AU733621B2 - 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 PDFInfo
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- AU733621B2 AU733621B2 AU39670/97A AU3967097A AU733621B2 AU 733621 B2 AU733621 B2 AU 733621B2 AU 39670/97 A AU39670/97 A AU 39670/97A AU 3967097 A AU3967097 A AU 3967097A AU 733621 B2 AU733621 B2 AU 733621B2
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- 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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- 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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- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- 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]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- 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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- C07D233/04—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
- 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
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Description
NOVEL COMPOUNDS AND COMPOSITIONS FOR TREATING DISEASES ASSOCIATED WITH TRYPTASE ACTIVITY 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 cells, is thought to be involved in neuropeptide processing and tissue inflammation. Tryptase concentrations are elevated in the bloodstream for several hours following anaphylaxis (Schwartz et al. (1987) 12 N. Eng. J. Med 316:1622-1626), are increased in nasal and lung lavage fluid from atopic subjects following specific antigen challenge (Castells et al. (1988) J. Allerg. Clin. Immunol.
141:563-568) and are elevated in lung lavage fluid of atopic asthmatics after endobronchial allergen challenge. Smokers often have striking elevations of bronchoalveolar lavage fluid tryptase levels, a finding that provides some support for the hypothesis that release of proteinase from activated mast cells could contribute to lung destruction in smoker's emphysema.
I: 18 (Celenteron et al. (1988) Chest 94:119-123). In addition, tryptase 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 hyper responsiveness of asthmatic bronchiolar tissue is believed to be the result of chronic inflammatory reactions, which 27 irritate and damage the epithelium lining the airway wall and promote pathological thickening of WO 98/04537 PCT/US97/13422- -2the underlying tissue. Bronchial biopsies in patients with only mild asthma have features of inflammation in the airway wall.
3 Allergic responses to inhaled allergens can initiate the inflammatory sequence. For example, allergens can activate mast cells and basophils, which are present in the epithelium and underlying smooth muscle tissue by binding IgE located on the cell surface. Activated mast cells 6 release a number of preformed or primary chemical mediators histamine) of the inflammatory response and generate numerous other secondary mediators of inflammation superoxide, lipid derived mediators, etc.) in situ. In addition, several large molecules 9 proteoglycans, tryptase, chymase, etc.) are released by degranulation of mast cells.
The release of these preformed mediators from mast cells probably accounts for the early bronchiolar constriction in the asthmatic reaction to air borne allergens. The early phase of the 12 asthmatic reaction peaks approximately fifteen minutes 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 twelve hours after exposure. This late reaction phase is accompanied by a marked increase in the number of inflammatory cells eosinophils, neutrophils, lymphocytes, etc.) infiltrating the bronchiolar tissue. The infiltrating cells are attracted to the site 18 by release of mast cell derived chemotactic agents and then become activated during the late reaction phase. The late asthmatic response is believed to be a secondary inflammatory reaction mediated in part by the secretory activity of granulocytes.
21 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) J Pharmacol. Exp. Ther. 248:947-951; and Tam et al. (1990) Am. J. Respir. Cell Mol.
24 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 27 fibrinogen a-chains and high molecular weight kinninogen, which suggests that tryptase plays a role with heparin as a local anticoagulant. Tryptase activates prostromelysin (pro-MMP-3) and procollagenase (pro-MMP-1) via MMP-3, which suggests that tryptase is involved in tissue inflammation and remodeling and joint destruction in rheumatoid arthritis. Further, WO 98/04537 PCT/US97/13422 -3administration 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). All of the above-described findings clearly indicate the applicability of tryptase inhibitors as therapeutic 6 agents 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 incorporated herein by reference.
SUMMARY OF THE INVENTION This application relates to a compound of Formula I: 12 -X 3
X
4
X
R2_X9_X8-X7_X6
I
in which:
X
5 is (C 3 1 4 )cycloalkylene, hetero(C3., 4 )cycloalkylene, (C6.
14 )arylene or hetero(C 5 1 4 )arylene;
X
4 and X 6 are independently (Co- 2 )alkylene; X' and X 9 are independently a covalent bond,
-C(O)N(R
3 18 -N(R 3
-S(O)
2
N(R
3
-N(R
3
)S(O)
2
-OC(O)N(R
3
-N(R
3
-N(R
3
)C(O)N(R
3 or wherein each R 3 is independently hydrogen, (Ci 3 )alkyl or (C 3 8 )cycloalkyl, with the proviso that X' and X 9 are not both covalent bonds; 21
X
3 and X 7 are independently
-C(O)N(R
3
-N(R
3 -S(0) 2
N(R
3
-N(R
3
)S(O)
2
-OC(O)N(R
3
-N(R
3 or -OC(O)O-, wherein R 3 is as defined above;
X
2 and X 8 are independently (Ci..a)alkylene, hetero(Cli 8 )alkylene,
-X
10
-X
11 or
-X
11 -Xl 0 wherein X 1 0 is (Co-4alkylene or hetero(C 3 -4alkylene and X 1 is (C3..8)cycloalkylene or hetero(C 3 8 )cycloalkylene;
R
1 is R 4 -Xl 2 or R 5 _X 1 3 wherein: R 4is amino, amidino, guanidino, 1-iminoethyl or methylamino.
X1 2 is (C4-6)alkylene, hetero (C4..
6 )alkylene, heterooxo(C 4 6 )alkylene,
OXO(C
46 )alkylene or _X 1 4
_X
1 5 _X 1 6 wherein
X
15 i S (C3.6)cycloalkylene, hetero(C 5 6 )arylene, hetero(C 3 -6)cycloalkylene or phenylene,
X
14 is (Cnl4)alkylene and X 16 is (Cnl 6 )alkylene, wherein the sum of n14 and n16 is 0, 1, 2, 3 or 4.
R 5is a group selected from azetidin-3-yl, benzoimidazol-4-yi, imidazol-1 -yI, imidazol-2-yl, imidazol-4-yI, 2-imidazolin-2-y, 2-imidazolin-3-yl, 2methylimidazol-1 -yl, 4-methylimidazol-1 -yl, 5-methylimidazol-1 -yl, 1 -methylpiperid- 3-yl, 1 -methylpiperid-4-yI, piperid-3-yl, piperid-4-yl, piperazin- l-yl, piperazin-2-yl, pyrid-3-yi, pyrid-4-yl, pyrimid in-4-yl, .pyrm idin-5-yl, pyrrolidin-3-yl, 1 5,6tetra hyd ropyrim id in-2-y, 1 4 ,5,6-tetrahydropyrimidin4yl and 1,4,5,6tetra hyd ropyrim id in-.5-y and any carboxylic ketone or thioketone derivative thereof, which group is optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (Cl-8)alkyl, (C3l1 4 )cycloalkyl, (C6.1 4 )aryl, (C6-1 4 )aryl(Cl.
4 )alkyl, (C1-8)alkanoyl, (Ci..a)alkyloxy, (C6-14)aryloxy, (C3-14)cycloalkyloxy, (Ci..
4 )alkyloxy, 6 7 6 7 :20 (Cl 18 )alkylthio, (C3.14)cycloalkylthio,
(C
6 .i4)arylthio and -NR R wherein R~ and R' are independently selected from hydrogen,
(C
1 8 )alkyl, (Ci..
8 )alkanoyl,
(C
3 14)cycloalkyl or (C6.i4)aryl and x 13 i (CO..
6 )alkylene, hetero (C2..6)alkylene, heterooxo(C 3 6 )alkylene, OXO(C2- 6 )alkylene or -X 7
X
8
X
9 ,wherein X 1 8 is as defined above forX 5
,X
7 i 25 (Cnl 7 )alkylene and X1 is (Cnig)alkylene, wherein the sum of n17 and n19 is 0, 1 or and R 2 is R 8
_X
20 or R 9
_X
21 wherein: R samino, 1 -iminoethyl or methylamino.
X
20 is (C4..
6 )alkylene, hete ro (C 4 6 a I kyle ne, heterooxo(C 46 )alkylene, OX(46akln or* ox(_.)lyeeo
X
22
-X
23
-X
24 wherein X 23 is as defined above for X 15
X
22 is (Cfl22)alkylene and X 24 is (Cfl24)alkylene, wherein the sum of n22 and n24 is 0, 1, 2, 3 or 4, HflAYLIB0hbc4346.doc with the proviso that when R8 is amino then X 20 is not (C4..6)alkylene or
OXO(C
4 6 )alkylene and n22 is not 1, 2, 3 or 4.
R
9 is as defined above for R 5 and xl is (CO..
6 )alkylene, hetero(C 26 )alkylene, heterooxo(0 3 6 )al kylene, OXO(0 2 6 )alkylene or -X 25
-X
26
-X
27 wherein X 26 is as defined above for X 15
X
25 is (Cn 2 5)alkylene and X 27 is (Cn 2 7)alkylene, wherein the sum of n25 and n27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heteroalkylene, heterocyloalkylene, phenylene, arylene and heteroarylene, as defined above, are optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (Cl- 8 )alkyl, (0 314 )cycloalkyl, (C 6 14 )aryl, (0 614 )aryl(0 1 4 )alkyl, (Cl- 8 )alkanoyl, (Ci..
8 )alkyloxy, (C6-.
14 )aryloxy, (C 3 14 )cycloal kyloxy, (O1A4)al kyloxy, (0 1 8 )alkylthio, (C3.
14 )cycloalkylthio,
(C
6 .i 4 )arylthio and -NR R wherein R 6 and R 7 are as defined above; with the proviso that covalent bonds do not occur between heteroatoms contained within R 1
X
2
X
4
X
6 X" and R 2 and any heteroatoms contained with X 3
X
5
X
7 and X 9 and the pharmaceutically acceptable salts, N-oxides, prodrugs derivatives and protected derivatives thereof.
A second aspect of this application relates to a compound of Formula 1: R in which:
X
4
-X
5
_X
6 together are (0 2 12 )alkylene or hetero(C 3 12 )alkylene;
X
1 and X 9 are independently a covalent bond, 3 or wherein each R 3 i independently hydrogen, (Cl 1 3 )alkyl or (C 38 )cycloalkyl, with the proviso that X 1 and X 9 are not both covalent bonds;
X
3 and X 7 are independently C(0)N(R 3 I:MayLibILIBC%04346.doc 6
-S(O)
2 N(R 3 -N(R 3 )S(0) 2 -OC(O)N(R 3 -N(R 3 N(R 3 )C (O)N(R or wherein R 3 is as defined above:
X
2 and X 8 are independently (Cia8)alkylene hetero(Cl- 8 )alkylene, -X 1 0
-X
1 or
X
1 1 -Xl 0 wherein X 10 is (Co- 4 )alkylene or hetero(C 3 -4alkylene and X 1 is (C3-8)cycloalkylene or hetero(C 3 8 )cycloalkylene;
R
1 is R 4 -Xl 2 or R 5 wherein: R 4 is amino, amidino, guanidino, 1-iminoethyl or methylamino.
X1 2 is (04..
6 )alkylene, hetero, (C4-6)alkylene, heterooxo(C 4 6 )alkylene,
OXO(C
46 )alkylene or _X 1 4 _X 15 _X 16 wherein X 15 i S (C3-6)cycloalkylene, hetero(Cs..
6 )arylene, hetero(C 3 -6)cycloalkylene or phenylene,
X
14 is (Cnl4)alkylene and X 16 is (Cnli6)alkylene, wherein the sum of n14 and n16 is, 01, 2, 3 or4.
R 5 is a group selected from azetidin-3-yl, benzoimidazol-4-y, imidazol-1 -yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2methylimidazol-1 -yl, 4-methylimidazol-1 -yl, 5-methylimidazol-1 -yl, 1 -methyl pipe rid- 3-yl, 1-methylpiperid-4-yl, piperid-3-yl, piperid-4-yl, piperazin-1-yI, piperazin-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-4-yl, pyrm id in-5-yl, pyrrolid in-3-yl, 1,4,5,6tetra hyd ropyrimid in-2.yl, 1 ,4,5,6-tetrahydropyrimidin.4.yI and 1,4,5,6tetra hyd ropyrim id in-5..yl and any carboxylic ketone or thioketone derivative thereof, which group is optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (0i- 8 )alkyl, (03-14)cycloalkyl, (C6,1 4 )aryl, (C6-14)aryI(Cl-.
4 )alkyl, (Cl- 8;c'alkanoyl, (CI.
8 )alkyloxy, (06-1 4 )aryloxy, (C3j 4)cycloalkyloxy,
(C
1 4)alkyloxy, (Cl 8 )alkylthio, (C3-14)cycloalkylthio, (C6.,4arylthio and -NR R wherein R 6 and R 7 are independently selected from hydrogen, (Cl 1 8 )alkyl, (C1-8)alkanoyl, (03..14)cycloalkyl :000 or (06-1 4 )aryl and X1 3 is (CO..6)alkylene, hetero (C2 6 )alkylene, hete'rooxo(0 36 )alkylene,
OXO(C
2 6 )alkylene or _X 1 7 _X 1 8 -X 1 9 wherein X 1 8 is as defined above for X1 5 X1 7 is (Cfll 7 )alkylene and X 1 9 is (Cnlg)alkylene, wherein the sum of n17 and n19 is 0, 1 or and R 2 is R 8
_X
20 or R 9
_X
21 wherein: oo: oR 8 is as defined above for R,
X
20 is (C 4 -6)alkylene, hetero(C 4 6 )alkylene, heteroOXO(C 4 6 )alkylene.
.0 IM~AYLIBMibc04346.doc WO 98/04537 PCT/US97/13422 -7oxo(C 4 6 )alkylene or -X 22
-X
23
-X
24 wherein X 23 is as defined above for X 1 5
X
2 2 is (Cn 2 2 )alkylene and X 2 4 is (C, 24 )alkylene, wherein the sum of n22 and n24 is 0, 1, 2, 3 or 4, 3
R
9 is as defined above for R 5 and
X
2 is (Co.
6 )alkylene, hetero(C2- 6 )alkylene, heterooxo(C 3 6 )alkylene, oxo(C2.
6 )alkylene or -X 2 5
-X
2 6
-X
27 wherein X 26 is as defined above for X 1 5
X
2 5 is 6 (C, 25 )alkylene and X 2 7 is (Cn 27 )alkylene, wherein the sum of n25 and n27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene, as defined above, are optionally substituted with one or more 9 radicals selected from halo, hydroxy, mercapto, (C, 8 _)alkyl, (C 3 1 4 )cycloalkyl, (C 6 14 )aryl, (C6- 1 4 )aryl(C.
4 )alkyl, (C 1 8 )alkanoyl, (C,.)alkyloxy, (C 6 1 4 )aryloxy, (C3.14)cycloalkyloxy, (CI.4)alkyloxy, 8 )alkylthio, (C 3 1 4 )cycloalkylthio, (C 6 1 4 )arylthio and -NR 6
R
7 wherein 12 R 6 and R 7 are as defined above; with the proviso that covalent bonds do not occur between heteroatoms contained within X 2
X
4
X
6
X
8 and R 2 and any heteroatoms contained with X 3
X
5
X
7 and X 9 and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
A third aspect of this invention is a pharmaceutical composition which contains a 18 compound of Formula I, or a 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 pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of Formula I or a pharmaceutically acceptable salt, N-oxide or prodrug derivative thereof.
24 A fifth aspect of this invention is the processes for preparing compounds of Formula I and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof as set forth in "Detailed Description of the Invention".
27 DETAILED DESCRIPTION OF THE INVENTION Definitions: WO 98/04537 PCT/US97/13422 -8- Unless otherwise stated, the following terms used in the specification and claims have the meanings given below: 3 "Alkanoyl" means the radical wherein R is alkyl as defined below, having overall the number of carbon atoms indicated 8 )alkanoyl includes the radicals formyl, acetyl, propionyl, butyryl, isobutyryl, crotonoyl, isocrotonyl, etc.).
6 "Alkyl", as in alkyl, arylalkyl, alkyloxy, alkylthio, means a straight or branched, saturated or unsaturated hydrocarbon radical having the number of carbon atoms indicated (C.)alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, 9 allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propynyl, etc.).
"Alkylene" means a straight, saturated or unsaturated hydrocarbon divalent radical having 12 the number of carbon atoms indicated (Co 6 )alkylene includes methylene (-CH 2 ethylene
(-(CH
2 2 vinylene ethynylene 2-propylene (-CH:CH-CH 2 1-propylene (-CH2-CH:CH-), tetramethylene (-(CH 2 4 pentamethylene 5 and hexamethylene
(-(CH
2 6 etc.). The term (Co)alkylene 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 8 )alkyloxy includes the radicals methoxy, ethoxy, 18 propoxy, isopropoxy, butoxy, isobutoxy, etc.).
"Alkylthio" means the radical -SR, wherein R is alkyl as defined above, having the number of carbon atoms indicated 8 )alkylthio includes the radicals methylthio, 21 ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, etc.).
"Animal" includes humans, non-human mammals dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, etc.) and non-mammals birds, etc.).
24 "Aryl", as in aryl, arylalkyl, aryloxy and arylthio, means an aromatic monocyclic or polycyclic hydrocarbon radical containing the number of carbon atoms indicated, wherein the carbon atom with the free valence is a member of an aromatic ring, and any carbocylic ketone or 27 thioketone derivative thereof (C 6 .,4)aryl includes phenyl, naphthyl, anthracenyl, phenanthrenyl, 1,2,3,4-tetrahydronaphth-5-yl, 1-oxo-1,2-dihydronaphth-6-yl, 1-thioxo- 1,2-dihydronaphth-7-yl, etc.).
"Arylene" means an aromatic monocyclic or polycyclic hydrocarbon divalent radical WO 98/04537 PCT/US97/13422 -9containing the number of carbon atoms indicated, wherein the carbon atoms with the free valence are members of an aromatic ring, and any carbocylic ketone or thioketone derivative thereof 3 (C 6 1 4 )arylene includes 1,4-phenylene, 1,3-phenylene, 1,4-naphthylene, 2 6 -naphthylene, 1, 4 -anthracenylene, 2 ,6-anthracenylene, 1, 6 -phenanthrenylene, 1,2,3, 4 -tetrahydro-5,8-naphthylene, I-oxo-1,2-dihydro-5,7-naphthylene, 6 1-thioxo-1,2-dihydro-5,8-naphthylene, etc.).
"Aryloxy" means the radical -OR, wherein R is aryl, as defined above, having the number of carbon atoms indicated
(C
6 4 )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
(C
6 1 4 )arylthio 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, wherein the carbon atom with the free valence is a member of a non-aromatic ring, and any carbocyclic ketone and thioketone derivative thereof (C3.,4)cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 18 bicyclo[2.2.2]octyl, 1,2,3,4-tetrahydronaphth-1 -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, wherein the carbon atoms with the free valence are members of a non-aromatic ring, and any carbocyclic ketone and thioketone derivative thereof (C3-6)cycloalkylene includes 1, 2 -cyclopropylene, 1,2-cyclobutylene, 24 1, 3 -cyclobutylene, 1,2-cyclopentylene, 1, 3 -cyclopentylene, 1,4-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-1 ,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, wherein R is cycloalkyl, as defined above, having the number of carbon atoms indicated
(C
3 1 4 )cycloalkyloxy includes the radicals cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc.).
WO 98/04537 PCTIUS97/13422 "Cycloalkylthio" means the radical -OR, wherein R is cycloalkyl, as defined above, having the number of carbon atoms indicated
(C
3 14 )cycloalkylthio includes the radicals 3 cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc.).
"Deprotecting" refers to removing any protective groups present after the selective reaction has been carried out.
6 "Disease" specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition which may be caused by, or incident to, medical or veterinary therapy applied to that animal, the "side effects" of such therapy.
9 "Halo" means fluoro, chloro, bromo or iodo.
"Heteroalkylene" means alkylene, as defined above, wherein I to 5 of the carbon atoms indicated is replaced by a heteroatom chosen from N, 0 or S azaalkylene, oxaalkylene and 12 thiaalkylene, respectively), with the proviso that the oxygen, nitrogen and sulfur atoms contained therein do not form bonds with other heteroatoms. For example, hetero(C 3 12 )alkylene is meant to encompass aza(C 3 )alkylene which includes 3 -azatrimethylene
(-NHCH
2
CH
2 2 -azatrimethylene
(-CH
2
*NH*CH
2 etc.; w-aza(C 25 )alkylene which includes 2-azaethylene
(-NH-CH
2 3-azatrimethylene, 4 -azatetramethylene
(-NH-CH
2
-CH
2
*CH
2 and
(-NH-CH
2
CH
2
*CH
2
*CH
2 oxa(C 3 )alkylene which includes as 18 3 -oxatrimethylene (-0-CH 2
-CH
2 2 -oxatrimethylene
(-CH
2
-O-CH
2 etc.; oxa(C 5 )alkylene such as 3 -oxapentamethylene
(-CH
2
-CH
2
O-CH,-CH
2 etc.; thia(C3)alkylene which includes 3 -thiatrimethylene
CH
2
*CH
2 2 -thiatrimethylene
(-CH,-S-CH
2 etc.; w-thia(C 2 4 )alkylene 21 which includes 2-thiaethylene
(-NH-CH
2 3 -thiatrimethylene and 4-thiatetramethylene
(-S-CH
2 -CH2,CH 2 diaza(C 6 )alkylene which includes 2
(..CH
2
-NH*CH
2
.CH
2 azaoxa(C 6 )alkylene which includes 2 24 (-CH 2
&OCH
2
-CH,.NH-CH
2 and the like.
"Heteroarylene" means arylene, as defined above, wherein 1 to 5 of the carbon atoms indicated are replaced by a heteroatom chosen from N, 0 or S hetero(C 5 6 )arylene includes 27 furylene, thienylene, pyrrolylene, imidazolylene, pyridylene, etc.).
"Heterocycloalkylene" means cycloalkylene, as defined above, wherein 1 to 5 of the carbon atoms indicated are replaced by a heteroatom. chosen from N, 0, or S hetero(C 3 14 )cycloalkylene includes 2 4 -pyrrolidinylene, 2 4 -pyrrolinylene, WO 98/04537 PCT/US97/13422 -11- 2 4 -imidazolinylene, 2 4 -imidazolinylene, 3 5 -pyrazolinylene, 1,4-piperidylene, 1, 4 -piperazinylene, 2 ,5-quinuclidinylene, 2 ,5-morpholinylene, 1.3-isoindolinylene, etc.).
3 "Heterooxoalkylene" means alkylene, as defined above, wherein one of the number of carbon atoms indicated is replaced by a heteroatom chosen from N, O or S and a carbon atom adjacent to the heteroatom is replaced by a carbonyl group azaoxoalkylene, 6 oxaoxoalkylene 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(C 3 )alkylene which includes 9 2-aza-3-oxotrimethylene
(-C(O)-NH-CH
2 3 -aza-2-oxotrimethylene
(-NH-C(O).CH
2 etc.; oxaoxo(C 3 )alkylene which includes 2 -oxa-3-oxotrimethylene
(-C(O)-O-CH
2 3 -oxa- 2 -oxotrimethylene
(-O-C(O)-CH
2 etc.; and thiaoxo(C 3 )alkylene which includes 12 2 -thia-3-oxotrimethylene 2 3-thia-2-oxotrimethylene
(-S-C(O)-CH
2 etc.
"Leaving group" has the meaning conventionally associated with it in synthetic organic chemistry, an atom or group displaceable under alkylating conditions, and includes, halogen, hydroxy, alkylsulfonloxy mesyloxy, ethanesulfonyloxy, etc.), arylsulfonyloxy benzenesulfonyloxy and tosyloxy, thienyloxy), dihalophosphinoyloxy, tetrahalophosphaoxy, and the like.
18 "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 21 substituted with one or more radicals" means that the group referred to may or may not be substituted in order to fall within the scope of the invention.
"Pharmaceutically acceptable N-Oxide" means compound in which nitrogens are in an 24 oxidized state O-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.
27 "Oxoalkylene" means alkylene, as defined above, wherein one of the number of carbon atoms indicated is replaced by a carbonyl group oxo(C 3 )alkylene includes 3 -oxotrimethylene
(-C(O)*CH*CH
2 etc..
"Pathology" of a disease means the essential nature, causes and development of the WO 98/04537 PCTIUS97/13422- -12disease as well as the structural and functional changes that result from the disease processes.
"Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical 3 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 which are pharmaceutically acceptable, 6 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, 9 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, 12 heptanoic acid, o-(4-hydroxybenzoyl)benzoic acid, 2 -hydroxyethanesulfonic acid, hydroxynaphthoic acid, lactic acid, lauryl sulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4 -methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, 4 4 '-methylenebis(3-hydroxy-2-ene-l-carboxylic acid), muconic acid, 2-naphthalenesulfonic acid, oxalic acid, 3-phenylpropionic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiary butylacetic acid, p-toluenesulfonic acid, trimethylacetic acid 18 and the like.
Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable 21 inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like.
24 "Phenylene" means the divalent aromatic radical -C 6
H
4 and includes 1,4-phenylene, 1, 3 -phenylene and the like.
"Pharmaceutically acceptable prodrug derivatives" means derivatives of compounds of 27 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 which have N-acylated piperidyl N-acylated azaalkylene -N(P)*CH2-CH 2 N-acylated amino -NH 2 N-acylated amidino WO 98/04537 PCT/US97/13422- -13- -C(NH)-NHP or -C(NP)-NH 2 N-acylated guanidino -NHC(NP)-NHP, -NH-C(NH)-NHP or -NHC(NP)-NH 2 groups, in which P is a group selected from 3 wherein R 1 0 can be (C 1 ,.,)alkyloxy or cis- 2 -(C.lo)alkanoyloxyphenylvinyl, 3-(C 1 1 )alkanoyloxybutyryl,
R"-X
28 wherein R" is carboxy and X 28 is (C 1 1 0 )alkylene or
-C(O)-O-CH(RI
2
)O*C(O)R'
3 wherein R 1 2 is hydrogen, (C 1 t, 0 )alkyl or (C 3 1 0 )cycloalkyl and R" is 6 (C, 1 1 )alkyl.
"Protective group" has the meaning conventionally associated with it in synthetic organic chemistry, a group which selectively blocks one reactive site in a multifunctional compound 9 such that a chemical reaction can be carried out selectively at another unprotected reactive site and which can be readily removed after the selective reaction is completed.
"Protecting agent" means an agent which will react with a multifunctional compound and 12 create a protective group at a reactive site.
"Protected derivatives" in reference to a compound or a group means a derivative of compound or group in which a reactive site or sites are blocked with protective groups.
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 tert-butoxycarbonyl, benzyloxycarbonyl and any other 18 suitable amino protective groups see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley Sons, Inc. 1981).
"Symptomatology" of a disease means any morbid phenomenon or departure from the 21 normal in structure, function or sensation experienced by the patient and indicative of the disease, their production and the indications they furnish.
"Therapeutically effective amount" means that amount which, when administered to an 24 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 27 symptoms of the disease, inhibiting the disease arresting its development) or relieving the disease causing regression of the disease).
The term means adding a quantity sufficient to achieve a stated function, to bring a solution to the desired volume 100%).
WO 98/04537 PCT/US97/13422- -14- The compounds of Formula I and the intermediates and starting materials 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 which R' is 4-amidinobenzyl, X' and X 9 each are X 2 is 9 1,4-piperazinylene,
X
7 is X' is 4,1-piperidylene and R 2 is R 9
-X
2 1 wherein R 9 is piperid-4-yl and X21 is 3-azatrimethylene, is illustrated by the following formula: 12
NH
H
2 N KH X3X4 N NN.2 0 P NX X6 PSNN"cs H 0
O
which compound is named: cis-I 5 -cyclooctylene 4 -(4-amidinobenzylcarbamoyl)- I -piperazinecarboxylate 4 2 -piperid-4-ylaminoethylcarbamoyl)- 1 -piperidinecarboxylate when X' and X 7 each are
X
4 and X 6 each are a covalent bond, X' is cis-1,5-cyclooctylene and P is hydrogen; 3- cis-5-[ 4 4 -amidinobenzylcarbamoyl)piperazin-1-ylcarbonyloxy]cyclooctyloxy- 18 carbonyl piperid- 4 -ylcarbonylamino)ethylamino]piperid -1-ylcarbonyl propionic acid when X 3 and X 7 each are X 4 and X 6 each are a covalent bond, X' is cis-1,5-cyclooctylene and P is 3 -carboxypropionyl; 21 4 4 4 -amidinobenzylcarbamoyl)piperazin- I1-ylcarbonyl]benzyl 4 2 -piperid-4-ylaminoethylcarbamoyl)- 1 -piperadinecarboxylate when X 3 is X 7 is
X
4 is a covalent bond, X 6 is methylene, X 5 is phenylene and P is hydrogen; 1 ,4-tetramethylene 4-amidinobenzylcarbamoyl-l-piperazinecarboxylate when X 3 and X 7 are each is and X 4
-X
5
-X
6 is 1 4 -tetramethylene -CH 2
-CH
2 .CH 2 .CH and N-4-a mid inobenzyl-4-{5-[4(2piperid-4yla i noethylca rbamoy)piperid- 1 ylIca rbonyl]va leryl}-1 -pi perazi neca rboxa mid e when X 3 and X7 are each is and X 4
-X
5
-X
6 is 1 ,4-tetramethylene -CH 2 .CH 2 .CH 2 -CH2_).
Presently Preferred Embodiments: While the broadest definition of this invention is set forth in the Summary of the Invention, certain compounds of Formula I are preferred. For example, lo preferred compounds of Formula I are those in which X 5 is cis-l 1, 5 -cyclooctylene and X 4 and X 6 each are a covalent bond, X 4
-X
5
-X
6 together are (C4..8)alkylene or X is 1,4-phenylene and X 4 and X 6 are (0o- 1 )alkylene;
X
1 and X 9 are independently a covalent bond,
-N(CH
3 or -S(O) 2 NH-, with the proviso that X 1 and X 9 are not both covalent bonds; X 3 and X 7 are independently or
X
2 and X 8 are independently
-X
10
-X
11 wherein X 10 is a covalent bond or methylene and X 1 1 is 4,1 -piperidylene or 1 ,4-piperazinylene;
R
1 is R _or R 5 -Xl 3 wherein R 4 is amidino, guanidino or methylamino,
X
12 is -X 14
X
15 _Xl 6 wherein X 15 is 1,4-phenylene or 1,4-piperidylene, X1 4 is (0fl14)alkylene and
X
1 6 is (Cfll6)alkylene, wherein the sum of n14 and n16 is 0, 1 or 2, R 5 is piperid-4-yl 20 and X 1 is (02-3)alkylene; and R 2 is R 8
_X
20 or R 9
_X
21 wherein R 8 is amino, amidino, guanidino, methylamino or 1-aminoethyl,
X
20 is -X 22
-X
23
-X
24 wherein X 23 is trans-i ,4-cyclohexylene, 1 ,4-phenylene, 4,1-pyridylene, 1 ,4-piperidylene, X2 2 is (Cfl22)alkylene and X 2 s(Cl24alkylene, wherein the sum of n22 and n24 is 1 or 2,
R
9 is benzoimidazol-5-yl, imidazol-4-yl, imidazol-4-yl, 2-imidazolin-2-yl, 4methylimidazol-1 -yl, 5-methylimidazol- 1 -yl, 1 -methylpiperid-4-yl, piperid-4-yI, piperazin-1 -yl, pyrid-3-yl, pyrid-4-yl, 1 4 ,5,6-tetrahydropyrimidin5yl or 1,4,5,6- *.*tetra hyd ro-2-d ioxopyrim id in5yl and X 1 is (CI-6)alkylene, ow-aza(0 25 )alkylene, 3- :oxotrimethylene, o0-thia(024)alkylene, 3 -oxo-2-azatrimethylene, 3-aza-2oxotreimthylene or -x 25 -x 2 6-x 27 wherein X 26 is 1 ,4-phenylene,
X
25 is (0fl25)alkylene 30 and X 27 is (Cfl27)alkylene, wherein the sum of n25 and n27 is 0 or 1; and the pharmaceutically acceptable salt, N-oxides, prodrug derivatives and protected derivatives thereof.
More preferred compounds of Formula I are those in which X 5 is cyclooctylene I:WAYLIB0ibc04346.doc WO 98/04537 PCTIUS97/13422- -16and X 4 and X 6 each are a covalent bond or X 4
-X
5
-X
6 together are (C 4 8 )alkylene; X' and X 9 are independently a covalent bond -C(O)NH- or -S(O) 2 NH-, with the proviso that 3 X' and X 9 are not both covalent bonds; X 3 and X 7 are independently or X 2 and X8 are independently -X'IO-X" wherein X 10 is a covalent bond or methylene and is 4,1-piperidylene or 1,4-piperazinylene; R' is R 4
-X'
2 wherein R 4 is amidino or guanidino and X' 2 6 is -X' 4
-XI
5
-X'
6 wherein X' 5 is 1,4-phenylene or 1,4-piperidylene, X' 4 is 1 4 )alkylene and X' 6 is (Cnl)alkylene, wherein the sum ofnl4 and nl 6 is 0, 1 or 2; and R 2 is R'-X 20 Or R 9
-X
2 1 wherein R' is amino or methylamino, X 2 0 is -X 2
X
2 3
-X
2 4 wherein X 2 3 is trans-1,4-cyclohexylene or 9 1,4-phenylene, X 22 is (Cn 2 2 )alkylene and X' 6 is (Cn 24 )alkylene, wherein the sum of n22 and n24 is 1 or 2, R 9 is imidazol- l-yl, imidazol-4-yl, 4-methylimidazol- I-yl, 5-methylimidazol- l-yl, piperid-4-yl or pyrid-4-yl and X 21 is (C-5.,)alkylene or 3-azatrimethylene; and the 12 pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
Particularly preferred compounds of Formula I are those in which XS is cis-1,5-cyclooctylene and X 4 and X 6 each are a covalent bond; X' and X 9 are independently or X 3 and X 7 each are X 2 and X 8 are independently wherein X'o is a covalent bond and X" is 1,4-piperazinylene; R' is R 4
-X'
2 wherein R 4 is 18 amidino or guanidino and X12 is -X' 4
-X'-X
1 6 wherein X' 5 is 1,4-phenylene, X' 4 is a covalent bond and X' 6 is methylene; and R 2 is R'-X2 0 Or R 9
-X
2 1 wherein R 8 is amino, X 2 0 is
-X
22
-X
23 -x 2 4 wherein X 23 is trans-1,4-cyclohexylene,
X
22 is a covalent bond and X 24 is 21 methylene, R' is piperid-4-yl and X 2 is ethylene or trimethylene; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
Particularly preferred compounds of Formula 1 are those in which X 4
-X
5
-X
6 together are 24 (C4.
8 )alkylene; X' and X 9 are independently or X 3 and X 7 are independently or X 2 and X 8 each are wherein XtO is a covalent bond and X" is 1, 4 -piperazinylene; R' is R 4
-X
1 2 wherein R4 is amidino or guanidino and X12 is -X' 4
-X
5
-X'
6 27 wherein X" is 1,4-phenylene, X' 4 is a covalent bond and X'6 is methylene; and R 2 is R 8
-X
2 0 wherein R' is amidino or guanidino and X 2 0 is -X 22
-X
23
-X
24 wherein X 23 is 1,4-phenylene, X 2 2 is a covalent bond and X 24 is methylene; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
WO 98/04537 WO 9804537PCTIUS97/13422.
-17- Most preferred compounds of Formula I are the following: 4-guanidinobenzyl 4 7 4 4 -guanidinobenzylcarbamoyl)piperazin-1-ylcarbonyl]- 3 heptanoyl)}-lI-piperazinecarboxamide; 4-guanidinobenzyl 4- 8 4 4 -guanidinobenzylcarbamoyl)piperazin.1 -ylcarbonyl]octanoyl 6 1 -piperazinecarboxamide; 4-guanidinobenzyl 4- 9 4 4 -guanidinobenzylcarbamoyl)piperazin-1 -ylcarbonyl]nonanoyl -1 -piperazinecarboxamide; 9 4-amidinobenzyl 4- 7 4 4 -amidinobenzylcarbamoyl)piperazin. I -ylcarbonyllheptanoyl)}- 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)-1 -piperazinecarboxylate], cis-l ,5-cyclooctylene 4 -(4-amidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4 4 -piperid-4-ylbutyryl)- 1 -piperazinecarboxylate; cis- 1 ,5-cyclooctylene trans- 4 -(4-aminocyclohexylmethylcarbamoyl)- 18 1 -piperazinecarboxylate 4 4 -guanidinobenzylcarbamoyl)- 1-piperazinecarboxylate; 4 4 -amidinophenylacetyl)-1I-piperazinecarboxylate 4 -(4-piperid-4-ylbutyryl)- I -piperazinecarboxylate; 21 1 ,4-tetramethylene di 4 4 -guanidinobenzylcarbamoy)- 1 -piperazinecarboxylate]; cis- 1,5-cyclooctylene 4 4 -guanidinobenzylcarbamoy)- 1-piperazinecarboxylate 4 2 -piperid-4-ylethylcarbamoyl)- 1 -piperazinecarboxylate; 24 4 -guanidinobenzyl 4- f 6- 4 4 -guanidinobenzylcarbamoyl)piperazin-. 1 -ylcarbonyl] hexanoyl 1 -piperazinecarboxamide; 27 cis- 1 ,5-cyclooctylene 4 4 -guanidinobenzylcarbamoyl). 1 -piperazinecarboxylate 4 4 -piperid-4-ylbutyryl)- 1 -piperazinecarboxylate; cis- 1,5 -cyclooctylene 4 4 -guanidinophenylacetyl)-lI-piperazinecarboxylate 4 2 -piperid-4-ylethylcarbamoyl)- 1-piperazinecarboxylate; WO 98/04537 PCT/US97/13422 -18- 4 4 -guanidinophenylacetyl)-1 -piperazinecarboxylate 4 4 -piperid-4-ylbutyryl)- 1 -piperazinecarboxylate; 3 4-guanidinobenzyl 4- 5-[ 4 4 -guanidinobenzylcarbamoyl)piperazin- -ylcarbonyl]valeryl} 1 -piperazinecarboxamide; 6 3-oxa-1,5-pentamethylene di[ 4 4 -guanidinophenylacetyl)piperazin-1-ylcarbonyl]; and 4 4 -amidinophenylacetyl)-1 -piperazinecarboxylate 4 2 -piperid-4-ylethylcarbamoyl)-1-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 pathology and/or symptomatology include asthma, allergic rhinitis, rheumatoid spodylitis, osteoarthritis, gouty arthritis, rheumatoid arthritis, arthritic conditions in general, urticaria, angioedema, eczematous dermatitis, anaphylaxis, hyper proliferative skin disease, peptic ulcers, 18 inflammatory bowel disease, ocular and vernal conjunctivitis, inflammatory skin conditions, and the like.
Suitable in vitro assays for measuring tryptase activity and the inhibition thereof by 21 compounds are known see Sturzebecher et al. (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 skill in the art.
For example, in vivo models for asthma are known see Larsen (1991) Experimental Models 27 of Reversible Airway Obstruction. In: West et al., eds. The Lung. Scientific Foundations Raven Press, New York). For further details of an in vitro model of asthma see Example 2, infra.
Further, in vivo models of inflammatory skin conditions (Walsh et al. (1995) Br. J. Pharmacol.
WO 98/04537 PCT/US97/13422 -19- 114: 1343-1350; and Armstrong et al. (1995) Prostaglandins 49: 205-224), arthritic conditions (Peacock et al. (1995) Cell Immunol. 160: 178-184; and Houri 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.
WO 98/04537 PCT/US97/13422 Administration and Pharmaceutical Compositions: In general, compounds of Formula I will be administered in therapeutically effective 3 amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another therapeutic agent. 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 6 the compound used and other factors. For example, therapeutically effective amounts of a compound of Formula I for the treatment of asthma may range from 0.1 micrograms per kilogram body weight (pg/kg) per day to 1 milligram per kilogram body weight (mg/kg) per day, 9 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 pig/day to 10 mg/day, typically 0.1 mg/day to mg/day.
12 Therapeutic agents that may be useful for administration in combination with compounds of Formula I in treating asthma include P-adrenergic agonists albuterol, terbutaline, formoterol, fenoterol, prenaline and the like), methylxanthines caffeine, theophylline, aminophylline, theobromine and the like), cromoglycates cromolyn, nedocromil, and the like) and corticosteroids beclomethasome, triamcinolone, flurisolide, dexamethasone and the like). In general, one of ordinary skill in the art, acting in reliance upon personal knowledge 18 and the disclosure of this application, will be able to ascertain a therapeutically 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 21 of the following routes: oral, systemic transdermal, intranasal or by suppository) or parenteral intramuscular, intravenous or subcutaneous). Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, 24 suspensions, elixirs, aerosols, or any other appropriate composition and are comprised of, in general, a compound of Formula I in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect 27 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, WO 98/04537 PCT/US97/13422 -21gelatin, 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 glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin 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 0.01%w to 10%w, preferably 0.3%w to l%w, 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
-X
2
-X
4
-X
5
-X
6
-X
8 and R 2 which subunits are connected via carbonyl, formyloxy, amide, sulfonamide, carbamate or urea linkages
-C(O)N(R
3 24 -N(R 3
-S(O)
2
N(R
3
-N(R
3
)S(O)
2
-OC(O)N(R
3
-N(R
3
-N(R
3
)C(O)N(R
3 or Methods for forming such linking groups are known and suitable reagents are readily available see, March, Advanced Organic Chemistry, 4th Ed. (Wiley 1992); Larock, 27 Comprehensive Organic Transformations (VCH 1989); and Furniss et al., 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 WO 98/04537 PCT/US97/13422 -22larger 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 analogous procedures.
Compounds of Formula I in which X 8 is 1, 4 -piperazinylene or 1, 4 -piperidylene and X 9 is or -N(R 3 or in which X 8 is 8 )alkylene and X 9 is -C(O)N(R 3 6 -OC(O)N(R 3 or -N(R 3
)C(O)N(R
3 can be prepared by reacting a compound of Formula 1: RI'-X-X2X 3x4
X
y8-X6 1 or a protected derivative thereof, with a compound of the formula R 2
-Y
9 or a protected 9 derivative thereof, wherein L is a leaving group, Y 9 is a bond, or -N(R 3
Y
8 is piperazin-1-yl, piperid-4-yl or HN(R 3 8 )alkyl, respectively, and each R 2
R
3
X
2
X
3
X
4
X
5
X
6 and X 7 are as defined in the Summary of the Invention, and then deprotecting when 12 necessary. Alternatively, compounds of Formula I in which X 8 is 1, 4 -piperazinylene or 1, 4 -piperidylene and X 9 is -NHC(O)- or in which X' is 8 )alkylene and X 9 is -NHC(0)N(R 3 can be prepared by reacting an appropriate compound of Formula 1, or a protected derivative thereof, with an isocyanate of the formula R 2 or a protected derivative thereof, and then deprotecting when necessary (for further details see Example 8, infra.).
In an analogous fashion, compounds of Formula I in which X 2 is 1,4-piperazinylene or 18 1, 4 -piperidylene and X' is or -N(R 3 or in which X 2 is (C.
8 s)alkylene and X' is -C(0)N(R 3 -OC(0)N(R 3 or -N(R 3
)C(O)N(R
3 can be prepared by reacting a compound of Formula 2: 2 1 y2-X3X4 R2_X9.X.-X7-X6 WO 98/04537 PCT/US97/13422- -23or a protected derivative thereof, with a compound of the formula or a protected derivative thereof, wherein L is a leaving group, Y' is a bond, or -N(R 3
Y
2 is 3 piperazin-l-yl, piperid-4-yl or HN(R')-(C.,)alkyl, respectively, and each R 2
R
3
X
3
X
4
X
5
X
6
X
7
X
8 and X 9 are as defined in the Summary of the Invention, and then deprotecting when necessary. Alternatively, compounds of Formula I in which X 2 is 1, 4 -piperazinylene or 6 1,4-piperidylene and X' is -NHC(O)- or in which X 2 is 8 )alkylene and X' is -NHC(O)N(R 3 can be prepared by reacting a compound of Formula 2, or a protected derivative thereof, with an isocyanate of the formula or a protected derivative thereof, and then deprotecting 9 when necessary (for further details see Example 14(b), infra.).
Compounds of Formula I in which R' equals R 2
X
2 and/or X 8 is 1, 4 -piperazinylene or 1,4-piperidylene; X' is or -N(R 3 and X 9 is or 12 -N(R 3 and/or in which X 2 and/or X 8 is 8 )alkylene; X' is -C(0)N(R 3
-OC(O)N(R
3 or
-N(R')C(O)N(R
3 and X 9 -C(0)N(R 3
-OC(O)N(R
3 or -N(R 3
)C(O)N(R
3 can be prepared by reacting a compound of Formula 3: Y2-X 3 x 4
X
Y -X 7
X
6 3 or a protected derivative thereof, with 2 or more molar equivalents of a compound of the formula or a protected derivative thereof, wherein L is a leaving group, Y' is a bond, or 18 -N(R 3
Y
2 and Y 8 are independently piperazin-1-yl, piperid-4-yl or HN(R 3 8 )alkyl and each
R
3
X
3
X
4
X
5
X
6 and X 7 are as defined in the Summary of the Invention, and then deprotecting when necessary. Alternatively, compounds of Formula I in which R' equals R2; X 2 21 and/or X' is 1, 4 -piperazinylene or 1,4-piperidylene; X' is -NHC(O)- and/or X 9 is -NHC(O)and/or in which X 2 and/or X 8 is 8 )alkylene and X' is -NHC(0)N(R 3 and/or X 9 is -NHC(0)N(R 3 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 or a protected derivative thereof, and then deprotecting when necessary (for further details see WO 98/04537 WO 9804537PCT/US97/13422 -24- Example 10, infra.).
Compounds of Formula I in which X' is -N(R 3 -N(R 3 or 3 -N(R 3
)C(O)N(R
3 can be prepared by reacting an amine of the formula R'-N(R 3 or a protected derivative thereof, with a compound of Formula 4: LC(O)-Y'
_X
2
X
3
X
4 R 2 _X 9 -X8-X 7 -X 4 6 or a protected derivative, wherein L is a leaving group, Y' is a bond, or -N(R 3 and each R',
R
2 1' X1, X 3
X
4 X1, X1, X 7
X
8 and X 9 are as defined in the Summary of the Invention (for further details see Example 20, infra.).
9 Compounds of Formula I in which X 2 is 1 4 -piperazinylene or 4,1 -piperidylene and X' is or -C(0)N(R 3 or in which X 2 is (C 1 8 )alkylene and X 3 is -N(R 3
-N(R
3 or -N(R 3 )C(0)N(R 3 can be prepared by reacting a compound of the 12 formula R'-X'-Y 2 or a protected derivative thereof, with a compound of Formula LC(O)-Y 3 _X 4
N
or a protected derivative thereof, wherein L is a leaving group, y 3 is a bond, or -N(R 3 y 2 is piperazin-1I-yl, piperid-4-yl or HN(R 3 18 )alkyl, respectively, and each R 3 X'I, XV, XV,
X
4
X
5
X
6
X
7
X
8 and X1 are as defined in the Summary of the Invention (for further details see Example 3 1, infra.).
18 Compounds of Formula I in which X 2 and X' each are 1 ,4-piperazinylene or 4 1-piperidylene and X 3 and X 7 are independently or -C(O)N(R 3 or in which X' and X 8 each are (C 18 )alkylene or hetero(C 1 .g)alkylene and X 3 and X 7 are independently WO 98/04537 PCT/US97/13422.
-N(R
3
-N(R
3 or -N(R 3
)C(O)N(R
3 can be prepared by reacting two or more molar equivalents of a compound of the formula R'-X'-Y 2 or a protected derivative thereof, with 3 a compound of Formula 6: LC(O)-y3-X45
X
LC(O)Y7-X 6 6 or a protected derivative thereof, wherein L is a leaving group, Y 3 and Y 7 are independently a 6 bond, or -N(R 3
Y
2 is piperazin-l-yl, piperid-4-yl, HN(R 3 8 )alkyl or
HN(R
3 )-hetero(C 1 8 )alkyl, respectively, and each X 4
X
5 and X 6 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 an acid chloride derivative) and an appropriate nucleophile in the presence of a suitable organic base N,N-diisopropylethylamine (DIEA), N-methylmorpholine, etc.
12 preferably DIEA) and suitable solvent N,N-dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane, etc.) at 20 to 30 0 C, typically at approximately 23 C, for several minutes to 24 hours. Alternatively, the acylation can be effected by reacting together an appropriate carboxylic acid and nucleophile in the presence of a suitable coupling reagent 1-( 3 -dimethylaminopropyl)-3-ethylcarbodiimide, etc.) and a suitable solvent DMF, etc.) at to 30 0 C, typically at approximately 23 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 materials 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 removal can be found in T.W. Greene, Protective Groups in Organic Synthesis, John Wiley Sons, Inc. 1981.
WO 98/04537 PCT/US97/13422_ -26- Generally, the starting materials 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 materials.
A convenient starting material for preparing compounds of Formula I in which X 3 and X 7 9 each are is a compound of Formula 7:
LC(O)-O-X
4 s
LC(O)-O-X
6 7 in which each X 4
X
5 and X 6 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 cis-1,5-cyclooctanediol, trans-1,4-cyclohexylendimethanol, 1,4-phenylenedimethanol, etc.) with triphosgene (for further details see Example 5, infra.).
Intermediates useful in preparing compounds of Formula I in which 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 R 4 is guanidino can be prepared by reacting a corresponding compound of Formula I in which R 4 is amino with cyanamide. The reaction is 21 carried out by treating the amine with hydrogen chloride and then reacting neat with an excess of cyanamide at approximately 65 0 C for about two hours (for further details see Example infra.).
24 Compounds of Formula I may be prepared as pharmaceutically acceptable acid addition WO 98/04537 PCT/US97/13422 -27salts by reacting the free base forms of a compound of Formula I with a pharmaceutically acceptable inorganic or organic acid. Alternatively, the pharmaceutically acceptable base 3 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 6 of compounds of Formula I are set forth in the definitions section of this application.
Alternatively, the salt forms of the compounds of Formula I may be prepared using salts of the starting materials or intermediates.
9 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 12 suitable base 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 hydrochloric acid, etc).
The N-oxides of compounds of Formula I can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound of Formula I with an oxidizing agent trifluoroperacetic acid, permaleic 18 acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, etc.) in a suitable inert organic solvent a halogenated hydrocarbon such as methylene chloride) at approximately 0 C. Alternatively, the N-oxides of the compounds of Formula I can be prepared from the 21 N-oxide of an appropriate starting material.
Compounds of Formula I in unoxidized form can be prepared from N-oxides of compounds of Formula I by treating with a reducing agent sulfur, sulfur dioxide, triphenyl 24 phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.) in an suitable inert organic solvent acetonitrile, ethanol, aqueous dioxane, etc.) at 0 to 80 °C.
Prodrug derivatives of the compounds of Formula I can be prepared by methods known to 27 those of ordinary skill in the art for further details see Saulnier et al.(1994), Bioorganic and Medicinal Chemistry Letters. 4:1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of Formula I with a suitable carbamylating agent 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, etc.).
WO 98/04537 PCT/US97/13422- -28- Protected derivatives of the compounds of Formula I can be made by means known 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 Sons, Inc. 1981.
In summary, an aspect of this invention is a process for preparing compounds of 6 Formula I, which process comprises: reacting a compound of Formula 1: R'-X -X2_X -X 4 Nx y 8
-X
7
-X
6 1 9 or a protected derivative thereof, with a compound of the formula R 2
-Y
9 or a protected derivative thereof, wherein L is a leaving group, Y 9 is a bond, or -N(R 3
Y
8 is piperazin-1-yl, piperid-4-yl or HN(R 3 respectively, and each R 2
R
3
X
2
X
3 12 X 4
X
5
X
6 and X 7 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I, in which X 8 is 1,4-piperazinylene or 1, 4 -piperidylene and X 9 is or -N(R 3 or in which X 8 is (C.,)alkylene and
X
9 is -C(O)N(R 3 -OC(0)N(R 3 or -N(R3)C(O)N(R3)-; reacting a compound of Formula 1, or a protected derivative thereof, with an isocyanate of the formula R 2 or a protected derivative thereof, and then deprotecting when 18 necessary, to give a compound of Formula I in which X 8 is 1,4-piperazinylene or 1, 4 -piperidylene and X 9 is -NHC(O)- or in which X 8 is (CJ 8 )alkylene and X 9 is -NHC(O)N(R 3 reacting a compound of Formula 2: 21 y 2
_X
3
X
4 R2X9_XX7X 6
R
2
-X
9
-X
8 -X7-X6 WO 98/04537 PCT/US97/13422- -29or a protected derivative thereof, with a compound of the formula or a protected derivative thereof, wherein L is a leaving group, Y' is a bond, or -N(R 3
Y
2 is 3 piperazin-1-yl, piperid-4-yl or HN(R 3 )-(CIs)alkyl, respectively, and each R 2
R
3
X
3
X
4
X
5
X
6
X
7
X
8 and X 9 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I in which X 2 is 1,4-piperazinylene or 6 1,4-piperidylene and X' is or -N(R 3 or in which X 2 is (Ci.
8 )alkylene and X' is -C(0)N(R 3 -OC(0)N(R 3 or reacting a compound of Formula 2, or a protected derivative thereof, with an isocyanate 9 of the formula or a protected derivative thereof, and then deprotecting when necessary, to give a compound of Formula I in which X 2 is 1,4-piperazinylene or 1,4-piperidylene and X' is -NHC(O)- or in which X 2 is 1 )alkylene and X' is -NHC(0)N(R 3 12 reacting a compound of Formula 3: Y2-X3 X4 Y-X7_X6 3 or a protected derivative thereof, with 2 or more molar equivalents of a compound of the formula or a protected derivative thereof, wherein L is a leaving group, Y' is a bond, or
-N(R
3
Y
2 and Y 8 are independently piperazin-1-yl, piperid-4-yl or 8 )alkyl and each
R
3
X
3
X
4
X
5
X
6 and X 7 are as defined in the Summary of the Invention, and then 18 deprotecting when necessary, to give a compound of Formula I in which R' equals R2; X 2 and/or
X
8 is 1,4-piperazinylene or 1,4-piperidylene; X' is or -N(R 3 and X 9 is or -N(R 3 and/or in which X 2 and/or X S is (Ci.
s )alkylene; X' is 21 -C(0)N(R 3 -OC(0)N(R 3 or -N(R 3
)C(O)N(R
3 and X 9 -C(0)N(R 3
-OC(O)N(R
3 or
-N(R
3
)C(O)N(R
3 reacting a compound of Formula 3, or a protected derivative thereof, with two or more 24 molar equivalents of an isocyanate of the formula or a protected derivative thereof, and then deprotecting when necessary, to give a compound of Formula I in which R' equals R 2 WO 98/04537 PCT/US97/13422
X
2 and/or X 8 is 1,4-piperazinylene or 1,4-piperidylene; X' is -NHC(O)- and/or X 9 is -NHC(O)and/or in which X 2 and/or X 8 is (C 1 8 )alkylene and X' is -NHC(O)N(R 3 and/or X 9 is 3 -NHC(O)N(R 3 reacting an amine of the formula R'-N(R 3 or a protected derivative thereof, with a compound Formula 4: 6 LC(O)-Y'-X2-X3-X4
X
R2-X 9
-X
8
X
7
-X
6 4 or a protected derivative thereof, wherein L is a leaving group, Y' is a bond, or -N(R 3 and each R 2
R
3
X
2
X
3
X
4
X
5
X
6
X
7
X
8 and X 9 are as defined in the Summary of the Invention, 9 and then deprotecting when necessary, to give a compound of Formula I in which X' is
-N(R
3
-N(R
3 or -N(R 3
)C(O)N(R
3 reacting a compound of the formula R'-X'-Y 2 or a protected derivative thereof, with a 12 compound of Formula LC(o)-Y3-XX4
X
R2-X9_X8_X 7
-X
6 or a protected derivative thereof, wherein L is a leaving group, Y 3 is a bond, or -N(R 3
Y
2 is piperazin-1-yl, piperid-4-yl or HN(R 3 .,)alkyl, respectively, and each R 2
R
3
X
1
X
2
X
3
X
4
X
5
X
6
X
7
X
8 and X 9 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I in which X 2 is 1, 4 -piperazinylene or 18 4,1-piperidylene and X 3 is or -C(0)N(R 3 or in which X 2 is (C,8.)alkylene and
X
3 is -N(R 3
-N(R
3 or -N(R 3
)C(O)N(R
3 reacting 2 or more molar equivalents of compound of the formula R'-X'-Y 2 or a WO 98/04537 PCT/US97/13422- -31protected derivative thereof, with a compound of Formula 6: LC(O)-Y3-X4
LC(O)Y
7
-X
6 6 3 or a protected derivative thereof, wherein L is a leaving group, Y 3 and Y 7 are independently a bond, or -N(R 3
Y
2 is piperazin-1-yl, piperid-4-yl, HN(R 3 )-(C,.8)alkyl or
HN(R
3 )-hetero(CI 8 )alkyl and each X 4
X
s and X 6 are as defined in the Summary of the 6 Invention, and then deprotecting when necessary, to give a compound of Formula I in which X 2 and X 8 each are 1,4-piperazinylene or 4,1-piperidylene and X 3 and X 7 are independently or -C(O)N(R 3 or in which X 2 and X 8 each are _)alkylene or hetero(C,.g)alkylene 9 and X 3 and X 2 are independently -N(R 3 or -N(R 3
)C(O)N(R
3 respectively; optionally reacting a compound of Formula I in which R 4 is amino with cyanamide to give a compound of Formula I in which R 4 is guanidino; 12 optionally further converting a compound of Formula I into a pharmaceutically acceptable salt; optionally further converting a salt form of a compound of Formula I to non-salt form; optionally further converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide; optionally further an N-oxide form of a compound of Formula I its unoxidized form; 18 optionally further converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and 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 wherein each R 2
R
3
X
2
X
3
X
4
X
5
X
6
X
7
X
8 and X 9 are as defined in their broadest definitions 24 set forth in the Summary of the Invention, with the processes applying particularly well to the presently preferred embodiments.
WO 98/04537 PCT/US97/13422 -32- Examples: EXAMPLE 1 3 tert-Butyl 4-aminobenzylcarbamate hydrochloride 4-Aminobenzylamine (50.34 g, 0.412 mol) in dichloromethane (200 mL) was placed in a one liter 3 neck round bottom flask fitted with a mechanical stirring apparatus and the solution 6 was cooled to 0 0 C. di-tert-Butyl dicarbonate (89.9 g, 0.412 mol.) in dichloromethane (200 mL) was added dropwise to the solution over 30 minutes 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 (MgSO 4 filtered and concentrated in vacuo giving a yellow oil. The oil was taken into ethyl ether methanol 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 yellow precipitate. The precipitate was collected by filtration and washed with additional ethyl ether (500 mL). Drying in vacuo gave tert-butyl 4-aminobenzylcarbamate hydrochloride (100.23 g, 0.387 mol, 94% yield) as a pale yellow solid; 'H-NMR (300MHz, DMSO-d 6 10.40-10.20 (br s, 3H), 7.40 (tr, 1H), 7.30 4H), 4.10 2H), 1.40 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 completely melted and then tert-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 between 60 and 65 0 C and then water (100 mL) was added. The aqueous mixture was cooled to room temperature and washed with ethyl ether (1 The organic phase was back extracted with water (2x, 100 mL) and the combined aqueous layers were washed with ethyl ether (500 WO 98/04537 PCT/US97/13422- -33mL), cooled in an ice water bath and then basified with aqueous sodium hydroxide (10 M, 100 mL) giving an insoluble oil which slowly crystallized. The crystals were collected by 3 filtration washed with water. Drying in vacuo gave tert-butyl 4 -guanidinobenzylcarbamate (18.3 g, 69.24 mmol, 70.8% yield) as a colorless crystalline solid; 'H-NMR (300MHz, DMSO-d 6 9.70 1H), 7.42 (tr, 1H), 7.40 4H), 7.25 2H), 7.15 2H), 4.10 2H), 1.40 6 9H).
EXAMPLE 3 tert-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 tert-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 minutes. The mixture was quenched with aqueous hydrochloric acid (0.1N, 200 mL) and the aqueous phase was washed with dichloromethane (50 mL). The combined organic layers were dried (MgSO 4 and filtered. Concentrating in vacuo gave tert-butyl 4 -chlorocarbonyl-l-piperazinecarboxylate (45.6 g, 71.6 mmol, 85% yield) as a yellow solid; 'H-NMR (300MHz, CDCl 3 3.70 2H), 3.60 2H), 3.50 4H), 1.50 9H).
18 EXAMPLE 4 tert-Butyl 4 -(4-guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate trifluoroacetate tert-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 minutes 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 0 C and then tert-butyl 4 -chlorocarbonyl-l-piperazinecarboxylate (39.3 g, 0.158 mol.), prepared as in Example 3, in WO 98/04537 PCT/US97/13422- -34dichloromethane (120 mL) was added. An additional amount of DIEA (30 mL) was added and the reaction mixture was allowed to warm to room temperature, 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 gave tert-butyl 4 4 -guanidinobenzylcarbamoyl)- 1-piperazinecarboxylate trifluoroacetate (62.0 g, 0.126 mol, 6 80% yield) as a pale yellow solid; 'H-NMR (300MHz, DMSO-d 6 10.15 1H), 9.10 (br s, 2H), 7.65 4H), 7.40 (tr, 1H), 7.25 (dd AB, 4H), 4.25 2H), 3.55 4H), 3.10 4H); Electrospray LRMS: Calculated for C 3
H
20 oN 6 0: MH': 277.4; MH 2 2 139.2, 9 Found: MH': 277.4; MH 2 2 139.3.
WO 98/04537 PCT/US97/13422 EXAMPLE di(chloroformate) 3 cis-1,5-Cyclooctanediol (20.2 g, 0.14 mol.) was taken into acetonitrile (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 warmed 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 from hexane gave 9 cis-l,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, CDCl 3 5.00-4.85 2H), 2.20-1.60 12H).
12 EXAMPLE 6 cis- ,5-Cyclooctylene chloroformate 4 -tert-butoxycarbonyl-1 -piperazinecarboxylate di(chloroformate) (1.91 g, 7.1 mmol), prepared as in Example 5, in dichloromethane (25 mL) was added dropwise to a mixture of tert-butyl 1-piperazinecarboxylate (1.3 g, 7.1 mmol) and DIEA (1.3 mL, 7.1 mmol) in dichloromethane (25 mL). The mixture was stirred 15 minutes at room temperature and then a workup with 0.1M aqueous hydrochloric acid 18 was performed. The dichloromethane layer was dried (MgSO 4 filtered and concentrated.
Purifying from the residue by silica gel flash chromatography using ethyl ether and hexanes as eluent gave cis-1,5-cyclooctylene chloroformate 4 -tert-butoxycarbonyl- 1-piperazinecarboxylate 21 (660 mg, 1.6 mmol, 22% yield) as a colorless oil; 'H-NMR (300MHz, CDCl 3 5.00-4.90 (m, 1H), 4.80-4.70 1H), 3.40 8H), 2.05-1.40 12), 1.40 9H).
WO 98/04537 PCT/US97/13422 -36- EXAMPLE 7 4 4 -guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate 3 4 -tert-butoxycarbonyl- 1 -piperazinecarboxylate tert-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 minutes 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 between 7 and 8 with 5M aqueous sodium hydroxide added dropwise.
9 cis-l,5-Cyclooctylene chloroformate 4 -tert-butoxycarbonyl- 1-piperazinecarboxylate (444.7 mg, 1.06 mmol), prepared as in Example 6, in THF (10 mL) was added to the aqueous solution and the pH was continually adjusted with 1M aqueous sodium hydroxide added dropwise until no 12 further change in pH was 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 white suspension. The suspension was allowed to stand for 15 to 30 minutes at room temperature and then the precipitate was collected by filtering and washed with water (2x, 15 mL). Drying in vacuo gave cis-1 4 4 -guanidinobenzylcarbamoyl)- 1-piperazinecarboxylate 4 -tert-butoxycarbonyl- 18 1-piperazinecarboxylate (527 mg, 0.82 mmol, 77% yield) as a colorless solid; 'H-NMR (300MHz, DMSO-d 6 7.05 2H), 7.00 (tr, 1H), 6.70 2H), 5.10 (br, 3H), 4.65 2H), 4.15 2H), 3.30 16H), 1.90-1.40 12H), 1.40 9H).
21 EXAMPLE 8 cis- 1,5-Cyclooctylene 4 4 -guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate 4 2 -piperid-4-ylethylcarbamoyl)-l-piperazinecarboxylate trifluoroacetate 24 (Compound 1) The following is the preparation of a compound of Formula I in which R' is 27 4 -guanidinobenzyl,
R
2 is 2-piperid-4-ylethyl, X' and X 9 each are X 2 and X' each are 1, 4 -piperazinylene,
X
3 and X 7 each are X 4 and X 6 each are a covalent bond and X 5 is WO 98/04537 PCTIUS97/13421 -37cis- 1 3 cis- I ,5-Cyclooctylene 4 4 -guanidinobenzylcarbamoy;)- I -piperazinecarboxylate 4 -tert-butoxycarbonyl- piperazinecarboxylate (818 mg, 1. 24 mmol.), prepared as in Example 7, was treated with TFA (2 mL) neat for 10 minutes. The mixture was concentration in vacuc 6 giving a colorless oil. The residue was triturated with ethyl ether (2x, 10 mL) and dried in vacuc giving a colorless foam. The residue was then taken into DMF (2 mL) and then DIBA (700 mL, mmol.) and tert-butyl 4 2 -isocyanatoethyl)-lI -piperidinecarboxylate (3.2 mL, 0.3 9 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 yellow solid. The solid was then treated with 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 gave cis- 1 ,-cyclooctylene 4 4 -guanidinobenzylcarbamoyl)- I -piperazinecarboxylate 4 2 -piperid-4-ylethylcarbamoyl). I -piperazinecarboxyl ate as an amorphous colorless solid; Plasma Desorption LRMS: Calculated for C 3 5
H
55
N,
0 0 6 MH': 712.9, Found: MHW: 713.2.
Proceeding as in Example 8 and substituting different starting materials the following 18 compounds of Formula I were prepared: cis- 1 ,5-cyclooctylene 4 4 -amninobenzylcarbamoyl). I -piperazinecarboxylate 4 4 -guanidinobenzylcarbamoyl). 1 -piperazinecarboxylate (Compound Calculated for 21 C 35 H1 50
NI
0 0 6 MW': 707.9, Found: MH': 707.7; cis- I ,5-cyclooctylene 4 4 -guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4 4 -piperidylmethylcarbamoyl). 1 -piperazinecarboxylate (Compound Calculated for 24 C 34
H
53
N]
0 0 6 MW: 698.9, Found: MH': 699.7; cis- I ,5-cyclooctylene 4 -(trans- 4 -amninocyclohexylmethylcarbamoyl)- 1 -piperazinecarboxylate, 4 4 -guanidinobenzylcarbamoyl). I -piperazinecarboxylate 27 (Compound Calculated for C 35
H
55
N
10 0 6 MW': 712.9, Found: MH': 713.6; cis- 1 ,5-cyclooctylene 4 4 -guanidinobenzylcarbamoyl)- I -piperazinecarboxylate WO 98/04537 PCTIUS97/13422, -38- 3 -piperid-4-ylpropylcarbamoyl. I -piperazinecarboxyl ate (Compound Calculated for
C
36
H
5 8
N
10 0 6 MH': 727.9 Found: MH': 727.9; 3 4 4 2 -piperid-4-ylethylcarbamoyl)piperazin- 1 -ylcarbonyljbenzyl 4 4 -guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate (Compound Calculated for
C
34
H
4 8
N
10 0 5 MH': 677.8 Found: MHW: 677.6; 6 4 4 3 -piperid-4-ylpropylcarbamoyl)piperazin.l -ylcarbonyllbenzyl 4 4 -guanidinobenzylcarbamoyl)1 -piperazinecarboxylate (Compound Calculated for
C
35
H
50
N
10 0 5 MH': 691.9 Found: MH': 691.5; 9 4 4 4 -piperid-4-ylbutylcarbamoyl)piperazin. I -ylcarbonyllbenzyl 4 4 -guanidinobenzylcarbamoyl)1 -piperazinecarboxylate (Compound Calculated for
C
36
H
52
N,
0 0 5 MH': 705.9 Found: MH': 705.9; 12 4 4 4 -guanidinobenzylcarbamoyl)piperazn- I -ylcarbonyl]benzyl 4 2 -piperid-4-ylethylcarbamoyl) I -piperazinecarboxylate (Compound Calculated for
C
34
H
48
N]
0 0 5 MHW: 677.8 Found: MW': 677.7; 4 4 4 -guanidinobenzylcarbamoyl)piperazin- I -ylcarbonyllbenzyl 4 3 -piperid-4-ylpropylcarbamoyl)-1 -piperazinecarboxyl ate (Compound 10); Calculated for
C
35
H
50
NI
0 0 5 MH': 691.9 Found: MW': 691.3; 18 4 4 2 -piperid-4-ylethylcarbamoyl)piperazin. I -ylcarbonylmethyl]benzyl 4 4 -guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate (Compound 11); Calculated for
C
3
,H
50
NI
0 0 5 MH': 691.9 Found: MH': 692.1; 21 4 4 3 -piperid-4-ylpropylearbamnoyl)piperazin. I -ylcarbonylmethyljbenzyl 4 4 -guanidinobenzylcarbamoyl)-.1 -piperazinecarboxylate (Compound 12); Calculated for
C
3 6
H
52
N
10 MH': 705.9 Found: MW': 705.6; 24 cis- 1 ,-cyclooctylene 4 4 -guanidinobenzylcarbamoyl)-.1 -piperazinecarboxylate 4 4 -methylaminomethylbenzylcarbamoyl). 1 -piperazinecarboxylate (Compound 13); Calculated for C 37
H
54
N
10 0 6 MW': 735.9 Found: MH': 735.7; 27 cis- 1,5-cyclooctylene 4 4 -guanidinophenylacetyl)-.1 -piperazinecarboxylate 4 2 -piperid-4-ylethylcarbamoyl)- 1 -piperazinecarboxylate (Compound 14); Calculated for
C
35
H
5 5
N
9 0 6 MH': 698.9, Found: MI-I': 698.2; cis- I ,5-cyclooctylene 4 4 -guanidinophenylacetyl)- I -piperazinecarboxylate WO 98/04537 PCT/US97/13422 -39- 4 3 -piperid-4-ypropylcarbamoyl). I-piperazinecarboxylate (Compound 15); Calculated for
C
3 6
H
57
N
9 0 6 MH': 712.9, Found: MW': 712.3; 3 cis- 1, ,-cyclooctylene 4 4 -guanidinobenzylcarbamoyl). 1 -piperazinecarboxylate, 4-(4-imidazol- I -ylbutylcarbamoyl)- 1 -piperazinecarboxylate (Compound 16); Calculated for
C
35 H1 5 3 N 11 0 6 MW': 724.9, Found: MH': .724.5; 6 cis- 1 ,5-cyclooctylene 4 4 -guanidinobenzylcarbamoyl)- I -piperazinecarboxylate 4 4 -imidazolin-2-ylaminobutylcarbamoyl). 1 -piperazinecarboxylate (Compound 17); Calculated for C 35 1-1 6
NI
2 0 6 MH': 741.9, Found: MW': 741.7; 9 cis- 1,5-cyclooctylene 4 -(xrans- 4 -aminocyclohexylmefiylcarbamoyl).
I -piperazinecarboxylate 4 4 -guanidinobenzylcarbamoyl). I -piperazinecarboxylate (Compound 18); Calculated for C 35
H
56
N,
0 0 6 MH': 713.9 Found: MH': 714. 1; 12 cis- 1 ,5-cyclooctylene 2-(l ltert-butryryloxymethoxycarbonylpiperid-4yl)ethylcarbanoyl- 1 -piperazinecarboxylate 4 4 -guanidinobenzylcarbamoyl). 1 -piperazinecarhoxylate (Compound 19); Calculated for C 42
H
66
N
10 0 10 MH': 872.1, Found: MW: 871.8; cis- 1 ,5-cyclooctylene 4 4 -guanidinobenzylcarbamoyl). 1 -piperazinecarboxylate 4-[2-(lI -methylpiperid-4-yl)ethylcarbamoyl]. 1 -piperazinecarboxylate (Compound 20); Calculated for C 36
H
58
N
10 0 6
MH
2 2 364.0, Found: MH 2 2 3 64.3; 18 cis- 1 ,5-cyclooctylene 4 4 -guanidinobenzylcarbamoyl). 1 -piperazinecarboxylate 4 3 -imidazolin-2-ylaminopropycarbmoyl)-1 -piperazinecarboxylate (Compound 21); Calculated for C 34
H
54
N
12 0 6 MH': 727.9, Found: MH': 728.0; 21 cis-1I,5-cyclooctylene 4 4 -guanidinophenylacetyl)-1 -piperazinecarboxylate l-iminoethyl)piperid4ylmethylcarbamoy] I -piperazinecarboxylate (Compound 22); Calculated for C 36
H
57 N, 106: MH': 740.9, Found: M1-I: 740.5; 24 cis- 1 ,-cyclooctylene 4 4 -guanidinobenzoylaminomethyl)-.1 -piperidinecarboxylate 4 2 -piperid-4-ylethylcarbamoyl)- 1 -piperazinecarboxylate (Compound 23); Calculated for
C
36
H
5 7
N
9 0 6 MH': 712.9, Found: MH': 711.6; 27 cis- 1 ,-cyclooctylene 4 4 -amidinobenzylcarbamoyl). I-piperazinecarboxylate l-methoxycarbonylpiperid-4yl)ethylcarbamoyl- 1 -piperazinecarboxyl ate (Compound 24); Calculated for C 37
H
57 Nq0 8 MH': 756.9, Found: MH': 756.7; and WO 98/04537 PCT1US97/13422.
3- {cis-5-[ 4 4 -amidinobenzylcarbamoyl)piperazin. 1 -ylcarbonyloxy]cyclooctyloxy.
carbonyl }piperazin- 1-ylcarbonylamino)ethyl]piperid-1 -ylcarbonyl }propionic acid 3 (Compound 25); Calculated for C 3 qH 60 Nq0 9 MHW: 799.0, Found: MH': 798.6.
Proceeding 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 -guanidinobenzylcarbamoyl)-I -piperazinecarboxylate 4 -imidazol-4-ylacetyl -piperazinecarboxylate (Compound 26); Calculated for
C
32
H
46
NI
0 0 6 MH': 667.8, Found: MH': 667.7; 9 cis- 1 ,5-cyclooctylene 4 4 -guanidinobenzylcarbamoyl)- 1-piperazinecarboxylate 4 -(E-3-imidazol-4-ylacryloyl)-l-piperazinecarboxylate (Compound 27); Calculated for
C
33
H
46
NO
0 6 MH': 679.9, Found: MH': 679.8; 12 cis- 1 ,-cyclooctylene 4 4 -guanidinobenzylcarbamoyl)- I-piperazinecarboxylate 4 3 -imidazol-4-ylpropiony} 1 -piperazinecarboxylate (Compound 28); Calculated for
C
33 H1 4 gN 10 0 6 MW': 681.8, Found: MW': 681.7; 1 5 cis-1I,5-cyclooctylene 4 4 -guanidinobenzylcarbamoyl)-1 I-piperazinecarboxylate 4 -(5-imidazol- I -ylvaleryl)- I -piperazinecarboxylate (Compound 29); Calculated for
C
35
H
52
NO
0 6 MH': 709.9, Found: MH': 709.5; 18 cis- 1 ,-cyclooctylene 4 4 -guanidinobenzylcarbamoyl)- I-piperazinecarboxylate 4 -(6-imidazol- I -ylhexanoyl)- I -piperazinecarboxylate (Compound 30); Calculated for
C
36
H
54
N
10 0 6 MH': 723.9, Found: MH': 723.4; 21 cis- 1 ,-cyclooctylene 4 4 -guanidinobenzylcarbamoyl)-1 I-piperazinecarboxylate 4 -(4-imidazol- I -ylmethylphenylacetyl). 1 -piperazinecarboxylate (Compound 3 Calculated for
C
39
H
52
N
10 0 6 MW-: 757.9, Found: MH': 757.2; 24 cis- 1 ,-cyclooctylene 4 4 -guanidinobenzylcarbamoyl) I -piperazinecarboxylate 4 -(4-imidazol-1I-ylmethylbenzoyl)-l1-piperazinecarboxylate (Compound 32); Calculated for
C
3 gH 50
N,
0 0 6 MW-: 743.9, Found: MH': 743.7; 27 cis- 1 ,-cyclooctylene 4 4 -guanidinobenzylcarbamoyl). I-piperazinecarboxylate 4 -(3-imidazol- I-ylmethylbenzoyl)-l1-piperazinecarboxylate (Compound 33); Calculated for WO 98/04537 PCTIUS97/13422 -41
C
3 8
H
50
NI
0 0 6 MH+: 743.9, Found: MH+: 743.6; cis- I ,S-cyclooctylene 4 4 -guanidinobenzylcarbamoyl) 1 -piperazinecarboxylate 3 4 -(7-imidazol- 1 -ylheptanoyl)- 1 -piperazinecarboxylate (Compound 34); Calculated for
C
3 7
H
5 6
N
10 0 6 MW+: 737.9, Found: MW': 737.6; cis- 1,5-cyclooctylene 4 4 -guanidinobenzylcarbamoyl) 1 -piperazinecarboxylate 6 4 6 -(2-methylimidazol-1I-yl)hexanoyl]-l -piperazinecarboxylate (Compound 35); Calculated for
C
37
H
56
N
10 0 6 MH': 737.9, Found: MW': 737.3; cis- 1 ,5-cyclooctylene 4 4 -guanidinobenzylcarbamoyl). 1-piperazinecarboxylate 9 4 -(4-imidazol-1I -ylphenoxyacetyl)-1I -piperazinecarboxylate (Compound 3 Calculated for
C
38
H
50
N
10 0 7 MW': 759.9, Found: MH+: 759.3; cis- 1,5-cyclooctylene 4 4 -guanidinobenzylcarbamoyl)-.1 -piperazinecarboxylate 12 4 6 4 -methylimidazol-1I-yl)hexanoyl]- I-piperazinecarboxylate and cis- 1,5 -cyclooctylene 4 4 -guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4 6 -(5-methylimidazol-1 -yl)hexanoyl]-1-piperazinecarboxylate as a mixture (Compound 37); Calculated for C 37
H
56
NI
0 0 6 MH': 737.9, Found: MW': 738.2; cis- 1,5 -cyclooctylene 4 4 -guanidinobenzylcarbamoyl)- I -piperazinecarboxylate 4 4 -piperid-4-ylbutyryl)-1 -piperazinecarboxylate (Compound 38); Calculated for 18 C 36 H1 57
N
9 0 6 MH': 712.9 Found: MH': 712.4; cis- 1 ,5-cyclooctylene 4 4 -guanidinophenylacetyl)-l1-piperazinecarboxylate 4 4 -piperid-4-ylbutyryl)-l1-piperazinecarboxylate (Compound 39); Calculated for 21 C 36
H
5 6
N
8 0 6 MW-: 697.9, Found: MH': 697.5; cis- 1,5-cyclooctylene 4 4 -guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate 4 2 -piperid-4-ylethyl)(methyl)carbamoyl- 1 -piperazinecarboxylate (Compound 40); Calculated 24 for C 36
H
58
N
10 0 6 MH': 727.9, Found: MHW: 727.6; cis- 1 ,-cyclooctylene 4 4 -guanidinophenylacetyl)-.1 -piperazinecarboxylate 4 2 -piperid-4-ylethyl)(methyl)carbamoyl. 1 -piperazinecarboxylate (Compound 4 Calculated 27 for C 36
H
57
N
9 0 6 MW': 712.9, Found: MH': 712.7; cis- 1 ,-cyclooctylene 4 4 -guanidinobenzylcarbamoyl). I-piperazinecarboxylate 4 2 -piperid-4-ylethoxycarbonyl). 1 -piperazinecarboxylate (Compound 42); Calculated for
C
3 sH 55
N
9 0 7 MH': 714.9, Found: MW*: 714.5; WO 98/04537 WO 9804537PCTIUS97/13421.
-42cis- 1 ,5-cyclooctylene 4 4 -guanidinobenzylcarbamoyl). 1 -piperazinecarboxylate 4 -(4-imidazol- 1 -ylphenylacetyl)- 1 -piperazinecarboxylate (Compound 43); Calculated for 3 C 38
H
50
N
10 0 6 MH': 743.9, Found: MW': 743.6; cis- 1 ,-cyclooctylene 4-(4-guanidinophenylacetyl)-1I-piperazinecarboxylate 4 -(6-imidazol- 1 -ylhexanoyl)- 1 -piperazinecarboxylate (Compound 44); Calculated for 6 C 36
H
53 N,0 6 MH': 708.9, Found: MH': 708.8; cis- 1 ,5-cyclooctylene 4 4 -guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4 3 -pyrid-4-ylthiopropionyl). 1-piperazinecarboxylate (Compound 45); Calculated for 9 C 35
H
49
N
9 0 6 MW': 724.9, Found: MH': 724.4; 4 4 -guanidinobenzylcarbony)- 1 -piperazinecarboxylate 4 -pyrid-4-ylthioacetyl- I -piperazinecarboxylate (Compound 46); Calculated for 12 C 3 4
H
47
N
9 0 6 MH-: 710.9, Found: MH': 710.8; cis- 1 ,5-cyclooctylene 4 4 -guanidinophenylacetyI)- I -piperazinecarboxylate 4 3 -pyrid-4..ylthiopropionyl)- I -piperazinecarboxylate (Compound 47); Calculated for
C
35
H
48
N
8 0 6 MH': 709.9, Found: MW': 709.3; cis- 1,5 -cyclooctylene 4 4 -guanidinobenzylcarbamoyl). I -piperazinecarboxylate 4 6 -imidazol-4-ylhexanoyl)>1 -piperazinecarboxylate (Compound 48); Calculated for 18 C 36
H
54
N
10 0 6 MH': 723.9, Found: MW': 723.5; cis- 1 ,S-cyclooctylene 4 -(benzoimidazol-6-ylcarbonyl)- I -piperazinecarboxylate 4 4 -guanidinobenzycarbioyl)> 1 -piperazinecarboxylate (Compound 49); Calculated for 21 C 35
H
47
N
10 0 6 MH': 703.8, Found: MH': 703.4; 4 4 -amidinobenzylcarbamoyl). I-piperazinecarboxylate 4 -(6-imidazol- I -ylhexanoyl)- 1 -piperazinecarboxylate (Compound 50); Calculated for 24 C 36 H5 3
N
9 0 6 MH': 708.9, Found: MW': 708.6; cis- 1 ,5-cyclooctylene 4 4 -amidinobenzoylaminomethyl)- I-piperidinecarboxylate 4 6 -imidazol-4-ylhexanoyl.. 1 -piperazinecarboxylate (Compound 5 Calculated for 27 C 37
H
5 4
N
8 0 6 MH': 707.9, Found: MH': 707.5; cis- 1 ,-cyclooctylene 4 4 -guanidinophenylacetyl)-1 I-piperazinecarboxylate 4 6 -imidazol-4-ylhexanoyl)- 1-piperazinecarboxylate (Compound 52); Calculated for
C
35
H
52
NI
0 0 6 MW-: 708.9 Found: MH': 708.4; WO 98/04537 PCTIUS97/13422- -43cis-1I,S-cyclooctylene 4 4 -guanidinophenylacetyl). 1 -piperazinecarboxylate 4 -pyrid-4-ylcarbamoylacetyl. 1 -piperazinecarboxylate (Compound 53); Calculated for 3 C 35
H
47
N
9 0 7 MW': 706.8, Found: MH': 706.3; cis-l ,S-cyclooctylene 4 4 -guanidinobenzylcarbamoyl). I-piperazinecarboxylate 4-(3 -pyrid- 4 -ylaminopropionyl). 1-piperazinecarboxylate (Compound 54); Calculated for 6 C 35
H
50
N
10 0 6 MH': 707.9, Found: MH': 707.3; cis- 1 ,5-cyclooctylene 4 4 -guanidinobenzylcarbamoyl). I -piperazinecarboxylate 3 -[pyrid-4-yl(tert-butoxycarbonyl)aminojpropionyl. I -piperazinecarboxylate (Compound 9 Calculated for C 40
H
58 NIO0 8
MH
2 2 404.5, Found: MH 2 2 404.2; cis- 1, 5 -cyclooctylene 4 4 -guanidinobenzylcarbamoyl). I -piperazinecarboxylate 4 3 -piperazin- 1 -ylcarbonylpropionyl)- I -piperazinecarboxylate (Compound 56); Calculated for 12 C 35
H
54
N
10 0 7 MH': 727.9, Found: MH': 727.5; cis- I ,5-cyclooctylene 4 4 -guanidinobenzylcarbamoyl). I -piperazinecarboxylate 4-piperid- 1 -ylcarbonylaminoacetyl- 1 -piperazinecarboxylate (Compound 57); Calculated for
C
35 H5 4
N
10 0 7 MH': 727.9, Found: MHW: 727.5; cis- 1 ,5-cyclooctylene 4 4 -guanidinobenzyicarbamoyl)- I -piperazinecarboxylate 4 -(5-imidazol-4-ylvaleryl). 1-piperazinecarboxylate (Compound 58); Calculated for 18 C 3 5Hs 2 NIoO 6 MW': 708.9, Found: MH': 709.4; cis- 1 ,-cyclooctylene 4 4 -amidinobenzoylaminomethyl)-1 -piperidinecarboxyl ate 4 -(3-piperazin- 1 -ylcarbonylpropionyl)- I -piperazinecarboxyl ate (Compound 59); Calculated for 21 C 36
H
54
N
8 0 7 MH': 711.9, Found: MW': 711.4; cis- 1 ,5-cyclooctylene 4 4 -amidinobenzoylaminomethyly.. 1-piperidinecarboxylate 4 -piperid-4-ylcarbonylaminoacetyl. 1-piperazinecarboxylate (Compound 60); Calculated for 24 C 36
H
54
N
8 0 7 MW': 711.9, Found: MH': 711.4; cis- I ,5-cyclooctylene, 4 3 2 -aminopyrimidin-5yl)propionyt]..I -piperazinecarboxylate 4 4 -guanidinobenzylcarbamoy1>1I piperazinecarboxylte (Compound 6 Calculated for 27 C 34
H
49
N
11 0 6 MI-I: 708.8, Found: MH': 708.4; cis- I ,5-cyclooctylene 4- [3 6 -aminopyrid-3-yl)propionyl] -1-piperazinecarboxylate 4 4 -guanidinobenzylcarbamoyl) 1 -piperazinecarboxylate (Compound 62); Calculated for
C
3 sH5oNoO0 6 MH+: 707.8, Found: MW': 707.4; WO 98/04537 WO 9804537PCTIUS97/13422- -44cis- 1,5-cyclooctylene 4 4 -guanidinobenzylcarbamoyl> 1 -piperazinecarboxylate 4- [4-(4-pyrid-4-ylthio)butyiyl]-l1-piperazinecarboxylate (Compound 63); Calculated for 3 C 36
H
5 ,Nq0 6 MW: 738.9, Found: MW': 738.4; cis- 1 4- 3 -(2-amino-2,4-dioxo- I 2 3 4 -tetrahydropyrimidin-5-y1)propionyl]. I -piperazinecarboxylate 6 4 4 -guanidinobenzylcarbamoyl)- 1-piperazinecarboxylate (Compound 64); Calculated for
C
34
H
48
N,
0 0 8 MW': 725.8, Found: MH': 725.2; cis- 1 ,5-cyclooctylene 4 4 -amidinobenzylcarbamoyl)> 1 -piperazinecarboxylate, 9 4 4 -piperid-4-ylbutyryl I) 1piperazinecarboxylate (Compound 65); Calculated for
C
36
H
56
N
8 0 6 MH': 697.9, Found: MW': 697.4; cis- 1 ,5-cyclooctylene 4 -(4-amidinobenzoylaminomethyl). 1-piperidinecarboxylate 12 4 4 -piperid-4-ylbutyryl)-1-piperazinecarboxylate (Compound 66); Calculated for
C
37 H5 7
N
7 0 6 MH': 696.9, Found: MH': 696.4; cis- 1 ,5-cyclooctylene I -amidinopiperid-4-ylacetyl)- 1 -piperidinecarboxylate 4-(6-imidazol- I -ylhexanoyl)- 1 -piperazinecarboxylate (Compound 67); Calculated for
C
35
H
57
N
9 0 6 MH': 700.9, Found: MW': 700.5; cis- 1 ,-cyclooctylene 4-(1 -amidino-4-piperidylacetyl). 1 -piperazinecarboxylate 18 4 4 -piperid-4-ylbutyryl)-1-piperazinecarboxylate (Compound 68); Calculated for
C
35
H-
60
N
8 0 6 MW+: 689.9, Found: MH+: 689.4; cis- I ,5-cyclooctylene, 1 -amidino-4-piperidylacetyl). I -piperazinecarboxylate 21 4 -(6-imidazol-1I -ylhexanoyl)-1I -piperazinecarboxylate (Compound 69); Calculated for
C
35
H
57
N
9 0 6 MW-: 700.9, Found: MW': 700.4; cis- 1 ,-cyclooctylene 4 4 -amidinobenzylcarbamoyly I -piperazinecarboxylate 24 4 6 -imidazoI-4-ylhexanoyl)- I -piperazinecarboxylate (Compound 70); Calculated for
C
36 H,1 3
N
9 0 6 MH+: 708.9, Found: MW+: 708.4; 4 4 -amidinobenzoylaminomethyl). I-piperidinecarboxylate 27 4 6 -imidazol-4-ylhexanoyl)- 1-piperazinecarboxy late (Compound 71); Calculated for
C
37
H
54
N
8 0 6 MW+: 707.9, Found: MW+: 707.4; cis- 1 ,5-cyclooctylene 4 4 -amidinophenylacetyl)- 1 -piperazinecarboxylate 4 6 -imidazol-1-ylhexanoyl)-l-piperazinecarboxylate (Compound 72); Calculated for WO 98/04537 WO 9804537PCT/US97/13422-
C
36
H
52
N
8 0 6 MW-: 693.9, Found: MW': 693.4; 4 -(4-amidinophenylacetyl)-1I-piperazinecarboxylate 3 4 -(4-piperid-4-ylbutyryl)- 1-piperazinecarboxylate (Compound 73); Calculated for
C
36
H-
55
N
7 0 6 MH': 682.9, Found: MW': 682.4; cis- 1,5-cyclooctylene 4 -(4-amidinophenylacetyl)- 1-piperazinecarboxylate 6 4 -(6-imidazol-4-ylhexanoyl). 1 -piperazinecarboxylate (Compound 74); Calculated for
C
36
H
52
N
8 0 6 MH': 693.9 MW-: 693.4; and cis- 1 ,5 -cyclooctylene 4 4 -amidinobenzylcarbamoyl)- 1 -piperazinecarboxy late 9 l-tert-butylcarbonyloxymethoxycarbonyl)piperid-4yletycarbamoyl)- I -piperazinecarboxylate (Compound 75); Calculated for C 42
H
65 Nq0 10 MH': 857.0 Found: MH': 856.6.
WO 98/04537 PCT/US97/13422 -46- EXAMPLE 9 cis- 1,5-cyclooctylene di(4-tert-butoxycarbonyl- 1 -piperazinecarboxylate) 3 cis-l,5-Cyclooctylene di(chloroformate) (3.69 g, 13.7 mmol.), prepared as in Example and DIEA (7.2 mL, 41 mmol.) were taken into DMF (25 mL) and tert-butyl 1-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 was partitioned between dichloromethane (50 mL) and water (50 mL) and the dichloromethane layer was washed with 0.1N aqueous hydrochloric acid (2x, 25 mL), dried (MgSO 4 and filtered.
9 Concentrating in vacuo gave cis-1,5-cyclooctylene di(4-tert-butoxycarbonyl- 1-piperazinecarboxylate) as an amorphous solid; 'H-NMR (300MHz, CDCl 3 4.80 2H), 3.40 (br s, 16H), 2.00-1.40 12H), 1.40 18H).
12 EXAMPLE cis- 1,5-cyclooctylene di[ 4 2 -piperid-4-ylethylcarbamoyl)-1 -piperazinecarboxylate] (Compound 76) The following is the preparation of a compound of Formula I in which R' and R 2 each are 2-piperid-4-ylethyl, X' and X 9 each are X 2 and X 8 each are 1,4-piperazinylene,
X
3 and
X
7 each are X 4 and X 6 each are a covalent bond and X 5 is 18 cis-1 ,5-Cyclooctylene di(4-tert-butoxycarbonyl-1 -piperazinecarboxylate) (47.9 mg, 0.088 mmol.), prepared as Example 9, was treated with TFA (1 mL) neat for 10 minutes 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 tert-butyl 4 2 -isocyanatoethyl)- -piperidinecarboxylate (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 with water (2x, 5 mL) and dried in vacuo giving a yellow solid. The solid was treated with TFA (2 mL) and the mixture was concentrated in vacuo. The residue was taken into water.
27 Purifying from the aqueous mixture by preparative reverse phase HPLC followed by WO 98/04537 WO 9804537PCTIUS97/13422- -47lyophillization gave cis- 1 ,5-cyclooctylene di[ 4 2 -piperid-4-ylethylcarbamoyl)- I -piperazinecarboxylate] as a colorless amorphous solid; Electrospray LRMS: Calculated for 3 C 3 4
H
60
N
8 0 6
MH
4 677.9, Found: MW': 677.6.
Proceeding as in Example 10 and substituting different starting materials di[ 4 4 -methylaminomethylbenzylcarbamoyl)-.1 -piperazinecarboxylate] 6 (Compound 77) was prepared; Calculated for C 3 8
H
56
N
8 0 6 MH': 721.9, Found: MH': 721.7.
Proceeding as in Example 10 and replacing the isocyanate with an activated ester the following compounds of Formula I were prepared: 9 cis- 1 ,-cyclooctylene di 4 -(4-piperid-4-ylbutyryl)- 1-piperazinecarboxylate] (Compound 78); Calculated for C 36
H
6 2
N
6 0 6 MH~: 675.9, Found: MH': 675.6; and para-dimethylenephenylene di 4 4 -piperid-4-ylbutyryl)- I-piperazinecarboxylate] 12 (Compound 79); Calculated for C 36
H
56
N
6 0 6 MW': 669.9, Found: MW: 669.4.
EXAMPLE 11I tert-Butyl 4-(3-imidazol- 1-ylpropylcarbamoyl)-l1-piperazinecarboxylate tert-Butyl 4 -chlorocarbonyl-1-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 mmnol) was added by syringe and the 18 mixture was stirred 12 hours. Dichloromethane (10 mnL) was added to the mixture and the organic layer was washed with water (Ilx, 10 mnL), dried (MNOW and filtered. Concentrating gave tert-butyl 4-(3-imidazol- 1 -ylpropylcarbamoyl)- 1 -piperazinecarboxylate (23 0 mg, 21 0.68 mmol, 90% yield) as a colorless oil; 'H-NMR (300OMHz, DMSO-d 6 7.60 11H), 7.20 (s, 111), 6.85 11H), 6.60 (tr, 111), 3.95 (tr, 2H1), 3.30 8H), 3.00 211), 1.80 (in, 2H), 1.40 (s, 9H).
WO 98/04537 PCT/US97/13422 -48- EXAMPLE 12 tert-Butyl 4-aminomethyl- 1-benzenecarbamate 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-tert-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, mL). The combined extracts were washed with saturated aqueous sodium chloride, dried 9 (MgSO 4 filtered and concentrated in vacuo giving a white solid. The solid was taken into methanol (30 mL), the solution was 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 gave tert-butyl 4 -aminomethyl-l-benzenecarbamate hydrochloride (7.2 g, 27.8 mmol, 61% yield) as a colorless solid; 'H-NMR (300MHz, DMSO-d,): 9.43 1H), 8.20 (br s, 3H), 7.40 (dd AB, 4H), 3.92 (m, 2H), 1.50 9H).
EXAMPLE 13 tert-Butyl 4-isocyanatomethyl- -benzenecarbamate: 18 tert-Butyl 4-aminomethyl- -benzenecarbamate hydrochloride (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) was added. The mixture was allowed to 21 warm to room temperature over 30 minutes and aqueous hydrochloric acid (0.5N, 100 mL) was added. The organic layer was dried (MgSO 4 and filtered. Concentrating gave tert-butyl 4 -isocyanatomethyl-1-benzenecarbamate (2.7 g, 11 mmol, 84% yield) as a yellow solid; 24 'H-NMR (300MHz, CDC 3 7.29 (dd AB, 4H), 6.55 (br s, 1H), 4.40 2H), 1.55 9H).
WO 98/04537 PCT/US97/13422 -49- EXAMPLE 14 4 4 -aminobenzylcarbamoyl)-1-piperazinecarboxylate 3 4-(3-imidazol- 1 -ylpropylcarbamoyl)- I -piperazinecarboxylate (Compound The following is the preparation of a compound of Formula I in which R' is 6 4-aminobenzyl,
R
2 is 3 -imidazol-l-ylpropyl, X' and X 9 each are
X
2 and X 8 each are 1, 4 -piperazinylene,
X
3 and X 7 each are X 4 and X 6 each are a covalent bond and X' is cis- 9 tert-Butyl 4 3 -imidazol--ylpropylcarbamoyl)- 1 -piperazinecarboxylate (225 mg, 0.67 mmol), prepared as in Example 11, was treated with TFA (1 mL) neat for 10 minutes. 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. cis-1 ,5-Cyclooctylene chloroformate 4 -tert-butoxycarbonyl-1-piperazinecarboxylate (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.
Additional dichloromethane (10 mL) was added and the organic layer was washed with saturated aqueous sodium bicarbonate (lx, 10 mL), dried (MgSO 4 and filtered. Concentrating gave crude cis- 1,5-cyclooctylene 4-(3-imidazol- 1 -ylpropylcarbamoyl)- I -piperazinecarboxylate 18 tert-butoxycarbonyl- 1 -piperazinecarboxylate adduct as a colorless foam.
The adduct prepared in Part was treated with TFA (1 mL) neat for 10 minutes 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 tert-butyl 4 -isocyanatomethyl- I-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.OM aqueous sodium hydroxide and then extracted with dichloromethane. The dichloromethane was dried (MgSO 4 and filtered.
27 Concentrating in vacuo gave cis-1,5-cyclooctylene 4-(4-aminobenzylcarbamoyl)- I -piperazinecarboxylate 4-(3-imidazol- I -ylpropylcarbamoyl)- I -piperazinecarboxylate as a colorless foam; 'H-NMR (300MHz, CDCl 3 7.45 1H), 7.10 2H), 7.05 1H), 6.90 (s, WO 98/04537 PCTIUS97/13422 1W), 6.60 2H), 4.85-4.70 (in, 4H), 4.30 211), 4.00 (ir, 2H), 3.50-3.30 (mn, 18H), 2.00 (mn, 2H), 1.
9 0-1.50 1211).
3 Proceeding as in Example 14 and substituting different starting materials the following compounds of Formula I were prepared: cis- 1,5 -cyclooctylene 4 4 -alninobenzylcarbamoyl). I -piperazinecarboxylate 6 4 2 -pyrid-4-ylethylciirbamoyl)-l1-piperazinecarboxylate (Compound 81); cis- 1 ,5-cyclooctylene 4 4 -aininobenzylcarbamoyl). I -piperazinecarboxylate 4-(3 -piperid-4-ylpropyl)- 1 -piperidinecarboxylate (Compound 82); and 9 cis-1I,5-cyclooctylene 4 4 -aminobenzylcarbamoyl)-1 -piperazinecarboxylate 4 4 -piperid-4-ylbutyl)- 1 -piperidinecarboxylate (Compound 8 3).
EXAMPLE 12 cis- 1 ,5-Cyclooctylene 4 4 -guanidinobenzylcarbainoy 1)-I-piperazinecarboxylate 4-(3 -imidazol- 1-ylpropylcarbamoyl)-l1-piperazinecarboxylate (Compound 84) The following is the preparation of a compound of Formula I in which R' is 4 -guanidinobenzyl, R' is 3 -imidazol-1I-ylpropyl, XV and X' each are X' and X' each are l, 4 -piperazinylene,
X
3 and X' each are
V
4 and X 6 each are a covalent bond and X 18 is cis- 1 ,-cyclooctylene.
cis- 1,5-Cyclooctylene 4 4 -aminobenzylcarbamoyl)-.1 -piperazinecarboxylate 4 3 -imidazo1- I ypropylcarbamoyl) I 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 (1 .0g) was added and the mixture was heated at 65 OC 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 residue was taken into water. Purify'ing from the aqueous mixture by preparative reverse phase HPLC gave cis- I ,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)- WO 98/04537 WO 9804537PCT/US97/13422 -51- 1 -piperazinecarboxylate 4-(3-imidazol- I -ylpropylcarbamnoyl)- I -piperazinecarboxylate as a colorless amorphous solid; Electrospray LRMS: Calculated for C 34
H
5 IN, 1 0 6 MH': 710.9, 3 Found: MH': 710.6.
Proceeding as in Example 15 and substituting different starting materials the following compounds of Formula I were prepared: 6 cis- 1,5 -cyclooctylene 4 4 -guanidinobenzylcarbamoyl)- I -piperazinecarboxylate 4 2 -pyrid-4-ylethylcarbamoyl)-l1-piperazinecarboxylate (Compound 85); Calculated for
C
35
H
50
N
10 0 6 MH': 707.9 Found: MH': 707.6; 9 cis- I ,5-cyclooctylene 3 -piperid-4-ylpropyl-lI-piperidinecarboxylate 4 4 -guanidinobenzylcarbamoyl) 1 -piperazinecarboxylate (Compound 86); and cis- 1,5 -cyclooctylene 4 4 -guanidinobenzylcarbamoyl)-l1-piperazinecarboxylate 12 4-piperid-4-ylbutyl- I -piperidinecarboxylate (Compound 87); Calculated for
C
37
H
60
N
8 0 5 MW': 697.9, Found: MH': 697.7.
EXAMPLE 16 1 5 cis- 1,5-cyclooctylene chioroformate 4-benzyloxycarbonyl- 1 -piperazinecarboxylate Benzyl I1-piperazinecarboxylate (1.0 g, 4.53 mmol, 1.0 equiv) and DIBA (0.88 mL, 4.98 nimol, 1. 1 equiv) in dichloromethane (25 mL) was added dropwise to cis- I 18 di(chloroformate) (1.2 g, 4.53 mmol, 1.0 equiv), prepared as in Example 5, in dichioromethane mL) at 0 0 C. The reaction mixture was stirred for 22 hours while allowing to warm to room temperature. The mixture was partitioned between dichloromethane, 0.05N aqueous hydrochloric 21 acid and saturated aqueous sodium chloride. The organic layer was dried (Na 2 SO,) over sodium sulfate and concentrated. Purifying the residue by flash column chromatography, eluting with and 30% ethyl acetate in hexanes, gave cis- 1 ,-cyclooctylene chloroformnate 24 4 -benzyloxycarbonyl- I piperazinecarboxylate 81 g, 1. 81 nimol, 40%) as a yellow oil; IR: 2939 2863 1770 1732 1696 'H NMR (300 MHz, CDCl 3 7.35 5 H), 5.15 2 4.95 (in, 1 4.75 (in, I 3.45 8 1.50 2.05 (mn, 12 H).
WO 98/04537 PCTIUS97/13422 -52- EXAMPLE 17 4 -Benzyloxycarbonylpiperazin-1-ylcarbonyloxy)cyclooctyloxycarbonyl]- 3 4-piperidinecarboxylic acid Isonipecotic acid (75 mg, 0.58 mmol, 1.1 equiv) and DIEA (0.23 mL, 1.33 mmol, equiv) were added to cis-1,5-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 OoC 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 gave crude 1-[cis-5-(4-benzyloxycarbonylpiperazin-1-ylcarbonyloxy)cyclooctyloxycarbonyl]- 4-piperidinecarboxylic acid (0.36 g) as a colorless oil; 'H NMR (300 MHz, CDCl 3 7.35 12 5.15 2 4.75 2 3.90 1 3.45 8 2.75 1 2.50 3 H), 1.50-1.90 16 H).
EXAMPLE 18 cis-1 ,5-Cyclooctylene 4 -benzyloxycarbonyl- I -piperazinecarboxylate -tert-butoxycarbonylpiperid-4-yl)ethylcarbamoyl]- I -piperidinecarboxylate l-Hydroxybenzotriazole hydrate (80 mg, 58.3 mmol, 1.1 equiv), tert-butyl 18 4 -(2-aminoethyl)-1-piperidinecarboxylate hydrochloride (0.14 g, 0.53 mmol, 1.0 equiv) and 4 -methylmorpholine (0.15 mL, 1.33 mmol, 2.5 equiv) were added to a solution of crude I -[cis-5-( 4 -benzyloxycarbonylpiperazin-1 -ylcarbonyloxy)cyclooctyloxycarbonyl]- 21 4 -piperidinecarboxylic acid (0.36 g, 0.53 mol, 1.0 equiv), prepared as in Example 17, in DMF mL). 1-( 3 -Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.13 g, 0.66 mnmol, 1.25 equiv) was added to the reaction mixture at 0 DC. The solution was stirred for 1.5 hours at 24 0 0 C and for 3 days at 23 0 C. The reaction mixture was partitioned between dichloromethane, 0.05N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water (two portions) and saturated aqueous sodium chloride. The organic layer was dried (Na 2
SO
4 and concentrated.
27 Purifying from the residue by flash column chromatography, eluting with 3% methanol in WO 98/04537 WO 9804537PCTIUS97/13422 -53dichioromethane, gave cis- 1,5-cyclooctylene 4-benzyloxycarbonyl- 1 -piperazinecarboxylate 4- 1 -ter-butoxycarbonylpiperid-4-yl)ethylcarbamoyl] -1I -piperidinecarboxylate 15 g, 3 0.2 mmol, 3 7% over two steps) as a yellow oil; 'H NMR (3 00 MHz, CDCl 3 7.35 5 5.15 2 4.80 (in, 2 4. 10 (in, 4 3.45 (in, 10 3.3 0 (mn, 2 2.70 (mn, 2 1. 50-1.90 (in, 23 1.45 9 Electrospray LRMS: calcd for C 40
H
62
N
5 0 9 (MHW): 756.97, obtained: 757.0.
6 EXAMPLE 19 cis- 1 ,5-Cyclooctylene 1 -piperazinecarboxylate I-tert-butoxycarbonylpiperid-4-yl)ethylcarbamoyl]. I-piperidinecarboxylate 9 Ethanol (3 mL) was added to cis- 1,5-cyclooctylene 4-benzyloxycarbonyl- I -piperazinecarboxylate 1-tert-butoxycarbonylpiperid-4-yl)ethylcarbamoyl] I -piperidinecarboxylate 15 g, 0.20 inmol, 1.0 equiv), prepared as in Example 18, and 12 5% palladium on carbon (75 ing, 0.50 wt equiv) under nitrogen. The mixture was stirred under hydrogen (1 atm) for 17 hours at 23 The reaction mixture was placed under nitrogen and filtered. Concentrating the filtrate gave cis- I ,5-cyclooctylene 1 -piperazinecarboxylate 4-[2-(l1 -tert-butoxycarbonylpiperid-4-y)ethylcarbmoy}.. I -piperidinecarboxylate (1 10 ing, 0. 18 mmol, 90%) as a colorless oil; 'H NMR (300 MHz, CDCI 3 5.5 (in, 1 4.9 (in, 2 4.75 (in, I 4.1 (in, 4 3.45 (in, 4 3.25 (in, 2 2.60-2.85 (in, 8 2.10 (in, 1 1.50-1.95 18 (in, 23 1.45 9 Electrospray LRMS: calcd for C 3
,H
56
N
5 0 7 622.83, obtained: 622.7.
WO 98/04537 PCT/US97/13422- -54- EXAMPLE 4 4 -guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 3 4 2 -piperid-4-ylethylcarbamoyl)-1 -piperidinecarboxylate (Compound 88) The following is the preparation of a compound of Formula I in which R' is 6 4 -guanidinobenzyl,
R
2 is 2-piperid-4-ylethyl, X' and X 9 each are X 2 is 1, 4 -piperazinylene,
X
8 is 4,1-piperidylene,
X
3 and X 7 each are X 4 and X 6 each are a covalent bond and X 5 is 9 Triphosgene (30 mg, 0.10 mmol, 0.58 equiv) and pyridine (30 mL, 0.39 mmol, 2.1 equiv) were added to cis-1,5-cyclooctylene 1-piperazinecarboxylate -tert-butoxycarbonylpiperid-4-yl)ethylcarbamoyl] -1 -piperidinecarboxylate (0.11 g, 12 0.18 mmol, 1.0 equiv), prepared as in Example 19, in dichloromethane (2 mL) at 0 0 C. The reaction mixture was stirred 3 hours at 00C. The mixture was partitioned between dichloromethane, 0.05N aqueous hydrochloric acid and saturated aqueous sodium chloride. The organic layer was dried (Na 2
SO
4 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 0 C and concentrated. The residue was taken into TFA in dichloromethane (4 mL) and the mixture was stirred 45 minutes at 23 0 C. The reaction mixture was concentrated and the residue was triturated with ether and dried in vacuo. Purifying 21 from the residue by preparative reverse phase HPLC and lyophillization gave 4 4 -guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4 2 -piperid-4-ylethylcarbamoyl)-1 -piperidinecarboxylate as a colorless amorphous solid; 24 Electrospray LRMS: calcd for C 3 6
H
58
N
9 0 6 O 712.91, obtained: 712.8 Proceeding as in Example 20 and substituting different starting materials the following compounds of Formula I were prepared: cis- 1,5-cyclooctylene 4 4 -guanidinophenylacetyl)- I -piperazinecarboxylate WO 98/04537 PCT/US97/13422- 4 3 -imidazol-4-ylpropylcarbamoyl)- 1-piperazinecarboxylate (Compound 89); Calculated for
C
34
H
50
N
10 0 6 MH+: 695.9, Found: MH': 695.4; 3 cis- 1, ,5-cyclooctylene 4-(4-guanidinophenylacety1)- 1 -piperazinecarboxylate 4-(2-imidazol-4-ylethylcarbamoyl)-l1-piperazinecarboxylate (Compound 90); Calculated for
C
33
H-
48
NI
0 0 6 MH+: 681.3, Found: MH+: 680.9; 6 cis- 1,5 -cyclooctylene, 4 -(4-guanidinophenylacetyl)- I -piperazinecarboxylate 4-(3 -imidazol- 1 -ylpropylcarbamoyl)- 1 -piperazinecarboxylate (Compound 9 Calculated for
C
34 H1 50
N
10 0 6 MW+: 695.9, Found: MH+: 694.9; 9 cis-1I,5-cyclooctylene 4 4 -guanidinophenylacetyl)-1I-piperazinecarboxylate 4-(4-imidazol- 1 -ylbutylcarbamoyl)- I -piperazinecarboxylate (Compound 92); Calculated for
C
35
H
53
N,
0 0 6 MH+: 709.9, Found: MW+: 709.4; and 12 cis-1I,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1I-piperazinecarboxylate 4-(3-imidazol- 1 -ylpropylcarbamoyl)- 1 -piperazinecarboxylate (Compound 93); Calculated for
C
35 H1 51
N
10 0 6 MH': 709.9, Found: MH+: 710.4.
EXAMPLE 21 3-Piperid-4-ylpropionic acid hydrochloride 4-Pyridineacrylic acid hydrochloride (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 gave 3 -piperid-4-ylpropionic acid hydrochloride (11.3 g; 58.1 24 mmol, 90%) as a colorless solid; 'H-NMR (3 00 MHz; DMSO-d 6 8.75 (hr s, 2H4), 3.15 2H4), 2.75 2H) 2.2 1.75 2H), 1.45 1.25 (hr q, 2H).
EXAMPLE 22 27 3-(l1-tert-Butyoxycarbonylpiperid-4yl)propionic acid (f 'I WO 98/04537 PCT/US97/13422 -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(tert-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 .ON 6 aqueous KHSO 4 and extracted with ethyl acetate (3x, 200 mL). The combined organic phases were washed with brine and dried (Na 2
SO
4 Concentrating in vacuo gave 3 4 -(1-tert-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, CDCl1): 4.10 (br d, 2H), 2.65 (br t, 2H), 2.35 2H), 1.70-1.50 3H), 1.45 9H), 1.20-0.95 2H).
EXAMPLE 23 12 tert-Butyl 4-benzyloxycarbonyl-1 -piperazinecarboxylate tert-Butyl 1-piperazinecarboxylate (2.01 g; 10.8 mmol) and DIEA (2.0 mL; 1.48 g; 11.5 mmol) in 50 mL of ice cold dichloromethane was treated with benzyl chloroformate (2.0 mL; 2.39 g; 14.0 mmol). The mixture was stirred for 42 hours and then partitioned between ethyl acetate and 0.5N KHSO 4 The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried (MgSO 4 and concentrated. Purifying 18 from the residue by chromatography over silica gel (ethyl acetate:hexane, 1:3) gave tert-butyl 4 -benzyloxycarbonyl-1-piperazinecarboxylate (3.33 g; 10.4 mmol, 96%) as a colorless solid; 'H-NMR (300 MHz, CDCl 3 7.35 (br s, 5H), 5.13 2H), 3.55-3.25 8H), 1.45 9H).
WO 98/04537 PCT/US97/13422- -57- EXAMPLE 24 Benzyl 1-piperazinecarboxylate hydrochloride 3 tert-Butyl 4-benzyloxycarbonyl- -piperazinecarboxylate (1.01g; 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 1,4-dioxane) was added giving a solution. The 6 solution was stirred for 30 minutes on the ice bath and then for 30 minutes 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 gave benzyl 9 1-piperazinecarboxylate hydrochloride (740 mg; 2.78 mmol, 88%) as a colorless solid; 'H-NMR (300 MHz, DMSO-d 6 9.25 (br s, 2H), 7.33 5H), 5.06 2H), 3.58 (br s, 4H), 3.04 4H).
EXAMPLE 12 tert-Butyl 4 2 4 -benzyloxycarbonylpiperazin- 1-ylcarbonylamino)ethyl]- 1 -piperidinecarboxylate 3-[4-(1-tert-Butoxycarbonyl)-4-piperidyl]propionic acid (2.16 g; 8.4 mmol), prepared as 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 gradually heated to reflux and kept 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 KHSO 4 The organic layer was washed with water, aqueous sodium bicarbonate and brine, dried (Na 2
SO
4 and concentrated. Purifying from the residue by chromatography on silica gel (ethyl acetate-hexane, 4:1; then pure ethyl acetate) gave 24 tert-butyl 4 2 4 -benzyloxycarbonylpiperazin-1 -ylcarbonylamino)ethyl]-1 -piperidinecarboxylate (3.84 g; 8.1 mmol, 96%) as a white solid; 'H-NMR (300 MHz, CDCl 3 7.35 5H), 5.15 (s, 2H), 4.50 (br t, 1H), 4.05 (br s, 2H), 3.55-3.45 4H), 3.40-3.30 4H), 3.25 2H), 2.65 (t, 27 2H), 1.70 2H), 1.45 11H), 1.20-1.00 2H).
WO 98/04537 PCT/US97/13422- -58- EXAMPLE 26 cis- 1,5-Cyclooctylene chloroformate 4-[ 2 4 -tert-butoxycarbonylpiperidin-4-yl)ethylcarbamoyl]- 3 1-piperazinecarboxylate tert-Butyl 4 2 4 -benzyloxycarbonylpiperazin-1 -ylcarbonylamino)ethyl]- 1-piperidinecarboxylate (2.03 g; 4.28 mmol), prepared as in Example 25, and 6 palladium-on-carbon (570 mg) suspended in ethanol (19 mL) was hydrogenated at atmospheric pressure overnight. The reaction mixture 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 di(chloroformate) (4.15g; 15.4 mmol), prepared as in Example 5, in ice cold dichloromethane (75 mL). The reaction mixture was stirred overnight and diluted with 12 aqueous KHSO 4 and dichloromethane. The aqueous phase was extracted with dichloromethane and the combined organic layers were washed with brine, dried (Na 2
SO
4 and concentrated.
Purifying from the residue by chromatography on silica gel (ethyl acetate-hexane, 3:1; then pure ethyl acetate) gave cis-1,5-cyclooctylene chloroformate 4-[ 2 4 -tert-butoxycarbonylpiperidin-4-yl)ethylcarbamoyl]-1-piperazinecarboxylate (1.02 g; 1.8 mmol, 42%) as a pale yellow oil; 'H-NMR (300 MHz, CDCI 3 5.00-4.90 1H), 4.85-4.75 18 1H), 4.35 (br t, 1H), 4.05 (br d, 2H), 3.50-3.40 4H), 3.35-3.30 4H), 3.25 2H), 2.65 2H), 2.05-1.55 17H), 1.40 9H), 1.25-1.00 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 0 C. A solution of CrO3 in aqueous H 2
SO
4 was added dropwise, while keeping the 24 internal temperature below 30 0 C, until an orange color persisted giving a suspension. The suspension was stirred for 45 minutes and filtered. The solids were washed with acetone (150 mL) and the combined filtrate and washings were stirred with 2-propanol (20 mL for 27 minutes. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was WO 98/04537 PCT/US97/13422 -59taken intoethyl acetate and the solution was washed with 0.5N aqueous KHSO 4 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 gave 6 4 -cyanophenylacetic acid (3.36 g; 20.7 mmol, 61%) as a white powder; 'H-NMR (300 MHz,
CDCI
3 7.63 2H), 7.40 2H), 3.72 2H).
EXAMPLE 28 9 tert-Butyl 4 4 -cyanophenylacetyl)- 1 -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 1-hydroxybenzotriazole hydrate (820 mg; 6.07 12 mmol) was suspended in THF (18 mL) and tert-butyl 1-piperazinecarboxylate (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 KHSO 4 The mixture was filtered and the solid collected was washed with water. Drying in vacuo gave tert-butyl 4 4 -cyanophenylacetyl)- 1-piperazinecarboxylate (1.68 g; 5.1 mmol, 92%) as a solid; 'H-NMR (300 MHz, CDCI 3 7.70 2H), 7.35 2H), 3.80 2H), 3.70-3.60 2H), 3 4 5 -3.30 6H), 1.40 9H).
18 EXAMPLE 29 tert-Butyl 4 4 -(N-hydroxyamidino)phenylacetyl]-1-piperazinecarboxylate tert-Butyl 4-(4-cyanophenylacetyl)-1-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 overnight giving a crystalline product. The crystals were isolated by filteration and washed with cold ethanol. Air-drying gave tert-butyl 4-[4-(N-hydroxyamidino)phenylacetyl]--piperazinecarboxylate (1.62 g; 4.5 mmol, 88%); WO 98/04537 PCT/US97/13422 'H-NMR (300 MHz, DMSO-d 6 9.60 1H) 7.60 2H), 7.20 2H), 5.75 2H), 3.70 (s, 2H), 3.40 (br s, 4H), 3.25 (br s, 4H), 1.40 9H).
3 EXAMPLE 4 -piperazin- -ylcarbonylmethylbenzamidine bis(trifluoroacetate) tert-Butyl 4 4 -(N-hydroxyamidino)phenylacetyl]-l-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 overnight. 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 gave 4-piperazin- -ylcarbonylmethylbenzamidine bis(trifluoroacetate) (1.04 g; 1.81 mmol, 100%) as a white solid; 'H-NMR (300 MHz, DMSO-d 6 9.30 4H), 9.15 (br s, 2H), 7.70 2H), 7.40 2H), 3.85 2H), 3.65 (br d, 4H), 4.20-3.90 4H).
WO 98/04537 WO 9804537PCT/US97/13422- -61- EXAMPLE 31 cis- 1,5-Cyclooctylene 4 -(4-arnidinophenylacetyl)- 1-piperazinecarboxylate 3 4 2 -piperid-4-ylethylcarbamoyl). 1 -piperazinecarboxylate (Compound 94) The following is the preparation of a compound of Formula I in which R' is 6 4-amidinobenzyl, R 2 is 2-piperid-4-ylethyl, XV is and X' is X' and X' each are 1 ,4-piperazinylene, X' and X' each are X 4 and X 6 each are a covalent bond and X' is cis- I 9 4 -Piperazin-1I-ylcarbonylmethylbenzarnidine bis(trifluoroacetate) (80 mg; 0. 17 mrnol), prepared as in Example 30, was dissolved in DMF (1.0 mL) and the solution was treated with DIBA (150 mL). cis- 1,5-Cyclooctylene chloroformate 12 4 2 4 -ter-butoxycarbonylpiperazin I -yl)ethylcarbamoyl]- 1-piperazinecarboxylate (100 mg), prepared as in Example 26, in DMF (1.0 mL) was added and the mixture was stirred overnight and concentrated in vacuo. The residue was dissolved in dichioromethane and TFA 1) and the 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 fractions gave cis- 1 ,5-cyclooctylene 4 -(4-amidinophenylacetyl)- I -piperazinecarboxylate 18 4 2 -piperid-4-ylethylcarbamoyl)-1-piperazinecarboxylate as a colorless solid; Electrospray LRMS: Calculated for C 35
H
54
N
8 0 8 MH': 683.9; MH 2 1 2 342.5, Found: MH': 683.8;
MH
2 1 2 342.3.
21 Proceeding as in Example 31 and substituting different starting materials the following compounds of Formula I were prepared: cis- 1 ,5-cyclooctylene 4-(l1 -arnidinopiperid-4-ylacety1)- 1 -piperazinecarboxylate 24 4 2 -piperid-4-ylethylcarbamnoyl)-lI-piperazinecarboxylate (Compound 95); Calculated for
C
34
H
59
N
9 0 6 MW': 690.9, Found: MH': 690.6; cis- 1 ,5-cyclooctylene 4 4 -amidinobenzoylaninomethyl). 1-piperidinecarboxylate 27 4 2 -piperid-4-ylethylcarbamoyl)-l1-piperazinecarboxylate (Compound 96); Calculated for WO 98/04537 WO 9804537PCT/US97/13422- -62-
C
36 H5 6
N
8 0 6 MH': 697.9, Found: MH': 697.7; cis- 1, 5-cyclooctylene 4 -(4-amidinobenzylcarbamoyl)- I -piperazinecarboxylate 3 4 2 -piperid-4-yl)ethylcarbamoyl]- 1 -piperazinecarboxylate (Compound 97); Calculated for
C
35
H
55
N
9 0 6 MW': 698.9, Found: MH': 698.7; cis- 1 ,5-cyclooctylene 4 -(4-amidinophenylsulfonylaminomethyl)-l1-piperidinecarboxylate 6 4 -(2-piperid-4-ylethylcarbamoyl)-1I -piperazinecarboxylate (Compound 98); Calculated for
C
35
H
56
N
8 0 7 MH': 733.9, Found: M1-I: 733.4; cis- I ,5-cyclooctylene 4-[2-(l1 -amidinopiperid-4-yl)ethylcarbamoyl].
9 1 -piperazinecarboxylate 4 2 -piperid-4-ylethylcarbamoyl)-1I-piperazinecarboxylate (Compound 99); Calculated for C 35
H
62
N,
0 0 6 MHW: 719.9, Found: MW': 719.5; 4 -(4-amidinophenylcarbamoylmethyl). I-piperidinecarboxylate 12 4 2 -piperid-4-ylethylcarbamoyl)-1I-piperazinecarboxylate (Compound 100); Calculated for
C
36
H-
56
N
8 0 6 MH': 697.9, Found: MH': 695.6; cis- 1,5-cyclooctylene 4 4 -N-methoxycarbonylamidinobenzylcarbamoyl)- 1 -piperazinecarboxylate 4 -(2-piperid-4-ylethylcarbamoyl)- 1 -piperazinecarboxylate (Compound 101); Calculated for C 37
H
57
N
9 0 8 MH': 756.9, Found: MW': 756.4; and cis- I ,5-cyclooctylene 4 4 -guanidinobenzylcarbamoyl)-lI-piperazinecarboxylate 18 3 -piperid-4-ylpropyl-1-piperidinecarboxylate (Compound 102); Calculated for
C
36
H
58
N
8 0s: MW': 683.9 Found: MW': 683.3.
EXAMPLE 32 21 1 ,5-Pentamnethylene di 4 4 -guanidinobenzylcarbamoyl)- I -piperazinecarboxylate] (Compound 103) The following is the preparation of a compound of Formula I in which R' and R' each are 24 4-guanidinobenzyl, XV and X 9 each are X 2 and X 8 each are I ,4-piperazinylene,
X
3 and
X
7 each are and X 4
-X
6
-X
5 together are tert-Butyl 4-(4-guanidinobenzylcarbwnoyl). I -piperazinecarboxylate trifluoroacetate 27 (306 mg, 0.62 mmol.) was treated with neat trifluoroacetic acid (IlmL) at room temperature over ten minutes to give a colorless homogeneous solution. The liquid was concentrated and the oily WO 98/04537 WO 9804537PCTIUS97/13422- -63residue triturated with diethyl ether (3x IlOmL) followed by drying in vacuo to a colorless foam.
The deprotected piperazine salt was then taken into DMF (2.5 mnL) followed by addition of 3 diisopropylethylamine (0.5 mL, 3.1 mmol.) and 1,5-n-pentylene di(chloroformate) (70 mg, 0.31 mmol.) and the mixture was allowed to stir for one hour at room temperature. The reaction mixture was concentrated and the residue was triturated with diethyl ether (3x 1 OmL) followed 6 by drying in vacuo. The crude material was taken into water (5 mL) and purified by preparative reverse phase HPLC and lyophilization to give 1 di [4-(4-guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate] as a colorless amorphous solid; 9 Electrospray LRMS: Calculated for C 33
H
48
N
12 0 6 MW': 709.8, Found: MH~: 709.3.
Proceeding as in Example 32 and substituting different starting materials the following compounds of formula I were prepared: 12 1 ,4-tetramethylene di 4 -(4-guanidinobenzylcarbamoyl)- I -piperazinecarboxylate] (Compound 104); Calculated for C 32
H
4 6
NI
2 0 6
MH
t 695.8, Found: MH': 695.8; 4-guanidinobenzyl 4- 4 4 -guanidinobenzylcarbamoyl)piperazin-1 -ylcarbonyl] valeryl}-1 I-piperazinecarboxamide (Compound 105); Calculated for C 32
H
4
N
2 0 4 MH': 663.8, Found: MH': 663.4; 4-guanidinobenzyl 18 4-f{ 6 4 4 -guanidinobenzylcarbamoyl)piperazin-I -ylcarbonyl] hexanoyl)}l-piperazinecarboxamide (Compound 106); Calculated for C 33
H
48
N
12 0 4 MW': 677.8, Found: MW': 677.4; 21 4-guanidinobenzyl 4-1{ 7 4 4 -guanidinobenzylcarbamoyl)piperazin-.I -ylcarbonyl] heptanoyll}- I-piperazinecarboxamide (Compound 107); Calculated for C 34
H
50
N
11 0 4 MH': 691.9, 24 Found: MH': 691.5; 4 -guanidinobenzyl 4 8 4 -(4-guanidinobenzylcarbamoyl)piperazinlI -ylcarbonyl]octanoyl}- 27 1 -piperazinecarboxamide (Compound 108); Calculated for C 37
]H
57
N
9 0 8 MW': 756.9, Found: MW': 756.4; WO 98/04537 WO 9804537PCTIUS97/13422 -64- 4-guanidinobenzyl 4- 9 4 4 -guanidinobenzylcarbamnoyl)piperazin- I -ylcarbonyljnonanoyl} 3 1 -piperazinecarboxamide (Compound 109); Calculated for C 36
H
54
N]
2 0 4 MH': 719.9, Found: MH': 719.5; 4-amidinobenzyl 6 4- 7 4 4 -amidinobenzylcarbamoyl)piperazin- 1 -ylcarbonyl]heptanoyl Il-piperazinecarboxamide (Compound 1 10); Calculated for C 34
H
48
N,
0 0 4 MH': 661.8, Found: MH': 661.3; 9 1 ,5-pentamethylene di[ 4 4 -guanidinophenylacetyl)piperazin-1 -ylcarbonyl] (Compound 1 11); Calculated for C 33
H
46
NI
0 0 4 MH': 647.8, Found: MH': 647.3; 1 ,6-hexaxnethylene di 4 4 -guanidinophenylacetyl)piperazin- I -ylcarbonyl] 12 (Compound 112); Calculated for C 34
H
48
N
10 0 4 MH': 661 Found: MI-I: 66 1; 1 ,7-heptamethylene di 4 4 -guanidinophenylacetyl)piperazin-1I-ylcarbonyl] (Compound 113); Calculated for C 35
H
50
N
10 0 4 MH~: 675.9, Found: MW': 675.4; and 3-oxa- 1 ,-pentamethylene di[ 4 4 -guanidinophenylacetyl)piperazin I -ylcarbonyl] (Compound 114); Calculated for C 3 2
H
44
N
10 0 7 MH': 681.8, Found: MH': 681.4.
EXAMPLE 32 18 In Vitro Assay of Tryptase Inhibition Mixtures of human tryptase (15 gg/mL) and test compound (varying concentrations) in Tris buffer (comprising: NaCi, 100 mM; Tris, 50 mM; 2 -[N-morpholine]ethane sulfonic acid, 21 2.5 mM, CaCI 2 0.5 mM; DMS0, 10%; glycerol, polyoxyethylenesorbitan monolaurate 0.05%; heparin, 25 ng/mL; and pH 8.2) were incubated for I hour at room temperature and then Tosyl-Gly-Pro-Lys-para.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 minutes. Apparent inhibition constants were calculated from the enzyme progress curves using standard mathematical models.
27 Human tryptase can be purified from human lung and skin tissue samples see Smith et al. (1984) J Bio. Chem. 59: 11046-11051; and Braganza et al. (1991) Biochem.
WO 98/04537 WO 9804537PCT/US97/13422- 4997-5007) and human mast cell line or obtained commerically ICN Biomedicals, Irvine California; Athens Research Technology, Athens, Georgia). Porcine intestinal mucosa 3 heparin and Tosyl-Gly-Pro-Lys-para-nitroanilide can be obtained from Sigma Chemical Company.
Proceeding as described in this application or by methods known to those of ordinary 6 skill the following compounds of Formula I were prepared and tested for tryptase inhibitory activity: Compound 1, Ki=0.O03giM; Compound 2, Kj=0.8 Compound 3, Ki=0.07PM; 9 Compound 4, Ki=0.00 1 jiM; Compound 5, Ki=0.2jiM; Compound 6, Kj= 1 ttM; Compound 7, Ki=0.3[tM; Compound 8, Ki=4jiM; Compound 9, Kj=O.4jM; Compound 10, Kj=jI M; Compound 11, Ki=0.O9jiM; Compound 12, Ki=0.2 gM; 12 Compound 13, Ki=0.O2jiM; Compound 14, Ki=0.OO4pM; Compound 15, Compound 16, Ki=0.9tiM; Compound 17, Ki=lIM; Compound 18, Kj=0.08jiM; Compound 19, Ki 1 l.2[tM; Compound 20, Kj=3.4jiM; Compound 21, Compound 22, Ki=0.2pM; Compound 23, Ki=4[iM; Compound 24, Kj=.3jiM; Compound 25, Ki=0.OO2pM; Compound 26, Kj=1 9jM; Compound 27, Ki=2jM; Compound 28, Ki=4jiM; Compound 29, K=l jI4M; Compound 3 0, Ki=0.03 1 jiM; 18 Compound 3 1, Kj=l jiM; Compound 32, Ki=2jiM; Compound 33, Kj=l [LM; Compound 34, Ki=3jiM; Compound 35, Kj=0.8jiM; Compound 36, Ki=0.6jiM; Compound 37, Ki=0.O7jiM; Compound 38, Ki=0.004pM; Compound 39, Kj=0.004jiM; 21 Compound 40, Ki=4jM; Compound 41, Ki=0.7[tM; Compound 42, Ki=0.02[tM; Compound 43, Kj=.4jiM; Compound 44, Ki=0.02pM; Compound 45, Ki=0.08jiM; Compound 46, Kj=1 jIM; Compound 47, Ki=0.3 jiM; Compound 48, K 1 =0.O9[tM; 24 Compound 49, Kj=2jM; Compound 50, Kj=0.08jiM; Compound 5 1, Kj=l jiM; Compound 52, Ki=0.O4jiM; Compound 53, Ki=6[tM; Compound 54, Ki=O. 1 jiM; Compound 55, K 1 =2jiM; Compound 56, Ki=10jiM; Compound 57, Ki=2jM; 27 Compound 58, Ki=0.1 jM; Compound 59, Kj=0.5jiM; Compound 60, Compound 6 1, Kj=41 jiM; Compound 62, Ki=0.2jiM; Compound 63, Ki=2[tM; WO 98/04537 PCT/US97/13422- -66- Compound 64, K,=1 M; Compound 65, K,=0.001 IM; Compound 66, Ki=0.02jtM; Compound 67, Ki=3pM; Compound 68, K,=0.04uM; Compound 69, 3 Compound 70, Ki=0.05uM; Compound 71, K,=0.8[tM; Compound 72, K,=0.1tM; Compound 73, Ki=0.0021M; Compound 74, K,=0.04pM; Compound 75, K,=0.01 M; Compound 76, K,=0.1 pM; Compound 77, K,=6pM; Compound 78, Ki=0.1 pM; 6 Compound 79, Ki=1 pM; Compound 84, Ki=0.06pM; Compound 85, K,=0.9tM; Compound 86, Ki=0.08uM; Compound 87, K,=0.05pM; Compound 88, Ki=0.1 tM; Compound 89, I M; Compound 90, 1 M; Compound 91, K,=0.1 pM; 9 Compound 92, K,=0.1 pM; Compound 93, K,=0.02pM; Compound 94, K,=0.007pM; Compound 95, Ki=0.02M; Compound 96, K,=0.02pM; Compound 97, K,=0.0009pM; Compound 98, K,=0.03pM; Compound 99, K,=0.05jpM; Compound 100, K,=0.009pM; 12 Compound 101, K,=0.04pM; Compound 102, K,=0.08pM; Compound 103, Ki=0.001 M; Compound 104, K,=0.003uM; Compound 105, Ki=0.04pM; Compound 106, K,=0.004piM; Compound 107, Ki=0.0001pM; Compound 108, K,=0.0005pM; Compound 109 K,=0.0007pM; Compound 110, K,=0.0008M; Compound 111, K,=0.3tM; Compound 112, K,=0.091aM; Compound 113 Ki=0.005pM; and Compound 114, K;=0.058jtM.
EXAMPLE 33 18 In Vivo Assay of Asthma Allergic sheep characterized as dual responders displaying early and late phases of bronchoconstriction) are challenged with antigen Ascaris suum). The sheep are 21 administered test compound or vehicle by aerosol inhalation at 0.5 hours before and at 4 and 24 hours post antigen challenge. Specific lung resistance (SRL) is monitored via an esophageal balloon catheter just prior to the first test 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 test 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% (PC 400 The PC 400 values are obtained by WO 98/04537 PCT/US97/13422 -67administering 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 a 6 60% decrease in PC 400 is observed).
Sheep treated with tryptase inhibitors do not exhibit late phase broncoconstriction at 4 to 8 hours post antigen challenge, SRL remained at basal levels). 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.
2 ORAL FORMULATION Compound of Formula I 10-100 mg Citric Acid Monohydrate 105 mg Sodium Hydroxide 18 mg Flavoring Water q.s. to 100 mL INTRAVENOUS FORMULATION Compound of Formula I 0.1-10 mg Dextrose Monohydrate q.s. to make isotonic Citric Acid Monohydrate 1.05 mg Sodium Hydroxide 0.18 mg Water for Injection q.s. to 1.0 mL WO 98/04537 PCTIUS97/13422- -68- TABLET FORMULATION Compound of Formula I 1% 3 Microcrystalline Cellulose 73% Stearic Acid Colloidal Silica 1%.
Claims (47)
1. A compound of Formula 1: 3 ~R -X -X-X-X R 2_ -x~8-x7x6 in which: X' is (C 3 14 )cycloalkylene, hetero(C 314 )cycloalkylene, (C 6 14 )arylene or 6 hetero(C 5 .1 4 )arylene; X 4 and X' are independently (CO. 2 )alkylene; X' and X 9 are independently a covalent bond, -C(O)N(R 3 9 -N(R 3 -S(O) 2 N(R 3 -N(R 3 )S(0) 2 -OC(O)N(R 3 -N(R 3 -N(R 3 )C(O)N(R 3 or -OC(O)O-,"wherein each W2 is independently hydrogen, (C 1 3 )alkyl or (C 3 8 )cycloalkyl, with the proviso that X' and X 9 are not both'covalent bonds; 12 X 3 and X' are independently -C(O)N(R 3 -N(R 3 -S(O) 2 N(R 3 -N(R 3 )S(0) 2 -OC(O)N(R 3 -N(R 3 -N(R 3 )C(O)N(R 3 or -OC(O)O-, wherein R 3 is as defined above; X 2 and X' are independently (C 1 8 )alkylene, hetero(C 1 8 )alkylene, -X" 0 or -XI 0 wherein X' 0 is (CO. 4 )alkylene or hetero(C 3 4 )alkylene and is (C 3 8 )cycloalkylene or hetero(C 3 8 )cycloalkylene; 1 8 RI is R 4 _X1 2 or R 5 -X 1 3 wherein: R 4 is amino, amidino, guanidino, 1 -irninoethyl or methylamino, X" 2 is (C 4 6 )alkylene, hetero(C 4 6 )alkylene, heterooXO(C 4 6 )alkylene, 21 oxo(C 4 6 )alkylene or _X1 4 _XIIXI 6 wherein X" 5 is (C 3 6 )cycloalkylene, hetero(CS 5 6 )arylene, hetero(C 36 )cycloalkylene or phenylene, X1 4 is (C 4 )alkylene and X 6 is 16 )alkylene, wherein the sum of n14 and n16 is 0, 1, 2, 3 or 4, 24 RI is a group selected from azetidin-3-yl, benzoimidazol-4-yl, imidazol-1 -yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yI, 2-imidazolin-3-yl, 2methylimidazol-1 -yl, 4-methylimidazol-1 -yl, 5-methylimidazol-1 -yI, 1 -methylpiperid-
3-yl, 1 -methylpiperid-4-yl, piperid-3-yl, piperid-4-yl, piperazin-1 -yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimid in-4-yl, pyrimid in-5-yl, pyrrolid in-3-yl, 1,4,5,6- tetrahydropyrimidine-2-yl, 1 ,4,5,6-tetrahydropyrimidine-4-y and 1,4,5,6- tetra hyd ropyrimid in-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, (Ci.. 8 )alkyl, (C 314 )cycloalkyl, (C 6 14 )aryl, (C 6 14 )aryl(Cl-4)alkyl, (C 1 8 )alkanoyl, (Cl. 8 )alkyloxy, (C 6 1 4 )aryloxy, (C 31 4)cycloalkyloxy, (C 1 4 )alkyloxy, (C1 8 )alkylthio, (031 4 )cycloal kylthio, (C 6 1 4arylthio and -NR R wherein R 6 and R 7 are independently selected from hydrogen, (Cl 18 )alkyl, (C 18 B)alkanoyl, (C 3 1 4cycloalkyl or (0e. 14 )aryl, and X 13 is (CO- 6 )alkylene, hetero(0 2 6 )alkylene, heterooxo(C 3 6 )alkylene, oxo(0 2 6 )alkylene or _l-l-l- wherein X 18 is as defined above for X 15 X 17 is (Cnl7)alkylene and X 19 is (Cnlg)alkylene, wherein the sum of nI 7 and n19 is 0, 1 or 2; and R 2 is R 8 _X 2 1_ or R 9 _X 21 wherein: R 8 is amino, 1 -iminoethyl or methylamino, X 20 is (C 46 )alkylene, hetero(C 4 6 )alkylene, heterooxo(0 46 )alkylene, ~~OXO(C 46 )alkylene or -X 2 X 3 X 4 ,wherein X 3 is as defined above forX 1 ,X 2 i (Cn 22 )alkylene and X 24 is (Cn 24 )alkylene, wherein the sum of n22 and n24 is 0, 1, 2, 3 or 4 with the proviso that when R 8 is amino then X 0 is not (0 4 6 )alkylene or OXO(0 4 6 )alkylene and n22 is not 1, 2, 3 or 4, R 9 is as defined above for R5 and x 2 l i S (CO- 6 )alkylene, hetero(C 26 )alkylene, heterooxo(C 36 )alkylene, 25 OXO(C 26 )alkylene or -X 25 -X 26 -X 27 wherein X 26 is as defined above for X 15 X 25 is (Cn 2 5)alkylene and X 27 is (Cn 27 )alkylene, wherein the sum of n25 and n27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene, as defined above, are optionally substituted with one or more :radicals selected from halo, hydroxy, mercapto, (Cl. 8 )alkyl, (C 3 1 4)cycloalkyl, (C 6 14)aryl, (C 6 .i 4 )aryl(Cl-4)alkyl, (Cli 8 )alkanoyl, (Cl 1 8 )alkyloxy, (C 614 )aryloxy, (C 3 1 4 )cycloal kyloxy. (Cl-4)alkyloxy, (Cl 18 )alkylthio, (C3..14)cycloalkylthio, (C6- 1 4)arylthio and -NR R R 6 and R 7 are as defined above; with the proviso that covalent bonds do Sot occur between heteroatoms contained within R 1 X 2 X 4 X 6 X 8 and R 2 and any '07'x- A 4eteroatoms contained with X 3 X 5 X 7 and X 9 and IADayt~ibULBC104346.doc 71 the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. 2. The compound of claim 1 in which: X 5 is cis-l ,5-cyclooctylene and X 4 and X 6 each are covalent bond or X 5 is 1,4- phenylene and X 4 and X 6 are (Co..i)alkylene; X1 and X 9 are independently a covalent bond, -C(O)NH-, -N(0H 3 or -S(O) 2 NH-; X 3 and X 7 are independently or X 2 and X 8 are independently -X 10 -X 11 wherein: X 0 is a covalent bond or methylene and X1 1 is 4, 1-piperidylene or l,4-piperazinylene; R 1 is R 4 -Xl 2 or R 5 _X 1 3 wherein; R 4 is amidino, guanidino or methylamino, x1 2 is -xl 4 -xl 5 _Xl 6 wherein X1 5 is 1,4-phenylene or 1,4-piperidylene, X1 4 is (Cfll4)alkylene and X 16 is (Cnis)alkylene, wherein the sum of n14 and n16 is 0, 1 or 2, R 5 is piperid-4-yI and X 13 is (C2..3)alkylene; and R 2 is R"- 20 or R 9 2 wherein: 20 R 8 is amino, methylamino or 1-iminoethyl, *x 20 is -X 22 -x 23 -X 24 wherein X 23 is trans- 1 4-cyclohexylene, -1,4-phenylene, 4,1-pyridylene, 1,4-piperidylene, X 2 is (Cfl 22 )alkylene and X 4 is (0fl24)alkylene, wherein the sum of n22 and n24 is 1 or 2, R 9 is benzoimidazol-5-yl, imidazol-1-yl, imidazol-4-yl, 2-imidazolin-2-yl,
4- 25 methylimidazol-1-yl,
5-methylimidazol-1 -yl, 1 -methylpiperid-4-yl, piperid-4-yl, piperazin-1-yl, pyrid-3-yl, pyrid-4-yl, l, 4 5 ,6-tetrahydropyrimidin5.yl or 1,4,5,6- tetra hyd ro-2-d ioxopyrim id in-5.yl and X 1 is (C1..6)alkylene, co-aza(C 2 -5)alkylene, 2-aza-3-oxotrimethylene, 3-aza-2- oxotrimethylene, 3-oxotri methylene, wo-thia(0 2 4)alkylene or -X 25 -X 26 _X 27 wherein X 26 is 1 ,4-phenylene, X 25 is (0fl25)alkylene and X 27 is (Cfl27)alkylene, wherein the sum of n25 and n27 is 0 or 1; and the pharmaceutically acceptable salt, N-oxides, prodrug derivatives and protected derivatives thereof. 'IR~ A 3 The compound of claim 2 in which X 5 is cis- 1 5-cyclooctylene and X 4 and ~-each are a covalent bond; X1 and X 9 are independently a covalent bond, 44, -C(0)NH- or -S(0) 2 NH-; X 3 and X 7 are independently or IMAYLIBOiC104346.doc 72 R R 2 is R 4 -X 12 wherein R 4 is amidino or gaunidino; and R 2 is R 8 -x 20 orR9_2 wherein R 8 is amino or methylamino, X 23 is trans-i 4 -cyclohexylene or 1,4- phenylene, R 9 is imidazol-1-yl, imidazol-4-yl, 4 -methylimidazoll1yl, piperid-4-yl or pyrid-4-yl and X 21 is (C1-5)alkylene or 3 -azatrimethylene; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. 4. The compound of claim 3 in which X 1 and X 9 are independently or X 3 and X 7 each are X 2 and X 8 each are -X 10 -X 11 wherein X1 is a covalent bond and X' 1 is l,4-piperazinylene; R 1 is R 4 -Xl 2 wherein R 4 is amidino or guanidino and X 12 is -Xl 4 -Xl 5 -Xl 6 wherein X1 5 is 1,4-phenylene, X 14 is a covalent bond and X1 6 is methylene; and R 2 is R 8 _X 20 or R 9 _X 21 wherein R 8 is amino, X 20 is -X 22 -X 23 -X 24 wherein X 23 is trans-i ,4-cyclohexylene, X 22 is a covalent bond and X 24 is methylene, R 9 is piperid-4-yl and X 21 is ethylene or trimethylene; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 4 in which X1 and X 9 each are R 1 is 4-amidinobenzyl and R 2 is 2-piperid-4-ylethyl, namely cis-1, ,5-cyclooctylene 4-(4- amid inobenzylcarbamoyl)-l. -piperazinecarboxylate 4 -(-piperid-4-ylethylcarbamoyl) -piperazinecarboxylate; and the pharmaceutically acceptable salts, N-oxides, 20 prodrug derivatives and protected derivatives thereof. The compound of Claim 4 in which X1 is X 9 is R 1 is 4- amidinobenzyl and R 2 is 3-piperid-4-ylpropyl, namely cis-1, ,5-cyclooctylene 4-(4- amidinobenzylcarbamoyl). 1-piperazinecarboxylate 4-(4-piperid-4-ylbutyryl)-l. piperazinecarboxylate; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
7. The compound of claim 4 in which X 1 and X 9 each are R' is 4-guanidinobenzyl and R 2 is trans- 4 -aminocyclohexylmethyl, namely cis-1 cyclooctylene trans- 4 4 -aminocyclohexylmethycarbamoyl). 1- piperazinecarboxylate 4-(4-guanid inobenzylcarbamoyl).1 -piperazinecarboxylate; and the pharmaceutically acceptable salts, NV-oxides, prodrug derivatives and protected derivatives thereof.
8. The compound of claim 4 in which X1 and X 9 each are R' is 4- amidinobenzyl and R 2 is 3-piperid-4-ylp ropy[, namely cis-1, ,5-cyclooctylene 4-(4- ammi inophenylacetyl)-l1-piperazincarboxylate 4-(4-piperid-4-ylbutyryl)- 1- LOAYLIBMibc04346.doc 73 piperazincarboxylate; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
9. The compound of claim 4 in which X 1 and X 9 each are R 1 is 4-guanidinobenzyl and R 2 is 2-piperid-4-ylethyl, namely cis-1,5-cyclooctylene 4-(4- guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4 2 -piperid-4- ylethylecarbamoyl)-l-piperazinecarboxylate; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 4 in which X' is X 9 is R 1 is 4- guanidinobenzyl and R 2 is 3 -piperid-4-ylpropyl, namely cis-1,5-cyclooctylene 4-(4- guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4 4 -piperid-4-ylbutyryl)-1- piperazinecarboxylate; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
11. The compound of Claim 4 in which X 1 is X 9 is R 1 is 4-guanidinobenzyl and R 2 is 2-piperid-4-ylethyl, namely 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 1 and X 9 each are R 1 is 4- guanidinobenzyl and R 2 is 3 -piperid-4-ylpropyl, namely 20 4-(4-guanidinophenylacetyl)-1-piperazinecarboxylate 4 4 -piperid-4-ylbutyryl)- 1-piperazinecarboxylate; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. S*
13. The compound of Claim 4 in which X 1 is X 9 is R 1 is 4-amidinobenzyl and R 2 is 2-piperid-4-ylethyl, namely 25 4 4 -amidinophenylacetyl)-l-piperazinecarboxylate 4 2 -piperid-4-ylethylcarbainoyl)-l-piperazinecarboxylate; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
14. A compound of Formula I, as set out in claim 1, said compound substantially as hereinbefore described with reference to any one of the examples. 30 15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of Claims 1 to 14 in combination with a pharmaceutically acceptable excipient.
16. A compound according to any one of Claims 1 to 14 or a composition according to claim 15 when used for treating a disease in an animal in which tryptase activity contributes to the pathology and/or symptomatology.
17. A compound according to any one of Claims 1 to 14 or a composition according to claim 15 for use in treating a disease in an animal in which tryptase ctivity contributes to the pathology and/or symptomatology I:DAYLIBcibc04346.doc
18. A method of treating a disease in an animal in which tryptase activity contributes to the pathology and/or symptomnatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of Formula 1: R I -x 'x -i in which: X 5 is (C3.14)cycloalkylene, hetero(0 3 i1 4 )cycloalkylene, (C6-14)arylene or hetero(C 5 14 )arylene; X 4 and X 6 are independently (0O-2)alkylene; X 1 and X 3 independently are a covalent bond, -C(O)N(R 3 -N(R 3 -S(O) 2 N(R 3 -N(R 3 )S(0) 2 -OC(0)N(R 3 -N(R 3 -N(R 3 )C(0)N(R 3 or wherein each R 3 is independently hydrogen, (0v- 3 )alkyl or (C3..)cycloalkyl; X 7 and X 9 are independently -C(0)N(R 3 -N(R 3 -S(O) 2 N(R 3 -N(R 3 )S (0) 2 -0C(O)N(R 3 -N(R 3 -N(R 3 )C(0)N(R 3 or wherein R 3 is as defined above; X8 *XOX-o X 2 and X 8 are independently (Ci..a)alkylene, hetero(Cl 1 8 )alkylene, 1 1 -o -X 11 -Xl 0 wherein X 1 0 is (Co-4)alkylene or hetero(C 3 -4)alkylene and X 1 is 20 0 3..)cycloalkylene or hetero(C 3 8 )cycloalkylene; :R 1 is R 4 _X 12 or R 5 -Xl 3 wherein: Ris amino, amidino, guanidino, 1-iminoethyl or methylamino, *X 1 IS (C4-6)alkylene, hetero(C 4 6 )alkylene, heterooxo(C 4 6 )alkylene, oxo (C4..6)alkylene or -x 14 -x 1 -x 16 wherein X1 5 is (C3-6)cycloalkylene, hetero (C5- 6 )arylene, hetero(C3. 6 )cycloalkylene or phenylene, X 14 is (0fl14)alkylene and X 16 is (0fl16)alkylene, wherein the sum of n 14 and n16 is 0, 1, 2, 3 or 4, R R 5 is a group selected from azetidin-3-yl, benzoimidazol-4-yl, 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, piperid-3-yl, 30 piperid-4-yl, piperazin-1-yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-4-yl, pyrrolidin-3-yl, 1 4 ,5,6-tetrahydropyrimidin2yl, 1,4,5,6- tetrahydropyrimidin-4-yl and 1,4, 5,6-tetrahydropyrimid in-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, (0 1 8 )alkyl, (03..14)cycloalkyl, (C6-14)aryl, (C6..14)aryl(Cl-4)alkyl, (Clia)alkanoyl, (Cl 1 8 )alkyloxy, ,~64)aryloxy, (03..14)cycloalkyloxy, (Cl-4)alkyloxy, (Cl 18 )alkylthio, _14-1 )CYCloalkylthio, (06.i 4 )arylthio and -NR R wherein R 6 and R 7 are IM~AYLIB060c~4346.doc independently selected from hydrogen, (C 1 e)alkyl, (C 18 )alkanoyl, (C3-1 4 )cycloalkyl or (C6- 4 )aryl and X 13 is (CO-6)alkylene, hetero(C 26 )alkylene, heterooxo(C 3 6 )alkylene, oxo(C 2 6 )alkylene or -X 17 -X 8 -X 1 9 wherein X' 8 is as defined above for X' 5 X17 is (Cn,17)alkylene and X 19 is (Cnig)alkylene, wherein the sum of n17 and n19 is 0, 1 or 2; and R 2 is R 8 -X 20 or R9_X 2 wherein: R 8 is amino, 1-iminoethyl or methylamino, X 20 is (C4-6)alkylene, hetero(C 4 6 )alkylene, heterooxo(C 4 6 )alkylene, oxo(C 4 6 )alkylene or -X 22 -X 23 -X 24 wherein X 23 is as defined above for X' 5 X 22 is (Cn 22 )alkylene and X 24 is (Cn 24 )alkylene, wherein the sum of n22 and n24 is 0, 1, 2, 3 or 4, with the proviso that when R 8 is amino then X 20 is not (C 4 -6)alkylene or oxo(C 4 6 )alkylene and n22 is not 1, 2, 3 or 4, R 9 is as defined above for R 5 and X 21 is (CO-6)alkylene, hetero(C 2 6 )alkylene, heterooxo(C 3 6 )alkylene, oxo(C 2 6 )alkylene or -X 25 -X 26 -X 27 wherein X 26 is as defined above for X' 5 X 25 is and X 27 is (Cn27)alkylene, wherein the sum of n25 and n27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene, as defined above, are optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (C1. 8 )alkyl, (C 3 -14)cycloalkyl, (C6-14)aryl, (C6- 14 )aryl(C1-4)alkyl, (C 18 )alkanoyl, (C 1 8 )alkyloxy, (C6-1 4 )aryloxy, (C 3 -1 4 )cycloalkyloxy, (C 1 -4)alkyloxy, (Cl 8 )alkylthio, (C 3 14 )cycloalkylthio, (C6- 14 )arylthio and -NR 6 R 7 wherein R 6 and R 7 are as defined above; with the proviso that covalent bonds do not occur between heteroatoms contained within X 2 X 4 X 6 X 8 and R 2 and any heteroatoms contained with X 3 X 5 X 7 and X 9 or a pharmaceutically acceptable salt, N-oxide or prodrug derivative thereof.
19. The method of Claim 18 in which the disease is selected from asthma, allergic rhinitis, rheumatoid spodylitis, osteoarthritis, gouty arthritis, rheumatoid arthritis, arthritic conditions in general, urticaria, angioedema, eczematous dermatitis, anaphylaxis, hyper proliferative skin disease, peptic ulcers, inflammatory 30 bowel disease, ocular and vernal conjunctivitis and inflammatory skin conditions.
20. The method of Claim 19 in which the disease is asthma.
21. The method of Claim 20 in which the compound is admistered in a aerosolized pharmaceutically acceptable carrier suitable for administration as an inhalant.
22. The method of Claim 21 in which the compound is administered with a therapeutically effective amount of a P-adrenergic agonist, a methylxanthine, a cromoglycate or a corticosteroid. sTRF
23. The method of Claim 22 in which the p-adrenergic agonist is selected from albuterol, terbutaline, formoterol, fenoterol and prenaline, the methylxanthine is selected from caffeine, theophylline, aminophylline and theobromine, the I:\ayLibLIBC04346.doc cromoglycate is selected from cromolyn and nedocromil and the corticosteriod is selected from beclomethasome, triamcinolone, flurisolide and dexamethasone.
24. The method of Claim 19 in which the disease is rheumatoid arthritis or conjunctivitis.
25. The method of Claim 24 in which the compound is administered in a pharmaceutically acceptable carrier suitable for topical administration.
26. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the Formula I as set out in Claim 18 in combination with a pharmaceutically acceptable excipient.
27. A compound of the Formula I, as set out in Claim 18, or a pharmaceutical composition according to claim 26 when used in a method of treating a disease in an animal in which tryptase activity contributes to the pathology and/or symptomatology of the disease.
28. A compound of the Formula I, as set out in Claim 18, or a is pharmaceutical composition according to claim 26, for use in treating a disease in an animal in which tryptase activity contributes to the pathology and/or symptomatology of the disease.
29. Use of a compound of the Formula I, as set out in Claim 18, in the manufacture of a pharmaceutical composition for treating a disease in an animal in 20 which tryptase activity contributes to the pathology and/or symptomatology of the disease.
30. A compound of Formula I: R'X'-X 2 -X -X 4 R2-X 9 -X -X 7 -X6 25 in which: X 4 -X 5 -X 6 together are (C2- 12 )alkylene or hetero(C 3 .12)alkylene; X 1 and X 9 are independently a covalent bond, -C(0)N(R 3 -N(R 3 -S(0) 2 N(R 3 -N(R 3 )S(0) 2 -OC(0)N(R 3 -N(R 3 -N(R 3 )C(O)N(R 3 or wherein each R 3 is independently 3 hydrogen, (Cl. 3 )alkyl or (C3-8)cycloalkyl, with the proviso that X' and X 9 are not both covalent bonds; X 3 and X 7 are independently -C(0)N(R 3 -N(R 3 -S(0) 2 N(R 3 -N(R 3 )S(O) 2 -OC()N(R 3 -N(R 3 -N(R 3 )C(O)N(R 3 or wherein R 3 is as defined above; X 2 and X 8 are independently (Ci-8)alkylene, hetero(C 1 .8)alkylene, -X 1 0 -X 1 or -X 1 -X 1 0 wherein X 10 is (Co-4)alkylene or hetero(C34)alkylene and X 11 is (C3-8)cycloalkylene or hetero(C3-8)cycloalkylene; R 1 is R 4 -X 1 2 or R 5 -X 13 wherein: I:aDAYLIBibc04346.doc R 4 is amino, amidino, guanidino, 1 -iminoethyl or methylamino, X1 2 is (C4-6)alkylene, hetero(C 4 -6)alkylene, heterooxo(C 4 -6)alkylene, oxo (C 4 -6)alkylene or -Xl 4 -Xl 5 -Xl 6 wherein K' 5 is (C3.6)cycloalkylene, hetero(C 5 -6)arylene, hetero(C 3 -6)CYCloalkylene or phenylene, X1 4 is (Cfll4)alkylene and X 16 is (Cfll6alkylene, wherein the sum of n14 and n16 is 0, 1, 2, 3 or 4, R 5 is a group selected from azetidin-3-yl, benzoimidazol-4-yl, yl imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2- methylimidazol-1 -yI, 4-methylimidazol- 1-yi, 5-methylimidazol- 1-yl, I -methylpiperid- 3-yI, 1 -methylpiperid-4-yl, piperid-3-yI, piperid-4-yl, piperazin-1 -yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-4-yl, pyrimid in-5-yl, pyrrolid in-3-yl, 1,4,5,6- tetra hyd ropyri mid in-2-yl, 1,4,5 ,6-tetra hyd ropy rim id i n-4-yl and 1 ,4,5,6-tetrahyd ropyrimid in-5-yl and any carbocyclic ketone or th ioketone derivative thereof, which group is optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (Ci..a)alkyl, (C3-4)cycloalkyl, (C 6 .i4)aryl, (C6-14aryl(Cl4alkyl,(Cl-8)alkanoyl, (Cl-8)alkyloxy, (C6- 14 )aryloxy, (Ca..i 4 )cycloalkyloxy, (Cl-4)alkyloxy, (Clia)alkylthio, (C3l1 4 )cycloalkylthio, (C 6 i 4 )arylthio and -NR R wherein R 6 and R 7 are independently selected from hydrogen, (C 1 8 )alkyl, 8 )alkanoyl, (C3.i4cycloalkyl or (C 6 -4aryl and X 13 is (Co-6)alkylene, hetero(C 2 -6)alkylene, heterooxo(C 36 )alkylene, 9* 20 OXO(C 2 6 )alkylene or -X 7 X 8 X 9 ,wherein X1 8 is as defined above forX 1 ,X 7 i (Cni 7 )alkylene and X 19 is (CnI 9 )alkylene, wherein the sum of n17 and n19 is 0, 1 or 2; and R 2 is R 8 _X 20 or R 9 _X 21 wherein: :R 8 is as defined above for R 4 x 20 iS(C4-6)alkylene, hetero(C 4 -6)alkylene, heterooxo(C 4 6 )alkylene, OXO(C 4 6 )alkylene or -X 22 -X 23 -X 24 wherein X 23 is as defined above for X 15 X 22 is (Cfl22)alkylene and X 24 is (C, 24 )alkylene, wherein the sum of n22 and n24 is 0, 1, 2, 3 cr 4, R9 is as defined above for R 5 and is (CO- 6 )alkylene, hetero(C 2 6 )a Ikylene, heterooxo(C 3 6 )alkylene, OXO(C 2 6 )alkylene or -X 25 -X 26 -X 27 wherein X 26 is as defined above for X 15 X 25 is *(Cn 2 5)alkylene and X 27 is (Cfl27)alkylene, wherein the sum of n25 and n27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene, as defined above, are optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, 8 )alkyl, (C 314 )cycloalkyl, (C 6 14 )aryl, (CS.l4aryl(ClA4)alkyl, (C1..8)alkanoyl, (C 1 8 )alkyloxy, (C6-1i 4 )aryloxy, (C3.14)cycloalkyloxy, (Cl-.4alkyloxy, (Cl- 8 )alkylthio, (C3.-1 4 )cycloalkylthio, (C6..l 4 )arylthio and -NR R wherein R 6 and R 7 are as defined above; with the proviso that covalent bonds do not occur between heteroatoms -1 Contained within R 1 X 2 X 4 X 6 X 8 and R 2 and any heteroatoms ontained with X 3 5 7 and X 9 and IM~AYLIB0ibc04346.doc 78 the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
31. The compound of Claim 30 in which: X 4 -X 5 -X 6 together are (C2..l)alkylene or hetero(C 3 -1o)alkylene; X1 and X 9 are independently a covalent bond, -C(O)NH-, -N(CH 3 or -S(0) 2 N H-; X 3 and X 7 are independently or X 2 and X 8 are independently -X 10 -X 1 1 wherein X 10 is a covalent bond or methylene and X 1 1 is 4,1-piperidylene or I ,4-piperazinylene; R 1 is R 4 _Xl 2 or R 5 -Xl 3 wherein: R 4 is amidino, guanidino or methylamino, x1 2 is -xl 4 -xl 5 -Xl 6 wherein X1 5 is 1,4-phenylene or 1,4-piperidylene, X 14 is (Cnl4alkylene and X 16 is (Cfll6)alkylene, wherein the sum of n14 and n16 is 0, 1 or 2, R 5 is piperid-4-yI and X1 3 is (C 2 3 )alkylene; and R 2 is R 5 -X 20 or R 9 _X 21 wherein: R 8 is amino, amidino, guanidino, methylamnino or 1-iminoethyl, x 20 is -x 22 -x 23 -X 24 wherein X 23 is trans-i ,4-cyclohexylene, 1 ,4-phenylene, 204,-pyridylene, 1,4-piperidylene, X 22 is Cf 2 alynendX 24 is(C2alyee wherein the sum of n22 and n24 is 1 or 2, R 9 is benzoimidazol-5-yl, imidazol-1-yl, imidazol-4-yl, 2-imidazolin-2-yl, 4- methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-methylpiperid-4-yl, piperid-4-yl, piperazin-1-yI, pyrid-3-yI, pyrid-4-yl, 1 ,4,5,6-tetrahydropyrimidin-5-yI or 1,4,5,6- tetra hyd ro-2-d ioxopyrim id in -5-yl and 21 is (Cl-6)alkylene, co-aza(C 2 5 )alkylene, 2-aza-3-oxotrimethylene, wherein X 26 is 1 ,4-phenylene, X 25 is (Cfl25)alkylene and X 27 is (Cfl27)alkylene, wherein the sum of n25 and n27 isO0 or 1; and 3the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. *32. The compound of Claim 31 in which X 4 -X 5 -X 6 together are (C 4 8 )alkylene or hbtero(C 4 -1o)alkylene; X1 and X 9 are independently a covalent bond, -C(0)NH- or -S(0) 2 N X 3 and X 7 are independently or R 1 is R 4 -XI 2 wherein R 4 is amidino or guanidino; and R 2 is R 8 _X 20 or R9X1_ wherein R 8is amino, amidino, guanidino or methylamino, X 23 is trans-i ,4- cyclohexylene or 1 ,4-phenylene, R 9 is imidazol-1-yl, imidazol-4-yl, 4- ~~~ethylimidazol- 1-yl, 5-methylimidazol-1-yl, piperid-4-yl or pyrid-4-yl and X 21 is ADAYLIU6ic4346.doc 79 or 3-azatrimethylene; and the pharmaceutically acceptable salts, N- oxides, prodrug derivatives and protected derivatives thereof.
33. The compound of Claim 32 in which X 1 and X 9 are independently or X 3 and X 7 are independently or X 2 and X 8 each are -X'O 10 -X" 1 wherein X 10 is a covalent bond and X 1 1 is 1,4-piperazinylene; R 1 is R 4 X12-, wherein R 4 is amidino or guanidino and X 12 is -X 14 -X 1 5 -X 6 wherein X 1 5 is 1,4- phenylene, X 14 is a covalent bond and X 16 is methylene; and R 2 is R 8 -X 2 0 wherein R8 is amidino or quanidino and X 20 is -X 22 -X 23 -X 24 wherein X 23 is l,4-phenylene, X 22 is a covalent bond and X 2 4 is methylene; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
34. The compound of Claim 33 in which X 4 -X 5 -X 6 together are hexamethylene; X 1 and X 9 each are X 3 and X 7 each are and R' and R 2 each are 4-guanidinobenzyl, namely 4-guanidinobenzyl 4 -{7-[4-(4-guanidinobenzylcarbamoyl)piperazin-1-ylcarbonyl]heptanoyl}- l-piperazinecarboxamide; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. The compound of Claim 33 in which X 4 -X 5 -X 6 together are heptamethylene; X' and X 9 each are X 3 and X 7 each are and R' and R 2 each are 4-guanidinobenzyl, namely 4-guanidinobenzyl 20 4-{8-[4-(4-guanidinobenzylcarbamoyl)piperazin-1-ylcarbonyl]octanoyl}- 1-piperazinecarboxamide; and the pharmaceutically acceptable salts, N-oxides prodrug derivatives and protected derivatives thereof. :9 36. The compound of Claim 33 in which X 4 -X 5 -X 6 together are V octamethylene; X' and X 9 each are X 3 and X 7 each are and R' and R 2 each are 4-guanidinobenzyl, namely 4-guanidinobenzyl 4-{9-[4-(4-guanidinobenzylcarbamoyl)piperazin-1-ylcarbonyl]nonanoyl}-1- piperazinecarboxamide; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
37. The compound of Claim 33 in which X 4 -X5_X 6 together are hexamethylene; X 1 and X 9 each are X 3 and X7 each are and R' and 2 each are 4-amidinobenzyl, namely 4-amidinobeozyl 4 7 4 4 -amidinobenzylcarbamoyl)piperazin-1-ylcarbonyl]heptanoyl)- piperazinecarboxamide; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
38. The compound of Claim 33 in which X 4 -X 5 -X 6 together are pentamethylene; X'and X 9 each are X 3 and X7 each are and R' and R 2 each are 4-guanidinobenzyl, namely 1,5-pentamethvlene di[4-(4- guanidinobenzylcarbamoyl)- 1 -piperazinecarboxylate]; and the pharmaceutically s acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. I\DAYLIBibcl4346.doc
39. The compound of Claim 33 in which X 4 -X 5 -X 6 together are tetramethylene; X' and X 9 each are X 3 and X 7 each are and R' and R each are 4-guanidinobenzyl, namely 1, 5 -tetramethylene di[ 4 4 -guanidinobenzylcarbamoyl)-1 -piperazinecarboxylate]; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof The compound of Claim 33 in which X 4 -X 5 -X 6 together are pentamethylene; X1 and X 9 each are X 3 and X7 each are and R 1 and R 2 each are 4 -guanidinobenzyl, namely 4 -guanidinobenzyl 4-{6-[4-(4-amidinobenzylcarbamoyl)piperazin-1-ylcarbonylhexanoyl}-l- piperazinecarboxamide; and the pharmaceutically acceptable salts, N-oxides prodrug derivatives and protected derivatives thereof.
41. The compound of Claim 33 in which X 4 -X 5 _X 6 together are 3- oxatetramethylene; X 1 and X 9 each are X 3 and X 7 each are and R' and R 2 each are 4-amidinobenzyl, namely 3 -oxa-1,5-pentamethylene di[4-(4- guanidinophenylacetyl)piperazin-l -ylcarbonyl]; and the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.
42. A compound of Formula I, as set out in Claim 30, said compound substantially as hereinbefore described with reference to any one of the examples. 20 43. A pharmaceutical composition comprising a therapeutically effective 00 amount of a compound of any one of claims 30 to 42 in combination with a pharmaceutically acceptable excipient.
44. A method of treating a disease in an animal in which tryptase activity S. contributes to the pathology and/or symptomatology of the disease, which method 25 comprises administering to the animal a therapeutically effective amount of compound of Formula I: RI-XI-X2-X -X se* **0 R2-X-X -X in which: so X4-XsX6 tOgether are (C2-12)alkylene or hetero(C3-12)alkylene; Vo. X' and X9 are independently a covalent bond, -N(R3)C(0)N(R3)- Or wherein each R3 is independently hydrogen, (C-3)alkyl or (C3-8)cycloalkyl, with the proviso that X' and X9 are not both covalent bonds; X3 and X7 are independently -N(R3)C(0)N(R3)- Or wherein R3 is as defined above; '44 I:\DAYLIBibc04346.doc X 2 and X 8 are independently (Ci..a)alkylene, hetero(Ci..a)alkylene, -X 10 -X 11 or -X 11 -X' 0 wherein X1 0 is (CO-4alkylene or hetero(C 3 4)alkylene and X 1 1 is. (C3..8)cycloalkylene or hetero(C3.B)cycloalkylene; R' is R 4 _X 1 2 or R 5 -X 13 wherein: R 4 is amino, amidino, guanidino, 1-iminoethyl or methylamino, X 12 is (C 4 -6)alkylene, hetero(C 4 6 )alkylene, heterooxo(C 4 6 )alkylene, OXO(C4-6)alkylene or -Xl 4 -x 5 -xl 6 wherein X 15 is (CS.6)cycloalkylene, hetero(C5s6)arylene, hetero(C 3 -6)cycloalkylene or phenylene, X 14 is (Cni 4 )alkylene and X 16 is (Cnl 6 )alkylene, wherein the sum of n14 and n16 is 0, 1, 2, 3 or 4, R 5 is a group selected from azetidin-3-yl, benzoimidazol-4-yl, yl imidazol-.1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yi, 2- methylimidazol-1 -yl, 4-methylimidazol-1 -yl, 5-methyl imidazol-1 -yI, 1 -methylpiperid- 3-yI, 1 -methylpiperid-4-yl, piperid-3-yl, piperid-4-y, piperazin- l-yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-4-yI, pyrimid in-5-yl, pyrrolidin-3 -1, 1 4 ,5,6-tetrahydropyrimidin-2.yl, 1 4 5 6-tetrahydropyrimidin-4.yl and 1,4,5,6- tetra hyd ropyrim id in-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..a)alkyl, (C3.14)cycloalkyl, (C 6 1 4 )aryl, (C 6 1 4 )aryl(C 4)alkyl, (C1..8)alkanoyl, (Cl1.8)alkyloxy, (C6..1 4 )aryloxy, (C 3 1 4)cycloalkyloxy, (C,4)alkyloxy, (C 1 )alkylthio, (C3..14)cycloalkylthio, *(C6ei 4 )arylthio and -NR 6 R 7 wherein R 6 and R 7 are independently selected from hydrogen, (Ci..a)alkyl, (Clia)alkanoyl, (C3..14)cycloalkyl or (C 6 .i4aryl and X1 3 is (CO..6)alkylene, hetero(C 2 6 )alkylene, heterooxo(C 3 6 )alkylene, OXO(C 2 -6)alkylene or -Xl 7 -Xl 8 -Xl9-, wherein X 18 is as defined above for X1 5 X 1 7 is (Cfll7)alkylene and X 1 9 is (Cfl19)alkylene, wherein the sum of n17 and n19 is 0, 1 or 2; and R 2 is R 8 _X 20 or R 9 _X 21 wherein: R 8 is as defined above forR, X 20 is (C 4 6 )alkylene, hetero(C 4 s)alkylene, heterooxo(C 46 )alkylene, OXO(C 4 6 )alkylene or -X 22 -X 23 _X 24 wherein X 23 is as defined above for X 15 X 22 is (Cfl22)alkylene and X 24 is (Cfl2 4 )alkylene, wherein the sum of n22 and n24 is 0, 1, 2, 3 or 4, :R 9 isas defined above for R 5 and X 2 1 is (Co-6)alkylene, hetero(C 2 6 )alkylene, heterooxo(C 3 .s)alkylene, OXO(C2-6)alkylene or -X 25 -X 26 -X 27 wherein X 26 is as defined above for X1 5 X 25 is (Cfl25)alkylene and X 27 is (Cfl27)alkylene, wherein the sum of n25 and n27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene, as defined above, are optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (Cl- 8 )alkyl, (C 6 1 4)aryloxy, (C3..14)cycloalkyloxy, (Ci.. 4 )alkyloxy, (C 1 8 )alkylthio, IM~AYLIBUbc04346.doc 82 (C3-14)cycloalkylthio, (C6- 1 4 )arylthio and -NR 6 R 7 wherein R 6 and R 7 are as defined above; with the proviso that covalent bonds do not occur between heteroatoms contained within R 1 X 2 X 4 X 6 X 8 and R 2 and any heteroatoms contained with X 3 X s X 7 and X 9 or a pharmaceutically acceptable salt, N-oxide or prodrug derivative thereof. The method of Claim 44 in which the disease is selected from asthma, allergic rhinitis, rheumatoid spodylitis, osteoarthritis, gouty arthritis, rheumatoid arthritis, arthritic conditions in general, urticaria, angioedema, eczematous dermatitis, anaphylaxis, hyper proliferative skin disease, peptic ulcers, inflammatory bowel disease, ocular and vernal conjunctivitis and inflammatory skin conditions.
46. The method of Claim 45 in which the disease is asthma.
47. The method of Claim 46 in which the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula I in a aerosolized pharmaceutically acceptable carrier suitable for administration as an 1i inhalant.
48. The method of Claim 47 in which the pharmaceutical composition further comprises a therapeutically effective amount of a p-adrenergic agonist, a methylxanthine, a cromoglycate or a corticosteroid.
49. The method of Claim 48 in which the p-adrenergic agonist is selected from albuterol, terbutaline, formoterol, fenoterol and prenaline, the methylxanthine is selected from caffeine, theophylline, aminophylline and theobromine, the cromoglycate is selected from cromolyn and nedocromil and the corticosteriod is selected from beclomethasome, triamcinolone, flurisolide and dexamethasone.
50. The method of Claim 45 in which the disease is rheumatoid arthritis or conjunctivitis.
51. The method of Claim 50 in which the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula I in a pharmaceutically acceptable carrier suitable for topical administration.
52. The compound according to any one of Claims 30 to 42 or a composition according to Claim 43 when used in treating a disease in an animal in which tryptase activity contributes to the pathology and/or symptomatology of the disease.
53. The compound according to any one of Claims 30 to 42 or a composition according to Claim 43 for use in treating a disease in an animal in which tryptase activity contributes to the pathology and/or symptomatology of the disease
54. Use of a compound according to any one of claims 30 to 42 in the manufacture of a medicament for treating a disease in an animal in which tryptase activity contributes to the pathology and/or symptomatology of the disease. The method, compound, composition, or use according to any one of SClaims 30 to 54 wherein the condition treated is asthma, allergic rhinitis, rheumatoid spodylitis, osteoarthritis, gouty arthritis, rheumatoid arthritis, arthritic I:\DAYLIBlibc04346.doc conditions in general, urticaria, angloedema, eczematous dermatitis, anaphylaxis, hyper proliferative skin disease, peptic ulcers, inflammatory bowel disease, ocular and vernal conjunctivitis and inflammatory skin conditions.
56. A process for preparing a compound of Formula 1: in which: X 5 is (C 3 1 4)CYCloalkylene, hetero(C 314 )cycloa Ikylene, (C6- 14 )arylene or hetero(C 514 )arylene and X 4 and X 6 are independently (CO-2)alkylene or lo together are (02- 12 )alkylene or hetero(0 3 12 )alkylene; X 1 and X 9 are independently a covalent bond, -C(0)N(R 3 -N(R 3 -S(0) 2 N(R 3 -N(R 3 )S(0) 2 -00(0)N(R 3 -N(R 3 -N(R 3 )C(0)N(R 3 or wherein each R 3 is independently hydrogen, (Cl 1 3 )alkyl or (C3-8)cycloalkyl, with the proviso that X 1 and X 9 are not both covalent bonds; X 3 and X 7 are independently -C(O)N(R 3 -N(R 3 -S(0) 2 N(R 3 -N(R 3 )S(0) 2 -OC(0)N(R 3 -N(R 3 3 )C(0)N(R 3 or wherein R 3 is as defined above; X 2 and X 8 are independently (Ci..a)alkylene, hetero(0 1 8 )alkylene, -X 10 -X 11 or :20 -X 11 -X 10 wherein X 1 0 is (CO-4alkylene or hetero(C 3 4 )alkylene and X 1 1 is (C3-8)cycloalkylene or hetero(C 3 a)cycloaikylene; ~R 1 is R-X- or R 5 1 wherein: R 4 is amino, amidino, guanidino, 1-iminoethyl or methylamino, X 12 is (04.. 6 )alkylene, hetero(0 4 6 )alkylene, heteroOXO(C 4 6 )alkylene, OXO(C4-6)alkylene or -Xl 4 -XI 5 -Xl 6 wherein X 15 is (03-6)cycloalkylene, hetero(C 5 6 )arylene, hetero(C 3 -6)cycloalkylene or phenylene, X s(0fl14)alkylene and X s(0fl16)alkylene, wherein the sum of n14 and n16 is 0, 1, 2,3 or 4, Ris a group selected from azetidin-3-yl, benzoimidazol-4-yl, yl imidazol-1-yi, 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 -methylpiperid-3-yl, 1 -methylpiperid-4-yl, piperid-3-yl, piperid-4-yl, piperazin-1 -yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1 4 ,5,6-tetrahydropyrimidin-2-yl, I, 4 ,5,6-tetrahydropyrimidin-4-y and 1 4 ,5,6-tetrahydropyrimidin-5-..yI and any carbocyclic ketone or thioketone derivative thereof, which group is optionally substituted with one or more radicals selected R~ 1 rom halo, hydroxy, mercapto, (Ci. 8 )alkyl, (01)ylakl 0.1)al, (C6-14)aryl(C1 4)alkyl, (Ci -8)alkanoyl, (Ci.. 8 )alkyloxy, (C6..14)aryloxy, IMAYLI8Urbc04346.doc (0 3 1 4cycloalkyloxy, (Cl-4)alkyloxy, (0 1 8 )al kyith jo, (C 3 14 )cycloalIkylth io, (0 6 14 )arylthio and -NR R wherein R 6 and R 7 are independently selected from hydrogen, (Cli 8 )alkyl, (C 1 8 )alkanoyl, (0 3 1 4cycloalkyl or (C 6 14 )aryl and X 13 is (CO. 6 )alkylene, hetero(C 2 6 )alkylene, heterooxo(C 36 )alkylene, OXO(C 2 6 )alkylene or -Xl 7 -Xl 8 -Xl 9 wherein X 1 8 is as defined above for X 15 X 17 is (Cn 17 )alkylene and X 1 9 is (Cnl)alkylene, wherein the sum of n17 and n19 is 0, 1 or 2; and R 2 is R 8 _X 20 or R 9 _X 21 wherein: R 8 is amino, 1 -iminoethyl or methylamino, X 20 is (C 4 6 )alkylene, hetero(C 4 6 )alkylene, heterooxo(C 4 6 )alkylene, OXO(C 46 )alkylene or -X 22 -X 23 -X 24 wherein X 23 is as defined above for X 15 X 22 _iS (Cn 22 )alkylene and X 24 is (Cn 24 )alkylene, wherein the sum of n22 and n24 is 0, 1, 2, 3 or 4, with the proviso that when R 8 is amino then X 20 is not (C 4 6 )alkylene or OXO(C 4 6 )alkylene and n22 is not 1, 2, 3 or 4, R 9 is as defined above for R 5 and X 21 is (CO 06 )alkylene, hetero(C 26 )alkylene, heterooxo(0 36 )alkylene, OXO(C 26 )alkylene or -X 25 -X 26 -X 27 wherein X 26 is as defined above for X 15 X 25 is (Cn 25 )alkylene and X 27 is (Cn 27 )alkylene, wherein the sum of n25 and n27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene, as defined above, are optionally substituted with one or more radicals selected from halo, hydroxy, mercapto, (C 1 8 )alkyl, (0 3 14 )cycloalkyl, :(C 6 14 )aryl, (C 6 4 )aryl(C-4)alkyl, (C 1 8 )alkanoyl, (Cl 1 8 )alkyloxy, (C 6 14 )aryloxy, *000 (C 314 )cycloalkyloxy, (Ci.. 4 )alkyloxy, (CI- 8 )alkylthio, (C 3 14 )CYCloal kylthio, 0 O 25 (C 614 )arylthio and -NR R wherein R 6 and R 7 are as defined above; with the proviso that covalent bonds do not occur .0 between heteroatoms contained within X 2 X 4 X 6 X 8 and R 2 and any heteroatoms contained with X 3 X 5 X 7 and X 9 and 0 the pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected :0.00: derivatives thereof, which process comprises: *:600: 30 reacting a compound of Formula 1: R I-X 'X 2 X 3 1X 0. 1 or a protected derivative thereof, with a compound of the formula R 2 -y 9 -C(O or a protected derivative thereof, wherein L is a leaving group, Y 9 is a bond, or 3NR 3 X1is X2prainX3y, pierd4-y or, X6R)( 1 sakl repctvly7n each R 1 R R 3 ,XXXXXX and X 7 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula 1, ~IZ nwih X~s1,4-piperazinylene or I:UDayUb1LIBC104346.doc 1,4-piperidylene and X 9 is or -N(R 3 or in which X 8 is (Ci.8)alkylene and X 9 is -C(O)N(R 3 -OC(O)N(R 3 or reacting a compound of Formula 1, or a protected derivative thereof, with an isocyanate of the formula R 2 or a protected derivative thereof, and then deprotecting when necessary, to give a compound of Formula I in which X' is 1,4- piperazinylene or 1,4-piperidylene and X 9 is -NHC(O)- or in which X 8 is (C1.8)alkylene and X 9 is -NHC(O)N(R 3 reacting a compound of Formula 2: Y 2 -X 3 -X X R2-X9-X-X7-X6 2 or a protected derivative thereof, with a compound of the formula or a protected derivative thereof, wherein L is a leaving group, Y 1 is a bond, or -N(R 3 Y 2 is piperazin-1-yl, piperid-4-yl or HN(R 3 )-(Ci 8 )alkyl, respectively, and each R 2 R 3 X 3 X 4 X 5 X 6 X 7 X 8 and X 9 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I in which X 2 is 1,4-piperazinylene or S. 1,4-piperidylene and X 1 is or -N(R 3 or in which X 2 is 20 (Cl-8)alkylene and X 1 is -C(0)N(R 3 -OC(0)N(R 3 or reacting a compound of Formula 2, or a protected derivative thereof, with an isocyanate of the formula or a protected derivative thereof, and then deprotecting when necessary, to give a compound of Formula I in which X 2 is 1,4- piperazinylene or 25 1,4-piperidylene and X 1 is -NHC(O)- or in which X 2 is (C18)alkylene and X 1 is -NHC(0)N(R 3 reacting a compound of Formula 3: X 4 yX7-X6/ 3 or a protected derivative thereof, with 2 or more molar equivalents of a compound of the formula or a protected derivative thereof, wherein L is a leaving group, Y 1 is a bond, or -N(R 3 Y 2 and Y 8 are independently piperazin-1-yl, piperid-4-yl or HN(R 3 1 8 )alkyl and each R 2 X 3 X 4 X 5 X 6 and X 7 are as defined in the Summary of the Invention, and then deprotecting when necessary, to I:DAYLIBlibc\04346.doc give a compound of Formula I in which R 1 equals R 2 X 2 and/or X 8 is 1,4- piperazinylene or 1,4-piperidylene; X 1 is or -N(R 3 and X 9 is or -N(R 3 and/or in which X 2 and/or X 8 is (C1.8)alkylene; X 1 is -C(0)N(R 3 -OC(0)N(R 3 or -N(R 3 )C(O)N(R 3 and X 9 -C(O)N(R 3 -OC(O)N(R 3 or -N(R)C(O)N(R 3 reacting a compound of Formula 3, or a protected derivative thereof, with two or more molar equivalents of an isocyanate of the formula or a protected derivative thereof, and then deprotecting when necessary, to give a compound of Formula I in which R 1 equals R 2 X 2 and/or X 8 is 1,4-piperazinylene or 1,4-piperidylene; X 1 is -NHC(O)- and/or X 9 is -NHC(0)and/or in which X 2 and/or X 8 is (Cl.8)alkylene and X 1 is -NHC(0)N(R 3 and/or X 9 is -NHC(O)N(R 3 reacting an amine of the formula R 1 -N(R 3 or a protected derivative thereof, with a compound Formula 4: LC(O)-Y'-X 2 -X 3 -X 4 X 5 R2-X9-X -X7 X6 4 or a protected derivative thereof, wherein L is a leaving group, Y' is a bond, or -N(R 3 and each R 1 R R 3 X 2 X 3 X 4 X 5 X 6 X 7 X 8 and X 9 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a S 20 compound of Formula I in which X 1 is -N(R 3 -N(R 3 or -N(R 3 )C(O)N(R 3 S reacting a compound of the formula R 1 -X'-Y 2 or a protected derivative thereof, with a compound of Formula LC(O)-Y 3 -X 4 R2-X9-X-X7X6 7 or a protected derivative thereof, wherein L is a leaving group, Y is a bond, or -N(R 3 2 is piperazin-1-yl, piperid-4-yl or HN(R 3 8 )alkyl, respectively, and each R 1 R 2 R 3 X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 and X 9 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I in which X 2 is 1,4-piperazinylene or 4,1-piperidylene and X 3 is or -C(O)N(R 3 or in which X 2 is (C1-8)alkylene and X 3 is -N(R 3 -N(R 3 or reacting 2 or more molar equivalents of compound of the formula R'-Xl-Y 2 or a protected derivative thereof, with a compound of Formula 6: I:\DAYLIBcibc\04346.doc LC(O)- y3- LC(O)Y7-X6/ 6 or a protected derivative thereof, wherein L is a leaving group, Y 3 and Y 7 are independently a bond, or -N(R 3 Y 2 is piperazin-1-yl, piperid-4-yl, HN(R 3 (Cl_8)alkyl or HN(R 3 )-hetero(Cl.a)alkyl and each R 1 X 1 X 4 X 5 and X 6 are as defined in the Summary of the Invention, and then deprotecting when necessary, to give a compound of Formula I in which X 2 and X 8 each are 1,4-piperazinylene or 4,1- piperidylene and X 3 and X 7 are independently or -C(O)N(R 3 or in which X 2 and X 8 each are (C1 8 )alkylene or hetero(C1.8)alkylene and X 3 and X 2 are independently -N(R 3 -N(R 3 or -N(R 3 )C(O)N(R 3 respectively; optionally reacting a compound of Formula I in which R 4 is amino with cyanamide to give a compound of Formula I in which R 4 is guanidino; optionally further converting a compound of Formula I into a pharmaceutically acceptable salt; optionally further converting a salt form of a compound of Formula I to non-salt form; optionally further converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide; S 20 optionally further an N-oxide form of a compound of Formula I its unoxidized form; S* optionally further converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and optionally further converting a prodrug derivative of a compound of Formula I 25 to its non-derivatized form.
57. A process for preparing a compound of Formula I, said Formula as set out in claim 56, said process, substantially as hereinbefore described with reference to any one of the examples.
58. A compound prepared by the process according to claim 56 or claim 57. Dated 2 June 1999 ARRIS PHARMACEUTICAL CORPORATION Patent Attorneys for the Applicant/Nominated Person SPRUSON&FERGUSON I:\DAYLIBibc\04346.doc
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2313996P | 1996-07-30 | 1996-07-30 | |
| US60/023139 | 1996-07-30 | ||
| US89577297A | 1997-07-17 | 1997-07-17 | |
| US08/895772 | 1997-07-17 | ||
| PCT/US1997/013422 WO1998004537A1 (en) | 1996-07-30 | 1997-07-30 | Novel compounds and compositions for treating diseases associated with tryptase activity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU3967097A AU3967097A (en) | 1998-02-20 |
| AU733621B2 true AU733621B2 (en) | 2001-05-17 |
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| AU39670/97A Ceased AU733621B2 (en) | 1996-07-30 | 1997-07-30 | Novel compounds and compositions for treating diseases associated with tryptase activity |
Country Status (17)
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| EP (1) | EP0934293A1 (en) |
| JP (1) | JP2001509787A (en) |
| KR (1) | KR20000029679A (en) |
| CN (1) | CN1073103C (en) |
| AU (1) | AU733621B2 (en) |
| CA (1) | CA2262542A1 (en) |
| CZ (1) | CZ29799A3 (en) |
| EE (1) | EE9900036A (en) |
| FI (1) | FI990171A7 (en) |
| HU (1) | HUP0003267A3 (en) |
| LV (1) | LV12291B (en) |
| NO (1) | NO990433L (en) |
| NZ (1) | NZ333713A (en) |
| PL (1) | PL331465A1 (en) |
| SI (1) | SI9720047A (en) |
| SK (1) | SK8599A3 (en) |
| WO (1) | WO1998004537A1 (en) |
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| US6221914B1 (en) | 1997-11-10 | 2001-04-24 | Array Biopharma Inc. | Sulfonamide bridging compounds that inhibit tryptase activity |
| US6613769B1 (en) * | 1998-02-06 | 2003-09-02 | Max-Planck-Gesellschaft zur Föderung der Wissenschaften. e.V. | Tryptase inhibitors |
| AU2924699A (en) * | 1998-02-06 | 1999-08-23 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Tryptase inhibitors |
| WO2000014097A2 (en) * | 1998-09-04 | 2000-03-16 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Novel pyranoses |
| PL356170A1 (en) * | 1999-08-10 | 2004-06-14 | Altana Pharma Ag | Diazocin-dione derivatives and their use s tryptase inhibitors |
| US6960588B1 (en) | 1999-09-14 | 2005-11-01 | Altana Pharma Ag | Tryptase inhibitors |
| AU1413301A (en) * | 1999-11-17 | 2001-05-30 | Sumitomo Pharmaceuticals Company, Limited | Diabetic remedy containing dipiperazine derivative |
| DE19955476A1 (en) * | 1999-11-18 | 2001-05-23 | Boehringer Ingelheim Pharma | Bis-basic compounds as tryptase inhibitors, process for their preparation and their use as medicaments |
| SI1244643T1 (en) * | 1999-12-20 | 2004-12-31 | Altana Pharma Ag | Tryptase inhibitors |
| DE60011300T2 (en) | 1999-12-20 | 2005-08-04 | Altana Pharma Ag | INHIBITORS OF TRYPTASE |
| AU2002238522B8 (en) * | 2001-01-31 | 2007-01-18 | Altana Pharma Ag | Diazocine derivatives and their use as tryptase inhibitors |
| EP1368317B1 (en) | 2001-02-21 | 2006-12-27 | Altana Pharma AG | Tryptase inhibitors |
| ES2287268T3 (en) | 2001-02-21 | 2007-12-16 | Nycomed Gmbh | TRIPTASE INHIBITORS. |
| JP2004525926A (en) * | 2001-03-15 | 2004-08-26 | アルタナ ファルマ アクチエンゲゼルシャフト | Tryptase inhibitor |
| WO2002074732A2 (en) * | 2001-03-15 | 2002-09-26 | Altana Pharma Ag | Tryptase-inhibitors |
| US6818787B2 (en) | 2001-06-11 | 2004-11-16 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
| US7232924B2 (en) | 2001-06-11 | 2007-06-19 | Xenoport, Inc. | Methods for synthesis of acyloxyalkyl derivatives of GABA analogs |
| US8048917B2 (en) | 2005-04-06 | 2011-11-01 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
| US7186855B2 (en) | 2001-06-11 | 2007-03-06 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
| CN1533270A (en) | 2001-06-11 | 2004-09-29 | ʲŵ��������˾ | Oral administered dosage form of GABA anolog prodrugs having reduced toxicity |
| JP2005508871A (en) | 2001-06-19 | 2005-04-07 | アルタナ ファルマ アクチエンゲゼルシャフト | Tryptase inhibitor |
| AU2005301970B2 (en) | 2004-11-04 | 2011-06-02 | Arbor Pharmaceuticals, Llc | Gabapentin prodrug sustained release oral dosage forms |
| TWI432188B (en) | 2008-12-19 | 2014-04-01 | Merz Pharma Gmbh & Co Kgaa | 1-amino-alkylcyclohexane derivatives for the treatment of inflammatory skin diseases |
| BRPI0923377A2 (en) * | 2008-12-19 | 2015-07-21 | Merz Pharma Gmbh & Co Kgaa | 1-Aminoalkylcyclohexane derivatives for the treatment of mast cell mediated diseases |
| FR3038605B1 (en) | 2015-07-06 | 2018-08-24 | Universite Amiens Picardie Jules Verne | VICINAL PRIMARY DIAMINS ASSOCIATED WITH CHELATING MOTIFS OF METALS AND / OR FREE RADICALS, ACTIVE AGAINST CARBONYL AND OXIDIZING STRESSES AND THEIR USE |
| US12275687B2 (en) | 2017-05-12 | 2025-04-15 | Riken | Class A GPCR-binding compound modifier |
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| US4845242A (en) * | 1987-04-28 | 1989-07-04 | Georgia Tech Research Corporation | Isocoumarins with basic substituents as serine proteases inhibitors, anticoagulants and anti-inflammatory agents |
| JPH08507768A (en) * | 1993-03-12 | 1996-08-20 | アリス ファーマシューティカル コーポレイション | Compositions and methods for the treatment of immune-mediated inflammatory diseases |
| US5525623A (en) * | 1993-03-12 | 1996-06-11 | Arris Pharmaceutical Corporation | Compositions and methods for the treatment of immunomediated inflammatory disorders |
| JPH10501238A (en) * | 1994-06-01 | 1998-02-03 | アリス ファーマシューティカル コーポレイション | Compositions and methods for treating mast cell mediated conditions |
| US6022969A (en) * | 1994-09-23 | 2000-02-08 | Axys Pharmaceuticals, Inc. | Compositions and methods for treating mast-cell mediated conditions |
| NZ305626A (en) * | 1995-03-24 | 2000-01-28 | Axys Pharm Inc | Reversible protease inhibitors |
| TW438591B (en) * | 1995-06-07 | 2001-06-07 | Arris Pharm Corp | Reversible cysteine protease inhibitors |
-
1997
- 1997-07-30 FI FI990171A patent/FI990171A7/en unknown
- 1997-07-30 KR KR1019997000757A patent/KR20000029679A/en not_active Withdrawn
- 1997-07-30 AU AU39670/97A patent/AU733621B2/en not_active Ceased
- 1997-07-30 EE EEP199900036A patent/EE9900036A/en unknown
- 1997-07-30 CN CN97196877A patent/CN1073103C/en not_active Expired - Fee Related
- 1997-07-30 NZ NZ333713A patent/NZ333713A/en unknown
- 1997-07-30 CA CA002262542A patent/CA2262542A1/en not_active Abandoned
- 1997-07-30 HU HU0003267A patent/HUP0003267A3/en unknown
- 1997-07-30 JP JP50913698A patent/JP2001509787A/en active Pending
- 1997-07-30 SK SK85-99A patent/SK8599A3/en unknown
- 1997-07-30 PL PL97331465A patent/PL331465A1/en unknown
- 1997-07-30 WO PCT/US1997/013422 patent/WO1998004537A1/en not_active Application Discontinuation
- 1997-07-30 SI SI9720047A patent/SI9720047A/en unknown
- 1997-07-30 CZ CZ99297A patent/CZ29799A3/en unknown
- 1997-07-30 EP EP97937066A patent/EP0934293A1/en not_active Withdrawn
-
1999
- 1999-01-29 NO NO990433A patent/NO990433L/en not_active Application Discontinuation
- 1999-02-18 LV LVP-99-27A patent/LV12291B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CZ29799A3 (en) | 1999-06-16 |
| FI990171L (en) | 1999-03-23 |
| SI9720047A (en) | 1999-08-31 |
| FI990171A7 (en) | 1999-03-23 |
| CN1226892A (en) | 1999-08-25 |
| CA2262542A1 (en) | 1998-02-05 |
| NO990433D0 (en) | 1999-01-29 |
| FI990171A0 (en) | 1999-01-29 |
| EP0934293A1 (en) | 1999-08-11 |
| SK8599A3 (en) | 2000-03-13 |
| LV12291B (en) | 2000-04-20 |
| HUP0003267A2 (en) | 2001-06-28 |
| AU3967097A (en) | 1998-02-20 |
| NO990433L (en) | 1999-03-25 |
| LV12291A (en) | 1999-06-20 |
| JP2001509787A (en) | 2001-07-24 |
| EE9900036A (en) | 1999-08-16 |
| KR20000029679A (en) | 2000-05-25 |
| NZ333713A (en) | 2000-12-22 |
| HUP0003267A3 (en) | 2002-02-28 |
| PL331465A1 (en) | 1999-07-19 |
| WO1998004537A1 (en) | 1998-02-05 |
| CN1073103C (en) | 2001-10-17 |
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