyl, X1 and X9 each are -NHC(O)-, X2 and X* each are l,4-piperazinylene, X3 and X7 each are -C(0)0-, X4 and X6 each are a covalent bond and X5 18 is cis-1,5-cyclooctylene. cis-1,5-Cyclooctylene 4-(4-aminobenzylcarbamoyl)-1 -piperazinecarboxylate 4-(3-imidazol-l-ylpropylcarbamoyl)-l-piperazinecarboxylate, prepared in Example 14, was 21 taken into methanol and ethyl ether and an excess of hydrogen chloride (4M in dioxane) was added. The mixture was concentrated and dried in vacuo. An excess of cyanamide (l.Og) was added and the mixture was heated at 65 °C for two hours giving a yellow solution. The mixture 24 was allowed to cool to room temperature and triturated with ethyl ether (3x, 10 mL). The insoluble residūe was taken into water. Purifying from the aqueous mixture by preparative reverse phase HPLC gavē cir-l,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- -51- LV 12291 1 -piperazinecarboxy!ate 4-(3-imidazol-l-ylpropylcarbamoyl)-l-piperazinecarboxylate as a colorless amorphous solid; Electrospray LRMS: Calculated for C34H5,Nn06: MH+: 710.9, 3 Found: MH+: 710.6.
Proceeding as in Example 15 and substituting different starting materiāls the following compounds of Formula I were prepared: 6 cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate 4-(2-pyrid-4-ylethylcarbamoyI)-l-piperazinecarboxylate (Compound 85); Calculated for C35H50Nl0O6: MH+: 707.9 Found: MH+: 707.6; 9 cri-l ,5-cyclooctylene 3-piperid-4-ylpropyl-l -piperidinecarboxylate 4-(4-guanidinooenzylcarbamoyl)-l-piperazinecarboxylate (Compound 86); and cis-1,5 -cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate 12 4-piperid-4-ylbutyl-l-piperidinecarboxylate (Compound 87); Calculated for C37H60N8Os: MH+: 697.9, Found: MH+: 697.7. EXAMPLE 16 15 cis-1,5-cyclooctylene chloroformate 4-benzyloxycarbonyl-1 -piperazinecarboxylate
Benzyl l-piperazinecarboxylate (1.0 g, 4.53 mmol, 1.0 equiv) and DIEA (0.88 mL, 4.98 mmol, 1.1 equiv) in dichloromethane (25 mL) was added dropwise to cis-1,5-cyclooctylene 18 di(chloroformate) (1.2 g, 4.53 mmol, 1.0 equiv), prepared as in Example 5, in dichloromethane (25 mL) at 0°C. The reaction mixture was stirred for 22 hours whiie allowing to warm to room temperature. The mixture was partitioned betvveen dichloromethane, 0.05N aqueous hydrochioric 21 acid and saturated aqueous sodium chloride. The organic layer was dried (Na2S04) over sodium sulfate and concentrated. Purifying the residue by flash column chromatography, eluting with 20 and 30% ethyl acetate in hexanes, gavē c/j-l,5-cyclooctylene chloroformate 24 4-benzyloxycarbonyl-l-piperazinecarboxylate (0.81 g, 1.81 mmol, 40%) as a yellow oil; IR: 2939 (s), 2863 (m), 1770 (s), 1732 (s), 1696 (s); Ή NMR (300 MHz, CDC13): 7.35 (s, 5 H), 5.15 (s, 2 H), 4.95 (m, 1 H), 4.75 (m, 1 H),3.45 (s, 8 H), 1.50-2.05 (m, 12 H). -52- EXAMPLE 17 l-[cz'i-5-(4-Benzyloxycarbonylpiperazin-l-ylcarbonyloxy)cyclooctyloxycarbonyl]-3 4-piperidinecarboxylic acid
Isonipecotic acid (75 mg, 0.58 mmol, 1.1 equiv) and DIEA (0.23 mL, 1.33 mmol, 2.5 equiv) were added to czs-l ,5-cyclooctylene chloroformate 4-benzyloxycarbonyl-6 l-piperazinecarboxylate (0.24 g, 0.53 mmol, 1.0 equiv), prepared as in Example 16, in dichloromethane (10 mL) at 0°C giving a white suspension. The suspension was stirred for 18 hours while allowing to warm to room temperature. The reaction mixture was partitioned 9 between dichloromethane and 0.05N aqueous hydrochloric acid. Concentrating the organic layer gavē crude 1 -[cw-5-(4-benzyloxycarbonylpiperazin-l -ylcarbonyloxy)cyciooctyloxycarbonylj-4-piperidinecarboxylic acid (0.36 g) as a colorless oil; ‘H NMR (300 MHz, CDC13): 7.35 (s, 5 12 H), 5.15 (s, 2 H), 4.75 (m, 2 H), 3.90 (m, 1 H), 3.45 (s, 8 H), 2.75 (m, 1 H), 2.50 (m, 3 H), 1.50-1.90 (m, 16 H). EXAMPLE 18 15 cis-1,5-Cyclooctylene 4-benzyloxycarbonyl-1 -piperazinecarboxyIate 4-[2-( 1 -/eri-butoxycarbonylpiperid-4-yl)ethylcarbamoyl]-1 -piperidinecarboxylate l-Hydroxybenzotriazole hydrate (80 mg, 58.3 mmol, 1.1 equiv), ter/-butyl 18 4-(2-aminoethyI)-l-piperidinecarboxylate hydrochloride (0.14 g, 0.53 mmol, 1.0 equiv) and 4-methylmorphoiine (0.15 mL, 1.33 mmol, 2.5 equiv) were added to a solution of crude 1 -[cz'i-5-(4-benzyloxycarbonylpiperazin-1 -ylcarbonyloxy)cyciooctyloxycarbonyl]-21 4-piperidinecarboxylic acid (0.36 g, 0.53 mol, 1.0 equiv), prepared as in Example 17, in DMF (5 mL). l-(3-Dimethylaminopropyl)-3-ethyIcarbodiimide hyarochloride (0.13 g, 0.66 mmol, 1.25 equiv) was added to the reaction mixture at 0 °C. The solution was stirred for 1.5 hours at 24 0°C and for 3 days at 23 °C. The reaction mixture was partitioned between dichloromethane, 0.05N aqueous hydrochloric acid, samrated aqueous sodium bicarbonate, water (two portions) and saturated aqueous sodium chloride. The organic layer was dried (Na2S04) and concentrated. 27 Purifying from the residue by flash column chromatography, eluting with 3% methanol in -53- LV 12291 dichloromethane, gavē cis-1,5-cyclooctylene 4-benzyioxycarbony 1-1 -piperazinecarboxylate 4-[2-(l-ferf-butoxycarbonylpiperid-4-yl)ethylcarbamoyl]-l-piperidinecarboxylate (0.15 g, 3 0.2 mmol, 37% over two steps) as a yellow oil; Ή NMR (300 MHz, CDC13): 7.35 (s, 5 H), 5.15 (s, 2 H), 4.80 (m, 2 H), 4.10 (m, 4 H), 3.45 (m, 10 H), 3.30 (m, 2 H), 2.70 (m, 2 H), 1.50-1.90 (m, 23 H), 1.45 (s, 9 H); Electrospray LRMS: calcd for C40H62NjO9 (ΜΗ*): 756.97, obtained: 757.0. 6 EXAMPLE19 cis-1,5-Cyclooctylene 1 -piperazinecarboxylate 4-[2-( 1 -terr-butoxycarbonylpiperid-4-yl)ethylcarbamoyl]-1 -piperidinecarboxy late 9 Ethanol (3 mL) was added to cis·-l,5-cyclooctylene 4-benzyloxycarbonyi- 1 -piperazinecarboxylate 4-[2-( 1 -ter/-butoxycarbonylpiperid-4-yl)ethylcarbamoyl]-l-piperidinecarboxylate (0.15 g, 0.20 mmol, 1.0 equiv), prepared as in Example 18, and 12 5% palladium on carbon (75 mg, 0.50 wt equiv) under nitrogen. The mixture was stirred under hydrogen (1 atm) for 17 hours at 23 °C. The reaction mixture was placed under nitrogen and filtered. Concentrating the filtrate gavē c:'s-l,5-cyclooctylene 1 -piperazinecarboxylate 15 4-[2-(l-tert-butoxycarbonylpiperid-4-yl)ethylcarbamoyl]-l-piperidinecarboxylate (110 mg, 0.18 mmol, 90%) as a colorless oii; Ή NMR (300 MHz, CDC13): 5.5 (m, 1 H), 4.9 (m, 2 H), 4.75 (m, 1 H), 4.1 (m, 4 H), 3.45 (m, 4 H), 3.25 (m, 2 H), 2.60-2.85 (m, 8 H), 2.10 (m, 1 H), 1.50-1.95 18 (m, 23 H), 1.45 (s, 9 H); Electrospray LRMS: calcd for C32H56Nj07 (MH+): 622.83, obtained: 622.7. -54- EXAMPLE 20 cw-l ,5-Cyclooctylene 4-(4-guanidinobenzylcarbamoyI)-1 -piperazinecarboxylate 3 4-(2-piperid-4-ylethylcarbamoyl)-l-piperidinecarboxylate (Compound 88)
The foliowing is the preparation of a compound of Formula I in which R1 is 6 4-guanidinobenzyl, R2 is 2-piperid-4-ylethyl, X1 and X9 each are -NHC(O)-, X2 is l,4-piperazinylene, X8 is 4,l-piperidylene, X3 and X7 each are -C(0)0-, X4 and X6 each are a covalent bond and X5 is cw-l,5-cyclooctylene. 9 Triphosgene (30 mg, 0.10 mmol, 0.58 equiv) and pyridine (30 mL, 0.39 mmol, 2.1 equiv) wereaddedto cis-1,5-cyclooctylene l-piperazinecarboxylate 4-[2-(l-/er/-butoxycarbonylpiperid-4-yl)ethylcarbamoyl]-l-piperidinecarboxylate (0.11 g, 12 0.18 mmol, 1.0 equiv), prepared as in Example 19, in dichloromethane (2 mL) at 0°C. The reaction mixture was stirred 3 hours at 0°C. The mixture was partitioned between dichloromethane, 0.05N aqueous hydrochloric acid and saturated aqueous sodium chloride. The 15 organic layer was dried (Na2S04) and concentrated giving a brown oil residue. 4-Guanidinobenzylamine dihydrochloride (43 mg, 0.20 mmol, 1.1 equiv) and DIEA (0.16 mL, 0.90 mmol, 5.0 equiv) in DMF (2 mL) were added to the residue giving a suspension. The 18 suspension was stirred 18.5 hours at 23 °C and concentrated. The residue was taken into 50% TFA in dichloromethane (4 mL) and the mixture was stirred 45 minūtes at 23 °C. The reaction mixture was concentrated and the residue was triturated with ether and dried in vacuo. Purifying 21 firom the residue by preparative reverse phase HPLC and lyophillization gavē cis-1,5-cyclooctylene 4-(4-guanidinoben2ylcarbamoyl)-1 -piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoyl)-l-piperidinecarboxylate as a colorless amorphous solid; 24 Electrospray LRMS: calcd for C36H58N906 (ΜΡΓ): 712.91, obtained: 712.8
Proceeding as in Example 20 and substituting different starting materiāls the following compounds of Formula I were prepared: 27 cis-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-1 -piperazinecarboxylate -55- LV 12291 4-(3-imidazol-4-ylpropylcarbamoyl)-l-piperazinecarboxylate (Compound 89); Calculated for C34H5oNio06: MH+: 695.9, Found: MH+: 695.4; 3 cis-1,5 -cycloocty lene 4-(4-guanidinopheny lacety 1)-1 -piperazinecarboxylate 4-(2-imidazol-4-ylethylcarbamoyl)-l-piperazinecarboxylate (Compound 90); Calculated for C33H48N10O6: MH+: 681.3, Found: MH+: 680.9; 6 cw-l ,5-cycIooctylene 4-(4-guanidinophenylacetyl)-l -piperazinecarboxylate 4-(3-imidazol-l-ylpropylcarbamoyl)-l-piperazinecarboxylate (Compound 91); Calculated for C34H50N10O6: MH+: 695.9, Found: MH+: 694.9; 9 cis-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-l -piperazinecarboxylate 4-(4-imidazol-l-ylbutylcarbamoyl)-l-piperazinecarboxylate (Compound 92); Calculated for C35H53N10O6: MH+: 709.9, Found: MH+: 709.4; and 12 cis-1,5-cyclooctylene 4-(4-guanidinoben2y lcarbamoyI)-1 -piperazinecarboxylate 4-(3-imidazol-l-ylpropylcarbamoyl)-l-piperazinecarboxylate (Compound 93); Calculated for C35H5IN,0O6: MH+: 709.9, Found: MH+: 710.4. 15 EXAMPLE 21 3-Piperid-4-ylpropionic acid hydrochloride 4-Pyridineacrylic acid hvdrochloride (12.0 g; 64.6 mmol) and 1.37 g of platinum oxide 18 was suspended in acetic acid (80 mL) and hydrogenated 12 hours at 50 to 60 psi. The mixture was diluted with water and filtered through a pad of celite. The solids were washed with water (200 mL) and the combined filtrate and washings were concentrated in vacuo giving a white 21 solid. The solid was suspended in a small amount of methanol and the mixture was diluted with diethyl ether (200 mL). The particulate matter was isolated by filtration and washed with diethyl ether and hexane. Air-drying gavē 3-piperid-4-ylpropionic acid hydrochloride (11.3 g; 58.1 24 mmol, 90%) as a colorless solid; ’H-NMR (300 MHz; DMSO-d6): 8.75 (br s, 2H), 3.15 (d, 2H), 2.75 (t, 2H) 2.2 (t, 2H), 1.75 (d, 2H), 1.45 (t, 2H), 1.25 (br q, 2H). EXAMPLE 22 27 3-(l -terr-Butyoxycarbonylpiperid-4-yl)propionic acid -56- 3-Piperid-4-ylpropionic acid (5.07 g; 26.2 mmol), prepared as in Example 21, was dissolved in 2N aqueous NaOH (40 mL; 80 mmol). THF (40 mL) and then 3 di(terf-butyl)dicarbonate (6.21 g; 28.4 mmol) was added giving a suspension. The suspension was stirred 22 hours, diluted with water and concentrated in vacuo. The residue was washed with diethyl ether (2x, 100 mL) and the aqueous phase was acidified to pH 2-3 with 1.0N 6 aqueous KHS04 and extracted with ethyl acetate (3x, 200 mL). The combined organic phases were washed with brine and dried (Na2S04). Concentrating in vacuo gavē 3- [4-(l-rerf-butoxycarbonyl)-4-piperidyl]propionic acid (6.21 g; 24.1 mmol, 92%) as a colorless 9 oil that crystallized on standing; ‘H-NMR (300 MHz, CDC13): 4.10 (br d, 2H), 2.65 (br t, 2H), 2.35 (t, 2H), 1.70-1.50 (m, 3H), 1.45 (s, 9H), 1.20-0.95 (m, 2H). EXAMPLE 23 12 feri-Butyl 4-benzy loxycarbony l-1 -piperazinecarboxylate ier/-Butyl l-piperazinecarboxylate (2.01 g; 10.8 mmol) andDIEA (2.0 mL; 1.48 g; 11.5 mmol) in 50 mL of ice cold dichloromethane was treated with benzyl chloroformate (2.0 mL; 15 2.39 g; 14.0 mmol). The mixture was stirred for 42 hours and then partitioned between ethyl acetate and 0.5N KHS04. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried (MgS04) and concentrated. Purifying 18 frorn the residue by chromatography over silica gel (ethyl acetate:hexane, 1:3) gavē reri-butyl 4- benzyloxycarbonyl-l-piperazinecarboxylate (3.33 g; 10.4 mmol, 96%) as a colorless solid; 'H-NMR (300 MHz, CDC13): 7.35 (br s, 5H), 5.13 (s, 2H), 3.55-3.25 (m, 8H), 1.45 (s, 9H). -57- LV 12291 EXAMPLE 24
Benzyl l-piperazinecarboxylate hydrochloride 3 feri-Butyl 4-benzyloxycarbonyl-l-piperazinecarboxylate (l.OIg; 3.16 mmol), prepared as in Example 23, was suspended in 4 mL of ethyl acetate. The suspension was cooled in an ice water bath and 4N hydrogen chloride (12 mL in l,4-dioxane) was added giving a solution. The 6 solution was stirred for 30 minūtes on the ice bath and then for 30 minūtes at room temperature. The reaction mixture was diluted with diethyl ether (75 mL) giving a precipitate. The precipitate was isolated by filtration and washed with diethyl ether. Drying in vacuo gavē ben2yl 9 l-piperazinecarboxylate hydrochloride (740 mg; 2.78 mmol, 88%) as a colorless solid; 'H-NMR (300 MHz, DMSO-d6): 9.25 (br s, 2H), 7.33 (s, 5H), 5.06 (s, 2H), 3.58 (br s, 4H), 3.04 (t, 4H). EXAMPLE 25 12 teri-Butyl 4-[2-(4-benzyloxycarbonylpiperazin-1 -ylcarbony lamino)ethyl]- 1 -piperidinecarboxylate 3-[4-(l-rerr-Butoxycarbonyl)-4-piperidyl]propionic acid (2.16 g; 8.4 mmol), prepared as 15 in Example 22, in dry benzene (28 mL) was treated with triethylamine (1.35 mL; 951 mg; 9.40 mmol) and diphenylphosphoryl azide (2.05 mL; 2.62 g; 9.53 mmol). The reaction mixture was graduaily heated to reflux and ķept at reflux for 3.5 hours. The mixture was cooled to room 18 temperature then added dropwise to a suspension of benzyl 1 -piperazinecarboxylate hydrochloride (2.44 g; 9.19 mmol), prepared as in Example 24, and triethylamine (1.40 mL; 1.02g; 10.0 mmol) in dry dichloromethane (10 mL). The reaction mixture was stirred for 43 21 hours and diluted with ethyl acetate and 0.5N KHS04. The organic layer was washed with water, aqueous sodium bicarbonate and brine, dried (Na2S04) and concentrated. Puriiymg from the residue by chromatography on silica gel (ethyl acetate-hexane, 4:1; then pure ethyl acetate) gavē 24 tert-b\ity\ 4-[2-(4-benzyloxycarbonylpiperazin-1 -ylcarbonylamino)ethyI]-1 -piperidinecarboxylate (3.84 g; 8.1 mmol, 96%) as a white solid; 'H-NMR (300 MHz, CDC13): 7.35 (s, 5H), 5.15 (s, 2H), 4.50 (br t, 1H), 4.05 (br s, 2H), 3.55-3.45 (m, 4H), 3.40-3.30 (m, 4H), 3.25 (q, 2H), 2.65 (t, 27 2H), 1.70 (s, 2H), 1.45 (s, 11H), 1.20-1.00 (m, 2H). -58- EXAMPLE 26 cis-1,5-Cyclooctylene chloroformate 4-[2-(4-fer/-butoxycarbonylpiperidin-4-yl)ethylcarbamoyl]-3 l-piperazinecarboxylate tert-Butyl 4-[2-(4-benzyloxycarbonylpiperazin-l-yicarbonylamino)ethyl]-l-piperidinecarboxylate (2.03 g; 4.28 mmol), prepared as in Example 25, and 10% 6 palladium-on-carbon (570 mg) suspended in ethanol (19 mL) was hydrogenated at atmospheric pressure ovemight. The reaction mixtuxe was filtered and the catalyst was washed with ethanol. The filtrate and washings were concentrated in vacuo and the residue was dissolved in 9 dichloromethane (30 mL) and treated with DIEA (500 mL). The solution was added dropwise to cw-l,5-cyclooctylene di(chloroformate) (4.15g; 15.4 mmol), prepared as in Example 5, in ice cold dichloromethane (75 mL). The reaction mixture was stirred ovemight and diluted with 0.5N 12 aqueous KHS04 and dichloromethane. The aqueous phase was extracted with dichloromethane and the combined organic layers were washed with brine, dried (Na2S04) and concentrated. Purifying from the residue by chromatography on silica gel (ethyl acetate-hexane, 3:1; then pure 15 ethyl acetate) gavē cžs-l,5-cyclooctylene chloroformate 4-[2-(4-ie/7-butoxycarbonylpiperidin-4-yl)ethylcarbamoyl]-l-piperazinecarboxylate (1.02 g; 1.8 mmol, 42%) as a pale yellow oil; ’H-NMR (300 MHz, CDC13): 5.00-4.90 (m, 1H), 4.85-4.75 18 (m, 1H), 4.35 (br t, 1H), 4.05 (br d, 2H), 3.50-3.40 (m, 4H), 3.35-3.30 (m, 4H), 3.25 (q, 2H), 2.65 (t, 2H), 2.05-1.55 (m, 17H), 1.40 (s, 9H), 1.25-1.00 (m, 2H). EXAMPLE 27 21 4-Cyanophenylacetic acid 2-(4-Cyanophenyl)ethanol (5.00 g; 34.0 mmol) was dissolved in acetone (140 mL) and cooled to 10-15°C. A solution of Cr03 in aqueous H2S04 was added dropwise, while keeping the 24 internai temperature below 30°C, until an orange color persisted giving a suspension. The suspension was stirred for 45 minūtes and filtered. The solīds were washed with acetone (150 mL) and the combined filtrate and washings were stirred with 2-propanol (20 mL) for 30 27 minūtes. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was -59- LV 12291 taken intoethyl acetate and the solution was washed with 0.5N aqueous KHS04j water and brine and concentrated. The residue was dissolved in dichloromethane and the solution was treated 3 with sodium hydroxide (1.56 g) in water (100 mL). The aqueous phase was extracted with dichloromethane and acidified to pH 1-2 with concentrated aqueous hydrochloric acid giving a precipitate. The precipitate was washed with water and air-dried. Drying in vacuo gavē 6 4-cyanophenylacetic acid (3.36 g; 20.7 mmol, 61%) as a white powder; 'H-NMR (300 MHz, CDC13): 7.63 (d, 2H), 7.40 (d, 2H), 3.72 (s, 2H). EXAMPLE 28 9 tert-Butyl 4-(4-cyanophenylacetyl)-l-piperazinecarboxylate A mixture of 4-cyanophenylacetic acid (890 mg; 5.52 mmol), prepared as in Example 27, ethylene dichloride (1.16 g; 6.07 mmol) and l-hydroxybenzotriazole hydrate (820 mg; 6.07 12 mmol) was suspended in THF (18 mL) and tert-butyl l-piperazinecarboxyiate (1.04 g; 5.60 mmol) and DIEA were added to give a homogenous solution. The solution was concentrated in vacuo and the residue was treated with 0.2N KHS04. The mixture was filtered and the solid 15 collected was washed with water. Drying in vacuo gavē teri-butyl 4-(4-cyanophenylacetyl)-l-piperazinecarboxylate (1.68 g; 5.1 mmol, 92%) as a solid; 'H-NMR (300 MHz, CDC13): 7.70 (d, 2H), 7.35 (d, 2H), 3.80 (s, 2H), 3.70-3.60 (m, 2H), 3.45-3.30 (m, 6H), 1.40 (s, 9H). 18 EXAMPLE 29 tert- Butyl 4-[4-(Ar-hydroxyamidino)phenylacetyl]-1 -piperazinecarboxy late terf-Butyl 4-(4-cyanophenylacetyl)-l-piperazinecarboxylate (1.68 g; 5.1 mmol), prepared 21 as in Example 28, in dry ethanol (10 mL) was treated with hydroxylamine hydrochloride (461 mg; 6.63 mmol) and triethylamine (924 mL, 671 mg; 6.63 mmol). The mixture was heated at reflux for 3.5 hours, cooled to room temperature and concentrated in vacuo. The residue was 24 dissolved in ethanol, filtered and the filtrate cooled ovemight giving a crystalline product. The crystals were isolated by filteration and vvashed with cold ethanol. Air-drying gavē tert-butvl 4-[4-(/V-hydroxyamidino)phenylacetyl]-l-piperazinecarboxylate (1.62 g; 4.5 mmol, 88%); -60- Ή-NMR (300 MHz, DMSO-d6): 9.60 (s, 1H) 7.60 (d, 2H), 7.20 (d, 2H), 5.75 (s, 2H), 3.70 (s, 2H), 3.40 (br s, 4H), 3.25 (br s, 4H), 1.40 (s, 9H). 3 EXAMPLE 30 4-piperazin-1 -y lcarbonylmethylbenzamidine bis(trifluoroacetate) tert-Butyl 4-[4-(iV-hydroxyamidino)phenylacetyI]-1 -piperazinecarboxylate (653 mg; 6 1.81 mmol), prepared as in Example 29, and 10% palladium-on-carbon (200 mg) were suspended in acetic acid (12 mL) and hydrogen was bubbled through the suspension ovemight. The reaction mixture was filtered and the catalyst was washed with acetic acid. The combined filtrate 9 and washings were concentrated in vacuo and the residue was dissolved in TFA. The solution stood for 1 hour and then was concentrated in vacuo. The residue was co-evaporated from a mixture of dichloromethane and methanol and then suspended in diethyl ether. The particulate 12 matter was collected by filtration. Drying gavē 4-piperazin-1 -ylcarbonylmethylbenzamidine bis(trifluoroacetate) (1.04 g; 1.81 mmol, 100%) as a white solid; 'H-NMR (300 MHz, DMSO-d6): 9.30 (d, 4H), 9.15 (br s, 2H), 7.70 (d, 2H), 7.40 (d, 2H), 3.85 (s, 2H), 3.65 (br d, 4H), 15 4.20-3.90 (m, 4H). -61- LV 12291 EXAMPLE 31 cis-1,5-Cyclooctylene 4-(4-amidinophenylacetyl)-l -piperazinecarboxylate 3 4-(2-piperid-4-y lethylcarbamoyl)-1 -piperazinecarboxylate (Compound 94)
The foIIowing is the preparation of a compound of Formula I in which R1 is 6 4-amidinobenzyl, R2 is 2-piperid-4-ylethyl, X1 is -C(O)- and X9 is -NHC(O)-, X2 and X8 each are l,4-piperazinylene, X3 and X7 each are -C(0)0-, X4 and X6 each are a covalent bond and X5 is cis-1 ,5-cyclooctylene. 9 4-Piperazin-l-ylcarbonylmethylbenzamidine bis(trifluoroacetate) (80 mg; 0.17 mmol), prepared as in Example 30, was dissolved in DMF (1.0 mL) and the solution was treated vvith DIEA (150 mL). cw-l,5-Cyciooctylene chloroformate 12 4-[2-(4-ten‘-butoxycarbony lpiperazin-1 -yl)ethylcarbamoy 1] -1 -piperazinecarboxylate (100 mg), prepared as in Example 26, in DMF (1.0 mL) was added and the mixture was stirred ovemight and concentrated in vacuo. The residue was dissolved in dichloromethane and TFA (1:1) and the 15 mixture was concentrated in vacuo. The residue was triturated with diethyl ether giving a foam residue. Purifying from the residue by preparative reverse phase HPLC and lyophilization of the pure ffactions gavē cz'jr-l,5-cyclooctylene 4-(4-amidinophenylacetyl)-l-piperazinecarboxylate 18 4-(2-piperid-4-ylethylcarbamoyl)-l-piperazinecarboxylate as a colorless solid; Electrospray LRMS: Calculated for C3SH54N808: MH+: 683.9; MH2+2/2: 342.5,, Found: MH+: 683.8; MH2+2/2: 342.3. 21 Proceeding as in Example 31 and substituting different starting materiāls the following compounds of Formula I were prepared: cis-1,5-cyclooctylene 4-( 1 -amidinopiperid-4-ylacety 1)-1 -piperazinecarboxylate 24 4-(2-piperid-4-ylethylcarbamoyl)-l-piperazinecarboxylate (Compound 95); Calculated for C34H59N906: MH+: 690.9, Found: MH+: 690.6; cw-l,5-cyclooctylene 4-(4-amidinobenzoylaminomethyl)-l-piperidinecarboxylate 27 4-(2-piperid-4-ylethylcarbamoyl)-l-piperazinecarboxylate (Compound 96); Calculated for -62- C36H56N806: MH+: 697.9, Found: ΜΗ*: 697.7; cw-l ,5-cyclooctylene 4-(4-amidinobenzylcarbamoyl)-l -piperazinecarboxylate 3 4-(2-piperid-4-yl)ethylcarbamoyl]-l-piperazinecarboxylate (Compound 97); Calculated for C3jHsjN906: MH+: 698.9, Found: MH*: 698.7; cis-1,5-cyclooctylene 4-(4-amidinophenylsulfonylaminomethyl)-l -piperidinecarboxylate 6 4-(2-piperid-4-ylethylcarbamoyl)-l-piperazinecarboxylate (Compound 98); Calculated for C3SH56N807: MH*: 733.9, Found: ΜΗ": 733.4; cis-1,5-cyclooctylene 4-[2-( 1 -amidinopiperid-4-yl)ethylcarbamoyl]-9 1 -piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoy l)-1 -piperazinecarboxy late (Compound 99); Calculated for C3JH62N10O6: MH+: 719.9, Found: MH+: 719.5; cis-1,5-cyclooctylene 4-(4-amidinophenylcarbamoylmethyl)-l -piperidinecarboxylate 12 4-(2-piperid-4~ylethylcarbamoyl)-l-piperazinecarboxylate (Compound 100); Calculated for C36H56N806: MH+: 697.9, Found: MH*: 695.6; cis-1,5-cyclooctylene 4-(4-Ar-methoxycarbonylamidinobenzylcarbamoyI)-15 1 -piperazinecarboxy late 4-(2-piperid-4-ylethylcarbamoyl)-1 -piperazinecarboxylate (Compound 101); Calculated for C37H57N908: MH+: 756.9, Found: MH+: 756.4; and cisA,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-l-piperazinecarboxylate 18 3-piperid-4-ylpropyl-l-piperidinecarboxylate (Compound 102); Calculated for C36H58N805: MH+: 683.9 Found: MH+: 683.3. EXAMPLE 32 21 1,5-Pentamethylene di[4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxylate] (Compound 103)
The follov/ing is the preparation of a compound of Formula I in which R1 and R2 each are 24 4-guanidinobenzyl, X' and X9 each are -NHC(O)-, X2 and X8 each are 1,4-piperazinylene, XJ and X7 each are -C(0)0- and X4-X6-X5 together are l,5-pentamethylene. teri-Butyl 4-(4-guanidinobenzylcarbamoyl)-l -piperazinecarboxyIate trifluoroacetate 27 (306 mg, 0.62 mmol.) was treated with neat trifluoroacetic acid (lmL) at room temperature over ten minūtes to give a colorless homogeneous solution. The liquid was concentrated and the oilv -63- LV 12291 residue triturated with diethyl ether (3x lOraL) followed by drying in vacuo to a colorless foam. The deprotected piperazine salt was then taken into DMF (2.5 mL) followed by addition of 3 diisopropylethylamine (0.5 mL, 3.1 mmol.) and l,5-n-pentylene di(chloroformate) (70 mg, 0.31 mmol.) and the m'ixture was allowed to stir for one hour at room temperature. The reaction mixture was concentrated and the residue was triturated with diethyl ether (3x lOmL) followed 6 by drying in vacuo. The crude material was taken into water (5 mL) and purified by preparative reverse phase HPLC and lyophiIization to give l,5-n-pentylene di[4-(4-guanidinobenzylcarbamoyl)-l-piperazinecarboxylate] as a colorless amorphous solid; 9 Electrospray LRMS: Calculated for C33H48Ni206: MH+: 709.8,, Found: MH+: 709.3.
Proceeding as in Example 32 and substituting different starting materiāls the foliowing compounds of formula I were prepared: 12 1,4-tetramethylene di [4-(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate] (Compound 104); Calculated for C32H46N1206: MH+: 695.8, Found: MIT: 695.8; 4-guanidinobenzyl 15 4- {5-[4-(4-guanidinobenzylcarbamoyl)piperazin-l -ylcarbony l] valeryl} -1 -piperazinecarboxamide (Compound 105); Calculated for C32H46N1204: MH+: 663.8, Found: MH+: 663.4; 4-guanidinobenzyl 18 4-{6-[4-(4-guanidinobenzylcarbamoyl)piperazin-l-ylcarbonyl]hexanoyl}- 1-piperazinecarboxamide (Compound 106); Calculated for C33H48N1204: MH+: 677.8,
Found: MH+: 677.4; 21 4-guanidinobenzyl 4-{7-[4-(4-guanidinobenzyIcarbamoyl)piperazin-1 -ylcarbonyi]heptanoyl}-l-piperazinecarboxamide (Compound 107); Calculated for C34H5oNI204: MH+: 691.9, 24 Found: MH+: 691.5; 4-guanidinobenzyl 4- {8-[4-(4-guanidinobenzylcarbamoyl)piperazin-1 -ylcarbonyl]octanoyl} -27 l-piperazinecarboxamide (Compound 108); Calculated for C37H57N908: MH+: 756.9,
Found: MH+: 756.4; -64- 4-guanidinobenzyl 4- {9-[4-(4-guanidinobenzylcarbamoyl)piperazin-1 -ylcarbony l]nonanoyl} - 3 l-piperazinecarboxamide (Compound 109); Calculated for C36H54N,204: MH+: 719.9,
Found: MH+: 719.5; 4-amidinobenzyl 6 4- {7- [4-(4-amidinobenzyicarbamoyl)piperazin-1 -ylcarbonyI]heptanoyl} - l-piperazinecarboxamide (Compound 110); Calculated for C34H48NI0O4: MH+: 661.8,
Found: MH+: 661.3; 9 1,5-pentamethylene di[4-(4-guanidinophenyIacetyl)piperazin-1 -ylcarbonyl] (Compound 111); Calculated for C33H46NI0O4: MH+: 647.8, Found: MH+: 647.3; 1.6- hexamethylene di[4-(4-guanidinophenylacetyl)pipera2in-l -ylcarbonyl] 12 (Compound 112); Calculated for C34H48Nio04: ΜΗ*: 661.8, Found: MH+: 661; 1.7- heptamethylene di[4-(4-guanidinophenylacetyl)piperazin-l -ylcarbonyl] (Compound 113); Calculated for C35HS0Ni0O4: MH+: 675.9, Found: MH1-: 675.4; and 15 3-oxa-1,5-pentamethyiene di[4-(4-guanidinophenylacetyl)piperazin-l -ylcarbonyl] (Compound 114); Calculated for C32H44N|o07: MH+: 681.8, Found: MH: 681.4. EXAMPLE 32 18 In Vitro Assay of Tryptase Inhibition
Mixtures of human tryptase (15 pg/mL) and tēst compound (varying concentrations) in Tris buffer (comprising: NaCl, 100 mM; Tris, 50 mM; 2-ļ7V-morpholine]ethane sulfonic acid, 21 2.5 mM, CaCI2, 0.5 mM; DMSO, 10%; glvcerol, 5%; polyoxyethylenesorbitan monolaurate (Tween-20), 0.05%; heparin, 25 ng/mL; and pH 8.2) were incubated for 1 hour at room temperature and then Tosyl-Gly-Pro-Lys-/?ara-nitroanilide was added such that the final 24 concentration of the assay mixture was 0.5 mM. Hydrolysis of the substrate was followed spectrophotometrically at (405 nm) for 5 minūtes. Apparent inhibition constants (Kj) were calculated from the enzyme progress curves using Standard mathematical models. 27 Human tryptase can be purified from human lung and skin tissue samples (e.g., see
Smith et al. (1984) J. Biol. Chem. 59: 11046-11051; and Braganza et ai. (1991) Biochem. -65- LV 12291 30: 4997-5007) and human mast celi line or obtained commerically (e.g., ICN Biomedicals, Irvine Califomia; Athens Research & Technology, Athens, Georgia). Porcine intestinal mucosa 3 heparin and Tosyl-Gly-Pro-Lys-pam-nitroaniIide can be obtained from Sigma Chemical Company.
Proceeding as described in this application or by methods known to those of ordinary 6 skill the folio wing compounds of Formula I were prepared and tested for tryptase inhibitory activity:
Compound 1, Κ;=0.003μΜ; Compound 2, Κ^Ο.δμΜ; Compound 3, Κ~0.07μΜ; 9 Compound 4, Kj=0.001 μΜ; Compound 5, Κ|=0.2μΜ; Compound 6, Κ^ΙμΜ;
Compound 7, Κ,=0.3μΜ; Compound 8, Κ;=4μΜ; Compound 9, Κ,·=0.4μΜ;
Compound 10, Κ,·=1μΜ; Compound 11, Κ|=0.09μΜ; Compound 12, Κ;=0.2μΜ; 12 Compound 13, Κ=0.02μΜ; Compound 14, Ki=0.004pM; Compound 15, Kj=0.5pM; Compound 16, Κ,=0.9μΜ; Compound 17, Κ(=1μΜ; Compound 18, Κ(=0.08μΜ;
Compound 19, Κ,=1.2μΜ; Compound 20, Kj=3.4pM; Compound 21, Κ,·=0.5μΜ; 15 Compound 22, Κ~0.2μΜ; Compound 23, Κ,·=4μΜ; Compound 24, Κ;=0.3μΜ;
Compound 25, Κ;=0.002μΜ; Compound 26, Κ;=19μΜ; Compound 27, Κ(=2μΜ;
Compound 28, Κ,·=4μΜ; Compound 29, Κί=1μΜ; Compound 30, Κ=0.031μΜ; 18 Compound 31, Kj=lμΜ; Compound 32, Κ;=2μΜ; Compound 33, Κ,=1μΜ;
Compound 34, Kj=3pM; Compound 35, Κ,=0.8μΜ; Compound 36, Κ—Ο.όμΜ;
Compound 37, Κ~0.07μΜ; Compound 38, Κ=0.004μΜ; Compound 39, Κ=0.004μΜ; 21 Compound 40, Κ,:=4μΜ; Compound 41, Kj=0.7pM; Compound 42, Κ,=0.02μΜ;
Compound 43, Κ(=0.4μΜ; Compound 44, Kj=0.02pM; Compound 45, Κ;=0.08μΜ;
Compound 46, Κ~1μΜ; Compound 47, Κ,·=0.3μΜ; Compound 48, K.f=0.09pM; 24 Compound 49, Kļ=2pM; Compound 50, Kj=0.08pM; Compound 51, Κ,·=1μΜ;
Compound 52, Κί=0.04μΜ; Compound 53, Κ;=6μΜ; Compound 54, Κ—Ο.ΙμΜ;
Compound 55, Κ~2μΜ; Compound 56, Κ~10μΜ; Compound 57, Κ~2μΜ; 27 Compoimd 58, Kj=0.1pM; Compound 59, Κ,=0.5μΜ; Compound 60, Κ(=5μΜ;
Compound 61, Κ(=41μΜ; Compound 62, Κ~0.2μΜ; Compound 63, Κ,=2μΜ; -66-
Compound 64, Κ^ΙμΜ; Compound 65, Κ=0.001 μΜ; Compound 66, Κ~0.02μΜ;
Compound 67, Κ~3μΜ; Compound 68, Κ(=0.04μΜ; Compound 69, Κ,=0.5μΜ; 3 Compound 70, Κ,=0.05μΜ; Compound 71, Κ;=0.8μΜ; Compound 72, Κ;=0.1μΜ;
Compound 73, Κρ=0.002μΜ; Compound 74, Κ|=0.04μΜ; Compound 75, Κ|=0.01μΜ;
Compound 76, Κ—Ο.ΙμΜ; Compound 77, Κ,·=6μΜ; Compound 78, Κ—Ο.ΙμΜ; 6 Compound 79, Kj=l μΜ; Compound 84, Κ,-0.06μΜ; Compound 85, Κ,=0.9μΜ;
Compound 86, Κ;=0.08μΜ; Compound 87, Κ;=0.05μΜ; Compound 88, Κ~0.1μΜ;
Compound 89, Κ^Ο.ΙμΜ; Compound 90, Kj=lpM; Compound 91, Κ^Ο.ΙμΜ; 9 Compound 92, Kj=0.1 μΜ; Compound 93, Κ,·=0.02μΜ; Compound 94, Κ~0.007μΜ;
Compound 95, Κ;=0.02μΜ; Compound 96, Κ=0.02μΜ; Compound 97, Κ(=0.0009μΜ; Compound 98, Κ,·=0.03μΜ; Compound 99, Kj=0.05pM; Compound 100, Kj=0.009pM; 12 Compound 101, Kj=0.04pM; Compound 102, Κ~0.08μΜ; Compound 103, Κ;=0.001μΜ; Compound 104, Κ,=0.003μΜ; Compound 105, Kļ=0.04pM; Compound 106, Κ~0.004μΜ; Compound 107, Κ—Ο.ΟΟΟΙμΜ; Compound 108, Kj=0.0005pM; Compound 109 Κ=0.0007μΜ; 15 Compound 110, Κ.=0.0008μΜ; Compound 111, Κ~0.3μΜ; Compound 112, Κ~0.09μΜ; Compound 113 Κ(=0.005μΜ; and Compound 114, Κ;=0.058μΜ. EXAMPLE 33 18 In Vivo Assay of Asthma
Allergic sheep characterized as dual responders (i.e., displaving early and late phases of bronchoconstriction) are challenged with antigen (e.g., Ascaris suum). The sheep are 21 administered tēst compound or vehicle by aerosol inhalation at 0.5 hours before and at 4 and 24 hours post antigen challenge. Specific lung rcsistance (SRL) is monitored via an esophageal balloon catheter just prior to the first tēst compound or vehicle treatment and every 0.5 to 1 hour 24 thereafter.
In addition, airway responsiveness is monitored 1 to 2 days prior to antigen challenge and just subsequent to administration of tēst compound or vehicle at 24 hours post antigen challenge. 27 For the purposes of this application, airway responsiveness is defined as the cumulative dose of carbachol required to increase SRL by 400% (PC400). The PC400 values are obtained by -67- LV 12291 administering 0 to 30 breath units of 1% carbachol (10 mg in 1 mL of PBS) by aerosol inhalation until SRl was increased by 400%. 3 Sheep treated with vehicle exhibit early phase bronchoconstriction from 0 to 4 hours post antigen challenge and late phase bronchoconstriction from 4 to greater than 8 hours post antigen challenge. In addition, vehicle treated sheep exhibit hyper responsiveness to carbachol (i.e., a 6 60% decrease in PC400 is observed).
Sheep treated with tryptase inhibitors do not exhibit late phase broncoconstriction (i.e., at 4 to 8 hours post antigen challenge, SRL remained at basai Ievels). Further, sheep treated with 9 tryptase inhibitors do not exhibit any hyper responsiveness to carbachol. EXAMPLE 34
Representative Pharmaceutical Formulations Containing a Compound of Formula I. 12 15 ORAL FORMULATION Compound of Formula I Citric Acid Monohydrate Sodium Hydroxide Flavoring Water
10-100 mg 105 mg 18 mg q.s. to 100 mL 18
INTRAVENOUS FORMULATION 21
Compound of Formula I Dextrose Monohydrate Citric Acid Monohydrate Sodium Hydroxide Water for Injection
0.1-10 mg q.s. to make isotonic 1.05 mg 0.18 mg q.s. to 1.0 mL 24 -68- TABLET FORMULATION Compound of Formula I 1% 3 MicrocrystaIline Celluiose 73% Stearic Acid 25% Colloidal Siiica 1%. -69- LV 12291 WE CLAIM: 1. A compound of Formula I: ιι'-χ'-χ^-χ4. ^χ5 r2-x9-x8-x7-x6^
I in which: X3 is (Co-i2)alkylene, hetero(C3-i2)alkylene, (C3-i4)cycloalkylene, hetero(C3.i4)cycloalkylene, (C6-i4)arylene or hetero(C5-i4)arylene; X4 and X6 are independently (Co.2)aIkylene; X1 and X9 are independently a covalent bond, -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(O)0-, wherein each R3 is independentiv hydrogen, (CIO)aIkyl or (C3.8)cycloaIkyl, with the proviso that X’ and X9 are not both covalent bonds; X3 and X7 are independentiy -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; X2 and X8 are independently (CM)aIkylene, hetero(Cļ.g)alkylene, -Xl0-X"- or -X"-X'°-, v/herein X!0 is (C0-))aIkylene or hetero(C3_ļ)alkylene and X11 is l,4-piperazinylene; R1 is R4-X'2- or R5-X13-, wherein: R4 is amino, amidino, guanidino, l-iminoerhvl or methviamino, X'2 is (C4^)alkylene, heĪero(C4^)alkylene, heterooxo(C4.6)alkylene, oxo(C4.6)alkylene or -Xl4-X'5-X'6-, wherein X!5 is (C3.6)cycloalkylene, hetero(C5^)arylene, hetero(Cļ.6)cycloaikylene or phenylene, X14 is (Cnl4)alkylene and X16 is (C„i6)alkylene, wherein the sum of nl4 and nl6 is 0, 1, 2, 3 or 4, R5 is a group selected from azetiain-3-yl, benzoimidazol-4-vl, benzoimicazol- -70- imidazol-l-yl, imidazol-2-yl, imidazo!-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methyIimidazol-l-yl, 4-methylimidazoI-l-yI, 5-methyiimidazol-l-yl, l-methylpiperid-3-yl, l-methylpiperid-4-yl, piperid-3-yl, piperid-4-yl, piperazin-l-yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yi, pyrimidin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1.4.5.6- tetrahydropyrimidin-2-yl, 1 ;4,5,6-tetrahydropyrimidin-4-yl and 1.4.5.6- tetrahydropyrimidin-5-yl and any carbocvclic ketone or thioketone derivative thereof, which group is optionalIy substituted with one or more radicals selected from balo, hydroxy, mercapto, (CM)aIkyl, (Ci.H)cycloaIkyl, (C6.u)aryi! (C6.,4)aryl(CM)alkyi, (C,.s)aIkanoyl, (CI.g)aIkyloxyJ (C6.u)aryloxy, (C3.14)cycloaikyloxy, (CM)alkyloxy, (C|.g)alkylthio, (C3_l4)cycloalkylthio, (C6.|4)aryltnio and -NR6R7, wherein R6 and R7 are independently selected from hydrogen, (CM)alkyl, (Cj.s)alkanoyl, (C3.I4)cycloalkyI or (Cj.j4)aiyl, and X13 is (Co.6)alkylene, hetero(C2.6)alkylene, heterooxo(Cw)alkylene, oxo(C2.6)alkylene or -XI7-X1S-X!9-, vvherein X18 is as defined above for X15, X17is (Cnl7)alkylene and X19 is (Cni9)aikylene, wherein the sum of nl 7 and nl9 is 0,1 or 2; and R2 is R*-X20- orR9-X2'-, wherein:
Rs is amino, 1 -iminoethyl or methylamino, X20 is (C^a^lene, hetero(C4^)alkyiene, heterooxo(C4.6)alkylene, oxo(C4^)alkylene or -Χ^-Χ^-Χ24-, wherein X23 is as defined above for X13, X~ is (Cn22)alkylene and X24 is (Cn24)alkylene, whersin the sum of n22 and n24 is 0, 1, 2, 3 or 4, with the proviso that when Rg is amino then X~° is not (C4.6)alkylene or oxa(C<w)alkylene and n22 is not 1,2, 3 or 4, R9 is as defined above for R5 and X21 is (C(W)alkyiene, hetero(C2^)alkylene, heterooxo(C3.6)alkylene, oxo(C2.6)aIkylene or -X25-X26-X27-, vvherein X26 is as defined above for X15, X25 is (Cn25)alkylene and X27 is (C^aU^lene, wherein the sum of n25 and n27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heterocycloalkylene, phenylene, arvlene and heteroarylene, as defined above, are optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (CM)alkyl, (C3.i4)cycloalkyl, (CM<ļ)aryl, (C6.,4)aryl(CM)aikyl, (C,.s)alkanoyl, (C,.8)aikyioxy, (C5.,4)aryloxy, (C3.14)cycloalkyloxy, -71- LV 12291 (CM)alkyloxy, (Cu)alkylthio, (Cj.K)cycloaikylthio, (C6_H)arylthio and -NR6R7, wherein R6 and R7 are as denned above; with the proviso that covalsnt bonds do not occur between heteroatoms contained within R1, X2, X4, X6, Xs and R2 and any heteroatoms contained with X3, X5, X7 and X9; and the pharmaceutically acceptable salts, Af-oxides, prodrug derivatives and protected derivatives thersof. 2. The compound of Claim 1 in which: X5 is cū-l,5-cyclooctylene and X4 and X6 each are a covalent bond or Xs is l,4-phenvlene and X4 and X6 are (CoJa^lene. X1 and X9 are independently a covalent bond, -C(O)-, -NHC(O)-, -C(0)NH-, -N(CH3)C(0)- or -S(0)2NH-; X3 and X7 are independently -C(O)- or -C(0)0-; X2 and X8 are independently -Χ^-Χ11-, vvherein: X10 is a covalent bond or methylene and Xn is l,4-piperazinylene; R1 is R4-X12- or R5-X13-, wherein: R4 is amidino, guanidino or methylamino, X12 is -X'4-X'5-X16-, wherein X15 is l,4-phenylene or 1,4-piperidylene, X14 is (Cnl4)alkylene and X16 is (Cnl6)alkylene. wherein the sum of nl4 and n!6 is 0, 1 or 2, R5 is piperid-4-yl and X13 is (C2.3)alkylene; and R2 is R8-X20- or R9-X21-, wherein: R8 is amino, methylamino or l-iminoethyI, X20 is -Χ^-Χ^-Χ24-, wnerein X23 is trans-1,4-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 is 1 or 2, R9 is benzoimidazoI-5-yl, imidazol-l-yl, imidazol-4-yl, 2-imidazolin-2-yl, 4-methyiimidazol-l-yl, 5-methyiimidazol-1 -yl, 1 -methylpiperid-4-yl, piperid-4-yl, -72- piperazin-1 -yl, pyrid-3-yl, pyrid-4-yl, l,4,5,6-tetrahydropyrimidin-5-yI or . 1,4,5,6-tetrahydro-2rdioxopyrimidin-5-yl and X21 is (C,^)alkylene, G>-aza(C2.<)alkylene, 2-aza-3-oxotrimethylene, 3-aza-2-oxotrimethylene, 3-oxotrimethylene, o-thia(C2^)alkylene or -Χ^-Χ^-Χ27-, wherein X26 is 1,4-phenylens, X25 is (Cn25)aikvlsne and X27is (Cn27)alkylene, wherein the sum of n25 and n27 is 0 or 1; and the pharmaceutically acceptabie salts, iV-oxides, prodrng derivatives and protected derivatives thereof. 3. The compound of Claim 2 in which X1 is c:s-\,5-cvdooctylene and X4 and X2 each are a covalent bond; X1 and X9 are independentlv a covalent bond, -C(O)-, -NHC(O)-, -C(0)NH- or -S(0)2NH-; X3 and X3 are independently -C(O)- or -C(0)0-; R1 is R4-X:2-, wnerein R4 is amidino or guanidino; and R1 is Rs-X20- or R9-X21-, wherein R8 is arnino or methylamino, X23 is trans-l,4-cyclohexylene or 1,4-phenylene, R9 is imidazol-l-yl, imidazol-4-yl, 4-methylimidazol-l-yl, 5-methylimidazol-l-yl, piperid-4-vl or pyrid-4-yl and X21 is (C1.5)alkylene or 3-azatrimethyiene; and the pharmaceutical!y acceptabie salts, A-oxides, prodrng derivatives and protected derivatives thereof. 4. The compound of Claim 3 in v/nich X1 and X9 are independently -C(O)- or -NHC(O)-; X3 and X3 each are -C(0)0-; X2 and X8 each are -X10-Xn-, wherein X10 is a covalent bond and X" is 1,4-piperazinylene; R1 is R4-X12-, wnerein R4 is amidino or guanidino and X!2 is -Xl4-Xl5-X16-, wherein X'5 is 1,4-phenylene, X14 is a covalent bond and X16 is methvlene; and R2 is R8-X20- or R9-X21-, v/herein R8 is amino, X20 is -X22-X--X24-, wherein X23 is trans-l ,4-cyclohexylene, X22 is a covalent bond and X24 is methyiene, R9 is piperid-4-yl and X2' is ethylene or trimethylene; and the pharmaceutically acceptabie salts, .V-oxides, prodrug derivatives and protected derivatives thereof. 1
The compound of Claim 4 in which X1 and X9 each are -NKC(O)-, R1 is 2 4-amidinobenzyl and R2 is 2-piperid-4-ylethyi, name!y cis-1.5-cvciooctylene 3 4-(4-amidinobenzylcarbamoyl)-1 -piperazinecarboxylate 4-(2-piperid-4-ylethyicarbamoyl)- -73- LV 12291 l-piperazinecarboxylate; and the phaimaceutically acceptable salts, A-oxides, prodrug derivatives and protected derivāti ves thereof. 6. The compound of Claim 4 in which X1 is -NHC(O)-, X9 is -C(O)-, R1 is 4-amidinobenzyl and R2 is 3-piperid-4-ylpropyl, namely cis-1,5-cyclooctylene 4-(4-amidinobenzylcarbamoyl)-1 -piperazinecarboxyiate 4-(4-piperid-4-ylbutyryl)-l-piperazinecarboxylate; and the pharmaceutically acceptable salts, A-oxides, prodrug derivatives and protected derivatives thereof. 7. The compound of Claim 4 in which X1 and X9 each are -NHC(O)-, R1 is 4-guanidinobenzyl and R2 is ira77S-4-aminocyclohexylmethyl, namely c/r-l,5-cyclooctylene rranj-4-(4-aminocyclohexylmethylcarbamoyl)-1 -piperazinecarboxyiate 4-(4-guanidinobenzylcarbamoyI)-l-piperazinecarboxylate; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. 8. The compound of Claim 4 in which X1 and X9 each are -C(O)-, R1 is 4-amidinobenzyl and R2 is 3-piperid-4-ylpropyI, namely cis-1,5-cyclooctyiene 4-(4-amidinopnenylacetyl)-1 -piperazinecarboxylate 4-(4-piperid-4-ylbutyryI)-l-piperazinecarboxylate; and the phaimaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. 9. The compound of Claim 4 in which X1 and X9 each are -NHC(O)-, R’ is 4-guanidinobenzyl and R2 is 2-piperid-4-ylethyl, namelv c2'r-l,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyI)-1 -piperazinecarboxylate 4-(2-piperid-4-ylethy lcarbamoyl)-l-piperazinecarboxylate; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. 10. The compound of Claim 4 in which X1 is -NHC(O)-, X9 is -C(O)-, R1 is 4-guanidinobenzyl and R2 is 3-piperid-4-ylpropyl, namely cri-1,5-cyclooctylene 4-(4-guanidinobenz>'lcarbamoyI)-l-piperazinecarboxylate 4-(4-piperid-4-ylbutyryl)- -74- l-piperazinecarboxylate; and the pharmaceutically acceptable salts, A'-oxides, prodrug derivatives and protected derivativss thereof. 11. The compound of Claim 4 in which X' is -C(O)-, X9 is -NHC(O)-, R1 is 4-guanidinoben2yl and R2 is 2-piperid-4-yiethyl, namely c/s-l,5-cyclooctyiene 4-(4-guanidinophenylacetyl)-1 -piperazinecarboxylate 4-(2-piperid-4-ylethylcarbamoyl)-l-piperazinecarboxylate; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. 12. The compound of Claim 4 in which X' and X9 each are -C(O)-, R1 is 4-guanidinobenzyl and R2 is 3-piņerid-4-yipropyl, namelv cis-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-1 -piperazinecarboxylate 4-(4-piperid-4-ylbutyryl)-l-piperazinecarboxylate; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. 13. The compound of Claim 4 in which X1 is -C(O)-, X9 is -NHC(O)-, R1 is 4-amidinobenzyl and R2 is 2-piperid-4-ylethyl, namely cis-1,5-cyclooctylene 4-(4-amidinophenylacetyl)-1 -piperazinecarboxy late 4-(2-piperid-4-ylethylcarbamoyl)-l-piperazinecarboxylate; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. 14. A pharmaceutical composition comprising a therapeutically etfective amount of a compound of Claim 1 in combination with a pharmaceutically acceptable excipient. 15. Use for treating a disease in an animal in which tryptase activity contributes to the pathology and/or svmptomatologv of the disease of a compound of Formula I: -75- LV 12291 κ’-χ'-χ^-χ4 /X5 r2-x9-x8-x7-x6^
I in which: X5 is (Co-i2)alkylene, hetero(C3-i2)alkylene, (C3-i4)cycloalkylene, hetero(C3-i4)cycIoalkylene, (C6-i4)arylene or hetero(C5.i4)arylene; X4 and Xs are independsntiy (C0.2)alkylene; X1 and X3 independentiy are a covalent bond, -C(O)-, -C(0)0-, -OC(O)-, -C(0)N(R3)-, -N(R3)C(0)-, -S(0),N(R3)-, -N(R3)S(0)r, -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, (CI0)alkyl or (C3.8)cycloalkyl; X7 and X9 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; X2 and Xs are independently (C,.8)alkylene, hetero(C,.g)aikylene, -X10-Xn- or -X!1-X10-, v/herein X1Q is (C(W)aikyiene or hetero(Cw)alkylene and X" is l,4-piperazinylene; R1 is R4-X12- or R5-X13-, wherein: R4 is amino, amidino, guanidino, l-iminoethyl or methylamino, X12 is (C4^)alkylene, heten^C^aikvlene, heterooxo(C4^)alkylene, oxo(C^)alkylene or -Xl4-X15-X16-, wherein X15 is (C3.6)cycloalkylene, hetero(C5.6)arylene, heiero(C3_6)cycloaIkylene or phenylene, X14 is (CnI4)alkyiene and X16 is (Cn,6)alkylene, wherein the sum of nl4 and nl6 is 0, 1, 2, 3 or 4, R5 is a group selected from azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl imidazol-l-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazoiin-2-yl, 2-imidazolin-3-yl, 2-methyiimidazol-l-yl, 4-methylimidazol-l-yl, 5-methylimidazol-l-yl, piperid-3-yl, piperid-4-yl, piperazin-l-yl, piperazin-2-yi, pyrid-3-yl, pyrid-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, l,4,5,6-tetrahydropyrimidin-2-yI, l,4,5,6-tetrahydropyrimidin-4-yl and l,4,5,6-ietxahydropyrimidin-5-yl andany -76- carbocycIic ketone or thioketone derivative thereof, which group is optionally substituted with one or more raaicals selected from halo, hydroxy, mercapto, (C|.g)alkyl, (C5.,4)cycloalkyl, (C^Jaiļd, (C5.l4)aryl(CM)alkyl, (C,.g)aīkanoyl, (C,.g)alkyloxy, (C6.14)aiyloxy, (C3.H)cycloalkyioxy, (CM)alkyloxy, (C,.s)alkylthio, (C3.14)cycloalkylthio, (C6.,4)aiylthio and -NR6R7, wherein R6 and R7 are independently selected from hvdrogen, (C,.g)alkyl, (Cj.j)aIkanoyl, (C3.t4)cycloalkyl or and X13 is (Co.6)aIkylene, hetero(C2^)aIkylene, heterooxo(C3.6)alkyiene, oxo(C2.6)alkylene or -XI7-XI8-X19-, wnerein X1* is as defined above for X15, X17 is (Cn|7)alkylene andX19 is(Oii9)alkyIene, wherein the sum of nl7 and nl9 is 0, 1 or 2; and R: is R*-X20- or R9-X21-, wherein:
Rs is amino, l-iminoethyl or methyiamino, X20 is (C4^)alkylene, hetero(Cw)alkylene, heterooxo(C4.6)alkyiene, oxo(C4^)aIkylene or -Χ^-Χ^-Χ24-, vvherein X23 is as defined above for X'5, X22 is (Cn22)alkylene and X24 is (Cn24)alkylene, wherein the sum of n22 and n24 is 0, 1,2, 3 or 4, with the proviso that when Rs is amino thenX20 is not (C4.6)alkylene or oxa(C4^)aikylene and n22 is not 1, 2, 3 or 4, R9 is as defined above for Rs and X21 is (Co_6)aikylene, hetero(Cw)alkyIene, heterooxo(C3H5)aikylene, oxo(C2.4)alkylene or -Χ^-Χ^-Χ27-, wnerein X26 is as defmed above for X'5, X" is (Cnl5)alkylene and X27 is (Cn27)alkylene, wherein the sum of n25 and n27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heterocycloalkyIene, phenvlene, arviene and heteroarylene, as defined above, are optiona!ly substimted with one or more radicals selected from halo, hydroxy, mercapto, (Ci_g)alkyl, (C3.I4)cycloalkyl, (G^Jarvl, (Ce.j4)aryl(CM)alkyl, (C,.g)alkanoyĻ (C,.g)aIkyloxy, (C6.l4)aryloxy, (C3.14)cvcloalkyloxy, (CM)alkyloxy, (C,.g)aIkylthio, (C3.l4)cycloalkylthio, (C^a^lthio and -NR6R7, wherein R6 and R7 are as defined above; with the proviso that covalent bonds do not occur bsrween heteroatoms contained within R1, X2, X4, X6, X8 and R2 and any heteroatoms contained with X3, Xs, X7 and X9; or a pharmaceutically acceptable salt, A-oxiae or prodrug derivative thereof. -77- LV 12291 16. The use of Claim 15 in v/nich the disease is seiected from asthma, allergic rhinitis, rheumatoid spodviitis, osteoarihritis, gouty arthritis, rheumatoid arthritis, arthrinc conditions in general, urticaiia, angioedema, eczematous dsrmatitis, anaphylaxis, hyper proliferative skin disease, peptic ulcers. inflamm2Īory boweI disease, ocuiar and vemal conjunctivitis and inflammatory skin conditions. 17. use of Claim 16 in whicn the disease is asthma. 18. The use of Claim , 17 in which the compound is administered in a aerosoiized pharmaceuticaliv acceptable cairier suitable for administration as an iahaiant. 19. The use of Claim 18 in which the compound is administered in combination with a therapeutically effective amount of a β-adrenergic agorist, a memyixanthine, a cromoglvcate or a corticosteroid. 'om ;d from om 20. The use of Claim 19 in which the β-adrenergic agonist is seiected aibuteroi, terbutaiine, formoterol, fenoterol and prenaiine, the methyLxanthine is sele: caffeine, theophyiline. aminophylline and theobromine, the cromoglvcate is seiected cromolyn and nedocromil and the corticosteriod is seiected from beclomethasome, triamcinolone, fmrisolide and dexamethasone. 21. The use of Claim 16 in which the disease is rheumatoid anhntis or coniuncti viris. 22. The use of Claim 21 in which the compound is administered in a pharmaceuticaliv ac ptabie carrier suitable for toņicai administration. 23. A compound of Formula I: -78- κ’-χ'-χ^-χ4^ ^Χ5 r2-x9-x8-x7-x6^
I in which: X4-X5-X6 together are (C2_J2)alkylene or hetero(C3.12)alkylene; X1 and X9 are independently a covalent bond, -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 each R3 is independently hydrogen, (C,.3)alkyl or (C3.8)cycloalkyI, with the proviso that X! and X9 are not both covalent bonds; X3 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; X2 and X* are independently (Cu8)alkylene, hetero(CU8)alkylene, -X10-Xu- or -X"-X10-, wherein X10 is (Cņ^alkļdene or hetero(Cj^)alkylene and X11 is · l,4-piperazinylene; R1 is R4-X!2- or Rs-X13-, wherein: R4 is amino, amidino, guanidino, l-iminoethyl or methyiamino, X12 is (C^)alkylene, hetero(CiU6)alkylene, heterooxo(C4.6)alkylene, oxo(C4^)alkylene or -X,4-Xl5-X16-, wherein X’5 is (C3^)cycloalkylene, hetero(C5Jarylene, hetero(C3.6)cycloalkyiene or phenylene, X'4 is (Cnl4)alkylene and X’6 is (C„l6)alkylene> wherein the sum of nl4 and nl6 is 0,1,2, 3 or 4, R3 is a group seiected from azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-vl imidazol-l-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazoiin-2-yl, 2-imidazolin-3-yl, 2-methyiimidazol-l-yl, 4-methyiimidazol-l-yl, 5-methylimidazol-l-yl, l-methylpiperid-3-yl, 1 -methylpiperid-4-yl, piperid-3-yl, piperid-4-yl, piperazin-l-yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yi, l ,4,5,6-tetrahydropyrimidin-2-yl, 1,4,5,6-tetrahydropyrimidin-4-yl and -79- LV 12291 1,4,5,6-tetrahydropyrimidin-5-yl and any carbocyclic ketone or thioketone derivative thereof, which group is optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (C,.s)alkyi, (C3.,4)cycloalkyl, (C6.u)aryl, (C6.M)aryl(CM)alkyl, (C,.l)alkanoyl, (Ci_8)alkyloxy, (C6.N)aiyloxy> (C3.H)cycloalkyloxy, (CM)alkyloxy, (C1.8)alkylthio, (C3_14)cycloalkylthio, (Q.|4)aryithio and -NR6R7, wherein R6 and R7 are indspendently selected from hydrogen, (C,.8)alkyl, (C..8)alkanoyl, (C3.ļ4)cycloalkyl or (C6.,4)aryi and X13 is (C0.6)alkylene, hetero(C2.6)alkylene, heterooxo(C3^)alkylene, oxo(C2.6)alkylene or -X17-Xl8-X19-, wherein X18 is as defmed above for XtJ, Xl7is (Cnl7)aikylene andX19 is (Cni9)alkylene, wherein the sum of nl7 and nl9 is 0,1 or 2; and R2 is R8-X20- or R9-X21-, wherein: R8 is as defined above for R4, X20 is (C4_6)alkyiene, hetero(Cw)aikylene, heterooxo(C4.6)alkvlene, oxo(C4^)aikylene or -X“-X23-X24-, v/herein X23 is as defined above for X15, X~ is (C^alkvlene and X24 is (Cn24)alkylene, wherein the sum of n22 and n24 is 0,1,2, 3 or 4, R9 is as defined above for R5 and X21 is (C0.6)alkylene, hetero(C2.6)alkylene, heterooxo(C3^)alkylene, oxo(C2.6)alkyiene or -Χ^-Χ^-Χ27-, wherein X26 is as defined above for X15, X25 is (Cn25)alkylene and X27 is (C^alkļdene, wherein the sum of n25 and n27 is 0,1 or 2; wherein each alkvlene, cycloalkylene, heīeroalkylene, heterocycloalkyiene, phenylene, arylene and heteroarylene, as defined above, are optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (C,.8)alkyl, (C3.l4)cycloalkyl, (C6.14)aryl, (C6.14)aryl(CM)alkyl, (C,.8)alkanoyl, (C,.8)alkyloxy, (C6.14)aryloxy, (C3.I4)cycloalkyloxy, (CM)alkyloxy, (C,_8)alkylthio, (C3.14)cycloalkylthio, (C^uļarvlthio and -NR6R7, wherein R6 and R7 are as defined above; with the proviso that covalent bonds do not occur betvveen heteroatoms contained within R1, X2, X4, X6, X8 and R2 and any heteroatoms contained with X3, X5, X7 and X9; and the pharmaceuticaily acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. -80- 24. The compound of Claim 23 in which: X4-X5-X6 together are (C2.I0)alkylene or hetero(C3_I0)aIkylene; X1 and X9 are independently a covalent bond, -C(O)-, -NHC(O)-, -C(0)NH-, -N(CH3)C(0)- or -S(0)2NH-; X3 and X7 are independently -C(O)- or -C(0)0-; X2 and X8 are independently -X10-X“-, wherein X10 is a covalent bond or methvlene and Xu is 1,4-piperazinvlene; R1 is R4-X12- or R5-X13-, vvherein: R4 is amidino, guanidino or methyiamino, X12 is -X'4-XlJ-X16-, whereinX15 is l,4-phenylene or 1,4-piperidylene, X14 is (Cnl4)alkylene and X16 is (Cnl6)alkylene, wherein the sum of n!4 and n!6 is 0, 1 or 2, R5 is piperid-4-yl and X13 is (C2.3)alkylene; and R2 is R8-X20- or R’OC2'-, wherein: R8 is amino, amidino, guanidino, methy!amino or 1 -iminoethyi, X20 is -Χ^-Χ^-Χ24-, wherein X23 is rraw-l,4-cyclohexyiene, l,4~phenylene, 4,l-pyridylene, 1,4-piperidylene, X22 is (Cn7-)alkylene andX24 is (Cn24)alkylene, wherein the sum of n22 and n24 is 1 or 2, R9 is benzoimidazol-5-yl, imidazol-l-vl, imidazol-4-yl, 2-imida2olin-2-yi, 4-methylimidazol-l-yl, 5-meīhyiimidazol-l-yI, l-methylpiperid-4-yl, piperid-4-yl, piperazin-l-yl, pyrid-3-yl, pyrid-4-yl, l,4,5,6-teĪrahydropyrimidin-5-yl or 1,4,5,6-tetrahydro-2-dioxopyiimidin-5-yl and X21 is (C,.6)alkyiene, G>-aza(C2.j)alkylene, 2-2za-3-oxotrimethylene, 3-aza-2-oxotrimethylene, 3-oxotrimethylene, Q-thia(CM)alkylene or -X2S-X26-X27-, wherein X2S is l,4-phenylene, X25 is (Cn25)alky!ene and X"7 is (Cn;7)alkylene, wherein the sum of n25 and n27 is 0 or 1; and the pharmaceutically acceptable salts, /7-oxides, prodrug derivatives and protected derivatives thereof. 25.
The compound of Claim 24 in which X4-X5-X6 together are (C-_s)alkylene or -81- LV 12291 hstsro(C4.10)alkylene; X’ and X9 are independently a covalent bond, -C(O)-, -NHC(O)-, -C(0)NH- or -S(0)2NH-; X3 and X7 are independently -C(O)· or -C(0)0-; R1 is R4-X12-, wherein R4 is amidino or guanidino; and R2 is R8-X20- or R9-X21-, wherein R8 is amino, amidino, guanidino or methylamino, X23 is trans-1,4-cyclohexvlene or l,4-phenylene, R9 is imidazol-l-vl, imidazol-4-yl, 4-methylmndazol-l-yI, 5-methyIimida2ol-l-yI, piperid-4-yi or pyrid-4-yl and X2! is (C,.5)alkylene or 3-azatrimethylene; and the pharmaceuticallv acceptable salts, iV-oxides, prodrug derivatives and protected derivatives thereof. 26. The compound of Claim 25 in which X1 and X9 are independently -C(O)- or -NHC(O)-; X3 and X7 are independentiy -C(O)- or -C(0)0-; X2 and X8 each are -X'°-X"-, wherein X'° is a covalent bond and X" is l,4-piperazinylene; R1 is R4-Xt2-, wherein R4 is amidino or guanidino and X12 is -X'4-X15-X16-, wherein X15 is l,4-phenylene, X14 is a covalent bond and X16 is methylene; and R2 is R8-X20-, wherein R8 is amidino or quanidino and X20 is -Χ^-Χ^-Χ24-, wherem X22 is l,4-phenylene, X~is a covalent bond and X24 is methvlene; and the pharmaceutically acceptabie salts, A-oxides. prodrug derivatives and protected derivatives thereof. 27. The compound of Claim 26 in which X4-Xs-X6 together are hexamethylene; X1 and X9 each are -NHC(O)-, X3 and X7 each are -C(O)- and R1 and R2 each are 4-guanidinobenzyl, namely 4-guanidino'oen2yl 4- {7-[4-(4-guanidinobenzy icarbamov l)piperazin-1 -ylcarbonyl]heptanoyI }-l-piperazinecarboxamide; and the phaimaceutically acceptable salts, A-oxides, prodrug derivatives and protected derivatives thereof. 28. The compound of Claim 26 in which X4-X5-X6 together are heptamethylene; X' and X9 each are -NKC(O)-, X3 and X7 each are -C(O)- and R1 and R2 each are 4-guanidinobenzyl; namely 4-guanidinoben2yl 4-{8-[4-(4-guanidinobenzylcarbamoyl)piperazin-l-ylcarbonyi]oc:anoyl}-l-piperazinecarboxamide; and the pharmaceutically acceptable salts, A-oxides, prodrug derivatives and protected derivatives thereof. -82- 29. The compound of Claim 26 in \vhich X4-Xs-X6 together ars octamethvlene; X1 and X9 each are -NHC(O)-, XJ and X7 each are -C(O)- and R' and R2 each are 4-guanidinobenzyl, namely 4-guanidinobenzyl 4-{9-[4-(4-gnanidinobenzylcarbamoyl)pipsrazin-l-ylcarbonyI]nonanoy!}-l-pipera2dnecarboxamide; and the pharmaceutically acceptabie salts, jV-oxides, prodrug derivatives and protected derivatives thereof. 30. The compound of Claim 26 in which X*-Xs-X6 together are hexamethylene; X1 and X9 each are -NHC(O)-, X3 and X7 each are -C(O)- and R1 and R2 each are 4-amidinobenzyl, namely 4-amiainobenzyl 4-{7-[4-(4-amidinobenz}dcarbamoyl)piperazin-1-ylcarbonyl]heptanoyI }-1-piperazinecarboxamide; and the phannaceuticaily acceptabie salts, .V-oxides, prodrug derivatives and protected derivatives thereof. 31. The compound of Claim 26 in which X4-X5-X6 together are pentamethvlene; X1 and X9 each are -NHC(O)-, X3 and X7 each are -C(0)0- and R1 and R2 each are 4-guanidinobenzyl, namely l,5-pentamethylene di[4-(4-guanidinobenzylcarbamoyl)-l-piperazinecarboxylate]; and the pharmaceutically acceptabie salts, A-oxides, prodrug derivatives and protected derivatives thereof. 32. The compound of Claim 26 in which X4-X5-X6 together are tetramethylene; X1 and X9 each are -NHC(O)-, X3 and X7 each are -C(0)0- and R1 and R2 each are 4-guanidinobenzyl, namely l,5-tetramethylene di[4-(4-guanidinobenzylcarbamoyl}-l-piperazinecarboxylate]; and the pharmaceutically acceptabie salts, X-oxides, prodrug derivatives and protected derivatives thereof. 33. Tne compound of Claim 26 in which X4-X5-X6 together are pentamethylene; X1 and X9 each are -NHC(O)-, X3 and X7 each are -C(O)- and R1 and R2 each are 4-guanidinobenzvl. namely 4-guanidinobenzyl 4-{6-[4-(4-amidinobenzylcarbamoyl)piperazin-l-ylcarbonyl]hexanoyl}- LV 12291 -S3- l-piperazinecarboxamide; and the phannacsutically acceptable salts, jV-oxides, prodrug dsrivatives and protected derivatives thereof. 34. The compound of Claim 26 in which X4-X3-Xs together are 3-oxatetramethylene; X1 and X9 each are -C(O)-, X3 and X7 each are -C(O)- and R‘ and R2 each are 4-amidinobenzyi, namely 3-oxa-l,5-pentamethylene di[4-(4-gnanidinophenylacetyI)piperazin-l-ylcarbonyI]; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. 35. A process for preparing a compound of Formula I: r'-x'-x2-x3-x4 R2-X9-X8-X7-X6' in which: X5 is (Co-i2)ulkylene, hetero(C3.]2)alkylene, (C3.i4)cycloalkylene, hetero(C3.]4)cycloalkylene, (C6-i4)arylene or hetero(C5.i4)arylene; X1 and X9 are independently a covalent bond, -C(O)-, -C(0)0-, -OC(O)-, -C(0)N(R3)-, -N(R3)C(0)-, -S(0);N(R3)-, -N(R3)S(0)r, -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, (C10)alkyi or (Cj.s)cycloalkyl, with the proviso that X1 and X9 are not both covalent bonds; X3 and X7 are independently -C(O)-, -C(0)0-, -OC(O)-, -C(0)N(R3)-, -N(R3)C(0)-, -S(0),N(R3)-, -NCR3)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; X2 and X* are independently (C|.8)alkylene, hetero(C).8)alkylene, -Xl0-Xu- or -X"-X10-, wherein X10 is (C^aU^lene or hetero(C3^)alkylene and X11 is l,4-piperazinylene; -84- R1 is R4-X12- or Rs-X13-, wherein: R4 is amino, amidino, guanidino, l-iminoethyl or methylamino, X12 is (Cw)alkylene, hetero(C4_6)alkylene, heterooxo(C4_6)aIkylene, oxo(Cw)alkylsne or -Xl4-X15-X16-, wherein X15 is (C3^)cycloalkylene, hetero(Cw)arylene, hetero(C3.6)cycloalkylene or phenylene, X14 is (CnH)aIkylene and X16 is (Cnl6)alkylene, wherein the sum of n!4 and nl6 is 0,1,2, 3 or4, R5 is a group seiected from azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yI imidazol-l-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazoIin-3-yl, 2-methylimidazol-1 -yl, 4-methylimidazol-1 -yl, 5-methylimidazoI-1 -yl, l-methylpiperid-3-yi, l-methylpiperid-4-yl, piperid-3-yl, piperid-4-yl, pipsrazin-l-yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-4-yl, pyrimiaiD-5-yi, pyrro!idin-3-yl, 1.4.5.6- tetrahydropyrimidin-2-yi, l,4,5,6-tetrahydropyrimidin-4-yl and 1.4.5.6- tetrahydropyrimidin-5-yl and any carbocyclic ketons or thioketone derivātive thereof, which group is optionaliy substituted with οηε or more radicals seiected from halo, hydroxy, mercapto, (C,.g)alkyl, (C3.M)cycloaIkyl, (C6.,4)aryl, (C5.I4)aryl(C,.4)alkyl, (Cj.s)alkanoyl, (C,.g)alkyioxy, (C6_H)aryloxy, (C3.14)cycloaIkyloxy, (CM)alkyloxy, (C,.g)alkyIthio, (C3.u)cycloalkylthio, (C6.14)ar}'ithio and -NR6R7, wherein R6 and R7 are independentiy seiected from hydrogen, (C1.g)alkyl, (C,.g)alkanoyl, (C3.u)cycloalkyl or (C6.14)aryl and X13 is (C0.6)alkylene, hetero(C2.6)alkyIene, heterooxo(C3.6)alkylene, oxo(C2.6)aikylene or -X17-X18-X19-, wherein X18 is as defmed above for X15, XI7is (Cn!7)alkyiene andX19 is(Cni9)alkylene, wherein t’ne sum of nl7 and nl9 is 0, 1 or 2; and R2 is R8-X20- or R’-Χ21-, wherein: R* is amino, l-iminoethyI or methylamino, X20 is (C4.6)alkylene, hetero(C4.6)alkylene, heterooxo(C4.6)alkylene, oxo(C4.6)alkylene or -X22-X23-X24-, wherein X23 is as defined above for X15, X"‘ is (Cn?7)alkylene and X24 is (Cn24)alkyrlene, vvherein the sum of n22 and n24 is 0, 1, 2, 3 or 4, with the proviso that when R8 is amino then X20 is not (C4.6)alkylene or oxa(C4.6)alxylene and n22 is not 1, 2, 3 or 4, R9 is as defmed above for R5 and X21 is (Co.6)alkylene, hetero(C2^)alkylene, heterooxo(C3.6)alkylene, -85- LV 12291 oxo(C2^)alkylene or -X2S-X24-X27-, wherein X24 is as defined above for X15, X25 is (Cn25)alkylene and X27 is (C^alkjdene, wherein the sum of n25 and n27 is 0, 1 or 2; wherein each alkylene, cycloaIkyIene, heterocycIoaIkylene, phsnyiene, aryiene and heteroarylene, as defined above, are optionaliy substituted with one or more radicals selected from halo, hydroxy, mercapto, (C,.8)alkyl, (C3.I4)cycIoaikyl, (C^a^l, (CW4)aryl(Cw)aIkyl, (C,.g)alkanoyi, (Cw)alkyloxy, (C6.14)aryloxy, (C3.l4)cycloalkyloxy, (CM)alkyioxy, (Cu)alkylthio, (C3.14)cycioaikyIthio, (€4.1,1)317111110 and -NR6R7, wherein R6 and R7 are as defined above; with the proviso that covalent bonds do not occur between heteroatoms contained within R', X2, X4, X6, Xs and R2 and any heteroatoms contained with X3, Xs, X7 and X9; and the pharmaceutically acceptabie salts, A-oxides, prodrug aerivatives and protected derivatives thereof, which process comprises: (a) reacting a compound of Formula 1:
r‘-x'-x2-x3-xV Υ8-χ7-Χ6 ^ 1 or a protected derivative thereof, with a compound of the formula R2-Y9-C(0)L, or a protected derivative thereof, wherein L is a leaving group, Y9 is a bond, -O- or -N(R3)-, Y8 is piperazin-l-yl or HN(RJ)-(C 1 .s)alkyl. respectivelv, and each R1, R2, R3, X1, X2, X4, X5, X6 and X7 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula 1, in which X* is l,4-piperazinylene and X9 is C(O)-, -OC(O)- or -N(R3)C(0)- or in which X8 is (C,.8)alkylene and X9 is -C(0)N(R3)-, -OC(0)N(R3)-or-N(R3)C(0)N(R3)-; (b) reacting a compound of Formula i, or a protected derivative thereof, with an isocyanate of the formula R2-NC(0), or a protected derivative thereof, and then deprotecting when necessary, to give a compound of Formula I in wnich X* is 1,4-piperazinyIene and X9 is -NHC(O)- or in which X8 is (Cj.8)alkylene and X9 is -NHC(0)N(R3)-; (c) ' reacting a compound 0 f Formula 2: -S6- γ2-χ3-χ*. r2-x9-x*-x7-x6' or a protected derivative thereof, with a compound of the formula R'-Y'-C(0)L, or a protected derivative thereof, wherein L is a leaving group, Υ1 is a bond, -0- or -N(R3)-, Υ2 is piperazin-l-yl or HN(R3)-(Ci.g)alkyl, respectivelv, and each R1, R2, R3, XJ, X4, X5, X6, X7, X* and X9 are as defined in the Summary of the Invention, and then deprotecting when necessaiy, to give a compound of Formula I in which X2 is l,4-piperazinylene and X1 is C(0)-, -OC(O)- or -N(R3)C(0)- or in which X2 is (Ci.8)alkylene and X1 is -C(0)N(R3)-, -0C(0)N(R3)- or -N(R3)C(0)N(R3)-; (d) reacting a compound of Formula 2, or a protected derivative thereof, with an isocyanate of the formula R'-NC(O), or a protected derivative thereof, and then deprotecting wnen necessary, to give a compound of Formula I in which X2 is l,4-piperazinyiene and X1 is -NHC(O)- or in which X2 is (Ci-8)alkylene and X1 is -NHC(0)N(R3)-; (e) reacting a compound of Formula 3: Y2-X3-X4· X5 Y8-X7-X6 3 or a protected derivative thereof, with 2 or more molar equivalents of a compound of the formula R'-Y1-C(0)L, or a protected derivative thereof, wherein L is a leaving group, Υ1 is a bond, -0- or -N(R3)-, Y2 and Yl are independently piperazin-l-yl HN(R3)-(C|.8)alkvl and each R1, R.3, X3, X4, X5, X6 and X7 are as defined in the Summarv of the Invention, and then deprotecting when necessary, to give a compound of Formula I in which R1 equais R2; X2 and/or X* is 1,4-piperazinylene and X1 is C(0)-, -0C(0)- or -N(RJ)C(0)-; and X9 is -C(0)-, -0C(0)- or -N(R3)C(0)- and/or in which X2 and/or X8 is (Ci.*)alkylene; X1 is -C(0)N(R3)-, -0C(0)N(R3)- or -N(R3)C(0)N(R3)-; and X9 -C(0)N(R3>, -0C(0)N(R3)- or -N(R3)C(0)N(R3)-; -87- LV 12291 (f) reacting a compound of Formula 3, or a protected derivative thereof, with two or mora molar equivalents of an isocyanate of the formula R’-NC(O), or a protected derivative thereof, and then deprotecting vvhen necessary, to give a compound of Formula I in wnich R1 equals R2; X2 and/or X8 is l,4-piperazinylene; X1 is -NHC(O)- and/or X9 is -NHC(O)- and/or in which X2 and/or X8 is (C,.4)alkylcne and X1 is -NHC(0)N(R3)- and/or X9 is -NHC(0)N(R3)-; (g) reacting an amine of the formula R’-N(R3)H, or a protected derivative thereof, with a compound Formula 4: ΙΑΟΐ-Υ'-χ^.χ* /χ5 r2-x9-x8-x7-x6/ 4 or a protected derivative thereof, vvherein L is a leaving group, Υ1 is a bond, -0- or -N(R3)- and each R1, R2, R3, X2, X3, X1, X5, X6, X7, Xs.and X9 are as defined in the Summary of the Invention, and then deprotecting w'nen necessary, to give a compound of Formula I in vvhich X1 is -N(R3)C(0)-, -N(R3)C(0)0- or -N(R3)C(0)N(R3)-; (h) reacting a compound of the formula R'-Χ'-Υ2, or a protected derivative thereof, with a compound of Formula 5:
LC(0)-Y3-xV /χ5 r2-x9-x8-x7oc 5 or a protected derivative thereof, wherein L is a leaving group, Y3 is a bond, -0- or -N(R3)-, Y2 is piperazin-l-yl or HN(R3)-(Ci-8)alkyĻ respectivelv. and each R1, R2, R3, X1, X2, XJ, X4, X5, X6, X7, X* and X9 are as defmed in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I in vvhich X2 is l,4-piperazinylene and XJ is -C(0)-, -C(0)0- or -C(0)N(R3)- or in v/hich X2 is (Ci.g)alkylene and X3 is -N(R3)C(0)-, -140^0(0)0- or -N(R3)C(0)N(R3)-; -88- (i) reacting 2 or more molar equivalents of compound of the formula R'-Χ'-Υ2, or a protected derivative thereof, with a compound of Formula 6:
LC(0)-Y3-XV
/XS LC(0)Y7-Xfi 6 or a protected derivative thereof, wherein L is a leaving group, Y3 and Y7 are independently a bond, -0- or -N(R3)-, Υ2 is piperazin-1 -yl HN(R3)-(C t.g)alkyl or HN(R3)-hetero(Cļ.g)alk}'I and each R1, X1, X4, XJ and X6 are as detined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I in whic’n X2 and X8 each are 1,4-piperazinylene and X3 and X7 are independently -C(0)-, -C(0)0- or -C(0)N(R3)- or in which X2 and X8 each are (C,.s)alkylene or hetero(C,.j)aIkylene and X3 and X2 are independently -N(R3)C(0)-, -N(R3)C(0)0- or -N(R3)C(0)N(R3)-, respectiveiv; (j) optionally reacting a compound of Formula I in which R4 is amino with cyanamide to give a compound of Formula I in which R4 is guanidino; (k) optionally further converting a compound of Formula I into a pnarmaceutically acceptable salt; (l) optionally further converting a salt form of a compound of Formula I to non-sait form; (m) optionally further converting an unoxiaized form of a compound of Formula ī into a pharmaceutically acceptable jV-oxide; (n) optionally further an N-oxide form of a compound of Formula I its unoxidized form; (o) optionalIy further converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and (p) optionally further converting a prodrug derivative of a compound of Formula I to its non-derivatized form.

Claims (33)

1 1LV 12291 Izgudrojuma formula 1. Savienojums ar formulu (I): ιι'-χ'-χ^χ^χν /XS R2-X9-X8-X7-X6^ I kurā: X5 ir Co-i2alkilēngrupa, hetero-C3-i2alkilēngrupa, C3-ucikloalkilēngrupa, hetero-C3-i4Cikloalkilēngrupa, C6-uarilēngrupa vai hetero-Cs.uarilēn-grupa; X4 un X6, neatkarīgi viens no otra, ir Co-2alkiiēngrupa; X1 un X9, neatkarīgi viens no otra, ir kovalentā saite, -CO-, -COO-, -O-CO-, -CONR3-, -NR3CO-, -S02NR3-, -NR3S02-, -OCONR3-, -NR3COO-, -NR3CONR3- vai -OCOO-, kur R3, neatkarīgi viens no otra, ir ūdeņraža atoms, Cioalkilgrupa vai C3.8cikloalkilgrupa, ar noteikumu, ka X1 un X9 abi vienlaikus nav kovalentā saite; X3 un X7, neatkarīgi viens no otra, ir -CO-, -COO-, -O-CO-, -CONR3-, -NR3CO-, -S02NR3-, -NR3S02-, -OCONR3-, -NR3COO-, -NR3CONR3-vai -OCOO-, kur R3 nozīmes ir jau minētās; X2 un X8, neatkarīgi viens no otra, ir C-i-aalkilēngrupa, hetero-C-i-salkilēngrupa, -X10-X11- vai -X11-X10-, kur X10 ir Co-4alkilēngrupa vai hetero-C3_4alkilēngrupa, X11 ir 1,4-piperazinilēngrupa; R1 ir R4-X12- vai R5-X13-, kur: R4 ir aminogrupa, amidīngrupa, guanidīngrupa, 1-iminoetilgrupa vai metilaminogrupa; X12 ir C4.6alkilēngrupa, hetero-C4-6alkilēngrupa, heterookso-C4-salkil-ēngrupa, okso-C4.6alkilēngrupa vai -X14-X15-X16-, kur X15 ir C3_6cikloalkilēngrupa, hetero-C5-6arilēngrupa, hetero-C3-6ciklo-alkilēngrupa vai fenilēngrupa, X14 ir Cnualkilēngrupa un X16 ir Cnisalkilēngrupa, kur n14 un n16 summa ir 0, 1, 2, 3 vai 4; R5 ir grupa no rindas: azetidin-3-ilgrupa, benzimidazol-4-ilgrupa, benzimidazoi-5-ilgrupa, imidazol-1-ilgrupa, imidazol-2-iIgrupa, imidazol-4-ilgrupa, 2-imidazolin-2-ilgrupa, 2-imidazolin-3-ilgrupa, 2 2-metilimidazol-1-iigrupa, 4-metiiimidazol-1 -ilgrupa, 5-metilimid-azol-1-ilgrupa, 1-metilpiperidin-3-ilgrupa, 1-metilpiperidin-4-ilgrupa, piperidin-3-iigrupa, piperidin-4-ilgrupa, piperazin-1-ilgrupa, piperazin-2-ilgrupa, piridin-3-iIgrupa, piridin-4-ilgrupa, pirimidin-4-ilgrupa, pirimidin-5-ilgrupa, pirolidin-3-ilgrupa, 1,4,5,6-tetrahidropirimidin-2-ilgrupa, 1,4,5,6-tetrah idropirimidin-4-iigrupa, 1,4,5,6-tetrahidropirim id in-5-ilgrupa, kā arī minēto grupu karbocikliskie okso- vai tioksoatvasinājumi, pie tam minētās grupas neobligāti aizvietotas ar vienu vai vairākiem aizvietotājiem no rindas: halogēna atoms, hidroksilgrupa, merkaptogrupa, Ci.8alkilgrupa, C3.i4cikloalkilgrupa, C6-i4aril-grupa, Cg-uaril-Ci^aikilgrupa, Ch.salkanoilgrupa, C6-i4ariIoksi-grupa, C3-ucikloalkiloksigrupa, C-Malkoksigrupa, Ci-salkiltio-grupa, C3.i4cikloalkiltiogrupa, C6-i4ari[tiogrupa un -NRSR7, kur R6 un R7, neatkarīgi viens no otra, ir aizvietotāji no rindas: ūdeņraža atoms, Ci-8alkilgrupa, Ci.8alkanoilgrupa, Cs-ucikloalkilgrupa un Ce-uarilgrupa; X13 ir Co-ealkilēngrupa, hetero-C2-6alkilēngrupa, heterookso-C3.salkil-ēngrupa, okso-C2-6alkilēngrupa, vai X17-X18-X19-, kur X18 ir ar jau minētām X15 nozīmēm, )Č7 ir Cnizalkilēngrupa un X19 ir Cnisalki-lēnarupa, pie kam n17 un n19 summa ir 0, 1 vai 2; R1 ir R8-X20-vai R9-X21-, kur: R8 is aminogrupa, 1-iminoetilgrupa vai metilaminogrupa, X20 ir C4-6aikilēngrupa, hetero-C4.6alkiiēngrupa, heterookso-C4.6alkilēngrupa, okso-C4.6alkilēngrupa vai X22-X23-X24-, kur X23 ir ar jau minētām X15 nozīmēm, X20 ir C^alkilēngrupa un X24 ir Cn24alkilēngrupa, pie kam n22 un n24 summa ir 0, 1, 2, 3 vai 4, ar noteikumu, ka tad, kad R8 ir aminogrupa, X20 nav C4.6alkil-ēngrupa vai oksa-C4-6alkilēngrupa un n22 nav 1,2, 3 vai 4; R9 ir ar nozīmēm, kuras jau minētas R5; X21 ir Co-ealkilēngrupa, hetero-C2-6alkilēngrupa, heterookso-C3.6alkilēngrupa, okso-C2-6aIkiiēngrupa vai X25-X26-X27-, kur X25 ir ar jau minētām X15 nozīmēm, X25 ir Cn25alkilēngrupa un X27 ir Cn27alkilēngrupa, pie kam jebkura no augstāk minētajām alkilēngrupām, cikloalkilēngrupām, heterocikloalkilēngrupām, fenilēngrupām, arilēngrupām un heteroariiēn-grupām ir neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas: halogēna atoms, hidroksilgrupa, merkaptogrupa, Ci-8alkilgrupa, C3.14ciklo-aikilgrupa, C6-i4arilgrupa, Ce-uaril-C^alkilgrupa, C-ļ.3alkanoilgrupa, Ci.8alkoksigrupa, Ce-uariloksigrupa, C3.i4cikloalkiloksigrupa, Ci_4alkoksigrupa, Ci.8alkiltiogrupa, C3.14cikloalkiltiogrupa, Cs-uariltiogrupa un -NR6R7, kur R6 un R7 ir ar jau minētām nozīmēm, ar noteikumu, ka starp heteroatomiem, kas ietilpst R1, X1, X2, Χδ, X8, R1 un heteroatomiem, kas ietilpst X3, X5, X7 un X nav kovalentās saites, kā arī tā farmaceitiski pieņemamās sālis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi. 1 Savienojums pēc 1. punkta, kurā: 2 1,4-fenilēngrupa un X2 un X6 abi ir C0.ialkilēngrupas; 3 X5 ir cis-1,5-ciklooktilēngrupa un X2 un X° abi ir kovalentās saites vai X5 ir 3 LV 12291 X4 un X6, neatkarīgi viens no otra, ir Co-ialkilēngrupa; X1 un X9, neatkarīgi viens no otra, ir kovalentā saite, -CO-, -NHCO-, -CONH-, -N(CH3)CO- vai -S02NH- X3 un X7, neatkarīgi viens no otra, ir -CO- vai -COO-; X2 un X8, neatkarīgi viens no otra, ir -X10-X11-, kur X10 ir kovalentā saite vai metilēngrupa, X11 ir 1,4-piperazinilēngrupa; R1 ir R4-X12- vai R5-X13-, kur: R4 ir amidīngrupa, guanidīngrupa vai metiiaminogrupa; X12 ir -X14-X15-X16-, kur X15 ir 1,4-fenilēngrupa vai 1,4- piperidinil-ēngrupa, X14 ir Cnualkilēngrupa un XTs ir Cni6alkilēngrupa, kur n14 un n16 summa ir 0, 1 vai 2; R5 ir piperidin-4-ilgrupa; X13 ir C2-3alkilēngrupa; R2 ir Rs-X20- vai R9-X21-, kur: R8 is aminoarupa, metiiaminogrupa vai 1-iminoetiIgrupa, X20 ir X22-X -X24-, kur X23 ir trans-1,4-cikloheksilēngrupa, 1,4-fenilēngrupa, 4,1-piridinilēngrupa, 1,4-piperidinilēngrupa, X22 ir Cn22aikilēngrupa un X24 ir C^alkilēngrupa, pie kam n22 un n24 summa ir 1 vai 2; R9 ir benzimidazol-5-ilgrupa, imidazol-1-ilgrupa, imidazol-4-ilgrupa, 2-imidazolin-2-ilgrupa, 4-metilimidazoM-ilgrupa, 5-metilimid-azol-1 -ilgrupa, 1 -metilpiperidin-4-ilgrupa, piperidin-4-ilgrupa, piperazin-1 -ilgrupa, piridin-3-ilgrupa, piridin-4-ilgrupa, 1,4,5,6-tetrahidropirimidin-5-ilgrupa vai 1,4,5,6-tetrahidro-2-diokso-pirimidin-5-ilgrupa; X21 ir Ci-6alkilēngrupa vai cū-aza-C2-5alkilēngrupa, 2-aza-3-oksotri-metilēngrupa, 3-aza-2-oksotrimetilēngrupa, 3-oksotrimetiiēn-grupa, co-tia-C2.4alkilēngrupa vai -X25-X26-X27-, kur X26 ir 1,4-fenilēngrupa, X25 ir Cn25alkilēngrupa un X27 ir Cn27alkilēngrupa, pie tam n25 un n27 summa ir 0 vai 1; kā arī tā farmaceitiski pieņemamās sālīs, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi.A compound of formula (I): wherein: X 5 is C 1-12 alkylene, hetero-C 3 - 22 alkylene, C3-Cycloalkylene, hetero-C3-4cycloalkylene, C6-uarylene or hetero-Cuarylenyl; X4 and X6, independently of one another, are Co-2alkylene; X1 and X9, independently of one another, are covalent bond, -CO-, -COO-, -O-CO-, -CONR3-, -NR3CO-, -SO2NR3-, -NR3SO2-, -OCONR3-, -NR3COO- , -NR3CONR3- or -OCOO-, wherein R3, independently of one another, is hydrogen, C10alkyl or C3-8cycloalkyl, provided that both 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-, wherein R3 is as defined above; X2 and X8, independently of one another, are C1-6alkylene, hetero-C1-6alkylene, -X10-X11- or -X11-X10-, wherein X10 is Co-4alkylene or hetero-C3-4alkylene, X11 is 1,4-piperazinylene ; R1 is R4-X12- or R5-X13-, wherein: R4 is amino, amidine, guanidine, 1-iminoethyl or methylamino; X12 is C4-6alkylene, hetero-C4-6alkylene, hetero-C4-C4-alkyl, oxo-C4-6alkylene or -X14-X15-X16-, wherein X15 is C3-6cycloalkylene, hetero-C5-6arylene, hetero-C3-6cyclo -alkylene or phenylene, X 14 is C 1-4 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 a group 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-long group, 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, wherein said groups are optionally substituted with one or more substituents from the group consisting of halogen, hydroxy, mercaptogroup, C 1-8 alkyl, C 3-14 cycloalkyl, C 6-4 aryl, C 1-4 aryl-C 1 C 1-4 alkyl, C 1-4 alkyloxy, C 3 -C 11 cycloalkyloxy igrupa, C-alkoxy, C1-6alkylthio, C3-4cycloalkylthio, C6-4ar [thiogroup and -NRSR7, wherein R6 and R7, independently of one another, are substituents: hydrogen, C1-8alkyl, C1-8alkanoyl , C 6 -cycloalkyl and C 6 -aryl; X13 is C-alkylalkylene, hetero-C2-6alkylene, heteroxo-C3alkylalkenyl, oxo-C2-6alkylene, or X17-X18-X19-, wherein X18 is as defined above for X15)) C7 is Cnisalkylene and X19 is Cnnixki-slow, wherein the sum of n17 and n19 is 0, 1 or 2; R1 is R8-X20- or R9-X21-, wherein: R8 is amino, 1-iminoethyl or methylamino, X20 is C4-6alkylene, hetero-C4-6alkylene, heteroxo-C4-6alkylene, oxo-C4-6alkylene or X22- X23-X24-, wherein X23 is as defined above for X15, X20 is C 1-4 alkylene, and X 24 is C 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, X20 is not C4-6alkyl or oxa-C4-6alkylene and n22 is not 1,2, 3 or 4; R9 has the meanings already mentioned in R5; X21 is Co-alkylalkylene, hetero-C2-6alkylene, heterooxo-C3-6alkylene, oxo-C2-6aalkylene, or X25-X26-X27-, wherein X25 is as defined above for X15, X25 is C1-2alkylene, and X27 is CN27 alkylene, with any of the above alkylene groups, cycloalkylene groups, heterocycloalkylene groups, phenylene groups, arylene groups and heteroarylene groups are optionally substituted with one or more substituents from the group consisting of halogen, hydroxy, mercaptogroup, C 1-8 alkyl, C 3-14 cycloalkyl, C 6-4 aryl, Ce -aryl-C 1-4 -alkyl, C 1-3 -alkanoyl, C 1-8 -alkoxy, C 1-4 -alkoxy, C 3-4 -cycloalkyloxy, C 1-4 -alkoxy, C 1-8 -alkylthio, C 3-14 -cycloalkylthio, C 6 -arylthio, and -NR 6 R 7 wherein R 6 and R 7 are as previously mentioned meanings, provided that there are no covalent bonds between the heteroatoms selected from R1, X1, X2, Χδ, X8, R1 and heteroatoms that are X3, X5, X7, and X, as well as pharmaceutically acceptable salts thereof , N-oxides, drug precursors, and protecting group-containing derivatives. 1 A compound according to claim 1 wherein: 2 1,4-phenylene and X 2 and X 6 are both C 1-6 alkylene; 3 X 5 is cis-1,5-cyclooctylene and X 2 and X 0 are both covalent bonds or X 5 is 3 LV 12291 X 4 and X 6, independently of one another, are C-alkylalkylene; X1 and X9, independently of one another, are a covalent bond, -CO-, -NHCO-, -CONH-, -N (CH3) CO-, or -SO2NH-X3 and X7 independently of one another -CO- or -COO-; X2 and X8 independently of one another are -X10-X11-, wherein X10 is a covalent bond or methylene group, X11 is 1,4-piperazinylene; R1 is R4-X12- or R5-X13-, wherein: R4 is an amidine group, a guanidine group, or a methylamino group; X 12 is -X 14 -X 15 -X 16-, wherein X 15 is 1,4-phenylene or 1,4-piperidinyl-ene, X 14 is C 1-4 alkylene and X T 8 is C 1-6 alkylene wherein n 14 and n 16 are 0, 1 or 2; R5 is piperidin-4-yl; X 13 is C 2-3 alkylene; R2 is R5-X20- or R9-X21-, wherein: R8 is amino, amino, 1-iminoethyl, X20 is X22-X-X24-, wherein X23 is trans-1,4-cyclohexylene, 1,4-phenylene, 4,1-pyridinylen, 1,4-piperidinylen, 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; R9 is benzimidazol-5-yl, imidazol-1-yl, imidazol-4-yl, 2-imidazolin-2-yl, 4-methylimidazo-1-yl, 5-methylimidazol-1-yl, 1-methylpiperidine-4 long group, 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; X21 is C1-6alkylene or cu-aza-C2-5alkylene, 2-aza-3-oxotrimethylene, 3-aza-2-oxotrimethylene, 3-oxotrimethylene, co-thia-C2-4alkylene or -X25-X26 -X 27- wherein X 26 is 1,4-phenylene, X 25 is C 25 alkylene, and X 27 is C n 27 alkylene, with n25 and n27 being 0 or 1; as well as its pharmaceutically acceptable salts, N-oxides, drug precursors, and protecting groups. 3. Savienojums pēc 2. punkta, kurā: X5 ir cis-1,5-ciklooktilēngrupa un X4 un X6 abi ir kovalentās saites; X1 un X9, neatkarīgi viens no otra, ir kovalentā saite, -CO-, -NHCO-, -CONH-, -N(CH3)CO- vai -S02NH- X3 un X7, neatkarīgi viens no otra, ir -CO- vai -COO-; R1 ir R4-X12-, kur: ir amidīngrupa vai guanidīngrupa; ir Rs-X20- vai R9-X21-, kur: R8 is aminogrupa vai metiiaminogrupa; X23 irtrans-1,4-cikloheksilēngrupa, 1,4-fenilēngrupa; R" /21 ir imidazol-1-ilgrupa, imidazol-4-ilgrupa, 4-metilimidazol-1-ilgrupa, 5-metilimidazol-1-ilgrupa, piperidin-4-ilgrupa, piridin-4-ilgrupa; ir Ci-5alkiiēngrupa vai 3-azatrimetilēngrupa, kā arī tā farmaceitiski pieņemamās sālis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi. 4The compound of claim 2, wherein: X 5 is cis-1,5-cyclooctylene and X 4 and X 6 are both covalent bonds; X1 and X9, independently of one another, are a covalent bond, -CO-, -NHCO-, -CONH-, -N (CH3) CO-, or -SO2NH-X3 and X7 independently of one another -CO- or -COO-; R1 is R4-X12-, wherein: is an amidine or guanidine; is R5-X20- or R9-X21-, wherein: R8 is amino or methyamino; X23 is trans-1,4-cyclohexylene, 1,4-phenylene; R " / 21 is imidazol-1-yl, imidazol-4-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, piperidin-4-yl, pyridin-4-yl; are C 1-5 alkylene or 3-azathimethylene as well as pharmaceutically acceptable salts, N-oxides, prodrugs and derivatives thereof. 4 4. Savienojums pēc 3. punkta, kurā: X1 un X1, neatkarīgi viens no otra, ir kovalentā saite, -CO-, -NHCO-; X3 un X7, neatkarīgi viens no otra, ir -COO-; X2 un X2, neatkarīgi viens no otra, ir -X3-X4-, kur X3 ir kovalentā saite, X4 ir 1,4-piperazinilēngrupa; R1 ir R4-X12-, kur: R4 ir amidīngrupa vai guanidīngrupa; X12 ir -X14-X15-X16-, kur X15 ir 1,4-fenilēngrupa, X14 ir kovalentā saite un X16 ir metilēngrupa; R2 ir R2-X20- vai R1-X21-, kur: R2 is aminogrupa; X20 ir X22-X-X24-, kur X23 ir trans-1,4-cikloheksilēngrupa; X22 ir kovalentā saite un X^4 ir metilēngrupa; R1 ir piperidin-4-ilgrupa; X21 ir etilēngrupa vai trimetilēngrupa, kā arī tā farmaceitiski pieņemamās sālis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi.The compound of claim 3, wherein: X 1 and X 1, independently of one another, are a covalent bond, -CO-, -NHCO-; X3 and X7, independently of one another, are -COO-; X2 and X2 independently of one another are -X3-X4-, wherein X3 is a covalent bond, X4 is 1,4-piperazinylen; R 1 is R 4 -X 12 - wherein: R 4 is amidine or guanidine; X 12 is -X 14 -X 15 -X 16-, wherein X 15 is 1,4-phenylene, X 14 is a covalent bond and X 16 is methylene; R2 is R2-X20- or R1-X21-, wherein: R2 is an amino group; X 20 is X 22 -X-X 24- wherein X 23 is trans-1,4-cyclohexylene; X 22 is a covalent bond and X 4 is methylene; R 1 is piperidin-4-yl; X21 is ethylene or trimethylene, as well as its pharmaceutically acceptable salts, N-oxides, drug precursors, and protecting group derivatives. 5. Savienojums pēc 4. punkta, kurā: X1 un X1 abi ir-NHCO-; R1 ir 4-amidinobenzilgrupa; R2 ir 2-piperidin-4-iletilgrupa; proti, cis-1,5-ciklooktilēndiola esteris ar 4-(4-amidinobenzilkarbamoil)-1- piperazīnkarbonskābi un 4-(2-piperidin-4-i!etiikarbamoil)-1 -piperazīnkarbon-skābi, kā arī tā farmaceitiski pieņemamās sālis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi.The compound of claim 4, wherein: X 1 and X 1 are both -NHCO-; R1 is 4-amidinobenzyl; R2 is 2-piperidin-4-ylethyl; namely, the cis-1,5-cyclooctylene diol ester with 4- (4-amidinobenzylcarbamoyl) -1-piperazinecarboxylic acid and 4- (2-piperidin-4-ylcarbamoyl) -1-piperazinecarboxylic acid as well as its pharmaceutically acceptable salts, N-oxides, drug precursors and derivatives containing protecting groups. 6. Savienojums pēc 4. punkta, kurā: X1 ir-NHCO-; X1 ir-CO-; R1 ir 4-amidinobenzilgrupa; R2 ir 3-piperidin-4-ilpropilgrupa; proti, cis-1,5-ciklooktilēndiola esteris ar 4-(4-amidinobenzilkarbamoil)-1- piperazīnkarbonskābi un 4-(4-piperidin-4-ilbutirii)-1 -piperazīnkarbonskābi, kā arī tā farmaceitiski pieņemamās sālis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi.The compound of claim 4, wherein: X 1 is -NHCO-; X1 is -CO-; R1 is 4-amidinobenzyl; R2 is 3-piperidin-4-ylpropyl; namely, the cis-1,5-cyclooctylene diol ester with 4- (4-amidinobenzylcarbamoyl) -1-piperazinecarboxylic acid and 4- (4-piperidin-4-ylbutyryl) -1-piperazinecarboxylic acid as well as its pharmaceutically acceptable salts, N-oxides, drug precursors and derivatives containing derivatives. 7. Savienojums pēc 4. punkta, kurā: X1 un X1 abi ir-NHCO-; R1 ir 4-guanidinobenzilgrupa; R2 ir trans-4-aminocikloheksilmetilgrupa, proti, cis-1,5-ciklooktilēndiola esteris ar trans-4-(4-aminocikloheksilmetil- karbamoil)-1-piperazīnkarbonskābi un 4-(4-guanidinobenzilkarbamoil)-1-piper-azīnkarbonskābi, kā arī tā farmaceitiski pieņemamās sālis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi. 1 X1 un X1 abi ir -CO-; 2 Savienojums pēc 4. punkta, kurā: 3 R1 ir 4-amidinobenzilgrupa; 4 R2 ir 3-piperidin-4-ilpropilgrupa; 5 5 LV 12291 proti, cis-1,5-ciklooktilēndiola esteris ar 4-(4-amidinofeniiacetil)-1 -piper-azīnkarbonskābi un 4-(4-piperidin-4-ilbutiril)-1-piperazīnkarbonskābi, kā arī tā farmaceitiski pieņemamās sālīs, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi.The compound of claim 4, wherein: X 1 and X 1 are both -NHCO-; R1 is 4-guanidinobenzyl; R2 is a trans-4-aminocyclohexylmethyl group, i.e., a cis-1,5-cyclooctylene diol ester with trans-4- (4-aminocyclohexylmethylcarbamoyl) -1-piperazinecarboxylic acid and 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylic acid as also pharmaceutically acceptable salts, N-oxides, prodrugs, and protecting groups. 1 X1 and X1 are both -CO-; 2 A compound according to claim 4, wherein: R 1 is 4-amidinobenzyl; 4 R2 is 3-piperidin-4-ylpropyl; 12291 namely, the cis-1,5-cyclooctylene diol ester with 4- (4-amidinopheniacetyl) -1-piperazinecarboxylic acid and 4- (4-piperidin-4-ylbutyryl) -1-piperazinecarboxylic acid as well as pharmaceutically acceptable salts thereof. salts, N-oxides, drug precursors, and protecting group derivatives. 9. Savienojums pēc 4. punkta, kurā: X1 un X9 abi ir -NHCO-; R1 ir 4-guanidinobenziIgrupa; R2 ir 2-piperidin-4-iletilgrupa, proti, cīs-1,5-ciklooktilēndiola esteris ar 4-(4-guanidinobenzilkarbamoil)-1-piperazīnkarbonskābi un 4-(2-piperidin-4-iletilkarbamoil)-1-piperazīnkarbon-skābi, kā arī tā farmaceitiski pieņemamās sālis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi.The compound of claim 4, wherein: X 1 and X 9 are both -NHCO-; R1 is 4-guanidinobenzyl; R2 is 2-piperidin-4-ylethyl, that is, cis-1,5-cyclooctylene diol ester with 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylic acid and 4- (2-piperidin-4-ylethylcarbamoyl) -1-piperazinecarboxylic acid as well as pharmaceutically acceptable salts, N-oxides, prodrugs, and protecting groups thereof. 10. Savienojums pēc 4. punkta, kurā: X1 ir -NHCO-; X9 ir -CO-; R1 ir4-guanidinobenzilgrupa; R2 ir 3-piperidin-4-ilpropilgrupa; proti, cis-1,5-ciklooktilēndiola esteris ar 4-(4-guanidinobenzilkarbamoiI)-1-piperazīnkarbonskābi un 4-(4-piperidin-4-ilbutirii)-1-piperazīnkarbonskābi, kā arī tā farmaceitiski pieņemamās sālis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi.The compound of claim 4, wherein: X 1 is -NHCO-; X9 is -CO-; R1 is 4-guanidinobenzyl; R2 is 3-piperidin-4-ylpropyl; namely, cis-1,5-cyclooctylene diol ester with 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylic acid and 4- (4-piperidin-4-ylbutyryl) -1-piperazinecarboxylic acid, as well as its pharmaceutically acceptable salts, N-oxides, drug precursors and derivatives containing derivatives. 11. Savienojums pēc 4. punkta, kurā: X1 ir -CO-; X9 ir-NHCO-; R1 ir 4-guanidinobenzilgrupa; R2 ir 2-piperidin-4-iletilgrupa, proti, cis-1,5-ciklooktilēndiola esteris ar 4-(4-guanidinofenilacetil)-1-piperazīnkarbonskābi un 4-(2-piperidin-4-iletilkarbamoil)-1-piperazīnkarbon-skābi un, kā arī tā farmaceitiski pieņemamās sālis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi.A compound according to claim 4 wherein: X 1 is -CO-; X9 is -NHCO-; R1 is 4-guanidinobenzyl; R2 is 2-piperidin-4-ylethyl, namely cis-1,5-cyclooctylene diol ester with 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylic acid and 4- (2-piperidin-4-yl-ethylcarbamoyl) -1-piperazinecarboxylic acid and, as well as its pharmaceutically acceptable salts, N-oxides, drug precursors, and protecting group derivatives. 12. Savienojums pēc 4. punkta, kurā: X1 un X9 abi ir -CO-; R1 ir 4-guanidinobenzilgrupa; R2 ir 3-piperidin-4-ilpropilgrupa; proti, cis-1,5-ciklooktilēndiola esteris ar 4-(4-guanidinofenilacetil)-1-piper-azīnkarbonskābi un 4-(4-piperidin-4-ilbutiril)-1-piperazīnkarbonskābi, kā arī tā farmaceitiski pieņemamās sālis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi.The compound of claim 4, wherein: X 1 and X 9 are both -CO-; R1 is 4-guanidinobenzyl; R2 is 3-piperidin-4-ylpropyl; namely, the cis-1,5-cyclooctylene diol ester with 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylic acid and 4- (4-piperidin-4-ylbutyryl) -1-piperazinecarboxylic acid as well as its pharmaceutically acceptable salt, N- oxides, drug precursors, and protecting group derivatives. 13. Savienojums pēc 4. punkta, kurā: X1 ir -CO-; X9 ir-NHCO-; R1 ir 4-amidinobenzilgrupa; R2 ir 2-piperidin-4-iletilgrupa, proti, cis-1,5-ciklooktilēndiola esteris ar 4-(4-amidinofenilacetil)-1-piperazīnkarbonskābi un 4-(2-piperidin-4-iletilkarbamoii)-1 -piperazīnkarbon- 6 skābi un, kā arī tā farmaceitiski pieņemamas sāiis, N-oksīdi, zaļu priekštečvielas un aizsarggrupas saturošie atvasinājumi.The compound of claim 4, wherein: X 1 is -CO-; X9 is -NHCO-; R1 is 4-amidinobenzyl; R2 is 2-piperidin-4-ylethyl, that is, the cis-1,5-cyclooctylene diol ester with 4- (4-amidinophenylacetyl) -1-piperazinecarboxylic acid and 4- (2-piperidin-4-yl-ethylcarbamoyl) -1-piperazinecarbon-6 acid and, as well as its pharmaceutically acceptable salts, N-oxides, green prodrugs and derivatives containing protecting groups. 14. Farmaceitiskā kompozīcija, kas ietver terapeitiski iedarbīgu daudzumu savienojuma pēc 1. punkta kopā ar farmaceitiski pieņemamu atšķaidītāju.A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 together with a pharmaceutically acceptable diluent. 15. Savienojuma ar formulu (I) ιι'-χ'-χ^χ^χΐ ^χ5 R2-X9-X8-X7-X6 ^ I kurā: X5 ir Co-i2alkilēngrupa, hetero-C3-i2alkilēngrupa, C3.14cikloalkilēngrupa, hetero-C3-14cikloalkilēngrupa, C6-i4anlēngrupa vai hetero-C5.i4arilēn-grupa; X4 un X6, neatkarīgi viens no otra, ir C0_2alkilēngrupa; X1 un X9, neatkarīgi viens no otra, ir kovalentā saite, -CO-, -COO-, -O-CO-, -CONR3-, -NR3CO-, -S02NR3-, -NR3S02-, -OCONR3-, -NR3COO-, -NR3CONR3- vai -OCOO-, kur R3, neatkarīgi viens no otra, ir ūdeņraža atoms, Ci^alkilgrupa vai C3-acikloalkilgrupa; X3 un X7, neatkarīgi viens no otra, ir -CO-, -COO-, -O-CO-, -CONR3-, -NR3CO-, -S02NR3-, -NR3S02-, -OCONR3-, -NR3COO-, -NR3CONR3-vai -OCOO-, kur R3 nozīmes ir jau minētās; X2 un X8, neatkarīgi viens no otra, ir C-i-aalkilēngrupa, hetero-C-i.aalkilēngrupa, -X10-X11- vai -X11-X10-, kur X10 ir Co.4aikilēngrupa vai hetero-C3.4alkilēngrupa, X11 ir 1,4-piperazinilēngrupa; R1 ir R4-X12- vai R5-X13-, kur: R4 ir aminogrupa, amidīngrupa, guanidīngrupa, 1-iminoetilgrupa vai metilaminogrupa; X12 ir C4.salkilēngrupa, hetero-C4.galkilēngrupa, heterookso-C4-6alkil-ēngrupa, okso-C4.aalkilēngrupa vai -X14-X15-X16-, kur X15 ir C3.scikloalkilēngrupa, hetero-Cs-aarilēngrupa, hetero-C3.3ciklo-alkilēngrupa vai feniiēngrupa, X14 ir Cni4alkilēngrupa un X16 ir Cn-isalkilēngrupa, kur n14 un n16 summa ir 0, 1,2, 3 vai 4; R5 ir grupa no rindas: azetidin-3-ilgrupa, benzimidazol-4-ilgrupa, benzimidazol-5-ilgrupa, imidazol-1-ilgrupa, imidazol-2-ilgrupa, imidazol-4-ilgrupa, 2-imidazoiin-2-ilgrupa, 2-imidazolin-3-ilgrupa, 2-metilimidazol-1-ilgrupa, 4-metilimidazol-1-ilgrupa, 5-metiiimid-azol-1 -ilgrupa, 1 -metiipiperidin-3-ilgrupa, 1 -metilpiperidin-4- ilgrupa, piperidin-3-ilgrupa, piperidin-4-ilgrupa, piperazin-1-ilgrupa, piperazin-2-ilgrupa, piridin-3-ilgrupa, piridin-4-ilgrupa, pirimidin-4-ilgrupa, pirimidin-5-ilgrupa, pirolidin-3-ilgrupa, 1,4,5,6-tetrahidropirimidin-2-ilgrupa, 1,4,5,6-tetrahidropirimidin-4-ilgrupa, 1,4,5,6-tetrahidropirimidin-5-ilgrupa, kā arī minēto grupu karbocikliskie okso- vai tioksoatvasinājumi, pie tam minētās 7 7 LV 12291 grupas neobligāti aizvietotas ar vienu vai vairākiem aizvietotājiem no rindas: halogēna atoms, hidroksilgrupa, merkaptogrupa, Ci-8alkilgrupa, C3-i4Cikloalkilgrupa, Cg-uaril-grupa, Ce-uaril-Ci^alkilgrupa, Ci.8alkanoilgrupa, C6-i4ariioksi-grupa, C3-uCikloalkiloksigrupa, Ci-4alkoksigrupa, Ci.8alkiltio-grupa, C3.i4cikloalkiltiogrupa, Ce-uariltiogrupa un -NRSR7, kur R6 un R7, neatkarīgi viens no otra, ir aizvietotāji no rindas: ūdeņraža atoms, Ci.3alkilgrupa, Ci.8alkanoilgrupa, C3.14cikloalkilgrupa un C6-i4arilgrupa; X13 ir Co-6alkilēngrupa, hetero-C2-galkilēngrupa, heterookso-C3.6alkil-ēngrupa, okso-C2-6alkilēngrupa, vai X17-X18-X19-, kur X19 ir ar jau minētām X15 nozīmēm, X17 ir Cni7alkilēngrupa un X19 ir Cnigalki-lēnarupa, pie kam n17 un n 19 summa ir 0, 1 vai 2; R2 ir R-X20- vai R9-X21-, kur: R8 is aminogrupa, 1-iminoetilgrupa vai metilaminogrupa, X20 ir C4-6alkilēngrupa, hetero-C4-6alkilēngrupa, heterookso-C4-6alkilēngrupa, okso-C4-salkilēngrupa vai X22-X23-X24-, kur X23 ir ar jau minētām X15 nozīmēm, X22 ir Cn22alkilēngrupa un X24 ir Cn24alkilēngrupa, pie kam n22 un n24 summa ir 0, 1, 2, 3 vai 4, ar noteikumu, ka tad, kad R8 ir aminogrupa, X20 nav C4-6alkil-ēngrupa vai oksa-C4-6alkilēngrupa un n22 nav 1, 2, 3 vai 4; R9 ir ar nozīmēm, kuras jau minētas R5; X21 ir Co-ealkilēngrupa, hetero-C2-6alkilēngrupa, heterookso-C3.galkilēngrupa, okso-C2-6alkilēngrupa vai X-X26-X27-, kur X26 ir ar jau minētām X15 nozīmēm, X25 ir Cn25alkilēngrupa un X27 ir Cn27alkilēngrupa, pie tam n25 un n27 summa ir 0, 1 vai 2, pie kam jebkura no augstāk minētajām alkilēngrupām, cikloalkilēngrupām, heterocikloalkilēngrupām, fenilēngrupām, arilēngrupām un heteroarilēn-grupām ir neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas: halogēna atoms, hidroksilgrupa, merkaptogrupa, Ci-aalkilgrupa, C3-i4ciklo-alkilgrupa, Cg-uarilgrupa, Ce-uaril-C-Malkilgrupa, Ci.galkanoilgrupa, Ci.8alkoksigrupa, C6-i4ariloksigrupa, C3-14cikloalkiloksigrupa, Ci.4alkoksigrupa, Ci.8alkiltiogrupa, C3.i4Cikloalkiltiogrupa, C6-uariltiogrupa un -NR6R7, kur R6 un R7 ir ar jau minētām nozīmēm, ar noteikumu, ka starp heteroatomiem, kas ietilpst R1, X2, X4, X6, X8, R2 un heteroatomiem, kas ietilpst X3, X5, X7 un X9 nav kovalentās saites, kā arī tā farmaceitiski pieņemamās sāls, N-oksīda, zāļu priekštečvielas vai aizsarggrupas saturošā atvasinājuma pielietojums medicīniskā preparāta ražošanai, kas paredzēts dzīvnieku slimību ārstēšanai, kurās patoloģija un/vai simptomatoloģija saistīta artriptāzes aktivitāti.A compound of formula (I) wherein: X 5 is C 1-12 alkylene, hetero-C 3-12 alkylene, C 3-14 cycloalkylene, hetero-C3-14cycloalkylene, C6-4aniline or hetero-C5-4 arylene; X4 and X6, independently of one another, are C 0-2 alkylene; X1 and X9, independently of one another, are covalent bond, -CO-, -COO-, -O-CO-, -CONR3-, -NR3CO-, -SO2NR3-, -NR3SO2-, -OCONR3-, -NR3COO- , -NR3CONR3- or -OCOO- wherein R3, independently of one another, is hydrogen, C1-6alkyl or C3-acycloalkyl; X3 and X7, independently of one another, are -CO-, -COO-, -O-CO-, -CONR3-, -NR3CO-, -SO2NR3-, -NR3SO2-, -OCONR3-, -NR3COO-, -NR3CONR3 -or -OCOO-, wherein R3 is as defined above; X2 and X8, independently of one another, are C1-6alkylene, hetero-C1-6alkylene, -X10-X11- or -X11-X10-, wherein X10 is Co.4alkylene or hetero-C3-4alkylene, X11 is 1.4 piperazinylene; R1 is R4-X12- or R5-X13-, wherein: R4 is amino, amidine, guanidine, 1-iminoethyl or methylamino; X12 is C4alkylene, hetero-C4 alkylene, heteroxo-C4-6alkyl, oxo-C4alkylene or -X14-X15-X16-, wherein X15 is C3-cycloalkylene, hetero-C3-arylene, hetero-C3 .3cycloalkylene or phenylene, X14 is C1-4alkylene, and X16 is Cn-isalkylene, where the sum of n14 and n16 is 0, 1,2, 3 or 4; R5 is a group of azetidin-3-yl, benzimidazol-4-yl, benzimidazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazin-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-long group, 1,4,5,6-tetrahydropyrimidin-2-yl, 1,4,5,6-tetrahydropyrimidin-4-yl, 1,4,5,6-tetrahydropyrimidin-5-yl, as well as said group carbocyclic oxo or thioxo derivatives, wherein said groups of 7 7 LV 12291 are optionally substituted with one or more substituents from halogen, hydroxy, mercapto, C 1-8 alkyl, C 3-14 cycloalkyl, C 8 uaryl, C 1-6 alkyl. C 1-8 alkyl, C 1-8 alkanoyl, C 6-14 aryloxy, C 3 -C 10 C icloalkyloxy, C 1-4 alkoxy, C 1-8 alkylthio, C 3-14 cycloalkylthio, C 1-4 arylthio, and -NRSR 7, wherein R 6 and R 7, independently of one another, are substituted by hydrogen, C 1-3 alkyl, C 1-8 alkanoyl, C 3 .14cycloalkyl and C6-4aryl; X13 is Co-6alkylene, hetero-C2-galkylene, heteroxo-C3-6alkyl, oxo-C2-6alkylene, or X17-X18-X19-, wherein X19 is as defined above for X15, X17 is Zn7alkylene and X19 is Cnigalki - a nylon, wherein the sum of n17 and n19 is 0, 1 or 2; R2 is R-X20- or R9-X21-, wherein: R8 is amino, 1-iminoethyl or methylamino, X20 is C4-6alkylene, hetero-C4-6alkylene, heteroxo-C4-6alkylene, oxo-C4-alkylene or X22- X23-X24-, wherein X23 is as defined above for X15, X22 is C1-2alkylene, and X24 is C1-2alkylene, wherein the sum of n22 and n24 is 0, 1, 2, 3 or 4, provided that when R8 is an amino group, X20 is not C4-6alkyl or oxa-C4-6alkylene and n22 is not 1, 2, 3 or 4; R9 has the meanings already mentioned in R5; X21 is Co-alkylkylene, hetero-C2-6alkylene, heteroxo-C3alkylene, oxo-C2-6alkylene or X-X26-X27-, wherein X26 is as defined above for X15, X25 is C11-C25 alkylene, and X27 is Cn27alkenyl; The sum of n25 and n27 is 0, 1, or 2, wherein any of the above alkylene groups, cycloalkylene groups, heterocycloalkylene groups, phenylene groups, arylene groups, and heteroarylene groups are optionally substituted with one or more substituents on the halogen atom, hydroxyl group, mercaptogroup, C1- alkyl, C3-14cycloalkyl, C1-6aryl, C1-6alkyl-C-Malkyl, C1-6alkanoyl, C1-8alkoxy, C6-4aryloxy, C3-14cycloalkyloxy, C1-4alkoxy, C1-8 alkylthio, C3-4cycloalkylthio, C6- uarylthio and -NR6R7, wherein R6 and R7 are of the same meaning as mentioned above, provided that there is no covalent bond between the heteroatoms of R1, X2, X4, X6, X8, R2 and heteroatoms included in X3, X5, X7 and X9 as well as t pharmaceutically acceptable salt, N-oxide, prodrug, or protecting derivatives use for the manufacture of the medicinal product intended for animal diseases where the pathology and / or symptomatology associated artriptāzes activity. 16. Pielietojums pēc 15. punkta, kurā minētā slimība ir no rindas: astma, alerģiskais rinīts, reimatoīdais spondilīts, osteoartrīts, podagra, reimatoīdais artrīts, dažāda veida artrītiskie stāvokļi, nātrene, angioedēma, ekzemātiskais dermatīts, anafilakse, hiperproliferatīva ādas slimība, peptiskā čūla, zarnu iekaisums, acu un pavasara konjuktivīts un ādas iekaisuma stāvokļi.16. The use according to claim 15, wherein said disease is from the group: asthma, allergic rhinitis, rheumatoid spondylitis, osteoarthritis, gout, rheumatoid arthritis, various types of arthritic conditions, urticaria, angioedema, eczema dermatitis, anaphylaxis, hyperproliferative skin disease, peptic ulcer , inflammation of the intestines, conjunctivitis of the eyes and spring, and inflammatory conditions of the skin. 17. Pielietojums pēc 16. punkta, kurā minētā slimība ir astma. 817. The use of claim 16 wherein said disease is asthma. 8 18. Pielietojums pēc 17. punkta, kurā savienojums tiek ievadīts kopa ar farmaceitiski pieņemamu aerosolu veidojošu nesēju, kas piemērots inhalācijai.Use according to claim 17, wherein the compound is administered together with a pharmaceutically acceptable aerosol-forming carrier suitable for inhalation. 19. Pielietojums pēc 18. punkta, kurā terapeitiski iedarbīgu daudzumu savienojuma ievada kopā ar β-adrenoreceptoru agonista, metilksantīna, kromoglikāta vai kortikosteroīda.Use according to claim 18, wherein the therapeutically effective amount of the compound is administered in combination with a β-adrenoreceptor agonist, methylxanthine, chromoglycate or corticosteroid. 20. Pielietojums pēc 19. punkta, kurā β-adrenoreceptoru agonists ir ņemts no rindas: albuterols, terbutalīns, fenoterols un prenalīns; metilksantīns ir ņemts no rindas: kofeīns, teofilīns, aminofilīns un teobromīns; kromoglikāts ir ņemts no rindas: kromolīns un nedokromils; kortikosterīds ņemts no rindas: beklometazons, triamcinolons, flunizolīds un deksametazons.The use according to claim 19, wherein the β-adrenoreceptor agonist is from the group: albuterol, terbutaline, phenoterol and prenaline; methylxanthine is taken from the line caffeine, theophylline, aminophylline and theobromine; chromoglycate is taken from the row: chromoline and nedocromil; corticosteride is taken from the group: beclomethasone, triamcinolone, flunizolide and dexamethasone. 21. Pielietojums pēc 16. punkta, kurā minētā slimība ir reimatoīdais atrīts vai konjunktivīts.Use according to claim 16, wherein said disease is rheumatoid or conjunctivitis. 22. Pielietojums pēc 21. punkta, kurā savienojums tiek ievadīts kopā ar farmaceitiski pieņemamu aerosolu veidojošu nesēju, kas piemērots uzklāšanai uz ādas.Use according to claim 21, wherein the compound is administered together with a pharmaceutically acceptable aerosol-forming carrier suitable for application to the skin. 23. Savienojums ar formulu (I): r‘-Xi-X2-X3-X4n. r2-x9-x8-x7-x6^ I kurā: X4-X5-X6 visi kopā ir C2-i2all<ilēngrupa vai hetero-C3.12alkilēngrupa; X1 un X9, neatkarīgi viens no otra, ir kovalentā saite, -CO-, -COO-, -O-CO-, -CONR3-, -NR3CO-, -S02NR3-, -NR3S02-, -OCONR3-, -NR3COO-, -NR3CONR3- vai -OCOO-, kur R3, neatkarīgi viens no otra, ir ūdeņraža atoms, Ci.3alkilgrupa vai C3.acikIoalkilgrupa, ar noteikumu, ka X1 un X9 abi vienlaikus nav kovalentā saite; X3 un X7, neatkarīgi viens no otra, ir -CO-, -COO-, -O-CO-, -CONR3-, -NR3CO-, -S02NR3-, -NR3S02-, -OCONR3-, -NR3COO-, -NR3CONR3-vai -OCOO-, kur R3 nozīmes ir jau minētās; X2 un X8, neatkarīgi viens no otra, ir Ci.8alkilēngrupa, hetero-C-i-aalkilēngrupa, -X10-X11- vai -X11-X10-, kur X10 ir Co-4alkilēngrupa vai hetero-C3.4alkilēngrupa, X11 ir 1,4-piperazinilēngrupa; R1 ir R4-X12- vai R5-X13-, kur: R4 ir aminogrupa, amidīngrupa, guanidīngrupa, 1-iminoetilgrupa vai metilaminogrupa; X12 ir C4.salkilēngrupa, hetero-C^salkilēngrupa, heterookso-C4.6alkil-ēngrupa, okso-C4.6alkilēngrupa vai -X14-X15-X16-, kur X15 ir C3.6cikloalkilēngrupa, hetero-Cs.garilēngrupa, hetero-Cs-gciklo- 9 Ί6 R X 13 R“ ,21 LV 12291 alkilēngrupa vai fenilēngrupa, X14 ir Cni4alkilēngrupa un X10 ir Cni6alkilēngrupa, kur n14 un n16 summa ir 0, 1, 2, 3 vai 4; ir grupa no rindas: azetidin-3-ilgrupa, benzimidazol-4-ilgrupa, benzimidazol-5'ilgrupa, imidazol-1-ilgrupa, imidazol-2-ilgrupa, imidazol-4-ilgrupa, 2-imidazolin-2-ilgrupa, 2-imidazolin-3-ilgrupa, 2-metiIimidazol-1 -ilgrupa, 4-metilimidazol-1 -ilgrupa, 5-metiIimid-azoi-1-ilgrupa, 1 -metiipiperidin-3-ilgrupa, 1 -metiipiperidin-4-ilgrupa, piperidin-3-ilgrupa, piperidin-4-iIgrupa, piperazin-1-ilgrupa, piperazin-2-ilgrupa, piridin-3-ilgrupa, piridin-4-ilgrupa, pirimidin-4-ilgrupa, pirimidin-5-ilgrupa, pirolidin-3-iIgrupa, 1,4,5,6-tetrahidropirimidin-2-ilgrupa, 1,4,5,6-tetrahidropirimidin-4-ilgrupa, 1,4,5,6-tetrahidropirimidin-5-ilgrupa, kā arī minēto grupu karbocikliskie okso- vai tioksoatvasinājumi, pie tam minētās grupas neobligāti aizvietotas ar vienu vai vairākiem aizvietotājiem no rindas: halogēna atoms, hidroksilgrupa, merkaptogrupa, Ci.3alkilgrupa, C3-i4cikloalkilgrupa, Ce-uaril-grupa, C6-i4aril-Ci_4alkilgrupa, Ci.3alkanoilgrupa, C6-i4ariloksi-grupa, C3.i4cikioalkiloksigrupa, C-i.4a!koksigrupa, Ci.3alkiltio-grupa, C3.14cikloalkiltiogrupa, Cs-uariltiogrupa un -NRSR7, kur R6 un R7, neatkarīgi viens no otra, ir aizvietotāji no rindas: ūdeņraža atoms, C-i-salkilgrupa, Ci.3alkanoilgrupa, C3.i4cikloalkilgrupa un C6-i4arilgrupa; ir Co-galkilēngrupa, hetero-C2-6alkilēngrupa, heterookso-C3.6alkil- ēngrupa, okso-C2-6alkilēngrupa, vai -X17-X18-X19-, kur X1S ir ar r19 jau minētām X13 nozīmēm, X17 ir Cni7alkilēngrupa un Xia ir Cnigalkilēngrupa, pie kam n17 un n19 summa irO, 1 vai 2; ir Ra-X20- vai R9-X21-, kur: Rs ir ar jau minētām R4 nozīmēm; X20 ir C4-6alkilēngrupa, hetero-C4-6alkilēngrupa, heterookso-C4-3alkilēngrupa, okso-C4-6alkilēngrupa vai -X22-X23-X24-, kur X23 ir ar jau minētām X15 nozīmēm, X22 ir Cn22alkilēngrupa un X24 ir Cn24alkilēngrupa, pie kam n22 un n24 summa ir 0, 1, 2, 3 vai 4; ir ar nozīmēm, kuras jau minētas R5; ir Co.6aikilēngrupa, hetero-C2.6alkilēngrupa, heterookso- ·« I !✓! IΛ m ** λ I Iv IΛ λ j-* *· > μ λ w25 C3.6alkilēngrupa, okso-C2-6alkilēngrupa vai -X43-X26-X27-, kur X 2S ir ar jau minētām X15 nozīmēm, X" ir Cn2salkilēngrupa un Υ?' ir Cn27alkilēngrupa, pie tam n25 un n27 summa ir 0, 1 vai 2, pie kam jebkura no augstāk minētajām alkilēngrupām, cikloalkilēngrupām, heterocikloalkilēngrupām, fenilēngrupām, arilēngrupām un heteroarilēn-grupām ir neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas: halogēna atoms, hidroksilgrupa, merkaptogrupa, Ci.3alkilgrupa, C3.i4ciklo-alkiigrupa, C6.14arilgrupa, C6-i4aril-Ci.4alkilgrupa, Ci.3alkanoilgrupa, Ci-aalkoksigrupa, C6.i4ariloksigrupa, C3.i4cikloalkiloksigrupa, Ci.4alkoksigrupa, Ci.3alkiltiogrupa, C3.14cikloalkiltiogrupa, Cs.14ariitiogrupa un -NR6R7, kur R6 un R7 ir ar jau minētām nozīmēm, ar noteikumu, ka starp heteroatomiem, kas ietilpst R1, X2, X4, Χδ, X3, R2 un heteroatomiem, kas ietilpst X3, X5, X7 un X nav kovalentās saites, kā arī tā farmaceitiski pieņemamās sālis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi. 10A compound of formula (I): r'-Xi-X2-X3-X4n. wherein x4-X5-X6 together are C2-12al < ylene or hetero-C3.12alkylene; X1 and X9, independently of one another, are covalent bond, -CO-, -COO-, -O-CO-, -CONR3-, -NR3CO-, -SO2NR3-, -NR3SO2-, -OCONR3-, -NR3COO- , -NR3CONR3- or -OCOO-, wherein R3, independently of one another, is hydrogen, C1-3 alkyl, or C3- cycloalkyl, provided that both 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-, wherein R3 is as defined above; X2 and X8, independently of one another, are C1-8alkylene, hetero-C1-6alkylene, -X10-X11- or -X11-X10-, wherein X10 is Co-4alkylene or hetero-C3-4alkylene, X11 is 1,4 piperazinylene; R1 is R4-X12- or R5-X13-, wherein: R4 is amino, amidine, guanidine, 1-iminoethyl or methylamino; X 12 is C 4 alkylene, hetero-C 1-6 alkylene, hetero-oxo-C 4-6 alkylenedio, oxo-C 4-6 alkylene, or -X 14 -X 15 -X 16-, wherein X 15 is C 3-6 cycloalkylene, hetero-C 6 -C 8 alkylene, hetero-Cs -cyclo-9-6 RX 13 R ', 21 LV 12291 alkylene or phenylene, X 14 is C 1-4 alkylene, and X 10 is C 1-6 alkylene, wherein the sum of n 14 and n 16 is 0, 1, 2, 3 or 4; is a group 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, piperidine -3-long group, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrrolidin-3 -Il, 1,4,5,6-tetrahydropyrimidin-2-yl, 1,4,5,6-tetrahydropyrimidin-4-yl, 1,4,5,6-tetrahydropyrimidin-5-yl, and carbocyclic groups of these groups oxo or thioxo derivatives, wherein said groups are optionally substituted with one or more substituents from the group consisting of halogen, hydroxy, mercaptogroup, C 1-3 alkyl, C 3-14 cycloalkyl, C 1-4 aryl, C 6-14 aryl-C 1-4 alkyl, C 1-3 alkanoyl, C6-4aryloxy, C3-4cycloalkyloxy a, C 1-4 cycloalkyl, C 1-3 alkylthio group, C 3-14 cycloalkylthio group, C 5 -arylthio group and -NRSR 7, wherein R 6 and R 7, independently of one another, are substituents of the hydrogen atom, C 1-6 alkyl, C 1-3 alkanoyl , C3-4cycloalkyl and C6-4aryl; is C 0 -C 8 alkylene, hetero-C 2-6 alkylene, hetero-oxo-C 3-6 alkylene, oxo-C 2-6 alkylene, or -X 17 -X 18 -X 19-, wherein X 1 S is the X 13 meanings already mentioned with R 19, X 17 is C 1-7 alkylene and Xia is A C 1-6 alkylene group wherein the sum of n 17 and n 19 is O, 1 or 2; is Ra-X20- or R9-X21-, wherein: R5 is as defined above for R4; X20 is C4-6alkylene, hetero-C4-6alkylene, heteroxo-C4-3alkylene, oxo-C4-6alkylene or -X22-X23-X24-, wherein X23 is as defined above for X15, X22 is CN22 alkylene, and X24 is C24 alkylene, at the sum of n22 and n24 is 0, 1, 2, 3 or 4; are with the meanings already mentioned in R5; is Co.6alkylene, hetero-C2-6alkylene, heterocyclo · «I! ✓! Λ m ** λ I Iv Λ λ j- * * · > μ λ w25 C3-6alkylene, oxo-C2-6alkylene or -X43-X26-X27- wherein X2S is as defined above for X15, X " is CN2alkylene and Υ? ' is a C n 27 alkylene group, the sum of n 25 and n 27 being 0, 1 or 2, wherein any of the above alkylene groups, cycloalkylene groups, heterocycloalkylene groups, phenylene groups, arylene groups and heteroarylene groups are optionally substituted with one or more substituents on the halogen atom, hydroxy group , mercaptogroup, C 1-3 alkyl, C 3-14 cycloalkyl, C 6-14 aryl, C 6 -C 11 arylC 1-4 alkyl, C 1-3 alkanoyl, C 1-4 alkoxy, C 6-14 aryloxy, C 3-4 cycloalkyloxy, C 1-4 alkoxy, C 1-3 alkylthio, C 3 .14cycloalkylthio, Cs.14thio, and -NR6R7, wherein R6 and R7 are of the same meaning as mentioned above, provided that between the heteroatoms included in R1, X2, X4, Χδ, X3, R2 and heteroatoms included in X3, X5, X7 and X is not a covalent bond, as well as its pharmaceutically acceptable salts, N-oxides, drug precursors, and protecting group-containing derivatives. 10 24. Savienojums pēc 23. punkta, kurā: X4-X5-X6 visi kopā ir C2-ioalkilēngrupa vai hetero-C3.i0alkilēngrupa; X1 un X9, neatkarīgi viens no otra, ir kovalentā saite, -CO-, -NHCO-, -CONH-, -N(CH3)CO- vai —S02NH-; X3 un X7, neatkarīgi viens no otra, ir -CO-, -COO-; X2 un X8, neatkarīgi viens no otra, ir -X10-X11- vai -X11-X10-, kur X10 ir kovalentā saite vai metilēngrupa un X11 ir 1,4-piperazinilēngrupa; R1 ir R4-X12- vai R5-X13-, kur: R4 ir amidīngrupa, guanidīngrupa vai metilaminogrupa; X12 ir -X14-X15-X16-, kur X15 ir 1,4-fenilēngrupa vai ^ 1,4-piperidinilēngrupa, X14 ir Cni4alkilēngrupa un Xi6 ir Cni6alkilēngrupa, kur n14 un n16 summa ir 0, 1 vai 2; R5 ir piperidin-4-ilgrupa; X13 ir C2.3alkilēngrupa; R2 ir R8-X20- vai R9-X21-, kur: R8 ir aminogrupa, amidīngrupa, guanidīngrupa, metilaminogrupa vai 1-iminoetilgrupa; X20 ir -X22-X23-X24-, kur X23 ir trans-1,4-cikloheksilēngrupa, 1,4-fenilēngrupa, 4,1-piridinilēngrupa, 1,4-piperidinilēngrupa, X22 ir Cn22alkilēngrupa un X24 ir Cn24alkilēngrupa, pie kam n22 un n24 summa ir 1 vai 2; R9 ir benzimidazol-5-ilgrupa, imidazol-1-ilgrupa, imidazol-4-ilgrupa, 2-imidazolin-2-ilgrupa, 4-metilimidazol-1-ilgrupa, 5-metilimid-azol-1-ilgrupa, 1-meti!piperidin-4-ilgrupa, piperidin-4-ilgrupa, piperazin-1-ilgrupa, piridin-3-ilgrupa, piridin-4-ilgrupa, 1,4,5,6-tetrahidropirimidin-5-ilgrupa vai 1,4,5,6-tetrahidro-2-diokso-pirimidin-5-ilgrupa; X21 ir Cļ^alkilēngrupa vai ω-aza-C2.5alkίlēngrupa, 2-aza-3-oksotri-metilēngrupa, 3-aza-2-oksotrimetilēngrupa, 3-oksotrimetilēn-grupa, CL>-tia-C2-4alkilēngrupa vai -X25-X2S-X27-, kur X26 ir 1,4-fenilēngrupa, X25 ir Cn25alkilēngrupa un X27 ir Cn27alkilēngrupa, pie tam n25 un n27 summa ir 0 vai 1, kā arī tā farmaceitiski pieņemamās sālis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi.24. The compound of claim 23, wherein: X4-X5-X6 together are C2-10alkylene or hetero-C3alkylene; X 1 and X 9, independently of one another, are a covalent bond, -CO-, -NHCO-, -CONH-, -N (CH 3) CO-, or -SO 2 NH-; X3 and X7 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 1,4-piperazinylen; R1 is R4-X12- or R5-X13-, wherein: R4 is amidine, guanidino or methylamino; X 12 is -X 14 -X 15 -X 16-, wherein X 15 is 1,4-phenylene or 1,4-piperidinylen, X 14 is C 1-4 alkylene, and X 16 is C 1-6 alkylene, wherein the sum of n 14 and n 16 is 0, 1 or 2; R5 is piperidin-4-yl; X 13 is C 2-3 alkylene; R2 is R8-X20- or R9-X21-, wherein: R8 is amino, amidine, guanidine, methylamino or 1-iminoethyl; X20 is -X22-X23-X24-, wherein X23 is trans-1,4-cyclohexylene, 1,4-phenylene, 4,1-pyridinylene, 1,4-piperidinylen, X22 is CN22alkylene, and X24 is CN24 alkylene, with n22 and the sum of n24 is 1 or 2; R9 is benzimidazol-5-yl, imidazol-1-yl, imidazol-4-yl, 2-imidazolin-2-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-methyl! piperidin-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 ω-aza-C 2-5 alkynyl, 2-aza-3-oxotrimethylene, 3-aza-2-oxotrimethylene, 3-oxotrimethylene, CL > -thia-C 2-4 alkylene or -X 25- X2S-X27-, wherein X26 is 1,4-phenylene, X25 is Cn25alkylene, and X27 is Cn27alkenyl, n25 and n27 being 0 or 1, and pharmaceutically acceptable salts, N-oxides, prodrugs and derivatives thereof . 25. Savienojums pēc 24. punkta, kurā: X4-X5-X6 visi kopā ir C4.aalkilēngrupa vai hetero-C4-ioalkilēngrupa; X1 un X9, neatkarīgi viens no otra, ir kovalentā saite, -CO-, -NHCO-, -CONH-, vai -S02NH-; X3 un X7, neatkarīgi viens no otra, ir-CO-, -C00-; R1 ir R4-X12, kur: R4 ir amidīngrupa vai guanidīngrupa; R2 ir R8-X20- vai R9-Xil-, kur: R8 ir aminogrupa, amidīngrupa, guanidīngrupa vai metilaminogrupa; X23 ir trans-1,4-cikloheksilēngrupa vai 1,4-fenilēngrupa; R9 ir imidazol-1-ilgrupa, imidazol-4-ilgrupa, 4-metilimidazol-1- ilgrupa, 5-metilimid-azol-1-ilgrupa, piperidin-4-iIgrupa, piridin-4-ilgrupa; X21 ir Ci.5alkilēngrupa vai 3-azatrimetilēngrupa, 11 11 LV 12291 kā arī tā farmaceitiski pieņemamās sēlis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi.25. The compound of claim 24, wherein: X4-X5-X6 are taken together as C4alkylene or hetero-C4-alkylalkylene; X 1 and X 9, independently of one another, are a covalent bond, -CO-, -NHCO-, -CONH-, or -SO 2 NH-; X3 and X7 independently of one another are -CO-, -C00-; R 1 is R 4 -X 12, wherein: R 4 is amidine or guanidine; R2 is R8-X20- or R9-Xyl-, wherein: R8 is amino, amidine, guanidine or methylamino; X23 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 1-5 alkylene or 3-aza-trimethylene, 11 11 EN 12291, as well as pharmaceutically acceptable fungi, N-oxides, drug precursors, and protecting group derivatives. 26. Savienojums pēc 25. punkta, kurā: X1 un X9, neatkarīgi viens no otra, ir -CO- vai -NHCO-; X3 un X7, neatkarīgi viens no otra, ir -CO-, -COO-; X2 un X8, neatkarīgi viens no otra, ir -X10-X11-, kur X10 ir kovalentā saite un X11 ir 1,4-piperaziniIēngrupa; R1 ir R4-X , kur: R4 ir amidīngrupa vai guanidīngrupa; X12 ir -X14-X15-X1S-, kur X15 ir 1,4-fenilēngrupa, X14 ir kovalentā saite, X16 ir metilēngrupa; R2 ir R8-X20-, kur: R8 ir amidīngrupa vai guanidīngrupa; X20 ir -X22-X23-X24-, kur X23 ir 1,4-fenilēngrupa, X22 ir kovalentā saite un X24 ir metilēngrupa; kā arī tā farmaceitiski pieņemamās sālis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi.The compound of claim 25, wherein: X 1 and X 9, independently of one another, are -CO- or -NHCO-; X3 and X7 independently of one another are -CO-, -COO-; X2 and X8, independently of one another, are -X10-X11- wherein X10 is a covalent bond and X11 is 1,4-piperazinyl; R 1 is R 4 -X, wherein: R 4 is amidine or guanidine; X 12 is -X 14 -X 15 -X 1 S- wherein X 15 is 1,4-phenylene, X 14 is a covalent bond, X 16 is methylene; R 2 is R 8 -X 2 O-, wherein: R 8 is amidine or guanidine; X 20 is -X 22 -X 23 -X 24- wherein X 23 is 1,4-phenylene, X 22 is a covalent bond and X 24 is methylene; as well as its pharmaceutically acceptable salts, N-oxides, drug precursors, and protecting group derivatives. 27. Savienojums pēc 26. punkta, kurā: X4-X5-X6 visi kopā ir heksametilēngrupa; X1 un X9 abi ir-NHCO-; X3 un X7 abi ir -CO-; R1 un R2 abi ir 4-guanidīnobenzilgrupa, proti, 4-{7-[4-(4-guanidinobenzilkarbamoil)piperazin-1-ilkarbonil]heptanoiipiperazīn- 1-(4-guanidinobenziI)karboksamīds, kā arī tā farmaceitiski pieņemamās sālis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi.27. The compound of claim 26, wherein: X4-X5-X6 are taken together as hexamethylene; X1 and X9 are both -NHCO-; X3 and X7 are both -CO-; R1 and R2 are both 4-guanidino-benzyl, that is, 4- {7- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] heptano-piperazine-1- (4-guanidinobenzyl) carboxamide, as well as its pharmaceutically acceptable salts, N- oxides, drug precursors, and protecting group derivatives. 28. Savienojums pēc 26. punkta, kurā: X4-X5-X6 visi kopā ir heptametilēngrupa; X1 un X9 abi ir-NHCO-; X3 un X7 abi ir -CO-; R1 un R2 abi ir 4-guanidīnobenzilgrupa, proti, 4-{7-[4-(4-guanidinobenziikarbamoil)piperazin-1-ilkarbonil]oktanoilpiperazīn-1- (4-guanidinobenzil)karboksamīds, kā arī tā farmaceitiski pieņemamās sālis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi.28. The compound of claim 26, wherein: X4-X5-X6 are collectively a heptamethylene group; X1 and X9 are both -NHCO-; X3 and X7 are both -CO-; R1 and R2 are both 4-guanidino-benzyl, namely, 4- {7- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] octanoyl-piperazine-1- (4-guanidinobenzyl) -carboxamide, as well as its pharmaceutically acceptable salts, N- oxides, drug precursors, and protecting group derivatives. 29. Savienojums pēc 26. punkta, kurā: X4-X5-X6 visi kopā ir oktametilēngrupa; X1 un X9 abi ir -NHCO-; X3 un X7 abi ir -CO-; R1 un R2 abi ir 4-guanidīnobenzilgrupa, proti, 4-{7-[4-(4-guanidinobenzilkarbamoil)piperazin-1-ilkarbonil]nonanoilpiperazīn- 1-(4-guanidinobenzil)karboksamīds, kā arī tā farmaceitiski pieņemamās sālis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi.29. The compound of claim 26, wherein: X4-X5-X6 are taken together as octamethylene; X1 and X9 are both -NHCO-; X3 and X7 are both -CO-; R1 and R2 are both 4-guanidino-benzyl, namely, 4- {7- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] nonanoylpiperazine-1- (4-guanidinobenzyl) carboxamide, as well as its pharmaceutically acceptable salts, N- oxides, drug precursors, and protecting group derivatives. 30. Savienojums pēc 26. punkta, kurā: 12 X4-X5-X6 visi kopā ir heksametilēngrupa; X1 un X9 abi ir -NHCO-; X3 un X7 abi ir -CO-; R1 un R2 abi ir 4-amidīnobenzilgrupa, proti, 4-{7-[4-(4-amidinobenzilkarbamoil)piperazin-1-ilkarbonil]heptanoilpiperazīn-1- (4-amidinobenziI)karboksamīds, kā arī tā farmaceitiski pieņemamās sālis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi.The compound of claim 26, wherein: X4-X5-X6 are all together hexamethylene; X1 and X9 are both -NHCO-; X3 and X7 are both -CO-; R1 and R2 are both 4-amidinobenzyl, namely 4- {7- [4- (4-amidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] heptanoylpiperazine-1- (4-amidinobenzyl) carboxamide, as well as its pharmaceutically acceptable salts, N- oxides, drug precursors, and protecting group derivatives. 31. Savienojums pēc 26. punkta, kurā: X4-X5-X6 visi kopā ir pentametilēngrupa; X1 un X9 abi ir -NHCO-; X3 un X7 abi ir -COO-; R1 un R2 abi ir 4-guanidīnobenzilgrupa, proti, 1.5- pentametilēndi[4-(4-guanidinobenzilkarbamoil)piperazīn-1-karboksamids], kā arī tā farmaceitiski pieņemamās sālis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi.31. The compound of claim 26, wherein: X4-X5-X6 together are pentamethylene; X1 and X9 are both -NHCO-; X3 and X7 are both -COO-; R 1 and R 2 are both 4-guanidino-benzyl, i.e., 1,5-pentamethylene di [4- (4-guanidinobenzylcarbamoyl) piperazine-1-carboxamide], as well as pharmaceutically acceptable salts, N-oxides, prodrugs, and protecting group derivatives. 32. Savienojums pēc 26. punkta, kurā: X4-X5-X6 visi kopā ir tetrametilēngrupa; X1 un X9 abi ir -NHCO-; X3 un X7 abi ir -COO-; R1 un R2 abi ir 4-guanidīnobenzilgrupa, proti, 1.5- tetrametilēndi[4-(4-guanidinobenzilkarbamoil)piperazīn-1-karboksamīds], kā arī tā farmaceitiski pieņemamās sālis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi.The compound of claim 26, wherein: X4-X5-X6 are taken together as tetramethylene; X1 and X9 are both -NHCO-; X3 and X7 are both -COO-; R 1 and R 2 are both 4-guanidino-benzyl, namely, 1,5-tetramethylenedi [4- (4-guanidinobenzylcarbamoyl) piperazine-1-carboxamide], as well as pharmaceutically acceptable salts, N-oxides, prodrugs, and protecting group derivatives. 33. Savienojums pēc 26. punkta, kurā: X4-X5-X6 visi kopā ir pentametilēngrupa; X1 un X9 abi ir-NHCO-; X3 un X7 abi ir -CO-; R1 un R2 abi ir 4-guanidīnobenzilgrupa, proti, 4-{6-[4-(4-amidinobenzilkarbamoil)piperazin-1-ilkarbonil]heksanoilpiperazīn-1- (4-amidinobenzil)karboksamīds, kā arī tā farmaceitiski pieņemamās sālis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi.33. The compound of claim 26, wherein: X4-X5-X6 together are pentamethylene; X1 and X9 are both -NHCO-; X3 and X7 are both -CO-; R1 and R2 are both 4-guanidino-benzyl, namely 4- {6- [4- (4-amidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] hexanoylpiperazine-1- (4-amidinobenzyl) carboxamide, as well as its pharmaceutically acceptable salts, N- oxides, drug precursors, and protecting group derivatives. 34. Savienojums pēc 26. punkta, kurā: X4-X5-X6 visi kopā ir 3-oksatrimetilēngrupa; X1 un X9 abi ir -CO-; X3 un X7 abi ir-CO-; R1 un R2 abi ir 4-amidinobenziigrupa, proti, di[4-(4-guanidinofeni!acetil)piperazin-1-ilkarbonil]-3-oksa-1,5-pentametilēns, kā arī tā farmaceitiski pieņemamās sālis, N-oksīdi, zāļu priekštečvielas un aizsarggrupas saturošie atvasinājumi. 13 LV 1229134. The compound of claim 26, wherein: X4-X5-X6 are taken together to form 3-oxattrimethylene; X1 and X9 are both -CO-; X3 and X7 are both -CO-; R1 and R2 are both 4-amidinobenzyl, that is, di [4- (4-guanidinophenylacetyl) piperazin-1-ylcarbonyl] -3-oxa-1,5-pentamethylene, and its pharmaceutically acceptable salts, N-oxides, drug precursors and derivatives containing derivatives. 13 EN 12291 35. Paņēmiens savienojuma ar formulu (I) r’-x’-x2-x3-x4* X5 r2-x9-x8-x7-x6 I kurā: X5 ir Co-i2alkilēngrupa, hetero-C3_i2alkilēngrupa, C3.i4cikioalkilēngrupa, hetero-C3.i4cikloalkilēngrupa, C6-i4arilēngrupa vai hetero-C5.i4arilēn-grupa; X4 un X6, neatkarīgi viens no otra, ir C0.2alkilēngrupa; X1 un X9, neatkarīgi viens no otra, ir kovalentā saite, -CO-, -COO-, -O-CO-, -CONR3-, -NR3CO-, -S02NR3-, -NR3S02-, -OCONR3-, -NR3COO-, -NR3CONR3- vai -OCOO-, kur R3, neatkarīgi viens no otra, ir ūdeņraža atoms, Ci.3alkilgrupa vai C3-sCikloalkilgrupa, ar noteikumu, ka X1 un X9 abi vienlaikus nav kovalentā saite; X3 un X7, neatkarīgi viens no otra. ir -CO-, -COO-, -O-CO-, -CONR3-, -NR3CO-, -S02NR3-, -NR3S02-, -OCONR3-, -NR3COO-, -NR3CONR3-vai -OCOO-, kur R3 nozīmes ir jau minētās; X2 un X8, neatkarīgi viens no otra, ir Ci.salkilēngrupa, hetero-Ci.8alkilēngrupa, -X10-X11- vai -X11-X10-, kur X10 ir Co-4alkilēngrupa vai hetero-C3.4alkilēngrupa, X11 ir 1,4-piperazinilēngrupa; R1 ir R4-X12- vai R5-X13-, kur: R4 ir aminogrupa, amidīngrupa, guanidīngrupa, 1-iminoetilgrupa vai metilaminogrupa; X12 ir C4_6alkilēngrupa, hetero-C4.6alkilēngrupa, heterookso-C4.6alkil-ēngrupa, okso-C4.salkilēngrupa vai -X14-X15-X16-, kur X15 ir C3.6cikloalkilēngrupa, hetero-C5.sarilēngrupa, hetero-C3.6ciklo-alkilēngrupa vai fenilēngrupa, X14 ir Cni4alkilēngrupa un X16 ir Cni6alkilēngrupa, kur n14 un n16 summa ir 0, 1,2, 3 vai 4; R5 ir grupa no rindas: azetidin-3-ilgrupa, benzimidazol-4-iigrupa, benzimidazol-5-ilgrupa, imidazol-1 -ilgrupa, imidazol-2-ilgrupa, imidazol-4-ilgrupa, 2-imidazolin-2-ilgrupa, 2-imidazolin-3-ilgrupa, 2-metilimidazol-1-ilgrupa, 4-metilimidazol-1-ilgrupa, 5-metilimid-azol-1-ilgrupa, 1 -metilpiperidin-3-ilgrupa, 1 -metilpiperidin-4-ilgrupa, piperidin-3-ilgrupa, piperidin-4-ilgrupa, piperazin-1-ilgrupa, piperazin-2-ilgrupa, piridin-3-ilgrupa, piridin-4-ilgrupa, pirimidin-4-ilgrupa, pirimidin-5-ilgrupa, pirolidin-3-ilgrupa, 1,4,5,6-tetrahidropirimidin-2-ilgrupa, 1,4,5,6-tetrahidropirimidin-4-ilgrupa, 1,4,5,6-tetrahidropirimidin-5-ilgrupa, kā arī minēto grupu karbocikliskie okso- vai tioksoatvasinājumi, pie tam minētās grupas neobligāti aizvietotas ar vienu vai vairākiem aizvietotājiem no rindas: halogēna atoms, hidroksilgrupa, merkaptogrupa, Ci.3alkilgrupa, C3.ucikloalkilgrupa, C6-i4aril-grupa, C6-i4aril-C-|.4alkilgrupa, Ci.8alkanoiIgrupa, C6-i4ariloksi- 14 grupa, C3-14cikioalkiloksigrupa, Ci.4alkoksigrupa, Ci-salkiltio-grupa, C3.-i4cikloalkiltiogrupa, Ce-uariltiogrupa un -NR6R7, kur R6 un R7, neatkarīgi viens no otra, ir aizvietotāji no rindas: ūdeņraža atoms, Ci-galkilgrupa, Ci.3aikanoilgrupa, C3.i4cikloalkilgrupa un Ce-uarilgrupa; X13 ir C0.6a!kilēngrupa, hetero-C2-6a[kiiēngrupa, heterookso-C3-salkil-ēngrupa, okso-C2-6alkilēngrupa, vai X17-X18-X19-, kur X18 ir ar jau minētām X13 nozīmēm, X1' ir Cnizalkiiēngrupa un X19 ir Cnigalki-lēnarupa, pie kam n17 un n19 summa ir 0, 1 vai 2; R2 ir R-X20- vai R9-X21-, kur: R8 is aminogrupa, 1-iminoetiigrupa vai metiiaminogrupa, X20 ir C4-6alkilēngrupa, hetero-C4-6alkilēngrupa, heterookso-C4.6alkilēngrupa, okso-C4.6alkiIēngrupa vai X22-X23-X24-, kur X23 ir ar jau minētām X15 nozīmēm, X22 ir Cn22alkilēngrupa un X24 ir Cn24alkilēngrupa, pie kam n22 un n24 summa ir 0, 1, 2, 3 vai 4, ar noteikumu, ka tad, kad R8 ir aminogrupa, X20 nav C^galkil-ēngrupa vai oksa-C4^alkilēngrupa un n22 nav 1, 2, 3 vai 4; R9 ir ar nozīmēm, kuras jau minētas R5; X21 ir Co-eaikilēngrupa, hetero-C2-6alkilēngrupa, heterookso-C3.6alkiiēngrupa, okso-C2-6alkilēngrupa vai X25-X25-X27-, kur X26 ir ar jau minētām X15 nozīmēm, X25 ir Cn25alkilēngrupa un X27 ir Cn27alkilēngrupa, pie kam jebkura no augstāk minētajām alkilēngrupām, cikloalkilēngrupām, heterocikloalkilēngrupām, fenilēngrupām, arilēngrupām un heteroarilēn-grupām ir neobligāti aizvietota ar vienu vai vairākiem aizvietotājiem no rindas: halogēna atoms, hidroksilgrupa, merkaptogrupa, Ci.8alkilgrupa, C3-i4ciklo-alkilgrupa, C6-i4arilgrupa, C6-i4ariI-C-i_4alkiIgrupa, Ci-aalkanoilgrupa, Cļ.galkoksigrupa, C6.i4anloksigrupa, C3.14cikloalkiloksigrupa, Ci.4alkoksigrupa, Ci_8alkiltiogrupa, C3.14cikloalkiItiogrupa, Cs-i4ariltiogrupa un -NR°R/, kur R6 un R7 ir ar jau minētām nozīmēm, ar noteikumu, ka starp heteroatomiem, kas ietilpst R1, X2, X4, X6, X8, R2 un heteroatomiem, kas ietilpst X3, X5, X' un X nav kovalentās saites, kā arī tā farmaceitiski pieņemamās sāls, N-oksīda, zāļu priekštečvielas vai aizsarggrupas saturoša atvasinājuma iegūšanai, kas ietver: (a) savienojuma ar formulu (1) ϊΐ'-χ'-χλχ^χ4^ ys-x7-x6 ^ 1 vai tā aizsargāta atvasinājuma iedarbību ar savienojumu, kura formula ir R2-Y9-CO-L, vai tā aizsargātu atvasinājumu, kurā, attiecīgi, L ir atšķeļama grupa, Y9 ir saite, -O- vai -NR3-, Y3 ir piperazin-1-iigrupa, piperidin-4-ilgrupa vai HNR3-Ci.salkilgrupa, R1, R2, R3, X1, X2, X3, X4, X5, X° un X' nozīmes atbilst 15 LV 12291 izgudrojuma īsā izklāstā dotajām, vajadzības gadījumā tai sekojošu aizsarggrupu atšķelšanu, iegūstot savienojumu ar formulu (I), kurā X8 ir 1,4-piperazinilēngrupa un X9 ir -CO-, -O-CO- vai -NR3CO-; vai arī X8 ir C-i. salkilēngrupa un X9 ir-CONR3-, -O-CONR3- vai -NR3CONR3-; (b) savienojuma ar formulu (1) vai tā aizsargāta atvasinājuma iedarbību ar izocianātu R2-NCO vai tā aizsargātu atvasinājumu, vajadzības gadījumā tai sekojošu aizsarggrupu atšķelšanu, iegūstot savienojumu ar formulu (I), kurā X8 ir 1,4-piperazinilēngrupa un X9 ir -NHCO-; vai arī X8 ir C-i-salkilēngrupa un X9 ir-NHCONR3-; (b) savienojuma ar formulu (2) Y2-X3-xV x! 2 rj.x’-x'-x7-x‘ vai tā aizsargāta atvasinājuma iedarbību ar savienojumu R1-Y1-CO-L, vai tā aizsargātu atvasinājumu, kurā, attiecīgi, L ir atšķeļama grupa, Y1 ir saite, -O-vai -NR3-, Y2 ir piperazin-1-ilgrupa vai HNR^Cvsaikiigrupa, R1, R2, R3, X3, X4, X5, X6, X7, X8 un X9 nozīmes atbilst izgudrojuma īsā izklāstā dotajām, vajadzības gadījumā tai sekojošu aizsarggrupu atšķelšanu, iegūstot savienojumu ar formulu (I), kurā X2 ir 1,4-piperazinilēngrupa un X1 ir -CO-, -O-CO- vai -NR3CO-; vai arī X2 ir Ci.salkilēngrupa un X1 ir -CONR3-, -O-CONR3- vai -NR3CONR3-; (d) savienojuma ar formulu (2) vai tā aizsargāta atvasinājuma iedarbību ar izocianātu R1-NCO vai tā aizsargātu atvasinājumu, vajadzības gadījumā tai sekojošu aizsarggrupu atšķelšanu, iegūstot savienojumu ar formulu (I), kurā X2 ir 1,4-piperazinilēngrupa un X1 ir -NHCO-; vai arī X2 ir Ci-ealkilēngrupa un X1 ir -NHCONR3-; y2-x3-x\ (e) savienojuma ar formulu (3) Y8-X7-X6' vai tā aizsargāta atvasinājuma iedarbību ar 2 vai vairāk moliem savienojuma R1-Y1-CO-L, vai tā aizsargāta atvasinājuma, kurā, attiecīgi, L ir atšķeļama grupa, Y1 ir saite, -0- vai -NR3-, Y2 un Y8, neatkarīgi viens no^ otra, ir piperazin-1 -ilgrupa vai HNR^Cļ.salkilgrupa, R1, R3, X3, X4, X5, X6 un X7 nozīmes atbilst izgudrojuma īsā izklāstā dotajām, vajadzības gadījumā tai sekojošu aizsarggrupu atšķelšanu, iegūstot savienojumu ar formulu (I), kurā R1 ir vienāds ar R2, X2 un/vai X8 ir 1,4-piperazinilēngrupa, X9 ir -CO-, -O-CO-vai -NR3CO-; un/vai X2 un/vai X3 ir Ci-galkilēngrupa, X1 ir -CONR3-, -0-CONR3- vai -NR3CONR3-, X9 ir -CONR3-, -O-CONR3- vai -NR3CONR3-; (f) savienojuma ar formulu (3) vai tā aizsargāta atvasinājuma iedarbību ar diviem vai vairāk moliem izocianāta R-NCO vai tā aizsargāta 16 atvasinājuma, vajadzības gadījumā tai sekojošu aizsarggrupu atšķelšanu, iegūstot savienojumu ar formulu (I), kurā R1 ir vienāds ar R2; X2 ir 1,4-piperazinilēngrupa un X1 ir -NHCO-; vai arī X2 ir Ci.8alkilēngrupa un X1 ir -NHCONR3-; (g) amīna ar formulu R1-NR3H vai tā aizsargāta atvasinājuma iedarbību ar savienojumu (4) ΙΧίΌΐ-Υ’-Χ^-Χ4^ 7 v6- r2-x9-x5-x'-x' 4 vai tā aizsargātu atvasinājumu, kurā, attiecīgi, L ir atšķeļama grupa, Y1 ir saite, -0- vai -NR3-, R1, R2, R3, X2, X3, X4, X5, X6, X7, X8 un X9 nozīmes atbilst izgudrojuma īsā izklāstā dotajām, vajadzības gadījumā tai sekojošu aizsarggrupu atšķelšanu, iegūstot savienojumu ar formulu (I), kurā X1 ir -NR3CO-, -NR3COO- vai -NR3CONR3-; (h) savienojuma ar formulu R1-X1-Y^ vai tā aizsargāta atvasinājuma iedarbību ar savienojumu (5) LC(0)-Y3-X4x r2-x9-xs-x7-x6' 5 vai tā aizsargātu atvasinājumu, kurā, attiecīgi, L ir atšķeļama grupa, Y3 ir saite, -O- vai -NR3-, Y2 ir piperazin-1-ilgrupa, piperidin-4-ilgrupa vai HNR3--Ci.8alkilgrupa, R1, R2, R3, X1, X2, X3, X4, X5, X6, X7, X8 un X9 nozīmes atbilst izgudrojuma īsā izklāstā dotajām, vajadzības gadījumā tai sekojošu aizsarggrupu atšķelšanu, iegūstot savienojumu ar formulu (I), kurā X2 ir 1,4-piperazinilēngrupa un X3 ir -CO-, -COO- vai -CONR3-; vai arī X2 ir Ci.8alkil-ēngrupa un X3 ir -NR3CO-, -NR3COO- vai -NR3CONR3-; (i) 2 vai vairāk molu savienojuma ar formulu R1-X1-Y2 vai tā aizsargāta atvasinājuma, iedarbību ar savienojumu (6) lc(0)-y3-xV LC(0)Y7-X6 6 kurā, attiecīgi, L ir atšķeļama grupa, Y3 un Y7, neatkarīgi viens no otra, ir saite, -O- vai -NR-, Y2 ir piperazin-1-ilgrupa, HNR3-Ci.8alkilgrupa vai HNR3-hetero-Cļ-aalkilgrupa, R1, X1, X4, X5 un X6 nozīmes atbilst izgudrojuma īsā izklāstā dotajām, vajadzības gadījumā tai sekojošu aizsarggrupu atšķelšanu, iegūstot savienojumu ar formulu (I), kurā X2 un X8 abi ir 1,4-piperazinilēngrupa un X3 un X7, neatkarīgi viens no otra, ir -CO-, -COO- vai -CONR3-; vai arī, attiecīgi, 17 17 LV 12291 X2 un X8 abi ir Ci-3alkilēngrupa vai hetero-C1.8alkilēngrupa un X3 un X2, neatkarīgi viens no otra, ir -NR3CO-, -NR3COO- vai -NR3CONR3-; (j) ja vajadzīgs, savienojumu ar formulu (I), kurā R4 ir aminogrupa, apstrādā ar ciānamīdu, iegūstot savienojumu ar formulu (l), kurā R4 ir guanidīngrupa; (k) ja vajadzīgs, savienojumu ar formulu (I) tālāk pārvērš farmaceitiski pieņemamā sālī; (l) ja vajadzīgs, savienojuma ar formulu (I) sāls formu tālāk pārvērš nesāls formā; (m) ja vajadzīgs, savienojuma ar formulu (I) neoksidēto formu tālāk pārvērš farmaceitiski pieņemama N-oksīda formā; (n) ja vajadzīgs, savienojuma ar formulu (I) N-oksīda formu tālāk pārvērš neoksidētā formā; (o) ja vajadzīgs, savienojumu ar formulu (I) no brīvas formas tālāk pārvērš atvasinājumā, kas ir farmaceitiski pieņemama priekštečviela; (p) ja nepieciešams savienojuma ar formulu (I) priekštečvieiu pārvērš savienojuma brīvā formā.A process for the preparation of a compound of formula (I) r'-x'-x2-x3-x4 * X5 r2-x9-x8-x7-x6-I wherein: X5 is C Co-Cēnalkylene, hetero-C222alkylene, C3. cycloalkylene, hetero- C3-4cycloalkylene, C6-4arylene or hetero-C5-4 arylene; X4 and X6, independently of one another, are C0-2alkylene; X1 and X9, independently of one another, are covalent bond, -CO-, -COO-, -O-CO-, -CONR3-, -NR3CO-, -SO2NR3-, -NR3SO2-, -OCONR3-, -NR3COO- , -NR3CONR3- or -OCOO-, wherein R3, independently of one another, is hydrogen, C1-3 alkyl or C3-8cycloalkyl, provided that both X1 and X9 are not simultaneously a covalent bond; X3 and X7, independently of each other. are -CO-, -COO-, -O-CO-, -CONR3-, -NR3CO-, -SO2NR3-, -NR3SO2-, -OCONR3-, -NR3COO-, -NR3CONR3- or -OCOO- wherein R3 is have already been mentioned; X2 and X8, independently of one another, are C1-6alkylene, hetero-C1-8alkylene, -X10-X11- or -X11-X10- wherein X10 is Co-4alkylene or hetero-C3-4alkylene, X11 is 1.4 piperazinylene; R1 is R4-X12- or R5-X13-, wherein: R4 is amino, amidine, guanidine, 1-iminoethyl or methylamino; X12 is C4-6alkylene, hetero-C4-6alkylene, hetero-oxo-C4-6alkyl, oxo-C4alkylene or -X14-X15-X16-, wherein X15 is C3-6cycloalkylene, hetero-C5-aralkylene, hetero-C3.6cyclo -alkylene or phenylene, X 14 is C 1-4 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 a group 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-long group, 1,4,5,6-tetrahydropyrimidin-2-yl, 1,4,5,6-tetrahydropyrimidin-4-yl, 1,4,5,6-tetrahydropyrimidin-5-yl, as well as said group carbocyclic oxo or thioxo derivatives, wherein said groups are optionally substituted with one or more substituents from the group consisting of halogen, hydroxy, mercaptogroup, C 1-3 alkyl, C 3 cycloalkyl, C 6-4 aryl, C 6 -C 14 aryl-C 1-4 alkyl , C 1-8 alkanoyl, C 6 -C 14 aryloxy- group 14, C 3-14 cycloalkyl rox, C 1-4 alkoxy, C 1-6 alkylthio, C 3-14 cycloalkylthio, C 1-4 arylthio, and -NR 6 R 7, wherein R 6 and R 7, independently of one another, are substituted by hydrogen, C 1-8 -alkyl, C 1-3 -alkanoyl, C3-4cycloalkyl and Ceuaryl; X13 is C0-6 alkylene, hetero-C2-6a [cyano, heteroxo-C3-salkyl-ene, oxo-C2-6alkylene, or X17-X18-X19-, wherein X18 is as defined above for X13, X1 'is Cisalalkylene and X19 are Cnigalki-slow, wherein the sum of n17 and n19 is 0, 1 or 2; R2 is R-X20- or R9-X21-, wherein: R8 is amino, 1-iminoethyl or methyamino, X20 is C4-6alkylene, hetero-C4-6alkylene, heteroxo-C4-6alkylene, oxo-C4-6alkylene or X22- X23-X24-, wherein X23 is as defined above for X15, X22 is C1-2alkylene, and X24 is C1-2alkylene, wherein the sum of n22 and n24 is 0, 1, 2, 3 or 4, provided that when R8 is an amino group, X 20 is not C 1-6 alkyl or oxa-C 4 alkylene and n 22 is not 1, 2, 3 or 4; R9 has the meanings already mentioned in R5; X21 is Co-eaicylene, hetero-C2-6alkylene, heteroxo-C3-6alkylene, oxo-C2-6alkylene or X25-X25-X27-, wherein X26 is as defined above for X15, X25 is CN25alkylene, and X27 is CN27 alkylene, with any of the above alkylene groups, cycloalkylene groups, heterocycloalkylene groups, phenylene groups, arylene groups and heteroarylene groups are optionally substituted with one or more substituents from halogen, hydroxy, mercaptogroup, C 1-8 alkyl, C 3-14 cycloalkyl, C 6-4 aryl, C 6 -IiIiI-C 1-4 alkylI, C 1-4 alkanoyl, C 1-10 alkoxy, C 1-4 alkyloxy, C 3-14 cycloalkyloxy, C 1-4 alkoxy, C 1-8 alkylthio, C 3-14 cycloalkyl group, C 1-4 arylthio and -NR ° R / R 6 are already present , provided that there is no covalent bond between the heteroatoms of R1, X2, X4, X6, X8, R2, and heteroatoms included in X3, X5, X 'and X, as well as pharmaceutically acceptable salts thereof; ls, N-oxide, drug precursor, or protecting group containing a derivative comprising: (a) exposure to a compound of formula (1) ϊΐ'-χ'-χλχ ^ χ4 ^ ys-x7-x6 ^ 1 or a protected derivative thereof having the formula R2-Y9-CO-L or a protected derivative thereof, wherein L is a leaving group, Y9 is a bond, -O-, or -NR3-, Y3 is piperazin-1-yl, piperidine-4 long-group or HNR3-C1-6alkyl, R1, R2, R3, X1, X2, X3, X4, X5, X0 and X 'have the meaning given to the deprotection of the protecting groups according to the invention, where appropriate, to give a compound of the formula (I) wherein X 8 is 1,4-piperazinylene and X 9 is -CO-, -O-CO- or -NR 3 CO-; or X8 is C-i. Salkylene and X9 are-CONR3-, -O-CONR3- or -NR3CONR3-; (b) exposure of a compound of formula (1) or a protected derivative thereof to isocyanate R2-NCO or a protected derivative thereof, optionally followed by the deprotection of a compound of formula (I) wherein X8 is 1,4-piperazinylene and X9 is -NHCO-; or X 8 is C 1 -C 6 alkylene and X 9 is -NHCONR 3 -; (b) Y2-X3-xV x of the compound of formula (2)! 2 rj.x'-x'-x7-x 'or exposure to a protected derivative of R1-Y1-CO-L, or a protected derivative thereof, wherein L is a leaving group, Y1 is a bond, -O-or- -NR3-, Y2 is piperazin-1-yl or HNR1-Cvsicyclic, R1, R2, R3, X3, X4, X5, X6, X7, X8, and X9 are as defined in the short description of the invention, optionally followed by the cleavage of the protecting groups resulting from the invention. a compound of formula (I) wherein X2 is 1,4-piperazinylene and X1 is -CO-, -O-CO- or -NR3CO-; or X2 is C1-6alkylene and X1 is -CONR3-, -O-CONR3- or -NR3CONR3-; (d) exposure of a compound of formula (2) or a protected derivative thereof to isocyanate R1-NCO or a protected derivative thereof, optionally followed by the deprotection of a compound of formula (I) wherein X2 is 1,4-piperazinylene and X1 is -NHCO-; or X2 is C1-6alkylene and X1 is -NHCONR3-; (e) the action of a compound of formula (3) Y8-X7-X6 'or a protected derivative thereof with 2 or more moles of the compound R1-Y1-CO-L or a protected derivative thereof wherein, respectively, L; is a cleavable group, Y1 is a bond, -O- or -NR3-, Y2 and Y8, independently of one another, are piperazin-1-yl or HNR1-C16 alkylalkyl, R1, R3, X3, X4, X5, X6 and the meanings of X7 correspond to the cleavage of the protecting groups, if necessary followed by a short description of the invention, to give a compound of formula (I) wherein R1 is equal to R2, X2 and / or X8 is 1,4-piperazinylene, X9 is -CO-, - O-CO or -NR 3 CO-; and / or X 2 and / or X 3 is C 1-8 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) exposure of a compound of formula (3) or a protected derivative thereof to two or more moles of isocyanate R-NCO or a protected derivative thereof, optionally followed by protecting groups, to give a compound of formula (I) wherein R 1 is equal to R 2 ; X2 is 1,4-piperazinylene 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 R1-NR3H or a protected derivative thereof with compound (4) ΙΧίΌΐ-Υ'-ΧΧ-Χ4 ^766-6-x9-x5-x'-x '4 or a protected derivative thereof; respectively, L is a digestible group, Y1 is a bond, -0- or -NR3-, R1, R2, R3, X2, X3, X4, X5, X6, X7, X8, and X9 are as defined in the short description of the invention, if necessary subsequent deprotection of the protecting groups to give a compound of formula (I) wherein X1 is -NR3CO-, -NR3COO- or -NR3CONR3-; (h) the action of a compound of formula R 1 -X 1 -Y 1 or a protected derivative thereof with compound (5) LC (O) -Y 3 -X 4 x r 2 -x 9 -xs-x 7 -x 6 'or a protected derivative thereof, wherein L is a leaving group, Y3 is a bond, -O- or -NR3-, Y2 is piperazin-1-yl, piperidin-4-yl or HNR3 - C1-8 alkyl, R1, R2, R3, X1, X2, X3, The meanings of X4, X5, X6, X7, X8, and X9 correspond to those described in the short description of the invention, optionally followed by the removal of protecting groups, to give a compound of formula (I) wherein X2 is 1,4-piperazinylene and X3 is -CO-, -COO - or -CONR3-; or X 2 is C 1-8 alkylamino and X 3 is -NR 3 CO-, -NR 3 CO- or -NR 3 -CONR 3 -; (i) Effect of 2 or more mole compounds of formula R1-X1-Y2 or a protected derivative thereof with compound (6) 1c (O) -y3-xV LC (0) Y7-X66 wherein, respectively, L is a leaving group , Y3 and Y7, independently of one another, are a bond, -O- or -NR-, Y2 is piperazin-1-yl, HNR3-C1-8 alkyl, or HNR3-hetero-C1-6 alkyl, R1, X1, X4, X5 and the meanings of X6 correspond to the cleavage of the protecting groups provided, if necessary, by a short description of the invention, to give a compound of formula (I) wherein X2 and X8 are both 1,4-piperazinylene and X3 and X7, independently of one another, are -CO-, -COO- or -CONR3-; or, respectively, 17 17 EN 12291 X2 and X8 are both C 1-3 alkylene or hetero-C 1-8 alkylene and X 3 and X 2, independently of one another, are -NR 3 CO-, -NR 3 CO- or -NR 3 -CONR 3 -; (j) treating a compound of formula (I) wherein R4 is amino if necessary with cyanamide to give a compound of formula (I) wherein R4 is guanidine; (k) optionally converting the compound of formula (I) into a pharmaceutically acceptable salt; (l) if necessary, converting the salt form of the compound of formula (I) to a salt form; (m) optionally converting the non-oxidized form of the compound of formula (I) into a pharmaceutically acceptable N-oxide form; (n) optionally converting the N-oxide form of the compound of formula (I) into a non-oxidized form; (o) optionally converting the compound of formula (I) from the free form into a derivative which is a pharmaceutically acceptable precursor; (p) converting the precursor of the compound of formula (I) into a free form of the compound if necessary.
LVP-99-27A 1996-07-30 1999-02-18 Novel compounds and compositions for treating diseases associated with tryptase activity LV12291B (en)

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