CZ29799A3 - Disubstituted cyclic compound, process of its preparation, pharmaceutical composition containing thereof and method of treating disease of animal - Google Patents

Abstract

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

Description

A disubstituted cyclic compound, a process for its manufacture, a pharmaceutical composition and a method for treating an animal disease

Technical field

The present invention relates to a disubstituted cyclic compound, to a process for its preparation, to a pharmaceutical composition, and to a method of treating an animal disease that is related to tryptase activity by administering novel trypsin inhibitors.

BACKGROUND OF THE INVENTION

Tryptase, the predominant protease secreted from human mast cells, is believed to be involved in the processing of neuropeptides and tissue inflammations. Tryptase concentrations are elevated in the bloodstream several hours after anaphylaxis [Schwartz et al., N. Eng. J. Med. 1987, 316, 1622-1626.], Are elevated in nasal and pulmonary lavage fluid from atopic subjects after treatment with a specific antigen [Castells et al., J. Allerg. Clin. Immunol. 1988, 141, 563-568.] And are elevated in the lung lavage fluid of atopic asthmatics following endobronchial administration of the allergen. Smokers often have markedly elevated tryptase levels in bronchoalveolar lavage fluid, a finding that supports the hypothesis that proteinase release from activated mast cells could contribute to lung destruction in smoking emphysema [Celenteron et al., Chest 1988, 94, 119-123 .]. In addition, tryptase has been shown to be a potent mitogen for fibroblasts, indicating that it is involved in pulmonary fibrosis and interstitial lung disease [Rose et al., J. Clin. Invest. 1991, 88, 493-499.].

Asthma is considered an inflammatory disorder [Hood et al .: in Immunology, Second Edition, Benjamin-Cummings (ed.), 1984.] and is often characterized as the progressive development of trachea and bronchial hyperresponsions to both immunospecific allergens and generally chemical and physical stimuli . The disease involves multiple biochemical mediators in both acute and chronic •

«· States. The hyperresponsiveness of asthmatic bronchial tissue is believed to be the result of chronic inflammatory reactions that irritate and damage the epithelial lining of airway walls and promote the pathological thickening of underlying tissue. Bronchial biopsy of patients with mild asthma only has signs of inflammation in the airway walls.

Allergic responses to inhaled allergens may initiate an inflammatory series. For example, allergens may activate mast cells and basophilic granulocytes that are present in the epithelium and underlying smooth muscle tissue by binding to IgE located on the cell surface. Activated mast cells release numerous, pre-formed or primary chemical mediators (eg, histamine) of the inflammatory response and generate numerous other secondary mediators of inflammation (eg, hyperoxide, fat-derived mediators, etc.) in situ. In addition, some large molecules (eg, proteoglycans, tryptase, chymase, etc.) are released by mast cell degranulation.

The release of these preformed mast cell mediators is possibly the cause of early bronchial constriction of the asthmatic response to airborne allergens. The early phase reaches a maximum asthmatic response approximately 15 minutes after exposure to allergens, and is usually followed by regeneration after one to two hours. 25 to 35 percent of the patient population has experience of further reducing respiratory function, with a maximum of six to twelve hours after exposure to allergens. This late reaction phase is accompanied by a significant increase in the number of inflammatory cells (eg eosinophils, neutrophils, lymphocytes, etc.) infiltrating bronchial tissue. Infiltrating cells are attracted to this site by release of mast cell-derived chemoactic agents and then activated during the late reaction phase. The late asthmatic response is believed to be a secondary inflammatory response mediated in part by granulocyte secretory activity.

Tryptase is associated with degradation of vasodilatory and bronchorelaxant neuropeptides [Caughey et al., J. Pharmacol.

Exp. Ter., 1988, 244, 133-137; Franconi et al., J. Pharmacol. Exp. Ther., 1988, 248, 947-951, and Tam et al., Am. J. Respir. Cell Mol. Biol. 1990, 3, 27-32.] And by modulating the bronchial response to histamine [Sekizawa et al., J. Clin. Invest. 1989, 83, 175-179.]. These findings suggest that tryptase can enhance bronchoconstriction in asthma by destroying bronchodilator peptides. Tryptase cleaves the high molecular weight α-chains of fibrinogen and kinninogen, suggesting that tryptase plays a role in heparin as a local anticoagulant. Tryptase activates postromelysin (pro-MMP-3) and procollagenase (pro-MMP-1) via MMP-3, suggesting that tryptase is associated with tissue inflammation and remodeling and joint destruction in rheumatoid arthritis. Tryptase inhibitor administration protects against the development of late and aerial hyperresponsive phase in allergen-treated sheep [Clark et al., Am. J. Respir. Crit. Care Med. 1995, 152, 2076-2083.] And inhibits the immediate skin response to intradermal injection of allergen in allergic sheep [Molinari et al .: Amer. Physiol. Soc. 1995, 79 (6), 1966-9

1970.]. All of the above findings clearly demonstrate the applicability of tryptase inhibitors as therapeutic agents in the treatment of asthma and other diseases associated with inflammation of the respiratory tract.

A description of these and other documents referred to in this application is incorporated herein by reference.

SUMMARY OF THE INVENTION

The present application relates to a disubstituted cyclic compound of formula I

R ¹ -X ¹ -X ² -X ³ -X ⁴ \ ₅

X ⁵ (I), r ² -x ⁹ -x ®-x ⁷ -x ^ wherein

X ⁵ represents C 3 -C 14 cycloalkylene, hetero

C 3 -C 14 cycloalkylene, C 6 -C 14 arylene or C 5 -C 14 heteroarylene,

X ⁴ and X ⁶ independently represent alkylene of 0 to 2 carbon atoms, X ¹ and X ⁹ independently represent a covalent bond, a group

-C (O) -, -C (O) O-, -OC (O) -, -C (O) N (R ³ ) -, -N (R ³ ) C (O) -, -

-S (O ₂ ) N (R ³ ) -, -N (R ³ ) S (O) ₂ -, -OC (O) N (R ³ ) -, -N (R ³ ) C (O) O- ,

-N (R ³ ) C (O) N (R ³ ) - or -OC (O) O-, wherein each R ^{3 is} independently hydrogen, C 1 -C 3 alkyl or C 3 -C 8 cycloalkyl; in that both X ¹ and X ^{9 are} not covalent bonds,

X ³ and X ⁷ independently represent -C (O) -, -C (O) O-,

-OC (O) -, -C (O) N (R ³ ) -, -N (R ³ ) C (O) -, -S (O 2) N (R ³ ) -, -N (R ³ ) S (O) 2 ~,

-OC (O) N (R ³ ) -, -N (R ³ ) C (O) O-, -N (R ³ ) C (O) N (R ³ ) - or -OC (O) O-, where R ³ is as defined above,

X ² and X ⁸ independently represent C 1 -C 8 alkylene, C 1 -C 8 heteroalkylene, -X ¹⁰ -X ¹¹ - or -X ¹¹ -X ¹⁰ -, wherein X ¹⁰ is C 1-4 alkylene C 3 -C 4 heteroalkylene and X ¹¹ is C 3 -C 8 cycloalkylene or C 3 -C 8 heterocycloalkylene,

R ¹ represents a group R ⁴ -X ¹² - or R ⁵ -X ¹³ - in which

R ⁴ represents an amino, amidine, guanidine, 1-iminoethyl or methylamine group,

X ¹² is C 4 -C 6 alkylene, C 4 -C 6 heteroalkylene, C 4 -C 6 heterooxoalkylene, C 4 -C 6 oxoalkylene or -X ¹⁴ -X ¹⁵ -X ¹⁶ -, wherein X ¹⁵ means cycloalkylene having 3 to 6 carbon atoms and heteroarylene having 5-6 carbon atoms, heterocycloalkylene having 3 to 6 carbon atoms or phenylene, X ¹⁴ represents alkylene I4 carbon atoms; and X ¹⁶ represents alkylene NL6 carbon atoms wherein the sum of NL4 and NL6 means 0, 1, 2, 3 or 4,

R ⁵ represents a group selected from azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-methylpiperid-3-yl, 1-methylpiperid-4-yl, piperidine- 3-yl, piperid-4-yl, piperazin-1-yl, piperazin-2-yl, pyrazole 3-yl, pyrid-4-yl, pyrimidin-4-yl, pyrimidin-5 -yl, pyrrolidin-3-yl, 1,4,5,6-tetrahydropyrimidin-2-yl, 1,4,5,6-tetrahydropyrimidin-4-yl, 1,4,5,6-tetrahydropyrimidin-5-yl and any carbocyclic ketone or thioketone derivative thereof, the group of which is optionally substituted with one or more groups selected from halogen, hydroxyl, mercapto, C 1 -C 8 alkyl, C 3 -C 14 cycloalkyl, C 6 aryl and C 14 alkyl, C 1 -C 4 aryl (C 1 -C 4) alkyl, C 1 -C 8 alkanoyl, C 1 -C 8 alkyloxy, C 6 -C 14 aryloxy, C 3 -C 14 cycloalkyloxy carbon atoms, C 1 -C 4 alkyloxy, C 1 -C 8 alkylthio, C 3 -C 14 cycloalkylthio, C 6 -C 14 arylthio and -NR ⁶ R ⁷ in which R ⁶ and R ⁷ are independently selected from hydrogen, alkyl of 1 to 8 carbon atoms, alkanoyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 14 carbon atoms or aryl of 6 to 14 carbon atoms, and

X ¹³ represents alkylene of 0-6 carbon atoms, heteroalkylene of 2-6 carbon atoms, heterooxoalkylene of 3-6 carbon atoms, oxoalkylene of 2-6 carbon atoms, or a group -X ¹⁷ -X ¹⁸ -X ¹⁹ - in which X ¹⁸ is as previously defined for X ^15, X ¹⁷ represents -alkylene with NL7 carbon atoms, and X ¹⁸ represents a nl8 -alkylene carbon atoms, wherein the sum NL7 nl8 and is 0, 1 or 2 and R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ - in which:

R ⁸ represents an amino, 1-iminoethyl or methylamine group,

X ²⁰ is C 4 -C 6 alkylene, C 4 -C 6 heteroalkylene, C 4 -C 6 heterooxoalkylene, C 4 -C 6 oxoalkylene or -X ²² -X ²³ -X ²⁴ - in which X ²³ is as defined above for X ¹⁵ , X ²² is alkylene of n 22 carbon atoms and X ²⁴ is alkyne of n 24 carbon atoms, wherein the sum of n22 and n24 is 0, 1, 2, 3 or 4, provided that if R ⁸ is amino, then X is not ²² alkylene having 4-6 carbon atoms or oxaalkylene having 4 to 6 carbon atoms and n22 is not 1, 2, 3 or 4,

R ⁹ means as above for R ⁵ and

X ²¹ represents alkylene of 0-6 carbon atoms, heteroalkylene of 2-6 carbon atoms, heterooxoalkylene of 3-6 carbon atoms, oxoalkylene of 2-6 carbon atoms, or the group -X ²⁵ -X ²⁶ -X ²⁷ - in which X ²⁶ is as previously defined for X ^15, X ²⁵ represents alkylene N25 carbon atoms, and X ²⁷ represents alkylene N27 carbon atoms, wherein the sum of n25 and n27 is 0, 1 or 2, wherein each of the above alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene is optionally substituted with one or more groups selected from halogen, hydroxyl, mercapto, C 1 -C 8 alkyl, C 3 -C 14 cycloalkyl, C 6 -C 14 aryl, aryl (C 6 -C 14) alkyl of 1 to 4 carbon atoms, C 1 -C 8 alkanoyl, C 1 -C 8 alkyloxy, C 6 -C 14 aryloxy, C 3 -C 14 cycloalkyloxy 1 to 4 at carbon atoms, C 1 -C 8 alkylthio, C 3 -C 14 cycloalkylthio, C 6 -C 14 arylthio and -NR ⁶ R ⁷ in which R ⁶ and R ⁷ are as defined above, provided that between the heteroatoms contained in R ¹ , X ² , X ⁴ , X ⁶ , X ⁸ and R ² and any heteroatoms in X ³ , X ⁵ , X ⁷ and X ⁹ do not present a covalent bond, and pharmaceutically acceptable salts thereof, the N-oxide, prodrug derivatives and protected derivatives.

A second aspect of the present invention relates to a disubstituted cyclic compound of formula I

R ¹ -X ¹ -X ² -X ³ -X ⁴ \ ₅

X ⁵ (I)

R ² -X ⁹ -X ⁸ -X ⁷ -X ^ wherein

X ⁴ -X ⁵ -X ⁶ together represent alkylene of 2 to 12 carbon atoms or heteroalkylene of 3 to 12 carbon atoms,

X ¹ and X ⁹ independently represent a covalent bond, -C (O) -, -C (O) O-, -OC (O) -, -C (O) N (R ³ ) -, -N (R ³⁾ IC (O) -, a group

-S (O ₂ ) N (R ³ ) -, -N (R ³ ) S (O) ₂ -, -OC (O) N (R ³ ) -, -N (R ³ ) C (O) 0 - , • · · 0

• 0 · · · · · · · · · · · · · · · · · · · · · · ·

0 0 0 0 ·

-N (R ³ ) C (O) N (R ³ ) - or -OC (O) O-, wherein each R ^{3 is} independently hydrogen, C 1 -C 3 alkyl or C 3 -C 8 cycloalkyl in that both X ¹ and X ^{9 are} not covalent bonds,

X ³ and X ⁷ independently represent -C (O) -, -C (O) O-,

-OC (O) -, -C (O) N (R ³ ) -, -N (R ³ ) C (O) -, -S (O 2) N (R ³ ) -, -N (R ³ ) S (O) 2 ~,

-OC (O) N (R ³⁾ -, -N (R ³⁾ C (O) O-, -N (R ³⁾ C (O) N (R ³⁾ - or -OC (O) O-, where R ³ is as defined above,

X ² and X ⁸ independently represent C 1 -C 8 alkylene, C 1 -C 8 heteroalkylene, -X ¹⁰ -X ¹¹ - or -X ¹¹ -X ¹⁰ -, wherein X ¹⁰ is C 1-4 alkylene C 3 -C 4 heteroalkylene and X ¹¹ is C 3 -C 8 cycloalkylene or C 3 -C 8 heterocycloalkylene,

R ¹ represents a group R ⁴ -X ¹² - or R ⁵ -X ¹³ -, wherein

R ⁴ represents an amino, amidine, guanidine, 1-iminoethyl or methylamine group,

X ¹² is C 4 -C 6 alkylene, C 4 -C 6 heteroalkylene, C 4 -C 6 heterooxoalkylene, C 4 -C 6 oxoalkylene or -X ¹⁴ -X ¹⁵ -X ¹⁶ -, wherein X ¹⁵ means cycloalkylene having 3 to 6 carbon atoms and heteroarylene having 5-6 carbon atoms, heterocycloalkylene having 3 to 6 carbon atoms or phenylene, X ¹⁴ represents alkylene I4 carbon atoms; and X ¹⁶ represents alkylene NL6 carbon atoms, wherein the sum of NL4 and n16 is 0, 1, 2, 3 or 4

R ⁵ represents a group selected from azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-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- 1,4,5,6-tetrahydropyrimidin-4-yl, 1,4,5,6-tetrahydropyrimidin-4-yl, 1,4,5,6-tetrahydropyrimidin-5-yl, and any carbocyclic ketone or thioketone thereof a derivative whose group is optionally substituted by one or more groups selected from a halogen atom, a hydroxyl, a group or a hydroxyl group;

C 1 -C 8 alkyl, C 1 -C 4 cycloalkyl, C 6 -C 14 aryl, C 1 -C 4 aryl (C 1 -C 4) alkyl, C 1 -C 8 alkanoyl , (C 1 -C 8) alkyloxy, (C 6 -C 14) aryloxy, (C 3 -C 14) cycloalkyloxy, (C 1 -C 4) alkyloxy, (C 1 -C 8) alkylthio, (C 3 -C 14) cycloalkylthio, arylthio 6 to 14 carbon atoms, and -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are independently selected from hydrogen, alkyl of 1-8 carbon atoms, alkanoyl of 1-8 carbon atoms, cycloalkyl of 3 to C 14 or C 6 -C 14 aryl;

X ¹³ represents alkylene of 0-6 carbon atoms, heteroalkylene of 2-6 carbon atoms, heterooxoalkylene of 3-6 carbon atoms, oxoalkylene of 2-6 carbon atoms, or a group -X ¹⁷ -X ¹⁸ -X ¹⁹ - in which X ¹⁸ is as above for X ¹⁵ , X ¹⁷ is alkylene of n 17 carbon atoms and X ¹⁹ is alkylene of n 18 carbon atoms, wherein the sum of n 17 and n 18 is 0, 1 or 2, and R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ - in which:

R ⁸ is as above for R ⁴ ,

X ²⁰ is C 4 -C 6 alkylene, C 4 -C 6 heteroalkylene, C 4 -C 6 heterooxoalkylene, C 4 -C 6 oxoalkylene or -X ²² -X ²³ -X ²⁴ - in which X ²³ is as defined above for X ¹⁵ , X ²² is alkylene with n 22 carbon atoms and X ²⁴ is alkylene with n 24 carbon atoms, wherein the sum of n 22 and n 24 is 0, 1, 2, 3 or 4,

R ⁹ is as above for R ^5a

X ²¹ represents alkylene of 0-6 carbon atoms, heteroalkylene of 2-6 carbon atoms, heterooxoalkylene of 3-6 carbon atoms, oxoalkylene of 2-6 carbon atoms, or a group -X ²⁵ -X ²⁶ -X ²⁷ - in which X ²⁶ is as previously defined for X ^15, X ²⁵ represents alkylene N25 carbon atoms, and X ²⁷ represents alkylene N27 carbon atoms, wherein the sum of n25 and n27 is 0, 1 or 2, wherein each of the above alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene is optionally substituted with one or more groups selected from halogen, hydroxyl, mercapto, alkyl of 1 to 8

carbon atoms, cycloalkyl of 3 to 14 carbon atoms, aryl of 6 to 14 carbon atoms, aryl (of 6 to 14 carbon atoms) alkyl of 1 to 4 carbon atoms, alkanoyl of 1 to 8 carbon atoms, alkyloxy groups of 1 to 8 atoms carbon, aryloxy of 6 to 14 carbon atoms, cycloalkyloxy of 3 to 14 carbon atoms, alkyloxy of 1 to 4 carbon atoms, alkylthio of 1 to 8 carbon atoms, cycloalkylthio of 3 to 14 carbon atoms, arylthio of 6 to 14 carbon atoms and -NR ⁶ R ⁷ in which R ⁶ and R ⁷ are as defined above, provided that between the heteroatoms contained in R ¹ , X ² , X ⁴ , X ⁶ , X ⁸ and R ² and any heteroatoms in X ³ , X ⁵ , X ⁷ and X ⁹ do not have a covalent bond, and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.

A third aspect of the invention relates to a pharmaceutical composition comprising a disubstituted cyclic 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 the invention relates to a method of treating an animal disease in which tryptase activity contributes to the pathology and / or symptomatology of the disease, comprising administering a therapeutically effective amount of a disubstituted cyclic compound of formula I or a pharmaceutically acceptable salt, N-oxide or prodrug derivative thereof this animal.

A fifth aspect of the invention relates to a process for preparing the disubstituted cyclic compounds of formula I and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof as set forth in the following detailed description of the invention.

Unless otherwise indicated, the following terms in the file and claims have the meanings indicated:

• * · ·

Alkanoyl means a -C (O) R group in which R is an alkyl group having the total number of carbon atoms listed below (e.g., C 1 -C 8 alkanoyl includes formyl, acetyl, propionyl, butyryl, isobutyryl, crotonoyl, isocrotonoyl, etc. group).

Alkyl, such as alkyl, arylalkyl, alkyloxy and alkylthio, means a straight or branched, saturated or unsaturated hydrocarbon group having the indicated number of carbon atoms (e.g., alkyl of 1 to 8 carbon atoms includes methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl, 2-propyl, etc. group).

Alkylene means a straight, saturated or unsaturated hydrocarbon divalent group having the specified number of carbon atoms (e.g., alkylene of 0-6 carbon atoms includes methylene (-CH ₂ -), ethylene (- (CH ₂ ) ₂ -), vinylene (-CH = CH-), ethinylene (~ C = C-), 2-propylene (-CH = CH-CH ₂ ), 1-propylene (-CH ₂ -CH = CH-), tetramethylene (- (CH ₂ ) ₄ -) , pentamethylene (- (CH ₂ ) ₅ -), hexamethylene (- (CH ₂ ) ₆ -), etc.). The term alkylene having 0 carbon atoms means a covalent bond.

Alkyloxy means a -OR group in which R is the above-mentioned alkyl having the specified number of carbon atoms (e.g., C 1 -C 8 alkyloxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy etc. groups).

Alkylthio means a -SR group in which R is the above-mentioned alkyl having the specified number of carbon atoms (e.g., alkyl of 1 to 8 carbon atoms includes methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio etc. groups).

The animal includes non-human mammals (eg, dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, etc.) and non-mammal animals (eg, birds, etc.).

• · ·

Aryl, such as aryl, arylalkyl, aryloxy and arylthio, means an aromatic monocyclic or polycyclic hydrocarbon group having the specified number of carbon atoms, wherein the free valence carbon atom is a member of the aromatic ring, and any carbocyclic ketone or thioketone derivative thereof (e.g. (C až-C patří) include phenyl, naphthyl, anthracenyl, phenanthrenyl, 1,2,3,4-tetrahydronaphth-5-yl, 1-oxo-1,2-dihydronaphth-6-yl, 1-thioxo-l, 2-dihydronaphth-7-yl, etc.).

Arylene means an aromatic monocyclic or polycyclic hydrocarbon divalent group having the specified number of carbon atoms, wherein the free valence carbon atoms are members of the aromatic ring, and any carbocyclic ketone or thioketone derivative thereof (eg, a 6 to 14 carbon 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, 1-oxo-1,2-dihydro-5,7-naphthylene, 1-thioxo-1,2-dihydro-5,8-naphthylene, etc.) .

Aryloxy means an -OR group in which R is the above aryl, with the specified number of carbon atoms (eg, aryloxy of 6 to 14 carbon atoms include phenoxy, naphthyloxy, anthracenyloxy, etc.).

Arylthio means a -SR group in which R is the above aryl with the specified number of carbon atoms (eg, arylthio groups of 6 to 14 carbon atoms include phenylthio, naphthylthio, anthracenylthio, etc.).

Cycloalkyl, as in cycloalkyl and cycloalkyloxy, means a saturated or unsaturated, monocyclic or polycyclic hydrocarbon group containing the specified number of carbon atoms, wherein the free valence carbon atom is a member of a non-aromatic ring and any carbocyclic ketone and thioketone derivative thereof (e.g. C 3 to C 14 atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-diooxocyclohexadienyl, 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 divalent group having the specified number of carbon atoms, wherein the free valence carbon atoms are members of the non-aromatic ring and any carbocyclic ketone and thioketone derivative thereof (e.g., cycloalkylene of 3 to 6 carbon atoms) , 2-cyclopropylene, 1,2-cyclobutylene, 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 , 2,5-dioxo-1,4-cyclohexylene, 5-thioxo-1,4-cyclohexylene, etc.).

Cycloalkyloxy means an -OR group in which R is the above-mentioned cycloalkyl with the specified number of carbon atoms (e.g., C 3 -C 14 cycloalkyloxy includes cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc.).

"Cycloalkylthio" means -SR in which R is the above cycloalkyl with the specified number of carbon atoms (eg, C 3 -C 14 cycloalkylthio includes cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc.).

Removal of a protecting group means removal of any protecting groups present after the selective reaction has been carried out.

The disease specifically encompasses any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused or caused by accidental medical or veterinary therapy applied to the animal, i.e., side effects of such therapy.

Haloegne atom means fluorine, chlorine, iodine.

or bromine

Heteroalkylene means the above-mentioned alkylene in which 1 to 5 of said carbon atoms are replaced by a heteroatom selected from nitrogen, oxygen or sulfur (e.g., azaalkylene, oxaalkylene and thiaalkylene) provided that the oxygen, nitrogen and sulfur atoms contained therein do not form bonds with other heteroatoms. For example, heteroalkylene having from 3 to 12 carbon atoms is meant to include azaalkylene 3 carbon atoms, which includes 3-azatrimethylene (-NH-CH ₂ -CH ₂ -), 2-azatrimethylene _(-CH2 .NH.CH ₂ -), etc. C 2 -C 5 azaalkylene comprising 2-azaethylene (-NH-CH ₂ -), 3-azatrimethylene, 4-azatetramethylene (-NH.CH ₂ .CH ₂ .CH ₂ -) and 5- azapentamethylen (-NH.CH ₂ .CH ₂ .CH ₂ .CH ₂ -), oxaalkylene 3 carbon atoms, which comprises 3-oxatrimethylen (-0.CH ₂ .CH ₂ -), 2-oxatrimethylen (-CH _second O.CH ₂ -), etc., oxaalkylene having 5 carbon atoms such as 3-oxapentamethylene (-CH ₂ .CH ₂ .CH ₂ .O.CH ₂ -), etc., thiaalkylen 3 carbon atoms, which comprises 3- thiatrimethylene (-S.CH ₂ .CH ₂ -), 2-thiatrimethylene (-CH ₂ .S.CH ₂ -) etc., ω-thiaalkylene of 2 to 4 carbon atoms, which includes 2-thiaethylene (-NH.CH ₂ -), 3-thiatrimethylene and 4-thiatetramethylene (-S.CH ₂ .CH ₂ --CH ₂ -), a 6-carbon diazaalkylene that includes 2,5-diazahexamethylene (-CH ₂ .NH.CH ₂ .CH ₂ .NH.CH ₂ -), azaoxaalkylene of 6 carbon atoms which includes 2-oxa-5-azahexamethylene (-CH ₂ O.CH ₂ .CH ₂ .NH.CH ₂ -) and the like.

Heteroarylene means the above-mentioned arylene wherein 1 to 5 of said carbon atoms are replaced by a heteroatom selected from nitrogen, oxygen or sulfur (eg, 5 to 6 carbon heteroarylene includes furylene, thienylene, pyrrolylene, imidazolylene, pyridylene, etc.).

Heterocycloalkylene means the above-mentioned cycloalkylene wherein 1 to 5 of said carbon atoms are replaced by a heteroatom selected from nitrogen, oxygen or sulfur (e.g., a C 3 -C 14 heterocycloalkylene includes 2,4-pyrrolidinylene,

2,4-pyrrolinylene, 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.).

Heterooxoalkylene means the above alkylene wherein one of said carbon atoms is replaced by a heteroatom selected from nitrogen, oxygen or sulfur and the carbon adjacent to the heteroatom is replaced by a carbonyl group (C = O), e.g., azaoxoalkylene, oxaoxoalkylene and thiaoxoalkylene, that oxygen, nitrogen and sulfur atoms contained therein do not form bonds with other heteroatoms. For example, C 4 -C 6 heterooxoalkylene is meant to include 3-carbon azaoxoalkylene, including 2-aza-3-oxotrimethylene (-C (O). NH ₂ CH ₂ -), 3-aza-2- oxotrimethylene (-NH.C (O) .CH ₂ -) etc., oxooxoalkylene of 3 carbon atoms, including 2-oxa-3-oxotrimethylene (-C (O) .O.CH ₂ -), 3-oxa -2-oxotrimethylene (-OC (O) .CH ₂ -) etc., and 3-carbon-thiaoxoalkylene, including 2-thia-3-oxotrimethylene (-C (O) .S.CH ₂ -), 3 thia-2-oxotrimethylene (-S-C (O) .CH ₂ -), etc.

The leaving group has the meaning conventionally associated with this meaning in synthetic organic chemistry, i.e., is an atom or a group substitutable under alkylation conditions, and includes a halogen atom, a hydroxyl group, an alkylsulfonyloxy group (e.g., mesyloxy, ethanesulfonyloxy, etc.), arylsulfonyloxy (e.g. benzenesulfonyloxy, tosyloxy and thienyloxy), dihalophosphinoyloxy, tetrahalophosphoxy and the like.

Optionally or optionally means that the event or circumstance described below may or may not occur, and that the description includes examples in which the event or circumstance occurs and examples in which it does not. For example, the term optionally substituted with one or more groups means that the group referred to may or may not be substituted to fall within the scope of the invention.

Pharmaceutically acceptable N-oxide means a compound in which the nitrogen atoms are in an oxidized state (i.e., 0 <-N), which is · · · · ♦, · · · · · It is pharmaceutically acceptable, as set forth below, and which has the desired pharmacological activity. The N-oxides of the disubstituted cyclic compounds of formula (I) may be prepared by methods known to those skilled in the art.

Oxoalkylene means the above-mentioned alkylene in which one of said carbon atoms is replaced by a carbonyl group (C = O), eg, a 3-carbon oxoalkylene comprises 3-oxotrimethylene (-C (O) .CH ₂ .CH ₂ -), etc. .

The pathology of the disease means the underlying natural causes and development of the disease as well as the structural and functional changes that result from the disease process.

Pharmaceutically acceptable means that it is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic, neither biologically nor otherwise undesirable, and includes such composition that is acceptable for veterinary use as well as for human pharmaceutical use.

Pharmaceutically acceptable salts means salts which are pharmaceutically acceptable as described above and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric and the like, or with organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, p-chlorobenzenesulfonic, cinnamon, citric, cyclopetanpropionic, 1,2-ethanedisulfonic, ethanesulfonic, fumaric, glucoheptane, gluconic, glutamic, glycolic, hexane, heptane, o- (4-hydroxybenzoylbenzoic, 2-hydroxyethanesulfonic, hydroxynaphthalic, lactic, laurylsulfonic, maleic, maleic, , methanesulfonic, 4-methylbicyclo [2.2.2] oct-2-ene-1-carboxylic, 4,4'-methylenebis (3-hydroxy-2-ene-1-carboxylic), muconic,

2-Naphthalenesulfonic, oxalic, 3-phenylpropionic, propionic, pyruvic, scicylic, stearic, succinic, tartaric, tert-butylacetic, p-toluenesulfonic, trimethylacetic acid and the like.

·· ··

· · · · · · · · · · · · · · · · · · · ·

Pharmaceutically acceptable salts also include base addition salts which may be formed when the acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like.

Phenylene means a divalent aromatic group -C ₆ H ₄ - and includes 1,4-phenylene, 1,3-phenylene and the like.

Pharmaceutically acceptable prodrug derivatives are derivatives of the disubstituted cyclic compounds of formula (I) which are pharmaceutically acceptable as described above and which are converted in vivo to the corresponding non-derivatized form of the disubstituted cyclic compound of formula (I).

Such prodrugs include disubstituted cyclic compounds of Formula I having N-acylated piperidyl (i.e. (P) C ₅ H ₉ -), N-acylated azalkylene (eg, -N (P) .CH ₂ --CH ₂ -) , An N-acylated amino group (i.e., -NH ₂ (P)), an N-acylated amidine group (i.e., -C (NP). NHP, -C (NH). NHP or -C (NP). NH ₂ ) , An N-acylated guanidine group (ie -NHC (NP). NHP, -NH.C (NH). NHP or -NH.C (NP), NH ₂ , wherein P is a group selected from -C (O) R ¹⁰ , wherein R ¹⁰ may be C ¹ -C 10 alkyloxy or cis-2-alkanoyloxy (C 1 -C 10) phenylvinyl, 3-alkanoyl (C 1 -C 10) oxybutyryl, R ¹¹ - X ²⁸ -, wherein R ¹¹ is carboxy and X ²⁸ is C 1 -C 10 alkylene or -C (O) .O.CH (R ¹² ), OC (O) R ¹³ , wherein R ¹² is hydrogen , an alkyl group of up to 10 carbon atoms or a cycloalkyl group of 3 to 10 carbon atoms and R ¹³ is an alkyl group of 1 to 10 carbon atoms; my carbon.

The protecting group has the conventional meaning associated with it in the field of synthetic organic chemistry, ie it means a group that selectively blocks one reaction site of a multifunctional compound so that the chemical reaction can take place selectively on another unprotected reaction site and which is readily removed upon completion of the selective reaction.

Protecting agent means one that reacts with a multifunctional compound and that burns out a protecting group at the reaction site.

Protected derivatives in reference to a compound or group mean a derivative of a compound or group in which the reactive site or reactive sites are blocked by protecting groups. Protected derivatives of the compounds of formula I are themselves active as tryptase inhibitors and are useful in the preparation of other disubstituted cyclic compounds of formula I. Suitable protecting groups for reactive nitrogen atoms include a target. butoxycarbonyl, benzyloxycarbonyl, and other suitable amine protecting groups (e.g., see T. W. Greene: Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., 1981).

Symptomatology of a disease means any disease phenomenon or deviation from normal in the structure, function, or sensation a patient has and indicating the disease, its onset and its acquisition.

A therapeutically effective amount means that the amount administered to the animal for treating the disease is sufficient to effect treatment of the disease.

The treatment or treatment of a disease includes both preventing the occurrence of the disease in an animal having it available for such disease but not yet having or showing symptoms of the disease, inhibiting the disease (ie, arresting its development) or reducing the disease (ie, causing disease regression).

The concept of q.s. means adding sufficient quantity to achieve the specified function, eg adjusting the solution to the desired volume • ·

(i.e., 100%).

The disubstituted cyclic compounds of formula (I), intermediates and starting materials used in their preparation are named according to IUPAC nomenclature rules, in which the characteristic groups have a decreasing priority for listing the following main groups: acids, esters, amides and amidines. Further, for the purposes of this application, when referring to a divalent group by a written description, the order of the numeral prepositions indicates the orientation of their attachment. Similarly, when referring to a divalent group by a formula, the manner in which the formula is written indicates the orientation of the attachment. For example a compound of formula I wherein R ¹ is 4-amidinobenzyl, X ¹ and X ⁹ represents -NHC (O) -, ^X2 is 1,4-piperazinylene, X ⁷ is -C (0) 0-, X ⁸ is 4,1-piperidylene and R ² is R ⁹ -X ²¹ , wherein R ⁹ is piperid-4-yl, and X ²¹ is

3-azatrimethylene, is illustrated by the following general formula

said compound being called cis-1,5-cyclooctylene 4- (4-amidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylaminoethylcarbamoyl) -1-piperidinecarboxylate when both X ³ and X ⁷ are -C (O) -, X ⁴ and X ^{6 both} represent a covalent bond, X ⁵ represents cis-1,5-cyclooctylene and P represents a hydrogen atom;

- {4- [2- (1- {cis-5- [4- (4 -amidinobenzylcarbamoyl) piperazin-1-ylcarbonyloxy] cyclooctyloxycarbonyl} piperid-4-ylcarbonylamino) ethylammonio] piperid-1- ylcarbonyl} propionic acid when both X ³ and X ⁷ are -C (O) O-, X ⁴ and X ⁶ are covalent; X ⁵ represents cis-1,5-cyclooctylene and P represents 3-carboxypropionyl;

4- [4- (4-amidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] benzyl 4- (2-piperid-4-ylaminoethylcarbamoyl) -1-piperidinecarboxylate when X ³ is -C (O) -, X ⁷ is -C (O) O-, X ⁴ is a covalent bond, X ⁶ is methylene, X ⁵ is phenylene and P is hydrogen;

1,4-tetramethylene-4-amidinobenzylcarbamoyl-1-piperazinecarboxylate when both X ³ and X ⁷ are -C (O) O-, X ⁴ -X ⁵ -X ⁶ is 1,4-tetramethylene (ie -CH ₂ CH ₂ , CH ₂ , CH ₂ -)

N-4 -amidinobenzyl 1-4 - {5- [4- (2-piperidin-4-ylaminoethylcarbamoyl) piperid-1-ylcarbonyl] valeryl} -1-piperazinecarboxamide, when X ³ and X ^{7 both} represent a group -C (O) - and X ⁴ -X ⁵ -X ⁶ is 1,4-tetramethylene (ie -CH ₂ .CH ₂ .CH ₂ --CH ₂ -).

Preferred embodiments of the present invention will be described in the following.

While the broadest definition of this invention is set forth in the Summary of the Invention, some disubstituted cyclic compounds of Formula I are preferred. For example, preferred disubstituted cyclic compounds of formula I are those wherein X ⁵ is cis-1,5-cyclooctylene and X ⁴ and X ⁶ are both covalent bond, X ⁴ -X ⁵ -X ⁶ together are C 4 -C 8 alkylene or X ⁵ is 1,4-phenylene and X ⁴ and X ⁶ are ethylene of 0 to 1 carbon atom, X ¹ and X ⁹ independently represent a covalent bond, -C (O) -, -NHC (O) -, -C (O) NH-, a group

-N (CH ₃ ) C (O) - or -S (O) ₂ NH-, wherein both X ¹ and X ^{9 do} not simultaneously represent a covalent bond, X ³ and X ⁷ independently represent-C (O) - or -C (0) 0-, X ² and X ⁸ independently represent a group -X ¹⁰ -X ¹¹ - wherein X ¹⁰ is a covalent bond or methylene and X @ ¹¹ is 4,1-piperidylene or 1,4-piperazinylene, R ¹ represents a group R ⁴ -X ¹² - or R ⁵ -X ¹³ -, wherein R ⁴ represents an amidine, guanidine or methylamine group, X ¹² represents a group -X ¹⁴ -X ¹⁵ -X ¹⁶ -, where X ¹⁵ represents 1,4- phenylene or 1,4-piperidylene, ^X14 is alkylene I4 carbon atoms, and X ¹⁶ represents alkylene NL6 carbon atoms wherein the sum of NL4 and NL6 is 0, 1 or • · · ·

• · · * • * *

2, R ⁵ is piperid-4-yl, X ¹³ is alkylene of 2 to 3 carbon atoms, and R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ - in which R ⁸ is amino, amidine, a guanidine, methylamino or 1-iminoethyl group, X ²⁰ represents a group -X ²² -X ²³ -X ²⁴ - in which X ²³ represents trans-1,4-cyclohexylene, 1,4-phenylene, 4,1-pyridylene,

1,4-piperidylene, X ²² represents alkylene n22 carbon atoms and X is alkylene having ²⁴ carbon atoms n24, wherein the sum of n22 and n24 is 1 or 2, ^R9 is benzoimidazol-5-yl, imidazol-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-yl pyrid-3-yl, pyrid-4-yl, 1,4,5,6-tetrahydro-5-yl or 1,4,5,6-tetrahydro-2-dioxopyrimidin-5-yl, X ²¹ represents alkylene 1 to 6 carbon atoms, ω-azaalkylene of 2 to 5 carbon atoms, 3-oxotrimethylene, ω-thiaalkylene of 2 to 4 carbon atoms, 3-oxo-2-azatrimethylene, 3-aza-2-oxotrimethylene or the group -X ²⁵ -X ²⁶ -X ²⁷ - in which X ²⁶ is 1,4-phenylene, X ²⁵ is alkylene of n 25 carbon atoms and X ²⁴ is alkylene of n 27 carbon atoms, wherein the sum of n25 and n27 is 0 or 1, and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.

More preferred disubstituted cyclic compounds of formula I are those wherein X ⁵ is cis-1,5-cyclooctylene and X ⁴ and X ^{6 both} represent a covalent bond or X ⁴ -X ⁵ -X ⁵ together are C 4 -C 8 alkyl X ¹ and X ⁹ are independently a covalent bond, -C (0) -, -NHC (O) -, -C (O) NHnebo -S (O) NH ₂ provided that both X ¹ and X ⁹ neznamenanjí covalent bond, X ³ and X ⁷ independently represent -C (O) - or -C (O) O-,

X ² and X ^{8 are each} independently -X ¹⁰ -X ¹¹ -, wherein X ¹⁰ is a covalent bond or methylene and X ¹¹ is 1,4-piperidylene or 1,4-piperazinylene, R ¹ is R ⁴ -X ¹² - wherein R ⁴ represents an amidine or guanidine group and X ¹² represents a group -X ¹⁴ -X ¹⁵ -X ¹⁶ - in which X ¹⁵ represents 1,4-phenylene or 1,4-piperidylene,

X ¹⁴ represents alkylene I4 carbon atoms, and X ¹⁶ represents alkylene NL6 carbon atoms, wherein the sum of NL4 and NL6 is 0 or 2, R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ - in wherein R ⁸ represents an amino or methylamino group, X ²⁰ represents a group

-X ²² -X ²³ -X ²⁴ - wherein X ²³ is trans-1,4-cyclohexylene; or

1,4-phenylene, X ²² is a-alkylene of n 22 carbon atoms, X ¹⁶ is a-alkylene of n 24 carbon atoms, wherein the sum of n22 and n24 is 1 or 2, R ⁹ is imidazol-1-yl, imidazol-4-yl , 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, piperid-4-yl or pyrid-4-yl and X ²¹ is a (C 1 -C 5) alkylene or 3-azatrimethylene, and pharmaceutically acceptable salts thereof, N-oxides, prodrug derivatives and protected derivatives.

Particularly preferred disubstituted cyclic compounds of formula I are those wherein X ⁵ is cis-1,5-cyclooctylene and X ⁴ and X ^{6 both} represent a covalent bond, X ¹ and X ⁹ independently represent -C (O) - or -NHC (O) -, X ³ and X ⁷ independently represent -C (O) O-, X ² and X ⁸ independently represent -X ¹⁰ -X ¹¹ -, wherein X ¹⁰ is a covalent bond and X ¹¹ is 1, 4-piperazinylene, R ¹ is R ⁴ -X ¹² -, wherein R ⁴ is amidine or guanidine, and X ¹² is -X ¹⁴ -X ¹⁵ -X ¹⁶ -, wherein X ¹⁵ is 1,4-phenylene, X ¹⁴ is a covalent bond and X ¹⁶ is methylene, R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ - in which R ⁸ is amino, X ²⁰ is -X ²² -X ²³ -X ²⁴ - wherein X ²³ is trans-1,4-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 pharmaceutically acceptable salts thereof, N- oxides, prodrug derivatives and protected derivatives.

Particularly preferred disubstituted cyclic compounds of formula (I) are those wherein X ⁴ -X ⁵ -X ⁶ together are C 4 -C 8 alkylene, X ¹ and X ⁹ are independently -C (O) - or -NHC ( O) -, X ³ and X ⁷ are both -C (O) O-, X ² and X ⁸ are both -X ¹⁰ -X ¹¹ - wherein X ¹⁰ is a covalent bond and X ¹¹ is 1,4-piperazinylene a group, R ¹ represents a group R ⁴ -X ¹² -, wherein R ⁴ represents an amidine or guanidine group and X ¹² represents a group -X ¹⁴ -X ¹⁵ -X ¹⁶ - in which X ¹⁵ represents 1,4-phenylene, X ¹⁴ is a covalent bond and X ¹⁶ is methylene, R ² is R ⁸ -X ²⁰ -, wherein R ⁸ is amino or guanidine, X ²⁰ is -X ²² -X ²³ -X ²⁴ -, wherein X ²³ is 1 4-phenylene, X ²² represents a covalent bond and X ²⁴ represents methylene, and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.

The most preferred disubstituted cyclic compounds of formula I are as follows:

4-guanidinobenzyl-4- {7- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] heptanoyl} -1-piperazinecarboxamide,

4-guanidinobenzyl-4- {8- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] octanoyl} -1-piperazinecarboxamide,

4-guanidinobenzyl-4- {9- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] nonanoyl} -1-piperazinecarboxamide,

4-amidinobenzy 1-4- {7- [4- (4-amidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] -heptanoyl} -1-piperazinecarboxamide, cis-1,5-cyclooctylene 4- (4-amidinobenzylcarbamoyl) -1- piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazincarboxylate,

1,5-Pentamethylene di [4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate], cis-1,5-cyclooctylene 4- (4-amidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-piperid-4-ylbutyryl) - 1-piperazinecarboxylate, cis-1,5-cyclooctylene trans 4- (4-aminocyclohexylmethylcarbamoyl) -1-piperazinecarboxylate 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate, cis-1,5-cyclooctylene 4- (4-amidinophenylacetyl) - 1-piperazinecarboxylate 4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate,

1,4-tetramethylene di [4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate], cis-1,5-cyclooctylene 4- (4-amidinophenylacetyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethycarbamoyl) - 1-piperazinecarboxylate,

4-Guanidinobenzyl 4- {6- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] hexanoyl} -1-piperazinecarboxamide, cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate, cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-pipe

9 9 9 and 9 9 9 razincarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazincarboxylate, cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate,

4-guanidinobenzyl-4- {5- [4- (4-guanidinobenzylcarbamoyl) -piperazin-1-ylcarbonyl] valeryl} -1-piperazinecarboxamide,

3-oxa-1,5-pentamethylene di [4- (4-guanidinophenylacetyl) piperazin-1-ylcarbonyl] and cis-1,5-cyclooctylene 4- (4-amidinophenylacetyl) -1-piperazinecarboxylate 4- (2-piperidino- 4-Ylethylcarbamoyl) -1-piperazinecarboxylate and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.

Pharmacology and usefulness will be described below.

The disubstituted cyclic compounds of this invention are tryptase inhibitors. As such, the disubstituted cyclic compounds of formula (I) are useful for the treatment of diseases, in particular inflammatory diseases caused by immunity, in which tryptase activity contributes to the pathology and / or symptomatology of the disease. For example, immune-mediated inflammatory diseases in which tryptase activity contributes to their pathology and / or symptomatology include asthma, allergic rhinitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, rheumatoid arthritis, arthritic conditions in general, urticaria, angioedema, eczematous dermatitis, eczematous dermatitis hyperproliferative skin diseases, peptic ulcers, inflammatory bowel disease, ocular conjunctivitis and conjunctival spring catarrh, inflammatory conditions on the skin and the like.

Suitable in vitro assays for measuring tryptase activity and its inhibition by compounds are known (e.g., see Sturzebecher et al., Biol. Chem. Hoppe-Seyler 1992, 373, 1025-1030). This assay typically measures the hydrolysis of a peptide base sub •

• 9 9 9

9

9 99 99 99 tryptase-induced loss. For further details of an in vitro assay for measuring tryptase activity, see Example 33 below.

Suitable in vivo models of inflammation are known to those skilled in the art. For example, in vivo models for asthma are known (e.g., see Larsen: Experimental Models of Reversible Airway Obstruction in West et al. (Ed.): The Lung: Scientific Foundations, Raven Press, New York 1991). For further details of the in vitro asthma model, see Example 2 below. Further, in vivo models of skin inflammatory conditions are known (Walsh et al., Br. J. Pharmacol. 1995, 114, 1343-1350, and Armstrong et al., Prostaglandins 1995, 49, 205-224), atritic conditions (Peacock et al. Cell Immunol., 1995, 160, 178-184, and Houri et al., Curr. Opin. Rheumatol. 1995, 7, 201-205, and gastrointestinal diseases (Anthony et al., Int. J. Exp. Pathol. 1995, 76, 215-224, and Carter et al., Dig Dis Dis Sci 1995, 40, 192-197). For further details of an in vivo asthma response measurement assay, see Example 34 below.

Administration and pharmaceutical compositions will be described below.

Generally, the disubstituted cyclic compounds of Formula I may be administered in therapeutically effective amounts by any conventional and acceptable means known in the art, either alone or in combination with another therapeutic agent. The therapeutically effective amount can be varied depending on the severity of the disease, the age and relative health of the subject, the activity of the compound being used, and other factors. For example, therapeutically effective amounts of a disubstituted cyclic compound of Formula I for the treatment of asthma may range from 0.1 micrograms per kilogram of body weight (Mg / kg) per day to 1 milligrams per kg of body weight (mg / kg) per day, typically 1. Mg / kg / day to 0.1 mg / kg / day. A therapeutically effective amount for an asthmatic human patient may range from 10 mg / day to 10 mg / day, typically 0.1 mg / day to 10 mg / day.

• ·

Therapeutic agents that may be useful for administration in combination with disubstituted cyclic compounds of Formula I in the treatment of asthma include β-adrenergic agonists (eg, albuterol, terbutaline, formoterol, phenoterol, prenalin, and the like), methylxanthines (eg, caffeine, theophylline) , aminophylline, theobromine and the like), cromoglycates (eg, cromolyn, denocromil and the like) and corticosteroids (eg, beclomethasone, triamcinolone, flurisolid, dexamethansone and the like). In general, a person skilled in the art, working according to his personal knowledge and as described herein, will be able to determine a therapeutically effective amount of a disubstituted cyclic compound of formula I for treating a given inflammatory disease.

The disubstituted cyclic compounds of formula I may be administered as pharmaceutical preparations by one of the following routes: orally, systemically (e.g., transdermally, intranasally, or by suppository) or parenterally (e.g., intramuscularly, intravenously, or subcutaneously). The compositions may exist in the form of tablets, pills, capsules, semi-solids, powders, sustained-release preparations, solutions, suspensions, elixirs, aerosols or any other appropriate preparation and contain a generally disubstituted cyclic compound of formula I in combination with at least one pharmaceutically acceptable excipient. . Acceptable excipients are nontoxic delivery aids which do not adversely affect the therapeutic benefit of the active ingredient. These excipients may exist in the form of a solid, a liquid, a semi-solid, or, in the case of an aerosol formulation, a gaseous excipient, which is usually available to the skilled artisan.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, milk powder and the like. The liquid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol, and various oils, among which:

4 44 44 include oil of petroleum, animal, vegetable or synthetic origin (eg peanut, soybean, mineral, sesame and etc.). Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse the active ingredient in the form of an aerosol. Inert gases suitable for this purpose are nitrogen, carbon dioxide, nitrous oxide, etc. Other suitable pharmaceutical carriers and their preparations are described in A. R. Alfonso: Remington's Pharmaceutical Sciences 1985, 17.

eds., Easton, Pa., Mack Publishing Company.

The amount of the disubstituted cyclic compound of formula (I) in the formulation may vary according to the type of formulation, the size of the unit dose, the type of excipients and other factors known to those skilled in the art. The preparation of a disubstituted cyclic compound of formula I for the treatment of asthma will generally contain from 0.01 to 10% by weight, preferably from 0.3 to 1% by weight. active ingredient, the remainder being one or more excipients. The pharmaceutical composition is preferably administered in a unit dosage form for continuous treatment or in a unit dosage form at will, if relief of symptoms is specifically required. Representative pharmaceutical compositions containing disubstituted cyclic compounds of Formula I are described in Example 34.

The next part of the description will be devoted to chemistry.

The disubstituted cyclic compounds of the invention consist of five different subunits (i.e., R ¹ -, -X ² -, -X ⁴ -X ⁵ -X ⁵ -, -X ⁸ - and R ² -) which are linked by a carbonyl bond, formyloxy -bond, amide bond, sulfonamide bond, carbamate bond or urea bond (i.e., -C (O) -, -C (O) O-,

-OC (O) -, -C (O) N (R ³ ) -, -N (R ³ ) C (O) -, -S (O 2) N (R ³ ) -, -N (R ³ ) S (O) 2 ~,

-OC (O) N (R ³ ) -, -N (R ³ ) C (O) O-, -N (R ³ ) C (O) N (R ³ ) -, or -O (C) O-.

Methods for forming these linking groups are known and appropriate.

The reagents are readily available (eg, see March: Advanced Organic Chemistry, 4th edition (Wiley 1992), Larock: Comprehensive Organic Transformations (VCH 1989) and Furnis et al. Vogel's Textbook of Practical Organic Chemistry, 5th Edition (Longman 1989).

Subunits containing disubstituted cyclic compounds of formula I may be assembled individually or as larger combinations of subunits. Following! The reaction schemes are representative of methods for producing the disubstituted cyclic compounds of formula I. It is to be understood that the compounds of formula I can be prepared by other analogous methods.

Disubstituted cyclic compounds of formula I wherein X ⁸ is 1,4-piperazinylene or 1,4-piperidylene and X ⁹ is -C (O) -, -OC (O) - or -N (R ³ ) C ( O) - or wherein X ⁸ is C 1 -C 8 alkylene and X ⁹ is -C (O) N (R ³ ) -, -OC (O) N (R ³ ) -, or -N (R ³⁾ ) C (O) N (R ³ ) -, may be prepared by reacting a disubstituted cyclic compound of formula I

R ¹ -X ¹ -X ² -X ³ -X ⁴ \

X ³ (I)

Y ° -X'-X 'or a protected derivative thereof with a disubstituted cyclic compound of the formula R ² -Y ⁹ -C (O) L or a protected derivative thereof, wherein L is a leaving group, Y ⁹ is a bond, -O - or -N (R ³ ) -, Y ⁸ represents piperazin-1-yl, piperid-4-yl or HN (R ³ ) -alkyl of 1 to 8 carbon atoms and each R ¹ , R ² , R 3 is ³ , X ¹ , X ² , χ ³ , χ ⁴ , χ ⁵ , x ⁶ and X ⁷ are as set forth in the Summary of the Invention, and then the protecting group is removed, if necessary. Or, a disubstituted cyclic compound of formula I wherein X ⁸ is 1 4-piperazinylene or 1,4-piperidylene and X ⁹ is a group.

-NHC (O) - or wherein X ⁸ is C 1 -C 8 alkylene and X ⁹ is -NHC (O) N (R ³ ) -, may be prepared by reacting the corresponding disubstituted cyclic compound of formula I or a protected derivative thereof with an isocyanate of the formula R ² -NC (O) or a protected derivative thereof, and then deprotecting if necessary (see Example 8 below for further details).

Similarly, disubstituted cyclic compounds of formula I wherein X ² is 1,4-piperazinylene or 1,4-piperidylene and X ¹ is -C (O) -, -OC (O) - or -N (R ³ ) C (O) or wherein X ² is C 1 -C 8 alkylene and X ¹ is -C (O) N (R ³ ) -, -OC (O) N (R ³ ) -, or -N (R ³ ). ³ ) C (O) N (R ³ ) -, can be prepared by reacting a disubstituted cyclic compound of formula II

Y ^{2 -} X ^{3 -} X ⁴

R ² -X ⁹ -X ⁸ -X ⁷ -X ^

X ⁵ (II) or a protected derivative thereof with a disubstituted cyclic compound of the general formula R ¹ -Y ¹ -C (O) L or a protected derivative thereof, wherein L is a leaving group and Y ¹ is a bond, -O- or - N (R ³ ) -, Y ² is piperazin-1-yl, piperid-4-yl or HN (R ³ ) -alkyl of 1 to 8 carbon atoms and each R ¹ , R ² , R ³ , X ³ X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ and X ⁹ are as set forth in the Summary of the Invention, and then the protecting group is removed, if necessary. Alternatively, disubstituted cyclic compounds of formula I wherein X ² is 1,4-piperazinylene or 1,4-piperidylene and X ¹ is -NHC (O) - or wherein X ² is C 1 -C 8 alkylene and X ¹ is -NHC (O) N (R ³ ) -, may be prepared by reacting the corresponding disubstituted cyclic compound of formula II or a protected derivative thereof with an isocyanate of formula R ² -NC (O) or a protected derivative thereof and then removing the protecting group group, if necessary (see Example 14 (b) below for further details).

, Compounds of formula I wherein R ¹ is R ^2, X ² and / or ^X8 is 1,4-piperazinylene or 1,4-piperidylene, X ¹ is -C (0) -, -0C ( O) or -N (R ³ ) C (O) - and X ⁹ is -C (O) -, -OC (O) -, or

-N (R ³ ) C (O) - and / or wherein X ² and / or X ⁸ is C 1 -C 8 alkylene, X ¹ is -C (O) N (R ³ ) -, -OC (O) N (R ³ ) - or -N (R ³ ) C (O) N (R ³ ) - and X ⁹ is -C (O) N (R ³ ) -, -OC (O) N ( R ³ ) or -N (R ³ ) C (O) N (R ³ ) -, may be prepared by reacting a disubstituted cyclic compound of formula III

Y ^{2 -} X ^{3 -} X ⁴ \ ₅

X ⁵ (III)

Y ⁸ -X ⁷ -X 4 or a protected derivative thereof with two or more equivalents of a compound of the general formula R ¹ -Y ¹ -C (O) L or a protected derivative thereof, wherein L represents a leaving group, Y ¹ represents a bond, - O- or -N (R ³ ) -, Y ² and Y ⁸ independently represent piperazin-1-yl, piperid-4-yl or HN (R ³ ) -alkyl of 1 to 8 carbon atoms and each R ¹ , R ³ , X ³ , X ⁴ , X ⁵ , X ⁶ and X ⁷ are as set forth in the Summary of the Invention, and then the protecting group is removed, if necessary. Or can be of a compound of formula I wherein R ¹ is R ^2, X ² and / or ^X8 is 1,4-piperazinylene or 1,4-piperidylene, X ¹ is -NHC (O) - and / or X ⁹ is -NHC (O) - and / or wherein X ² and / or X ⁸ is C 1 -C 8 alkylene, X ¹ is -NHC (O) N (R ³ ) - and / or or X ⁹ is a group -NHC (O) N (R ³ ) -, produced by reacting a disubstituted cyclic compound of formula III or a protected derivative thereof with two or more molar equivalents of an isocyanate of formula R ¹ -NC (O) or a protected derivative thereof, and then deprotecting if necessary (see Example 10 below for further details).

····

Disubstituted cyclic compounds of formula I wherein X ¹ is -N (R ³ ) C (O) -N (R ³ ) C (O) O- or -N (R ³ ) C (O) N (R ³ ). ³ ) -, may be prepared by reacting an amine of the formula R ¹ -N (R ³ ) H or a protected derivative thereof with a disubstituted cyclic compound of formula IV

LC (O) -Y ¹ -X ² -X ³ -X ⁴ \ ₅

X ⁵ (IV) r ² -x ⁹ -x ⁸ -x ⁷ -x ^ or a protected derivative thereof in which L represents a leaving group, Y ¹ represents a bond, -O- or -N (R ³ ) - and each R ¹ , R ² , R ³ , X ² , X ³ , x ⁴ , x ⁵ , x ⁶ , x ⁷ , x ⁸ and X ⁹ are as set forth in the Summary of the Invention (see Example 20 below for further details).

Disubstituted cyclic compounds of formula I wherein X ² is 1,4-piperazinylene or 1,4-piperidylene and X ³ is -C (O) -, -C (O) O- or -C (O) N ( R ³ ) - or wherein X ² is C 1 -C 8 alkylene and X ³ is -N (R ³ ) C (O) -, -N (R ³ ) C (O) O-, or -N ( R ³ ) C (O) N (R ³ ) -, may be prepared by reacting a compound of formula R ¹ -X ¹ -Y ² or a protected derivative thereof with a disubstituted cyclic compound of formula V

LC (O) -Y ³ -x ^4, ₅ x ⁵ (V) r ² -x ⁹ -x ⁸ -x ⁷ -x ^ or a protected derivative thereof in which L represents a leaving group, Y ³ represents a bond or a group - O- or -N (R ³ ) -, Y ² represents piperazin-1-yl, piperid-4-yl or HN (R ³ ) -alkyl of 1 to 8 carbon atoms and each R ¹ , R ² , R ³ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ and X ⁷ , X ⁸ and X ⁹ are as set forth in the Summary of the Invention (see Example 31 below for further details).

Disubstituted cyclic compounds of formula I wherein X ² and X ⁸ are both 1,4-piperazinylene or 1,4-piperidylene and X ³ and X ⁷ independently represent -C (O) -, -C (O) O-, or

-C (O) N (R ³ ) - or wherein X ² and X ⁸ are both C 1 -C 8 alkylene or C 1 -C 8 heteroalkylene and X ³ and X ⁷ independently represent -N (R ³ ) C (O) -, -N (R ³ ) C (O) O- or

-N (R ³ ) C (O) N (R ³ ) -, may be prepared by reacting two or more molar equivalents of a compound of formula R ¹ -X ¹ -Y ² - or a protected derivative thereof with a disubstituted cyclic compound of formula VI

LC (O) -Y ³ -X ⁴ \ ₅

X ⁵ (VI)

LC (O) Y ⁷ -X ⁶ or a protected derivative thereof in which L represents a leaving group, Y ³ and Y ⁷ independently represent a bond or a group -O- or -N (R ³ ) -, Y ² represents piperazine-1 - yl, piperid-4-yl, HN (R ³ ) -alkyl of 1 to 8 carbon atoms or HN (R ³ ) -heteroalkyl of 1 to 8 carbon atoms and each R ¹ , X ¹ , X ⁴ , X ⁵ and X ⁶ is as set forth in the Summary of the Invention (see Example 32 below for further details).

The acylation reactions described above can be carried out by reacting the activated ester (e.g., acid chloride derivative) and the appropriate nucleophile in the presence of a suitable organic base (e.g., Ν, Ν-diisopropylethylamine (DIEA), N-methylmorpholine etc., preferably DIEA) and a suitable solvent. (e.g., N, N-dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane, etc.) at 20-30 ° C, typically at about 23 ° C, for several minutes to 24 hours. The acylation can also be carried out by reacting the appropriate carboxylic acid and nucleophile in the presence of a suitable condensing reagent (e.g. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide etc.) and a suitable solvent (e.g. DMF etc.) at 20-30 ° C, typically at about 23 ° C, for several hours to several days. The production reactions described above

4

of the disubstituted cyclic compounds of formula I and the conditions for carrying out these reactions are illustrative. One skilled in the art will recognize that additional reaction conditions and other starting materials can be used to produce the compounds of the invention.

Deprotection can be accomplished by any means which deprotects and provides the desired product in reasonable yield. A detailed description of useful methods for forming and removing protecting groups can be found in T.W. Green: Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., 1981.

In general, the starting materials useful for making the disubstituted cyclic compounds of formula I and the intermediates useful for making the disubstituted cyclic compounds of formula I are commercially available or can be readily prepared by those skilled in the art. For example, intermediates useful for making the disubstituted cyclic compounds of Formula I are conventionally prepared by the above-described acylation reactions. If necessary, a suitable chemistry of protection is used to direct the reaction to the desired reaction site if more than one reaction site is present in the starting materials.

A suitable starting material for the preparation of the disubstituted cyclic compounds of formula I wherein both X ³ and X ⁷ is -C (O) O- is a disubstituted cyclic compound of formula VII

LC (O) -O ⁴ X (VII)

wherein X ⁴ , X ⁵ and X ⁶ are as set forth in the Summary of the Invention. For example, disubstituted cyclic compounds of formula VI wherein L is chlorine may be prepared by reacting a corresponding diol (e.g., cis-1,5-cyclooctanediol, trans-1,4-cyclohexylenedimethanol, 1-chloro), or a diol. , 4-phenylenedimethanol, etc.) with triphosgene (see Example 5 below for further details).

Intermediates useful for the preparation of the disubstituted cyclic compounds of formula I wherein the intermediate contains an amidine group can be prepared by reacting the corresponding nitrile with hydrogen chloride in ethanol followed by reaction with ammonia.

Other Methods for Making Disubstituted Cyclic Compounds of Formula I: Disubstituted cyclic compounds of formula I wherein R ⁴ is guanidine can be prepared by reacting a corresponding disubstituted cyclic compound of formula I wherein R ⁴ is amino with cyanamide. The reaction is carried out by treating the amine with hydrogen halide followed by reacting with an excess of cyanamide at about 65 ° C for two hours (see Example 15 below for further details).

Disubstituted cyclic compounds of formula (I) may be prepared as pharmaceutically acceptable acid addition salts by reacting a disubstituted cyclic compound of formula (I) in base form with a pharmaceutically acceptable inorganic or organic acid. The pharmaceutically acceptable base addition salts of the disubstituted cyclic compounds of formula I can be prepared by reacting the disubstituted cyclic compound of formula I in acid form with pharmaceutically acceptable inorganic or organic bases. Inorganic or organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of the disubstituted cyclic compounds of Formula I are listed in the definitions section of this application. The disubstituted cyclic compounds of formula I in the form of salts can be prepared using salts of the starting materials or intermediates.

Disubstituted cyclic compounds of formula (I):

0000 00 0000 00 0 0 0 0 0 0 0 0 0 0 0 00 000000 0 0 0 0 0 0 0 0 0 0 0 00 000000 0 0 0 0 0 The free acid or free base form may be prepared from the corresponding base addition salts or acid addition salts. For example, the disubstituted cyclic compounds of formula I in the form of an acid addition salt may be converted to the corresponding free base by reaction with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). The disubstituted cyclic compounds of formula (I) in the form of a base addition salt can be converted to the corresponding free acids by reaction with a suitable acid (e.g., hydrochloric acid, etc.).

The N-oxides of the disubstituted cyclic compounds of formula (I) may be prepared by methods known to those skilled in the art. For example, N-oxides can be prepared by reacting the non-oxidized form of a disubstituted cyclic compound of formula I with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, m-chloroperbenzoic acid, etc.) in a suitable inert organic solvent (e.g. hydrocarbon (such as methylene chloride) at about 0 ° C. The N-oxides of the disubstituted cyclic compounds of formula (I) may also be prepared from the N-oxide of the corresponding starting material.

Disubstituted cyclic compounds of formula I in unoxidized form can be prepared from N-oxides of disubstituted cyclic compounds of formula I by reaction with a reducing agent (e.g. sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, etc.). in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane) at 0 to 80 ° C.

Prodrugs of the disubstituted cyclic compounds of Formula I may be prepared by methods known to those skilled in the art (e.g., see Saulnier et al., Bioorganic and Medicinal Chemistry Letters 1994, 4, 1985 for further details). For example, the appropriate prodrugs may be prepared by reacting a non-derivatized disubstituted cyclic compound of the general formula: 9 9 9 9 4 4 4 4 · · ♦ · 9 9 4 4

4 9 9 4 4 4 9 9

944 9 44 94 44 49 of formula I with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate, p-nitrophenyl carbonate, etc.).

The protected derivatives of the disubstituted cyclic compounds of formula (I) may be prepared by means known to those skilled in the art. A detailed description of the methods useful for forming protecting groups and removing them can be found in T.W. Greene: Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.

In summary, an aspect of the present invention is a process for the production of disubstituted cyclic compounds of formula I, comprising:

a) reacting the disubstituted cyclic compound of formula I

R ¹ -X ¹ -X ² -X ³ -X ⁴ \

X ³ (I)

Y 0 -X'-X 'or a protected derivative thereof with a compound of formula R ² -Y ⁹ -C (O) L or a protected derivative thereof, wherein L is a leaving group, Y ⁹ is a bond, -O- or -N (R ³ ) -, Y ⁸ is piperazin-1-yl, piperid-4-yl or HN (R ³ ) -alkyl of 1 to 8 carbon atoms and each R ¹ , R ² , R ³ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ and X ⁷ are as set forth in the Summary of the Invention, and then the protecting group is removed, if necessary, so as to obtain a disubstituted cyclic compound of formula I wherein X ⁸ is 1,4-piperazinylene or 1,4-piperidylene and X ⁹ is -C (O) -, -OC (O) - or -N (R ³ ) C (O) - or wherein X ⁸ is alkylene having 1-8 carbon atoms, and X ⁹ is -C (O) N (R ³⁾ -, -OC (O) N (R ³⁾ - or -N (R ³⁾ C (O) N ( R ³ ) -,

b) reacting of a compound of formula I or a protected derivative thereof with an isocyanate of the formula ^R2 -NC (O) or a protected derivative thereof and after deprotection if necessary, gives disubstituted ···· ·· ·· <· * ··· ····· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

.... A cyclic compound of formula I wherein X is

1,4-piperazinylene or 1,4-piperidylene and X ⁹ is -NHC (O) - or wherein X ® is C 1 -C 8 alkylene and X ⁹ is -NHC (O) N (R ³ ) -,

c) reacting the disubstituted cyclic compound of formula II

Y ^{2 -} X ^{3 -} X ⁴ \ ₅

X ⁵ (II) r ² -x ⁹ -x ⁸ -x ⁷ -x ^ or a protected derivative thereof with a compound of the formula R ¹ -Y ¹ -C (O) L or a protected derivative thereof, wherein L is a leaving group and Y ¹ is a bond, -O- or -N (R ³ ) -, Y ² is piperazin-1-yl, piperid-4-yl or HN (R ³ ) -alkyl of 1 to 8 carbon atoms and each R ¹ , R ² ,

R ³ , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ® and X ⁹ are as set forth in the Summary of the Invention, and then the protecting group is removed, if necessary, to yield a disubstituted cyclic compound of formula Wherein X ² is 1,4-piperazinylene or

1,4-piperidylene and X ¹ is -C (O) -, -OC (O) - or -N (R ³ ) C (O) - or wherein X ² is C 1 -C 8 alkylene and X ¹ is -C (O) N (R ³ ) -, -OC (O) N (R ³ ) - or -N (R ³ ) C (O) N (R ³ ) -,

d) reacting the disubstituted cyclic compound of formula II or a protected derivative thereof with an isocyanate of the formula R ¹ -NC (O) or a protected derivative thereof and removing the protecting group, if necessary, to obtain a disubstituted cyclic compound of formula I wherein: X ² is

1,4-piperazinylene or 1,4-piperidylene and X ¹ is -NHC (O) - or wherein X ² is C 1 -C 8 alkylene and X ¹ is -NHC (O) N (R ³ ) -,

e) reacting the disubstituted cyclic compound of formula III;

X ⁵ (III)

Y ² -X ³ -X ⁴ \

7_ _ν /

Υ ° -Χ'-Χ 'or a protected derivative thereof with two or more equivalents of a compound of the formula R ¹ -Y ¹ -C (O) L or a protected derivative thereof, wherein L represents a leaving group, Y ¹ represents a bond, - O- or -N (R ³ ) -, Y ² and Y ⁸ independently represent piperazin-1-yl, piperid-4-yl or HN (R ³ ) -alkyl of 1 to 8 carbon atoms and each R ¹ , R ³ , X ³ , X ⁴ , X ⁵ , X ⁶ and X ⁷ are as set forth in the Summary of the Invention, and then the protecting group is removed, if necessary, to yield a disubstituted cyclic compound of formula I wherein R ¹ is equal to R ² , X ² and / or X ⁸ is 1,4-piperazinylene or 1,4-piperidylene, X ¹ is -C (O) -, -OC (O) - or -N (R ³ ) C (O) -, X ⁹ represents a group -C (O) -, -OC (O) - or -N (R ³ ) C (O) - and / or wherein X ² and / or X ⁸ represents alkylene with 1 X ¹ is -C (O) N (R ³ ) -, -OC (O) N (R ³ ) - or -N (R ³ ) C (O) N (R ³ ) - and X ⁹ stands for gr -C (O) N (R ³ ) -, -OC (O) N (R ³ ) - or -N (R ³ ) C (O) N (R ³ ) -,

f) reacting a disubstituted cyclic compound of formula III or a protected derivative thereof with two or more molar equivalents of an isocyanate of formula R ¹ -NC (O) or a protected derivative thereof, and removing the protecting group, if necessary, to obtain a disubstituted cyclic compound of formula (I) wherein R ¹ is 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 (O) - and / or wherein X ² and / or X ⁸ is C 1 -C 8 alkylene, X ¹ is -NHC (O) N (R ³ ) - and / or X ⁹ is -NHC (O) N (R ³ ) -,

g) reacting an amine of formula R ¹ -N (R ³ ) H or a protected derivative thereof with a disubstituted cyclic compound of formula IV

LC (O) -Y ¹ -X ² -X ³ -X ⁴ \ ₅

X ⁵ (IV) r ² -x ⁹ -x ⁸ -x ⁷ -x ^ or a protected derivative thereof, wherein L is a leaving group, Y ¹ is a bond, -O- or -N (R ³ ) - and each R ¹ , R ² , R ³ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ and X ⁹ are as set forth in the Summary of the Invention, and then the protecting group is removed if necessary so as to obtain a disubstituted cyclic compound of formula I wherein X ¹ is -N (R ³ ) C (O) -, -N (R ³ ) C (O) O- or -N (R ³ ) C (0) N (R ³ ) -,

h) reacting a compound of formula R ¹ -X ¹ -Y ² or a protected derivative thereof with a disubstituted cyclic compound of formula V

LC (O) -Y ³ -X ⁴ \ ₅

X ⁵ (V) r ² -x ⁹ -x ⁸ -x ⁷ -x ^ or a protected derivative thereof in which L represents a leaving group, Y ³ represents a bond or a group -O- or -N (R ³ ) -, Y ² represents piperazin-1-yl, piperid-4-yl or HN (R ³ ) -alkyl of 1 to 8 carbon atoms 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 set forth in the Summary of the Invention, and then the protecting group is removed, if necessary, to yield a disubstituted cyclic compound of formula I wherein X ² is 1,4-piperazinylene or 1,4-piperidylene and X ³ is -C (O) -, -C (O) O- or -C (O) N (R ³ ) - or wherein X ² is alkylene with C 1 -C 8 and X ³ is -N (R ³ ) C (O) -, -N (R ³ ) C (O) O-, or -N (R ³ ) C (O) N (R) ³ ) -,

i) reacting two or more molar equivalents of a compound of formula R ¹ -X ¹ -Y ² or a protected derivative thereof with a disubstituted cyclic compound of formula VI

LC (O) -Y ³ -X ⁴ \ ₅

X ⁵ (VI)

LC (O) Y ⁷ -X ⁶ or a protected derivative thereof in which L represents a leaving group, Y ³ and Y ⁷ independently represent a bond or a group -O- or -N (R ³ ) -, Y ² represents piperazine-1 - yl, piperid-4-yl, HN (R ³ ) -alkyl of 1 to 8 carbon atoms or HN (R ³ ) -heteroalkyl of 1 to 8 carbon atoms 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 obtain a disubstituted cyclic compound of formula I wherein X ² and X ⁸ represents

1,4-piperazinylene or 1,4-piperidylene and X ³ and X ⁷ independently represent -C (O) -, -OC (O) - or -C (O) N (R ³ ) - or wherein X ² X ⁸ is C 1 -C 8 alkylene or C 1 -C 8 heteroalkylene and X ³ and X ² independently represent -N (R ³ ) C (O) -, -N (R ³ ) C (O) O- or -N (R ³ ) C (O) N (R ³ ) -,

j) optionally reacting a disubstituted cyclic compound of formula I wherein R ⁴ is an amino group with cyanamide to form a disubstituted cyclic compound of formula I wherein R ⁴ is a guanidine group,

k) optionally further converting the disubstituted cyclic compound of Formula I to a pharmaceutically acceptable salt thereof,

l) optionally further converting the salt of the disubstituted cyclic compound of formula I to a non-salt form;

m) optionally further converting the non-oxidized form of the disubstituted cyclic compound of formula to a pharmaceutically acceptable N-oxide,

n) optionally further converting the disubstituted compound of formula I in the N-oxide form to the non-oxidized form,

(o) optionally further converting a non-derivatized disubstituted compound of Formula I into a pharmaceutically acceptable prodrug derivative; and

p) optionally further converting the disubstituted prodrug derivative of the cyclic compound of Formula I into its derivative in its reduced form.

In the above method, reference to Formula I is one in which each of 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 set forth in their broadest definitions set forth in the Summary of the Invention, the method being particularly well applied to the presently preferred embodiments.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Tert-Butyl 4-aminobenzylcarbamate hydrochloride

4-Aminobenzylamine (50.34 g, 0.412 mole) in dichloromethane (200 mL) was placed in a 1 L 3-neck round bottom flask with mechanical stirring apparatus. This solution was cooled to 0 ° C. To this solution was added dropwise di-tert-butyl dicarbonate (89.9 g, 0.412 mmol) in dichloromethane (200 mL) over 30 minutes. The resulting suspension was stirred at 0 ° C for two hours. An almost homogeneous solution is obtained. The dichloromethane solution was washed successively with aqueous sodium hydroxide (1.0 M, 500 mL) and water (500 mL). The organic layer was dried (MgSO 4, filtered and concentrated in vacuo to give a yellow oil. This oil was taken up in ethyl ether with methanol (2: 1, 225 mL) and the solution was cooled to 0 ° C, acidified with hydrogen chloride in dioxane. (4.0M, 115 mL, 0.412 mol) and combined with ethyl ether (200 mL) to give a thick light yellow precipitate, which was filtered off and washed with additional ethyl ether (500 mL), and dried under vacuum to give tert-butyl 1-4 hydrochloride. -aminobenzylcarbamate (100.23 g, 0.387 mol, 94% yield) as a pale yellow solid ¹ H NMR (300 MHz, DMSO-d ₆ ): 10.40-10.20 (broad s, 3 H), 7.40 (t, 1H), 7.30 (s, 4H), 4.10 (d, 2H), 1.40 (s, 9H).

«· · · · ·

Example 2 tert -Butyl-4-guanidinobenzylcarbamate

Cyanamide (100 g, 2.4 mol) was placed in a 500 ml round bottom flask and heated to 60-65 ° C until the material had completely melted. Then tert-butyl 4-aminobenzylcarbamate hydrochloride (25.3 g, 97.8 mmol), prepared as in Example 1, was added directly to the liquid cyanamide to give a yellow solution. This solution was stirred at a temperature between 60 and 65 ° C for two hours. Water (100 mL) was then added. The aqueous mixture was cooled to room temperature and washed with ethyl ether (1 L). The organic phase was extracted again with water (2 x 100 mL) and the combined aqueous layers were washed with ethyl ether (500 mL), cooled in an ice bath, and then basified with aqueous sodium hydroxide (10M, 100 mL). An insoluble oil is obtained which crystallizes slowly. The crystals were collected by filtration and washed with water. Drying in vacuo provided tert-butyl 4-guanidinobenzylcarbamate (18.3 g, 69.24 mmol, 70.8% yield) as a colorless crystalline solid. ¹ H NMR Spectrum (300 MHz, DMSO-d ₆ ): 9.70 (s, 1H), 7.42 (t, 1H), 7.40 (s, 4H), 7.25 (d, 2H) 7.15 (d, 2H), 4.10 (d, 2H), 1.40 (S, 9H).

Example 3 Butyls 1-4-chlorocarbonyl-1-piperazinecarboxylate

Trifosgene (25 g, 84.2 mmol) was dissolved in dichloromethane (200 mL) and the resulting solution was cooled to 0 ° C. To a solution of triphosgene was added dropwise a mixture of tert-butyl 1-piperazinecarboxylate (40 g, 214.8 mmol) and pyridine (35 mL, 432.7 mmol) in dichloromethane (100 mL) and the reaction mixture was allowed to warm to 30 minutes over 30 min. rooms. The reaction mixture was diluted with aqueous hydrochloric acid (0.1N, 200 mL) and the aqueous phase was washed with dichloromethane (50 mL). The combined organic layers were dried (magnesium sulfate) and filtered. Concentration in vacuo afforded tert-butyl 4-chlorocarbonyl-1-piperazinecarboxylate (45.6 g, 71.6 mmol, 85%). ** yield) as a yellow solid. ¹ H NMR spectrum (300 MHz,

CDCl3): 3.70 (s, 2H), 3.60 (m, 2H), 3.50 (m, 4H), 1.50 (s, 9H).

Example 4

Tert -Butyl-4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate trifluoroacetate tert -Butyl-4-guanidinobenzylcarbamate (41.77 g, 0.158 mmol), prepared as in Example 2, was reacted with trifluoroacetic acid at room temperature for 30 minutes. (TFA) (100 mL). The resulting almost colorless liquid was concentrated in vacuo to 45 ° C, the residue was triturated with ethyl ether (3 x 400 mL) and dried in vacuo to a colorless foam. The residue was dissolved in methanol (200 mL). DIEA (55 mL, 0.32 mol, amount based on estimated excess of TFA present) was then added to the solution. The mixture was cooled to 0 ° C. Then tert-butyl 4-chlorocarbonyl-1-piperazinecarboxylate (39.3 g, 0.158 mol), prepared in Example 3, in dichloromethane (120 mL) was added. An additional amount of DIEA (30 mL) was added and the reaction mixture was allowed to warm to room temperature. Stir 12 hours and concentrate in vacuo to an orange oil.

This oil was combined with water (200 mL). A thick precipitate is obtained. Recrystallization of this precipitate from acetonitrile and ether gave tert-butyl 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate trifluoroacetate (62.0 g, 0.126 mol, 80% yield) as a pale yellow solid. ¹ H NMR spectrum (300 MHz,

DMSO-d _6): 10.15 (s, IH), 9.10 (br s, 2H), 7.65 (s, 4H),

7.40 (t, 1H), 7.25 (dd AB, 4H), 4.25 (d, 2H), 3.55 (m, 4H),

3.10 (s, 4H). Mass Spectrum (Electrospray, LRMS) calcd: 277.4 (MH ⁺ ), 139.2 (MH ₂ ⁺² / 2), found: 277.4 (MH ⁺ ), ^c 13 ^H 20 ^N 6 ° 3 (MH ₂ + ^2/2 ).

«···

Example 5 cis-1,5-Cyclooctylene di (chloroformate) cis-1,5-Cyclooctanediol (20.2 g, 0.14 mol) was dissolved in acetonitrile (250 mL). To this mixture was added potassium carbonate (41.4 g, 0.3 mol). A supernatant is obtained. The suspension was cooled to 0 ° C under nitrogen and phosgene (1.9 M in toluene, 220 mL, 0.42 mol) was added dropwise over one hour. The suspension was warmed to room temperature and stirred for 12 hours. Ether (1 L) was then added. The suspension is filtered from insoluble salts and concentrated. Recrystallization of the residue from hexane gave cis-1,5-cyclooctylene di (chloroformate) as a colorless crystalline solid. Further purification can be carried out by flash chromatography on silica gel, eluting with a 10: 1 mixture of hexane and ethyl acetate. ¹ H NMR spectrum (300 MHz, CDCl ₃ ): 5.00-4.85 (m, 2H), 2.20-1.60 (m, 12H).

Example 6 cis-1,5-Cyclooctylene chloroformate 4-tert-butoxycarbonyl-1-piperazecarboxylate cis-1,5-Cyclooctylene 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 at room temperature for 15 minutes and then treated with 0.1 M aqueous hydrochloric acid. The dichloromethane layer was dried (magnesium sulfate), filtered and concentrated. Purification of the residue by flash chromatography on silica gel, eluting with ethyl ether and hexane as eluent, afforded cis-1,5-cyclooctylene chloroformate 4-tert-butoxycarbonyl-1-piperazinecarboxylate (660 mg, 1.6 mmol, 22% yield) as a colorless oil. ¹ H NMR Spectrum (300 MHz, CDCl ₃ ): 5.00 to 4.90 (m, 1H), 4.80 to 4.70 (m, 1H), 3.40 (S, 8H), 2.05 to 1.40 (m, 12H), 1.40 (s, 9H).

• · · »0

• 0

Example 7 cis-1,5-Cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4-tert-butoxycarbonyl-1-piperazinecarboxylate tert. Butyl 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate trifluoroacetate (393.7 mg, 1.06 mmol), prepared as in Example 4, was treated with pure trifluoroacetic acid (1 mL) at room temperature for 10 minutes. The mixture was concentrated in vacuo. A colorless oil is obtained. This oil is taken up in water (15 ml) and the pH of the aqueous solution is adjusted dropwise to between 7 and 8 with aqueous 5M sodium hydroxide added. Cis-1,5-Cyclooctylene chloroformate 4-tert-butoxycarbonyl-1-piperazinecarboxylate (444, 7 mg (1.06 mmol), prepared as in Example 6, in tetrahydrofuran (10 mL) was added to the aqueous solution and the pH was continuously adjusted with 1 M aqueous sodium hydroxide added dropwise until a pH change was observed. The mixture was concentrated in vacuo by removing most of THF and then ethyl ether (5 mL) and 5M aqueous sodium hydroxide (enough to adjust pH to 14) were added to give a thick white suspension. The suspension is allowed to stand for 15 to 30 minutes at room temperature. The precipitate was then collected by filtration and washed with water (2 x 15 mL). Drying in vacuo afforded cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4-tert-butoxycarbonyl-1-piperazinecarboxylate (527 mg, 0.82 mmol, 77% yield) as a colorless solid. ¹ H NMR Spectrum (300 MHz, DMSO-d ₆ ): 7.05 (d, 2H), 7.00 (t, 1H), 6.70 (d, 2H), 5.10 (broad S, 3H) 4.65 (m, 2H), 4.15 (s, 2H), 3.30 (s, 16H), 1.90-1.40 (m, 12H), 1.40 (s, 9H).

Example 8 cis-1,5-Cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate trifluoroacetate (compound 1)

Following production of a compound of formula I in which R ¹ ·· · · · • «· is 4-guanidinobenzyl, ^R2 is 2-piperid-4-ylethyl, X ¹ and X ⁹ represents -NHC (O) -, X ² X ⁸ is 1,4-piperazinylene, X ² and X ⁷ are both -C (O) O-, X ⁴ and X ⁶ are both covalent and X ⁵ is cis-1,5-cyclooctylene.

The cis-1,5-Cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4-tert-butoxycarbonyl-1-piperazinecarboxylate (818 mg, 1.24 mmol), prepared as in Example 7, was reacted with neat for 10 minutes. TFA (2 mL). The mixture was concentrated in vacuo. A colorless oil is obtained. The residue was triturated with ethyl ether (2 x 10 mL) and dried in vacuo. A colorless foam is obtained. The residue was taken up in DMF (2 mL) followed by DIEA (700 mL, 4.0 mmol) and tert-butyl 4- (2-isocyanatoethyl) -1-piperidinecarboxylate (3.2 mL, 0.39M in DMF) was added. , 1.25 mmol). The mixture was stirred for 12 hours. It is then concentrated in vacuo. The residue was triturated with water (2 x 5 ml) and dried in vacuo. A yellow solid is obtained. This solid was then treated with TFA (2 mL) and the mixture was concentrated in vacuo. The residue is shaken into water. Purification of the aqueous mixture by preparative reverse phase HPLC afforded cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate as an amorphous colorless solid. Mass spectrum (plasma desorption, LRMS): calculated for C ₃₅ H ₅₅ N ₁₀ O ₆ :

712.9 (MH ⁺ ), found: 713.2 (MH ⁺ ).

Following the procedure of Example 8 and using various starting materials, the following disubstituted cyclic compounds of formula I were prepared:

cis-1,5-cyclooctylene 4- (4-aminobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (compound 2); for ₅₀ 35Η ^ Ν ₁₀ Ο ₆ Calculated: 707.9 (MH ^+), found: 707.7 (MH ^+), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4 (piperidylmethylcarbamoyl) -1-piperazinecarboxylate (compound 3); calcd. for C ₃₄ H ₅₃ N ₁₀ O ₆ 698.9 (MH ⁺ ), found 699.7 (MH ⁺ ), 9 9 9 ', 9 9 9 9 9 9 «» ·· 9 9 9 999 9 10

9 9 9 9 cis-1,5-Cyclooctylene 4- (trans-4-aminocyclohexylmethylcarbamoyl) -1-piperazinecarboxylate 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate ( Compound 4); for C ₃₅ H ₅₅ N ₁₀ O ₆ calculated: 712.9 (ΜΗ *), found: 713.6 (MH +), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazine from incarboxylate 3 -piperid-4-ylpropylcarbamoyl-1-piperazinecarboxylate (compound 5); calculated for C ₃₆ H ₅₈ N ₁₀ O ₆ 727.9 (*), found: 727.9 (*),

4- [4- (2-piperid-4-ylethylcarbamoyl) piperazin-1-ylcarbonyl] benzyl 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (Compound 6); Calcd for C ₃₄ H ₄₈ N ₁₀ O ₅ 677.8 (MH +), found:

677.6 (MH ⁺ ),

4- [4- (3-piperid-4-ylpropylcarbamoyl) piperazin-1-ylcarbonyl] benzyl 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (Compound 7); for C ₃₅ H ₅ O io ⁿ ° 5: calculated: 691.9 (MH +) found:

691.5 (MH ⁺ ),

4- [4- (4-piperid-4-ylbutylcarbamoyl) piperazinylcarbonyl] benzyl 1-4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (Compound 8); Calcd for C ₃₆ H ₅₂ N ₁₀ O ₅ 705.9 (MH ⁺ ), found:

705.9 (MH ⁺ ),

4- [4- (4-guanidinobenzylcarbamoyl) -1-piperazin-1-ylcarbonyl] benzyl 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate (Compound 9); calculated for C ₃₄ H ₄₈ N ₁₀ O ₅ 677.8 (MH ⁺ ), found 677.7 (MH ⁺ ),

4- [4- (4-guanidinobenzylcarbamoyl) -1-piperazin-1-ylcarbonyl] benzyl 4- (3-piperid-4-ylpropylcarbamoyl) -1-piperazinecarboxylate (Compound 10); for C ₃₅ H ₁₀ N _5Q O ₅ Calculated: 691.9 (MH ^+), found: 691.3 (ΜΗ *)

4- [4- (2-piperidin-4-ylethylcarbamoyl) piperazin-1-ylcarbonylmethyl] benzyl 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (Compound 11); calculated: 691.9 (*), found: 692.1 (MH ⁺ ),

4- [4- (3-piperid-4-ylpropylcarbamoyl) piperazin-1-ylcarbonyl Imethyl] benzyl 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (Compound 12); for C ₃ ^H 52 ^{N 10} ° 5 calculated: 705.9 (ΜΗ *), found: 705.6 (ΜΗ *), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1 • ·

piperazinecarboxylate 4- (4-methylaminomethylbenzylcarbamoyl) -1-piperazinecarboxylate (Compound 13); for C ₃₇ H ₅₄ N ₁₀ O ₆ calculated:

735.9 (MH ⁺ ), found: 735.7 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate ( Compound 14); for ^C 3 ^H 55 ^N ₅ ^O 9 6 Calculated: 698.9 (MH ^+), found: 698.2 (MH ^+), cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- (3-piperid-4-ylpropylcarbamoyl-1-piperazinecarboxylate (Compound 15) calcd. For C ₃₆ H ₅₇ N ₉ O ₆ 712.9 (MH ⁺ ), found: 712.3 (MH ⁺ ), cis-1, 5-Cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-imidazol-1-ylbutylcarbamoyl) -1-piperazinecarboxylate (Compound 16) calcd for C ₃₅ H ₅₃ N ₁₁ O ₆ 724.9 (MH ⁺ Found: 724.5 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-imidazolin-2-ylaminobutylcarbamoyl) -1-piperazinecarboxylate (Compound 17); for ^C 35 ^H 56 ^N 12 ° 6 calculated: 741.9 (MH ⁺ ), found: 741.7 (MH ⁺ ), cis-1,5-cyclooctylene 4- (trans-4-aminocyclohexylmethylcarbamoyl) -1-piperazinecarboxylate 4 - (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (compound 18) calculated for C ₃₅ H ₅₆ N _W O ₆ :

713.9 (MH ⁺ ), found: 714.1 (MH ⁺ ), cis-1,5-cyclooctylene 2- (1-tert-butyryloxymethoxycarbonylpiperid-4-yl) ethylcarbamoyl) -1-piperazinecarboxylate 4- (4-guanidinobenzylcarbamoyl) - 1-piperazinecarboxylate (compound 19); for ^C 42 ^H 66 ^{N 10 O 10} calculated: 872.1 (MH ⁺ ), found: 871.8 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- [ 2- (1-methylpiperid-4-yl) ethylcarbamoyl] -1-piperazinecarboxylate (Compound 20); for C ₃₆ H _{5 S} N _{1 ()} O ₆ Calculated: 364.0 (MH ₂ ²⁺ / 2), found: 364.3 (MH ₂ ²⁺ / 2), cis-1,5-cyclooctylene 4- (4 -guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (3-imidazolin-2-ylaminopropylcarbamoyl) -1-piperazinecarboxylate (Compound 21); for C ₃₄ H ₅₄ N ₁₂ O ₆ calculated: 727.9 (MH ⁺ ), found: 728.0 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-pi · · ·

4- [1- (1-Imonoethyl) piperid-4-ylmethylcarbamoyl] -1-piperazinecarboxylate perazinecarboxylate (Compound 22); for ^C 36 ^H 57 ^N 11 ° 6 calculated: 740.9 (MH ⁺ ), found: 740.5 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinobenzoylaminomethyl) -1-piperazinecarboxylate 4- ( 2-piperid-4-yl-ethylcarbamoyl) -1-piperazinecarboxylate (compound 23); for C ₃₆ H ₅₇ N _? O ₆ calculated:

712.9 (MH ⁺ ), found: 711.6 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-amidinobenzylcarbamoyl) -1-piperazinecarboxylate 2- (1-methoxycarbonylpiperid-4-yl) ethylcarbamoyl-1 -piperazinecarboxylate (compound 24); for ^C 37 ^H 57 ^N 9 ° 8 calculated: 756.9 (MH ⁺ ), found: 756.7 (MH ⁺ ), and

- {4- [2- (4- {cis-5- [4- (4-amidinobenzylcarbamoyl) piperazin-1-ylcarbonyloxy] cyclooctyloxycarbonyl} piperazin-1-ylcarbonylamino) ethyl] piperid-1-ylcarbonyl} propionic acid (Compound 25 ); calcd for C ₃₉ H ₆₀ N ₉ O ₉ 799.0 (MH ⁺ ), found 798.6 (MH ⁺ ).

When proceeding as in Example 8 and replacing the isocyanate with the active ester, the following disubstituted cyclic compounds of formula I are prepared:

cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4-imidazol-4-ylacetyl-1-piperazinecarboxylate (Compound 26); for C ₃₂ H ₄₆ N ₁₀ O ₆ calculated: 667.8 (MH ⁺ ), found: 667.7 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- ( E-3-imidazol-4-ylacryloyl) -1-piperazinecarboxylate (compound 27); for ^c 33 ^H 46 ^N ₁₀ O ₆ calculated: 679.9 (MH ⁺ ), found: 679.9 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (3- imidazol-4-ylpropionyl) -1-piperazinecarboxylate (compound 28); for C ₃₃ H ₄₈ N ₁₀ O ₆ calculated: 681.8 (MH ⁺ ), found: 681.7 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- ( 5-imidazol-1-ylvaleryl) -1-piperazinecarboxylate (compound 29); for ^c 35 H ₅₂ N ₁₀ O ₆ calculated: 709.9 (MH ⁺ ), found: 709.5 (MH ⁺ ),

cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (6-imidazol-1-ylhexanolyl) -1-piperazinecarboxylate (compound 30); for ^c ₃₆ H ₅₄ N ₁₀ O ₆ calculated 723.9 (MH ⁺ ), found: 723.4 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4 -imidazol-1-ylmethyl-phenylacetyl) -1-piperazinecarboxylate (compound 31); calculated for C ₃ H ₅₂ N ₁₀ O ₆ :

757.9 (MH ⁺ ), found: 757.2 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-imidazol-1-ylmethylbenzoyl) -1-piperazinecarboxylate ( Compound 32); for C ₃₈ H ₅₀ N ₁₀ O ₆ calculated: 743.9 (MH ⁺ ), found: 743.7 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- ( 3-imidazol-1-ylmethylbenzoyl) -1-piperazinecarboxylate (compound 33); for Ο _3θ Η _5θ Ν _1θ Ο ₆ calculated: 743.9 (MH ⁺ ), found: 743.6 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (7 imidazol-1-ylheptanoyl) -1-piperazinecarboxylate (Compound 34; calculated for C ₃₇ H ₅₆ N ₁₀ O ₆ 737.9 (MH ⁺ ), found: 737.6 (MH ⁺ ), cis-1,5-) Cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- [6- (2-methylimidazol-1-yl) hexanoyl] -1-piperazinecarboxylate (Compound 35): calculated for C ₃ H ₅₆ N ₁₀ O ₆ :

737.9 (MH ⁺ ), found: 737.3 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-imidazol-1-ylphenoxyacetyl) -1-piperazinecarboxylate ( Compound 36); for C ₃₈ H ₅₀ N _W O ₇ Calculated: 759.9 (MH ^+), found: 759.3 (MH ^+), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- [ 6- (4-methylimidazol-1-yl) hexanoyl] -1-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 N _W O ₆ 737.9 (MH ⁺ ), found: 738.2 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- ( 4-piperid-4-ylbutyryl) -1-piperazine • carboxylate (compound 38); for C ₃₆ H ₅₇ N _? O ₆ calculated: 712.9 (MH ⁺ ), found: 712.4 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate (compound 39); Calcd for C ₃₆ H ₅₆ N _g O ₆ 697.9 (MH ⁺ ), found:

697.5 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethyl) (methyl) carbamoyl-1-piperazinecarboxylate (compound 40); for ^C 36 ^H 58 ^{N 10} ° calculated 727.9 (MH ⁺ ), found: 727.6 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- ( 2-piperid-4-yl-ethyl) (methyl) carbamoyl-1-piperazinecarboxylate (compound 41); calculated for C ₃₆ H ₅₇ N ₉ O ₆ :

712.9 (MH ⁺ ), found: 712.7 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- [2-piperid-4-ylethoxycarbonyl) -1- piperazinecarboxylate (compound 42); for C ₃₅ H ₅₅ N ₉ O ₇ calculated: 714.9 (MH ⁺ ), found: 714.5 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- ( 4-Imidazol-1-yl-phenylacetyl) -1-piperazinecarboxylate (Compound 43); for C ₃₈ H ₅₀ N ₁₀ O ₆ calculated: 743.9 (MH ⁺ ), found: 743.6 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- ( 6-imidazol-1-ylhexanoyl) -1-piperazinecarboxylate (Compound 44); for C ₃₆ H ₅₃ N ₉ O ₆ calculated 708.9 (MH ⁺ ), found: 708.8 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- ( 3-pyrid-4-ylthiopropionyl) -1-piperazinecarboxylate (Compound 45); Calcd for C ₃₅ H ₄₉ N ₉ O ₆ 724.9 (MH ⁺ ), found: 724.4 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4-pyrid -4-ylthioacetyl-1-piperazinecarboxylate (Compound 46); Calcd for C ₃₄ H ₄₇ N ₉ O ₆ 710.9 (MH ⁺ ), found: 710.8 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- ( 3-pyrid-4-ylthiopropionyl) -1-piperazinecarboxylate (compound 47); Calcd for C ₃₅ H ₄₈ N ₈ O ₆ 709.9 (MH ⁺ ),

Found: 709.3 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (6-imidazol-4-ylhexanoyl) -1-piperazinecarboxylate (Compound 48); calculated for C ₃₆ H ₅₄ N ₁₀ O ₆ 723.9 (MH ⁺ ), found: 723.5 (MH ⁺ ), cis-1,5-cyclooctylene 4- (benzoimidazol-6-ylcarbonyl) -1-piperazinecarboxylate 4 - (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (compound 49); for C ₃₅ H ₄₇ N _W O ₆ calculated: 703.8 (MH ⁺ ), found: 703.4 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-amidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- ( 6-imidazol-1-ylhexanoyl) -1-piperazinecarboxylate (Compound 50); for C ₃₆ H ₅₃ N ₉ O ₆ calculated 708.9 (MH ⁺ ), found: 708.6 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-amidinobenzolaminomethyl) -1-piperidinecarboxylate 4- ( 6-imidazol-4-ylhexanoyl) -1-piperazinecarboxylate (Compound 51); for C ₃₇ H ₅₄ N _g O ₆ calculated: 707.9 (MH ⁺ ), found: 707.5 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- ( 6-imidazol-1-ylhexanoyl) -1-piperazinecarboxylate (Compound 52); for C ₃₅ H ₅₂ N ₁₀ O ₆ calculated 708.9 (MH ⁺ ), found: 708.4 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4-pyrid -4-ylcarbamoylacetyl-1-piperazinecarboxylate (Compound 53); for C ₃₅ H ₄₇ N ₉ O ₇ calculated: 706.8 (MH ⁺ ), found: 706.3 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- ( 3-pyrid-4-ylaminopropionyl) -1-piperazinecarboxylate (Compound 54); for C ₃₅ H ₅₀ N ₁₀ O ₆ calculated: 707.9 (MH ⁺ ), found: 707.3 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 3- [ pyrid-4-yl (tert-butoxycarbonyl) amino] propionyl-1-piperazinecarboxylate (compound 55); for C ₄₀ H ₅₈ N ₈ O _1Q Calculated: 404.5 (MH ₂ ²⁺ / 2), found: 404.2 (MH ₂ ²⁺ / 2), cis-1,5-cyklooktylen4- (4guanidinobenzylcarbamoyl) 4- (3-piperazin-1-ylcarbonylpropionyl) -1-piperazinecarboxylate -1-piperazinecarboxylate (Compound 56); calculated for C ₃₅ H ₅₄ N ₁₀ O ₇ :

727.9 (MH ⁺ ), found: 727.5 (MH ⁺ ),

cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4-piperid-1-ylcarbonylaminoacetate^1-1-?¹? ® once an incarboxylate (compound 57); why₃₅H₅₄N₁₀O₇ Calcd .: 727.9 (MH +)⁺), found: 727.5 (MH +)⁺cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (5-imidazol-4-ylvaleryl) -1-piperazinecarboxylate (compound 58); for^C35^H52^N°10 ° calculated: 708.9 (MH +)⁺), found: 709.4 (MH +)⁺cis-1,5-cyclooctylene 4- (4-amidinobenzoylaminomethyl) -1-piperidinecarboxylate 4- (3-piperazin-1-ylcarbonylpropionyl) -1-piperazinecarboxylate (Compound 59); why₃₆H₅₄N₈O₇ calculated:

711.9 (MH ⁺ ), found: 711.4 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-amidinobenzoylaminomethyl) -1-piperidinecarboxylate 4-piperid-4-ylcarbonylaminoacetyl-1-piperazinecarboxylate (Compound 60 ); for C ₃₆ H ₅₄ N ₈ O ₇ calculated: 711.9 (MH ⁺ ), found: 711.4 (MH ⁺ ), cis-1,5-cyclooctylene 4- [3- (2-aminopyridin-5-yl)] propionyl] -1-piperazinecarboxylate 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (Compound 61); for C ₃₄ H ₄₉ N ₁₁ O ₆ calculated: 708.8 (MH ⁺ ), found: 708.4 (MH ⁺ ), cis-1,5-cyclooctylene 4- [3- (6-aminopyrid-5-yl)] propionyl] -1-piperazinecarboxylate 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (Compound 62); for C ₃₅ H ₅₀ N ₁₀ O ₆ calculated: 707.8 (MH ⁺ ), found: 707.4 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4 [4] - (4-pyrid-4-ylthio) butyryl] -1-piperazinecarboxylate (compound 63); calculated for C ₃₆ H ₅₁ N ₉ O ₆ 738.9 (MH ⁺ ), found 738.4 (MH ⁺ ), cis-1,5-cyclooctylene 4- [3- (2-amino-2,4-) dioxo-1,2,3,4-tetrahydropyrimidin-5-yl) propionyl] -1-piperazinecarboxylate 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (Compound 64); for C ₃₄ H ₄₈ N ₈ O _1Q Calculated: 725.8 (MH ^+), found: 725.2 (MH ^+), cis-1,5-cyclooctylene 4- (4-amidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- ( 4-piperid-4-ylbutyryl) -1-piperazinecarboxylate (compound 65); calcd for C ₃₆ H ₅₆ N ₈ O ₆ 697.9 (MH ⁺ ), found: 697.4 (MH ⁺ ), • «

• ·

cis-1,5-cyclooctylene 4- (4-amidinobenzoylaminomethyl) -1-piperidinecarboxylate 4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate (Compound 66); calculated for C ₃₇ H ₅₇ N ₇ O ₆ 696.9 (MH ⁺ ), found 696.4 (MH ⁺ ), cis-1,5-cyclooctylene 4- (1-amidinopiperid-4-ylacetyl) -1- piperidinecarboxylate 4- (6-imidazol-1-ylhexanoyl) -1-piperazinecarboxylate (Compound 67); for C ₃₅ H ₅₇ N ₉ O ₆ calculated: 700.9 (MH ⁺ ), found: 700.5 (MH ⁺ ), cis-1,5-cyclooctylene 4- (1-amidino-4-piperidylacetyl) -1- piperazinecarboxylate 4- (4-piperid-1-ylbutyryl) -1-piperazinecarboxylate (compound 68); for C ₃₅ H ₆₀ N ₈ O ₆ calculated: 689.9 (MH ⁺ ), found: 689.4 (MH ⁺ ), cis-1,5-cyclooctylene 4- (1-amidino-4-piperidylacetyl) -1- piperazinecarboxylate 4- (6-imidazol-1-ylhexanoyl) -1-piperazinecarboxylate (compound 69); for C ₃₅ H ₅₇ N ₉ O ₆ calculated: 700.9 (MH ⁺ ), found: 700.4 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-amidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- ( 6-imidazol-1-ylhexanoyl) -1-piperazinecarboxylate (compound 70); for C ₃₆ H ₅₃ N ₉ O ₆ calculated: 708.9 (MH ⁺ ), found: 708.4 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-amidinobenzoylaminomethyl) -1-piperidinecarboxylate 4- ( 6-imidazol-4-ylhexanoyl) -1-piperazinecarboxylate (compound 71); for C ₃₇ H ₅₄ N ₈ O ₆ calculated: 707.9 (MH ⁺ ), found: 707.4 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-amidinophenylacetyl) -1-piperazinecarboxylate 4- ( 6-imidazol-1-ylhexanoyl) -1-piperazinecarboxylate (compound 72); for ^C 36 ^H 52 ^N 8 ° 6 ⁱⁿ YP ° read: 693.9 (MH ⁺ ), found:

693.4 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-amidinophenylacetyl) -1-piperazinecarboxylate 4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate (Compound 73); Calcd for C ₃₆ H ₅₅ N ₇ O ₆ 682.9 (MH ⁺ ), found:

682.4 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-amidinophenylacetyl) -1-piperazinecarboxylate 4- (6-imidazol-4-ylhexanoyl) -1-piperazinecarboxylate (compound 74); Calcd for C ₃₆ H ₅₂ N ₈ O ₆ 693.9 (MH ⁺ ), found:

693.4 (MH ⁺ ) and cis-1,5-cyclooctylene 4- (4-amidinobenzylcarbamoyl) -1-β-perazinecarboxylate 4- [4- (2- (1-tert-butylcarbonyloxymethoxycarbonyl) piperidine- 4-ylethylcarbamoyl) -1-piperazinecarboxylate (compound 75); Calcd for C ₄₂ H ₆₅ N ₉ O ₁₀ 857.0 (MH ⁺ ), found:

856.6 (MH ⁺ ).

Example 9 cis-1,5-Cyclooctylene di (4-tert-butoxycarbonyl-1-piperazinecarboxylate) cis-1,5-Cyclooctylene di (chloroformate) (3.69 g, 13.7 mmol), prepared as in Example 5, and DIEA (7.2 mL, 41 mmol) was dissolved in DMF (25 mL) and tert-butyl 1-piperazinecarboxylate (5.1 g, 27.4 mmol) was added. The mixture was stirred at room temperature for 12 hours and then concentrated in vacuo. A semi-solid residue is obtained. This residue was partitioned between dichloromethane (50 mL) and water (50 mL). The dichloromethane layer was washed with 0.1 N aqueous hydrochloric acid (2 x 25 mL), dried (magnesium sulfate), and filtered. Concentration in vacuo afforded cis-1,5-cyclooctylene di (4-tert-butoxycarbonyl-1-piperazinecarboxylate) as an amorphous solid. ¹ H NMR spectrum (300 MHz, CDCl ₃ ): 4.80 (m, 2H), 3.40 (broad s, 16H), 2.00 to 1.40 (m, 12H), 1.40 (s,

18H).

Example 10 cis-1,5-Cyclooctylene di [4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate] (compound 76)

This example is the preparation of a disubstituted cyclic compound of formula I wherein R ¹ and R ² are both 2-piperid-4-ylethyl, X ¹ and X ⁹ are both -NHC (O) -, X ² and X ⁸ are both

1,4-piperazinylene, X ³ and X ⁷ are both -C (O) O-, X ⁴ and X ⁶ are both a covalent bond and X ⁵ are cis-1,5-cyclooctylene.

cis-1,5-Cyclooctylene di (4-tert-butoxycarbonyl-1-piperazinecarboxylate) (47.9 mg, 0.088 mmol), prepared as in Example 4

9, was treated with pure TFA (1 mL) for 10 minutes. A colorless oil is obtained. The mixture was concentrated in vacuo and the residue was triturated with ethyl ether (2 x 5 mL) and dried repeatedly in vacuo. An amorphous solid is obtained. This solid residue was dissolved in DMF (5 mL) and DIEA (100 mL, 0.05 mmol) and tert-butyl 4- (2-isocyanatoethyl) -1-piperidinecarboxylate (460 mL, 0.39M in ethyl acetate) was added to the solution. DMF, 0.18 mmol). The mixture was stirred for 12 hours and concentrated in vacuo. The residue was triturated with water (2 x 5 ml) and dried in vacuo. A yellow solid is obtained. This solid was treated with TFA (2 mL) and the mixture was concentrated in vacuo. The residue was dissolved in water. Purification of the aqueous mixture by preparative reverse phase HPLC followed by lyophilization afforded cis-1,5-cyclooctylene di [4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate] as a colorless amorphous solid. Mass spectrum (electrospray, LRMS): Calcd. For C ₄₅ H ₆₀ N ₈ O ₆ :

677.9 (MH ⁺ ), found: 677.6 (MH ⁺ ).

When proceeding as in Example 10 and using other starting materials, cis-1,5-cyclooctylene di [4- (4-methylaminomethylbenzylcarbamoyl) -1-piperazinecarboxylate] was prepared (compound 77); For C ₃₈ H ₅₆ N ₈ O ₆ calculated: 721.9 (MH ⁺ ), found: 721.7 (MH ⁺ ).

When proceeding as in Example 10 and replacing the isocyanate with the active ester, the following disubstituted cyclic compounds of formula I are prepared:

cis-1,5-cyclooctylene di [4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate] (compound 78); for C ₃₆ H ₆₂ N ₆ O ₆ calculated:

675.9 (MH ⁺ ), found: 675.6 (MH ⁺ ) and para-dimethylenophenylene di [4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate] (compound 79); calculated for C ₃₆ H ₅₆ N ₆ O ₆ :

669.9 (MH ⁺ ), found: 669.4 (MH ⁺ ).

«999 • 9 9999

Example 11 Tert -Butyl 4-chlorocarbonyl-1-piperazinecarboxylate (188 mg, 0.76 mmol), prepared as in Example 3, was dissolved in dichloromethane butyl 4- (3-imidazolyl-1-propylcarbamoyl) -1-piperazo-incarboxylate (10 mL) and DIEA (150 mL, 0.86 mmol) was added. 1- (3-Aminopropyl) imidazole (100 mL, 0.84 mmol) was added via syringe and the mixture was stirred for 12 hours. Dichloromethane (10 mL) was added to the mixture, and the organic layer was washed with water (1 x 10 mL), dried over magnesium sulfate and filtered. Concentration gave tert-butyl 4- (3-imidazol-1-ylpropylcarbamoyl) -1-piperazinecarboxylate (230 mg, 0.68 mmol, 90% yield) as a colorless oil. ¹ H NMR spectrum (300 MHz, DMSO-d ₆ ): 7.60 (s, 1H), 7.20 (s, 1H), 6.85 (s, 1H), 6.60 (t, 1H), 3.95 (t, 2H), 3.30 (s, 8H), 3.00 (q, 2H), 1.80 (m, 2H), 1.40 (s, 9H).

Example 12

Tert-Butyl 4-aminomethyl-1-benzenecarbamate hydrochloride

4-Aminobenzylamine (5.56 g, 45.6 mmol) was dissolved in water (45 mL) and citric acid (9.63 g, 50 mmol) was added. To this solution was added dropwise di-tert-butyl dicarbonate (9.94 g, 45.5 mmol) in dioxane (20 mL) and the mixture was stirred at room temperature for 48 hours. A yellow suspension is obtained. The suspension was filtered, the aqueous solution basified with excess solid sodium carbonate and extracted with ethyl acetate (3 x 35 mL). The combined extracts were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo to give a white solid. This solid was dissolved in methanol (30 mL), acidified with hydrogen chloride in dioxane (4M, 8.4 mL, 33.6 mmol) and then ethyl ether (100 mL) was added. A suspension is obtained. The solid material was isolated by filtration. Drying in vacuo afforded tert-butyl 4-aminomethyl-1-benzenecarbamate hydrochloride (7.2 g, 27.8 mmol, yield 9). ♦ · ··

4 9 • »· * 9 9 9 9

%) as a colorless solid. ¹ H NMR Spectrum (300 MHz, DMSO-d ₆ ): 9.43 (s, 1H), 8.20 (broad s, 3H), 7.40 (dd AB, 4H), 3.92 (m, 2H) 1.50 (s, 9H).

Example 13 Butyl 4-isocyanate omethyl 1-1-benzene carbamate

Tert-Butyl-4-aminomethyl-1-benzenecarbamate hydrochloride (3.39 g, 13.1 mmol), prepared as in Example 12, was dissolved in dichloromethane (120 mL) at 0 ° C and pyridine (4 mL) was added. , 3 mL, 53 mmol) and triphosgene (1.3 g, 4.4 mmol). The mixture was allowed to warm to room temperature over 30 minutes and aqueous hydrochloric acid (0.5N, 100 mL) was added. The organic layer was dried over magnesium sulfate and filtered. Concentration gave tert-butyl 4-isocyanometomethyl-1-benzenecarbamate (2.7 g, 11 mmol, 84% yield) as a yellow solid. ¹ H NMR Spectrum (300 MHz, CDCl ₃ ): 7.29 (dd AB, 4H), 6.55 (broad s, 1H), 4.40 (s, 2H), 1.55 (s, 9H).

Example 14 cis-1,5-Cyclooctylene 4- (4-aminobenzylcarbamoyl) -1-piperidinecarboxylate 4- (3-imidazol-1-ylpropylcarbamoyl) -1-piperazinecarboxylate (Compound 80)

This example is the preparation of a disubstituted cyclic compound of formula I wherein R ¹ and R ² are 4-aminobenzyl, R ² is 3-imidazol-1-ylpropyl, X ¹ and X ⁹ are both -NHC (O) -, X ² X ⁸ is 1,4-piperazinylene, X ³ and X ⁷ are both -C (O) O-, X ⁴ and X ⁶ are both a covalent bond and X ⁵ is cis-1,5-cyclooctylene.

a) tert -Butyl 4- (3-imidazol-1-ylpropylcarbamoyl) -1-piperazinecarboxylate (225 mg, 0.67 mmol), prepared as in Example

11, was allowed to react for 10 minutes with pure TFA (1 mL). The mixture was concentrated in vacuo and the residue was taken up in dichloromethane (10 mL).

• ·

To this solution was added excess DIEA (1.0 mL), 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 this 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 (1 x 10 mL), dried over magnesium sulfate, and filtered. Concentration affords the crude cis-1,5-cyclooctylene 4- (3-imidazol-1-ylpropylcarbamoyl) -1-piperazinecarboxylate t-butoxycarbonyl-piperazinecarboxylate adduct as a colorless foam.

b) The adduct produced in part a) is reacted with pure TFA (1 ml) for 10 minutes and then concentrated in vacuo. The residue was dissolved in DMF (10 mL) and excess DIEA (1.5 mL) and tert-butyl 1-4-isocyanatomethyl-1-benzenecarbamate (165 mg, 0.67 mmol), prepared as in Example 13, were added. the mixture was stirred for 12 hours and concentrated in vacuo. The residue was treated with pure TFA and the mixture was concentrated in vacuo. The residue was dissolved in water (15 mL) and the aqueous solution was extracted with ethyl ether (1 x 15 mL). The aqueous layer was basified with 1.0 M aqueous sodium hydroxide and then extracted with dichloromethane. The dichloromethane was dried over magnesium sulfate and filtered. Concentration in vacuo afforded cis-1,5-cyclooctylene 4- (4-aminobenzylcarbamoyl) -1-piperidinecarboxylate 4- (3-imidazol-1-ylpropylcarbamoyl) -1-piperazinecarboxylate as a colorless foam. ¹ H NMR spectrum (300 MHz, CDCl ₃ ): 7.45 (s, 1H), 7.10 (d, 2H), 7.05 (s, 1H), 6.90 (s, 1H), 6, 60 (d, 2H), 4.85-4.70 (m, 4H), 4.30 (d, 2H), 4.00 (t, 2H), 3.50-3.30 (m, 18H) 2.00 (m, 2H), 1.90-1.50 (s, 12H).

When proceeding as in Example 14a and using other starting materials, the following disubstituted cyclic compounds of formula I were prepared:

cis-1,5-cyclooctylene 4- (4-aminobenzylcarbamoyl) -1-piperidinecarboxylate 4- (2-pyrid-4-ylethylcarbamoyl) -1-piperazinecarboxylate (compound 81), cis-1,5-cyclooctylene 4- (4- aminobenzylcarbamoyl) -1-pipe

4- (3-piperid-4-ylpropyl) -1-piperidinecarboxylate (compound 82) and cis-1,5-cyclooctylene 4- (4-aminobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-piperid-4-ylbutyl) - 1-piperidinecarboxylate (Compound 83).

Example 15 cis-1,5-Cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (3-imidazol-1-ylpropylcarbamoyl) -1-piperazinecarboxylate (Compound 84)

This example is the preparation of a compound of formula I wherein R ¹ is 4-guanidinobenzy1, R ² is 3-imidazol-l-yl-propyl, X ¹ and X ⁹ represents -NHC (O) -, X ² and X ⁸ X is both 1,4-piperazinylene, X ³ and X ⁷ are both -C (O) O-, X ⁴ and X ⁶ are both covalent bond and X ⁵ is cis-1,5-cyclooctylene.

cis-1,5-Cyclooctylene 4- (4-aminobenzylcarbamoyl) -1-piperazinecarboxylate 4- (3-imidazol-1-ylpropylcarbamoyl) -1-piperazinecarboxylate, prepared as in Example 14, was dissolved in methanol and ethyl ether and an excess was added. hydrogen chloride (4M in dioxane). The mixture was concentrated and dried in vacuo. Excess cyanamide (1.0 g) was added and the mixture was heated to 65 ° C for two hours. A yellow solution is obtained. The mixture was allowed to cool to room temperature and triturated with ethyl ether (3 x 10 mL). The insoluble residue is dissolved in water. Purification of this aqueous mixture by preparative reverse phase HPLC afforded cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (3-imidazol-1-ylpropylcarbamoyl) -1-piperazinecarboxylate as a colorless amorphous solid. Mass spectrum (electrospray, LRMS) calcd. For C ₃₄ H ₅₁ N ₁₁ O ₆ 710.9 (MH ⁺ ), found 710.6 (MH ⁺ ).

When proceeding as in Example 15 and using other starting materials, the following disubstituted cycles were prepared.

Organic compounds of formula I:

cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (2-pyrid-4-ylethylcarbamoyl) -1-piperazinecarboxylate (compound 85); for C ₃₅ H ₅₀ N ₁₀ O ₆ calculated: 707.9 (MH ⁺ ), found: 707.6 (MH ⁺ ), cis-1,5-cyclooctylene 3-piperid-4-ylpropyl-1-piperidinecarboxylate 4- ( 4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (Compound 86) and cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4-piperid-4-yl-butyl-1-piperidinecarboxylate (Compound 87); Calcd for C ₃₇ H ₆₀ N ₈ O ₅ 697.9 (MH ⁺ ), found: 697.7 (MH ⁺ ).

Example 16 cis-1,5-Cyclooctylene chloroformate 4-benzyloxycarbonyl-1-piperazinecarboxylate

Benzyl 1-piperazinecarboxylate (1.0 g, 4.53 mmol, 1.0 eq) and DIEA (0.88 mL, 4.98 mmol, 1.1 eq) in dichloromethane (25 mL) was added dropwise to cis-1,5-cyclooctylene di (chloroformate) (1.2 g, 4.53 mmol, 1.0 eq), prepared in Example 5, in dichloromethane (25 mL) at 0 ° C. The reaction mixture was stirred for 22 hours while allowing to warm to room temperature. This mixture was partitioned between dichloromethane, 0.05N aqueous hydrochloric acid and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate and concentrated. Purification of the residue by flash column chromatography eluting with 20 and 30% ethyl acetate in hexanes gave cis-1,5-cyclooctylene chloroformate 4-benzyloxycarbonyl-1-piperazinecarboxylate (0.81 g, 1.81 mmol, 40%) as a yellow oil . IR: 2939 (s), 2863 (m), 1770 (s), 1732 (s), 1696 (s). ¹ H NMR spectrum (300 MHz, CDCl ₃ ): 7.35 (s, 5H), 5.15 (s, 2H), 4.95 (m, 1H), 4.75 (m, 1H), 3, 45 (s, 8H), 1.50-2.05 (m, 12H).

0 0 0 0

0 0 «• S ·· ··

Example 17 1- [cis-5- (4-Benzyloxycarbonylpiperazin-1-ylcarbonyloxy) cyclooctyloxycarbonyl] -4-piperidinecarboxylic acid

Isonipecotic acid (75 mg, 0.58 mmol, 1.1 eq.) And DIEA (0.23 mL, 1.33 mmol, 2.5 eq.) Were added to cis-1,5-cyclooctylene chloroformate 4-benzyloxycarbonyl. 1-piperazinecarboxylate (0.24 g, 0.53 mmol, 1.0 eq), prepared as in Example 16, in dichloromethane (10 mL) at 0 ° C. A white suspension is obtained. The suspension was stirred for 18 hours while allowing to warm to room temperature. The reaction mixture was partitioned between dichloromethane and 0.05N aqueous hydrochloric acid. Concentration of the organic layer gave crude 1- [cis-5- (4-benzyloxycarbonylpiperazin-1-ylcarbonyloxy) cyclooctyloxycarbonyl] -4-piperidinecarboxylic acid (0.36 g) as a colorless oil. ¹ H NMR Spectrum (300 MHz, CDCl ₃ ): 7.35 (s, 5H), 5.15 (s, 2H), 4.75 (m, 2H), 3.90 (m, 1H), 3, 45 (s, 8H), 2.75 (m, 1H), 2.50 (m, 3H), 1.50 to 1.90 (m,

16H).

Example 18 cis-1,5-Cyclooctylene-4-benzyloxycarbonyl-1-piperazinecarboxylate 4- [2- (1-tert-butoxycarbonylpiperidin-4-yl) ethylcarbamoyl] -1-piperidinecarboxylate

1-Hydroxybenzotriaxol hydrate (80 mg, 58.3 mmol, 1.1 eq), tert-butyl 4- (2-aminoethyl) -1-piperidinecarboxylate hydrochloride (0.14 g, 0.53 mmol, 1, 0 eq) and 4-methylmorpholine (0.15 mL, 1.33 mmol, 2.5 eq) were added to a solution of crude 1- [cis-5- (4-benzyloxycarbonylpiperazin-1-ylcarbonyloxy) cyclooctyloxycarbonyl] -4 piperidine carboxylic acid (0.36 g, 0.53 mol, 1.0 eq), prepared as in Example 1, in DMF (5 mL). 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.13 g, 0.66 mmol, 1.25 eq) was added to the reaction mixture at 0 ° C. This solution was stirred at 0 ° C for 1.5 hours and at 23 ° C for three days. The reaction mixture was partitioned between dichloromethane, 0.05N aqueous acid.

hydrochloric acid, saturated aqueous sodium bicarbonate, water (two aliquots) and saturated aqueous sodium chloride. The organic layer was dried (sodium sulfate) and concentrated. Purification from the residue by flash column chromatography, eluting with 3% methanol in dichloromethane, afforded 4- [2- (1-tert-butoxycarbonylpiperodin-4-yl) ethylcarbamoyl] - cis-1,5-cyclooctylene 4-bezyloxycarbonyl-1-piperazinecarboxylate 1-piperidinecarboxylate (0.15 g, 0.2 mmol, 37% over two steps) as a yellow oil. ¹ H NMR spectrum (300 MHz, CDCl ₃ ): 7.35 (s, 5H), 5.15 (s, 2H), 4.80 (m, 2H), 4.10 (m, 4H), 3, 45 (s, 10H), 3.30 (m, 2H), 2.70 (m, 2H), 1.50-1.90 (m, 23H). Mass spectrum (electrospray, LRMS): Calcd. For C ₄₀ H ₆₂ N ₅ O ₉ 756.97 (MH ⁺ ), found: 757.0 (MH ⁺ ).

Example 19 cis-1,5-Cyclooctylene 1-piperazinecarboxylate 4- [2- (1-tert-butoxycarbonylpiperid-4-yl) ethylcarbamoyl] -1-piperidinecarboxylate

4- [2- (1-tert-Butoxycarbonylpiperazin-4-yl) ethylcarbamoyl] -1-piperidinecarboxylate (0.15 g, 0.20 mmol, 1) to cis-1,5-cyclooctylene 4-benzyloxycarbonyl-1-piperazinecarboxylate 1.0 eq), prepared as in Example 18, was added ethanol (3 mL) and 5% palladium on carbon (75 mg, 0.50 eq) under nitrogen. The mixture was stirred under hydrogen (0.1 MPa) for 17 h at 23 ° C. The reaction mixture was transferred under nitrogen and filtered. Concentration of the filtrate gave cis-1,5-cyclooctylene 1-piperazinecarboxylate 4- [2- (1-tert-butoxycarbonylpiperid-4-yl) ethylcarbamoyl] -1-piperidinecarboxylate (110 mg, 0.18 mmol, 90%) as colorless oil. ¹ H NMR Spectrum (300 MHz, CDCl ₃ ): 5.5 (m, 1H), 4.9 (m, 2H), 4.75 (m, 1H), 4.1 (m, 4H), 3, 45 (m, 4H), 3.25 (m, 2H), 2.60 to 2.85 (m, 8H), 2.10 (m, 1H), 1.50 to 1.90 (m, 23H) 1.45 (s, 9H). Mass spectrum (Electrospray LRMS) for C ₃₂ H ₅₆ N ₅ O ₇ Calculated: 622.83 (MH ^+), found 622.7.

I · ·· · ·

Example 20 cis-1,5-Cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperidinecarboxylate (Compound 88)

This example is the preparation of a compound of formula I wherein R ¹ is 4-guanidinobenzyl, ^R2 is 2-piperid-ylethyl, X ¹ and X ⁹ represents -NHC (O) -, X ² is 1, 4-piperazinylene, X ⁸ is 4,1-piperidylene, X ³ and X ⁷ are both -C (O) O-, X ⁴ and X ⁶ are both covalent bond and X ⁵ is cis-1,5-cyclooctylene.

Trifosgene (30 mg, 0.10 mmol, 0.58 eq.) And pyridine (30 mL, 0.39 mmol, 2.1 eq.) Were added to cis-1,5-cyclooctylene 1-piperazinecarboxylate 4- [2]. - (1-tert-butoxycarbonylpiperid-4-yl) ethylcarbamoyl] -1-piperidinecarboxylate (0.11 g, 0.18 mmol, 1.0 eq), prepared as in Example 19, in dichloromethane (2 mL) at 0 Deň: 32 ° C. The reaction mixture was stirred at 0 ° C for 3 hours. This mixture was partitioned between dichloromethane, 0.05 N aqueous hydrochloric acid and saturated aqueous sodium chloride. The organic layer was dried (sodium sulfate) and concentrated. A brown oily residue is obtained. To the residue was added 4-guanidinobenzylamine dihydrochloride (43 mg, 0.20 mmol, 1.1 eq) and DIEA (0.16 mL, 0.90 mmol, 5.0 eq) in DMF (2 mL). A suspension is obtained. The suspension was stirred at 23 ° C for 18.5 hours and concentrated. The residue was dissolved in 50% TFA in dichloromethane (4 mL) and stirred at 23 ° C for 45 min. The reaction mixture was concentrated and the residue was triturated with ether and dried in vacuo. Purification from reverse phase preparative HPLC and lyophilization afforded cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazincarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperidinecarboxylate as a colorless amorphous solid substance. Mass spectrum (electrospray, LRMS) calcd. For C ₃₆ H ₅₈ N ₉ O ₆ 712.91 (MH ⁺ ), found: 712.8.

Following the procedure of Example 20 and using other starting materials, the following disubstituted cyclic compounds of formula (I) were prepared:

cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- (3-imidazol-4-ylpropylcarbamoyl) -1-piperazinecarboxylate (compound 89); for <2 ₃₄ Η _5θ Ν _1θ Ο ₆ calculated:

695.9 (MH ⁺ ), found: 695.4 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- (2-imidazol-4-ylethylcarbamoyl) -1- piperazinecarboxylate (compound 90); for C ₃₃ H ₄₈ N ₁₀ O ₆ calculated: 681.3 (MH ⁺ ), found: 680.9 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- ( 3-imidazol-ylpropylcarbamoyl) -1-piperazinecarboxylate (compound (91) for C ₃₄ H ₅₀ N ₆ O calculated _1Q:

695.9 (MH ⁺ ), found: 694.4 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- (4-imidazol-4-ylbutylcarbamoyl) -1-piperazinecarboxylate ( compound 92); calculated for C ₃₅ H ₅₃ N ₁₀ O ₆ :

709.9 (MH ⁺ ), found: 709.4 (MH ⁺ ), and cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (3-imidazol-1-ylpropylcarbamoyl) -1-piperazinecarboxylate (compound (93); calculated for C ₃₅ H ₅₁ N ₁₀ O ₆ :

709.9 (MH ⁺ ), found: 710.4 (MH ⁺ ).

Example 21

3-Piperid-4-yl-propionic acid hydrochloride

4-Pyridineacrylic acid hydrochloride (12.0 g, 64.6 mmol) and 1.37 g platinum oxide were suspended in acetic acid (80 mL) and hydrogenated at 350-420 kPa for 12 hours. 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. A white solid is obtained. This solid was suspended in a small amount of methanol, and the mixture was diluted with diethyl ether (200 mL). The precipitated material was collected by filtration and washed with diethyl ether and hexane. Air-drying gave 3-piperid-4-yl-propionic acid hydrochloride (11.3 g,

58.1 mmol, 90%) as a colorless solid. ¹ H NMR Spectrum (300 MHz, DMSO-d ₆ ): 8.75 (broad s, 2H), 3.15 (d, 2H), 2.75 (t, 2H), 2.22 (t, 2H) 1.75 (d, 2H), 1.45 (t, 2H), 1.25 (broad q, 2H).

Example 22

3- (1-tert-Butoxycarbonylpiperid-4-yl) propionic acid

3-Piperid-4-yl-propionic 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) was added followed by di (tert-butyl) dicarbonate (6.21 g, 28.4 mmol). A suspension is obtained. The suspension was stirred for 22 hours, diluted with water and concentrated in vacuo. The residue was washed with diethyl ether (2 x 100 mL). The aqueous phase was acidified with 0.1 N aqueous potassium bisulfate to pH 2-3 and extracted with ethyl acetate (3 x 200 mL). The combined organic phases were washed with brine and dried (sodium sulfate). Concentration in vacuo afforded 3- (1-tert-butoxycarbonylpiperid-4-yl) propionic acid (6.21 g, 24.1 mmol, 92%) as a colorless oil which crystallized on standing. ¹ H NMR spectrum (300 MHz, CDCl ₃ ): 4.10 (broad d, 2H), 2.65 (broad t, 2H), 2.35 (t, 2H), 1.70 to 1.50 (m 3H), 1.45 (s, 9H), 1.20-0.95 (m, 2H).

Example 23 Butyl 4-benzyloxycarbonyl-1-piperazinecarboxylate t-butyl 1-piperazinecarboxylate (2.01 g, 10.8 mmol) and DIEA (2.0 mL, 1.48 g, 11.5 mmol) in 50 mL ice-cooled dichloromethane was treated with benzyl chloroformate (2.0 mL, 2.39 g, 14.0 mmol). The mixture was stirred for 42 hours. It was then partitioned between ethyl acetate and 0.5N KHSO ₄ . The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (magnesium sulfate) and concentrated. Purification of the residue by silica gel chromatography (ethyl acetate: hexane,

4 4 4 4 4 4 • 4 ·· 4 44 44 4 44 44

1: 3) tert-butyl 4-benzyloxycarbonyl-1-piperazinecarboxylate (3.33 g, 10.4 mmol, 96%) was obtained as a colorless solid. ¹ H NMR spectrum (300 MHz, CDCl ₃ ): 7.35 (broad s, 5H), 5.13 (s,

2H), 3.55-3.25 (m, 8H), 1.45 (s, 9H).

Example 24

Benzyl 1-piperazinecarboxylate hydrochloride tert -Butyl 4-benzyloxycarbonyl-1-piperazinecarboxylate (1.01 g, 3.16 mmol), prepared as in Example 23, was suspended in 4 mL of ethyl acetate. This suspension was cooled in an ice water bath and 4N hydrogen chloride (12 mL in 1,4-dioxane) was added. A solution is obtained. This solution was stirred in an ice bath for 30 minutes and at room temperature for 30 minutes. The reaction mixture was diluted with diethyl ether (75 mL). A precipitate was obtained. The precipitate was collected by filtration and washed with diethyl ether. Drying in vacuo afforded benzyl 1-piperazinecarboxylate hydrochloride (740 mg, 2.78 mmol, 88%) as a colorless solid. ¹ H NMR spectrum (300 MHz,

DMSO-d _6): 9.25 (br s, 2H), 7.33 (s, 5H), 5.06 (s, 2H), 3.58 (br s, 4H), 3.04 (t, 4H).

Example 25 Butyl 4- [2- (4-benzyloxycarbonylpiperazin-1-ylcarbonylamino) ethyl] -1-piperidinecarboxylate

3- (1-tert-Butoxycarbonylpiperid-4-yl) 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 maintained at reflux for 3.5 hours. The mixture was cooled to room temperature and added dropwise to a suspension of benzyl 1-piperazinecarboxylate hydrochloride (2.44 g, 9.19 mmol) prepared as in Example 14 and triethylamine (1.40 mL, 1.02 g, 10, 0 mmol) in dry dichloro-

methane (10 mL). The reaction mixture was stirred for 43 hours and diluted with ethyl acetate and 0.5N KHSO ₄ . The organic layer was washed with water, aqueous sodium bicarbonate and brine, dried (sodium sulfate) and concentrated. Purification of the residue by silica gel chromatography (ethyl acetate / hexane 4: 1 then pure ethyl acetate) gave tert-butyl 4- [2- (4-benzyloxycarbonylpiperazin-1-ylcarbonylamino) ethyl] -1-piperidinecarboxylate (3.84) g, 8.1 mmol, 96%) as a white solid. ¹ H NMR spectrum (300 MHz, CDCl ₃ ): 7.35 (s, 5H), 5.15 (s, 2H), 4.50 (broad t, 1H), 4.05 (broad s, 2H), 3.55-3.45 (m, 4H), 3.40-3.30 (m, 4H), 3.25 (q, 2H), 2.65 (t, 2H), 1.70 (s, 2H), 1.45 (s, 11H), 1.20-1.00 (m, 2H).

Example 26 cis-1,5-Cyclooctylene chloroformate 4- [2- (4-tert-butoxycarbonylpiperidin-4-yl) ethylcarbamoyl] -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 10% (w / w) palladium on carbon (570 mg) suspended in ethanol (19 mL) were hydrogenated overnight atmospheric pressure. 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 dichloromethane (30 mL) and treated with DIEA (500 mL). This solution was added dropwise to cis-1,5-cyclooctylene di (chloroformate) (4.15 g, 15.4 mmol), prepared as in Example 5, in ice-cooled dichloromethane (75 mL). The reaction mixture was stirred overnight and diluted with 0.5 N aqueous potassium bisulfate and dichloromethane. The aqueous phase was extracted with dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification of the residue by silica gel chromatography (ethyl acetate-hexane 3: 1 then pure ethyl acetate) afforded 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. ¹ H NMR spectrum (300 MHz, CDCl ₃ ):

• ·

5.00-4.90 (m, 1H), 4.85-4.75 (m, 1H), 4.35 (broad t, 1H), 4.09 (broad d, 2H), 3.50-4 3.40 (m, 4H), 3.35 to 3.30 (m, 4H), 3.25 (q, 2H), 2.65 (t, 2H), 2.05 to 1.55 (m, 17H),

1.40 (s, 9H), 1.25-1.00 (m, 2H).

Example 27

4-Cyanophenylacetic acid

2- (4-Cyanophenyl) ethanol (5.00 g, 34.0 mmol) was dissolved in acetone (140 mL) and cooled to 10-15 ° C. A solution of chromium trioxide in aqueous sulfuric acid is added dropwise, maintaining the internal temperature below 30 ° C until the suspension has a permanent orange color. The suspension was stirred for 45 minutes and filtered. The solids were washed with acetone (150 mL). The combined filtrate and washings were stirred with 2-propanol (20 mL) for 30 minutes. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with 0.5 N aqueous potassium hydrogen sulfate, water, brine and concentrated. The residue was dissolved in dichloromethane and the solution was treated 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 to give a precipitate. The precipitate was washed with water and air dried. Drying in vacuo gave 4-cyanophenylacetic acid (3.36 g, 20.7 mmol, 61%) as a white powder. ¹ H NMR Spectrum (300 MHz, CDCl ₃ ): 7.63 (d, 2H), 7.40 (d, 2H), 3.72 (s, 2H).

Example 28 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 mmol) was suspended in THF (18 mL). Add tert-butyl 1-piperazinecarboxylate (1.04 g, 5.60 mmol) and DIEA. A homogeneous solution is obtained.

····

«·

This solution was concentrated in vacuo and the residue was treated with 0.2N KHSO ₄ . The mixture was filtered and the solid collected and washed with water. Drying in vacuo afforded tert-butyl 4- (4-cyanophenylacetyl) -1-piperazinecarboxylate (1.68 g, 5.1 mmol, 92%) as a solid. ¹ H NMR Spectrum (300 MHz, CDCl ₃ ): 7.70 (d, 2H), 7.35 (d, 2H), 3.80 (m, 2H), 3.70-3.60 (m, 2H) 3.45-3.30 (m, 6H), 1.40 (s, 9H).

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 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 dissolved in ethanol, filtered and the filtrate was cooled overnight. A crystalline product is obtained. These crystals were collected by filtration and washing with cold ethanol. Air drying gave tert-butyl 4- [4- (N-hydroxyamidino) phenylacetyl] -1-piperazinecarboxylate (1.62 g, 4.5 mmol, 88%). ¹ H NMR Spectrum (300 MHz, DMSO-d ₆ ): 9.60 (s, 1H), 7.60 (d, 2H), 7.20 (d, 2H), 5.75 (S, 2H), 3.70 (s, 2H), 3.40 (wide s, 4H), 3.25 (wide s, 4H), 1.40 (s, 9H).

Example 30

4-Piperazin-1-ylcarbonylmethylbenzamidine bis (trifluoroacetate) tert-butyl 4- [4- (N-hydroxyamidino) phenylacetyl) -1-piperazinecarboxylate (653 mg, 1.81 mmol), prepared as in Example 29, and 10% The palladium on carbon (200 mg) was suspended in acetic acid (12 mL). Hydrogen is bubbled through the suspension overnight. The reaction mixture was filtered and the catalyst was washed with acid

acetovou. The combined filtrate and washings were concentrated in vacuo. The residue was dissolved in TFA. The solution was allowed to stand for 1 hour and then concentrated in vacuo. The residue was evaporated from a mixture of dichloromethane and methanol and then suspended in diethyl ether. The solid material was filtered off. Drying gave 4-piperazin-1-ylcarbonylmethylbenzamidine bis (trifluoroacetate) (1.04 g, 1.81 mmol, 100%) as a white solid. ¹ H NMR Spectrum (300 MHz, DMSO-d ₆ ): 9.30 (d, 4H), 9.15 (broad S, 2H), 7.70 (d, 2H), 7.40 (d, 2H) 3.85 (s, 2H), 3.65 (broad d, 4H), 4.20-3.90 (m, 4H).

Example 31 cis-1,5-Cyclooctylene 4- (4-amidinophenylacetyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate (Compound 94)

This example is the preparation of a disubstituted cyclic compound of formula I wherein R ¹ is 4-amidinobenzyl, R ² is 2-piperid-4-ylethyl, X ¹ is -C (O) -, X ⁹ is -NHC (O X ² and X ⁸ are 1,4-piperazinylene, X ³ and X ⁷ are both -C (O) O-, X ⁴ and X ⁶ are both covalent bonds and X ⁵ are cis-1,5-cyclooctylene.

4-Piperazin-1-ylcarbonylmethylbenzamidine bis (trifluoroacetate) (80 mg, 0.17 mmol), prepared as in Example 30, was dissolved in DMF (1.0 mL) and this solution was treated with DIEA (150 mL). Add cis-1,5-cyclooctylene chloroformate 4- [2- (4-tert-butoxycarbonylpiperazin-1-yl) ethylcarbamoyl] -1-piperazinecarboxylate (100 mg), prepared as in Example 26, in DMF (1.0 mL) The mixture was stirred overnight and concentrated in vacuo. The residue was dissolved in dichloromethane and TFA (1: 1) and this mixture was concentrated in vacuo. The residue was triturated with diethyl ether. A foamed residue is obtained. Purification from the residue by reverse phase preparative HPLC and lyophilization of the pure fractions gave cis-1,5-cyclooctylene 4- (4-amidinophenylacetyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate » · As a colorless solid. Mass spectrum (Electrospray LRMS) for C ₃₅ H ₅₄ Ngog Calculated: 683.9 (MH ^+), 342.5 (MH2 ^{+ 2/2),} found: 683.8 (MH ^+), 342.3 (MH2 ⁺² / 2).

When proceeding as in Example 31 and using other starting materials, the following disubstituted cyclic compounds of formula I were prepared:

cis-1,5-cyclooctylene 4- (1-amidinopiperid-4-ylacetyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate (compound 95), for C ₃₄ H _5? N ₉ O ₆ calculated: 690.0 (MH ⁺ ), found: 690.6 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-amidinobenzoylaminomethyl) -1-piperidinecarboxylate 4- (2-piperid-4) -ylethylcarbamoyl) -1-piperazinecarboxylate (compound 96) calculated for C ₃₆ H ₅₆ N ₈ O ₆ 697.9 (MH ⁺ ), found: 697.7 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-amidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate (compound 97) calcd for C ₃₅ H ₅₅ N ₉ O ₆ 698.9 (MH ⁺ ), found: 698, 7 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-amidinophenylsulfonylaminomethyl) -1-piperidinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate (compound 98), for C ₃₅ H ₅₆ N ₈ O ₇ calculated:

733.9 (MH ⁺ ), found: 733.4 (MH ⁺ ), cis-1,5-cyclooctylene 4- [2- (1-amidinopiperid-4-yl) ethylcarbamoyl] -1-piperazinecarboxylate 4- (2-piperidino- 4-ylethylcarbamoyl) -1-piperazinecarboxylate (compound 99) calcd. For C ₃₅ H ₆₂ N _W O ₆ 719.9 (MH ⁺ ), found: 719.5 (MH ⁺ ), cis-1,5- Cyclooctylene 4- (4-amidinophenylcarbamoylmethyl) -1-piperidinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate (Compound 100), calculated for C ₃₆ H ₅₆ N ₈ O ₆ :

697.9 (MH ⁺ ), found: 695.6 (MH ⁺ ), cis-1,5-cyclooctylene 4- (4-N-methoxycarbonylamidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1- piperazinecarboxylate (compound 101) calcd for C ₃₇ H ₅₇ N ₉ O ₈ 756.9 (MH ⁺ ), found: 756.4 (MH ⁺ ), and cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1 • ·

-piperazinecarboxylate 3-piperid-4-ylpropylcarbamoyl-1-piperidinecarboxylate (compound 102) calculated for C ₃₆ H ₅₈ N ₈ O ₅ 683.9 (MH ⁺ ), found: 683.3 (MH ⁺ ).

Example 32

1,5-Pentamethylene di [4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate] (compound 103)

This example is the preparation of a disubstituted cyclic compound of formula I wherein R ¹ and R ² are both 4-guanidinobenzyl, X ¹ and X ⁹ are both -NHC (O) -, X ² and X ⁸ are 1,4-piperazinylene, X ³ and X ⁷ are both -C (O) O-, and X ⁴ -X ⁶ -X ⁵ together are 1,5-pentamethylene.

Tert-Butyl 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate trifluoroacetate (306 mg, 0.62 mmol) was treated with pure trifluoroacetic acid (1 mL) at room temperature for 10 minutes. A colorless homogeneous solution is obtained. This liquid was concentrated and the oily residue was triturated with diethyl ether (3 x 10 mL) followed by drying under vacuum to a colorless foam. The deprotected piperazine salt was dissolved in DMF (2.5 mL) followed by the addition of diisopropylethylamine (0.5 mL, 3.1 mmol) and 1,5-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 (3 x 10 mL). This is followed by drying under vacuum. The crude material was dissolved in water (5 mL) and purified by reverse phase preparative HPLC. Lyophilization gave 1,5-pentylene di [4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate] as a colorless amorphous solid. Mass spectrum (electrospray, LRMS): Calcd. For C ₃₃ H ₄₈ N ₁₂ O ₆ : 709.8 (MH ⁺ ), found:

709.3 (MH ⁺ ).

When proceeding as in Example 32 and using other starting materials, the following disubstituted cyclic compounds of formula I were prepared:

ft ft. · · ♦

ftftft · ft ft · ftft

1,4-tetramethylenedi [4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate] (compound 104), calculated for θ3 ₂ ^Η 46 ^Ν °2 ° 6:

695.8 (MH ⁺ ), found: 695.8 (MH ⁺ ),

guanidinobenzy 1-4 - {5- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] valeryl} -1-piperazinecarboxamide (compound 105), calcd for C ₃₂ H ₄₆ N ₁₂ O ₄ 663.8 (MH ⁺ ), found: 663.4 (MH ⁺ ),

4-guanidinobenzyl-4- {6- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] hexanoyl} -1-piperazinecarboxamide (compound 106), calcd. For C ₃₃ H ₄₈ N ₁₂ O ₄ 677.8 (MH) ⁺ ), found:

677.4 (MH ^&lt; ^{+ &gt;} ),

4-guanidinobenzyl-4- {7- [4- (4-guanidinobenzylcarbamoyl) piperazinylcarbonyl] heptanoyl} -1-piperazinecarboxamide (compound 107), calcd for ^C 34 ^H 21 ^{N 2} ° 4: 691 9 (MH ⁺ ), found: 691.5 (MH ⁺ ),

4-guanidinobenzy 1-4- {8- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] octanoyl} -1-piperazinecarboxamide (compound 108), calcd for C ₃₇ H ₅₇ N ₉ O ₈ 756.9 ( MH ⁺ ), found:

756.4 (MH ^&lt; ^{+ &gt;} ),

4-guanidinobenzy 1-4- {9- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] nonanoyl} -1-piperazinecarboxamide (compound 109), calcd. For C ₃₆ H ₅₄ N ₁₂ O ₄ : 719.9 ( MH ⁺ ), found:

719.5 (MH ^&lt; ^{+ &gt;} ),

4-amidinobenzyl 4- {7- [4- (4-cyclopropylcarbamoyl amidinobenzo Jpiperazin L-ylkarbony1] heptanoyl} -1-piperazinecarboxamide (Compound 110), for C ₃₄ H ₄₈ N _Q1 O ₄ Calculated: 661.8 (MH ⁺ ), found: 661.3 (MH ⁺ ),

1,5-pentamethylene di [[4- (4-guanidinophenylacetyl) piperazin-1-ylcarbonyl] (compound 111), calculated for C ₃₃ H ₄₆ N ₁₀ O ₄ 647.8 (MH ⁺ ), found: 647.3 (MH) ⁺ ),

1,6-hexamethylene di [[4- (4-guanidinophenylacetyl) piperazin-1-ylcarbonyl] (compound 112), calculated for C ₃₄ H ₄₈ N ₁₀ O ₄ :

661.8 (MH ⁺ ), found: 661 (MH ⁺ ),

1,7-heptamethylene di [[4- (4-guanidinophenylacetyl) piperazin-1-ylcarbonyl] (compound 113), calculated for C ₃₅ H ₅₀ N ₁₀ O ₄ 675.9 (MH ⁺ ), found: 675.4 (MH) ⁺ ), and

3-Oxa-1,5-pentamethylene di [[4- (4-guanidinophenylacetyl)] ··········

piperazin-1-ylcarbonyl] (compound 114) calcd for ^C 32 ^H 44 ^{N 10} ° 681.8 (MH ⁺ ), found 681.4 (MH ⁺ ).

Example 32

In vitro tryptase inhibition assay

Mixture of human tryptase (15 Mg / ml) and test compound (various concentrations) in Tris buffer (containing: 100 mM NaCl, 50 mM Tris, 2.5 mM 2- [N-morpholine] ethanesulfonic acid, 0.5 mM CaCl ₂ , 10% DMSO, 5% glycerol, 0.05% polyoxyethylene sorbitan monolaurate (Tween-20), 25 ng / ml heparin, pH 8.2) were incubated for 1 hour at room temperature. Tosyl-Gly-Pro-Lys-p-nitroanilide was then added to a final concentration of 0.5 mM. Substrate hydrolysis was monitored spectrophotometrically (405 nm) for 5 minutes. Apparent inhibition constants (K _f ) were calculated from the enzyme progression curves using standard mathematical models.

Human tryptase was purified from human lung and skin tissue samples (see, e.g., Smith et al .: J. Biol. Chem. 1984, 59, 11046-11051, and Braganza et al .: Biochem. 1991, 30, 4997-5007) and a human mast cell line or has been obtained commercially (eg, ICN Biomedicals, Irvine, California; Athens Research & Technology, Athens, Greece). Porcine intestinal mucosal heparin and tosyl-Gly-Pro-Lys-p-nitroanilide were purchased from Sigma Chemical Company.

The following disubstituted cyclic compounds of formula (I) were produced by the procedure described in this application or by methods known to those skilled in the art and tested for their tryptase inhibiting activity:

Compound 1, K _f = 0.003 μΜ, Compound 2, K ,. = 0.8 μΜ, compound 3, Kj = 0.07 μΜ, compound 4, K, - = 0.001 μΜ, compound 5, K, = 0.2 μΜ, compound 6, K, · = 1 μΜ, compound 7, Kj = 0.3 μΜ, compound 8, K ₁ - = 4 μΜ, compound 9, K _i = 0.4 μΜ, serve 9 · 99 99 • 9 9 9 9

value 10, K, - = 1 μΜ, compound 11, Κ, = 0.09 μΜ, compound 12, Κ, · = 0.2 μΜ, compound 13, Κ _{ = 0.02 μΜ, compound 14, Κ, = 0.004 μΜ, compound 15, Κ ₁ = 0.5 μΜ, compound 16, = 0.9 μΜ, compound 17, Κ ,. = 1 μΜ, compound 18, Κ, - = 0.08 μΜ, compound 19, κ ,. = 1.2 μΜ, compound 20, K _i = 3.4 μΜ, compound 21, Κ, · = 0.5 μΜ, compound 22, Κ ,. = 0.2 μΜ, compound 23, Κ ,. = 4 μΜ, compound 24, K _i = 0.3 μΜ, compound 25, Κ ,. = 0.002 μΜ, compound 26, Κ ,. = 19 μΜ, compound 27, Κ ₍ = 2 μΜ, compound 28, K _f = 4 μΜ, compound 29, K _f = 1 μΜ, compound 30, Κ ₅ = 0.031 μΜ, compound 31, K _l - = 1 μΜ, compound 32, K _f = 2 μΜ, compound 33, Κ, = 1 μΜ, compound 34, K _s = 3 μΜ, compound 35, Κ- = 0.8 μΜ, compound 36, K _i = 0.6 μΜ, compound 37, K _l - = 0,07 μΜ, compound 38, K, = 0,004 μΜ, compound 39, Kj = 0,004 μΜ, compound 40, K _i = 4 μΜ, compound 41, K, = 0,7 μΜ, compound 42 , K, = 0.02 μΜ, compound 43, Kj = 0.4 μΜ, compound 44, K _i = 0.02 μ2, compound 45, K _i = 0.08 μΜ, compound 46, Κ ,. = 1 μΜ, compound 47, K = 0.3 μΜ, compound 48, K _f = 0.09 μΜ, compound 49, K _f = 2 μΜ, compound 50, K _f = 0.08 μΜ, compound 51, Κ, = 1 μΜ, compound 52, K, = 0.04 μΜ, compound 53, K ,. = 6 μΜ, compound 54, K _; = 0.1 μΜ, compound 55, K = 2 μΜ, compound 56 , K, = 10 μΜ, compound 57, K, - 2 μΜ, fusion to 58, K, · = 0.1 μΜ, compound 59, K, = 0.5 μΜ, compound 60, Kj = 5 μΜ, compound 61, K, = 41 μΜ, compound 62, K ,. = 0.2 μΜ, compound 63, Kj = 2 μΜ, compound 64, Κ, - = 1 μΜ, compound 65, K. = 0.001 μΜ, compound 66, K ,. = 0,02 μΜ, compound 67, K _i = 3 μΜ, compound 68, Kj = 0,04 μΜ, compound 69, Κ, - = 0,5 μΜ, compound 70, = 0,05 μΜ, compound 71, K _; = 0.8 μΜ, compound 72, K, = 0.1 μΜ, compound 73, Κ _; = 0.002 μΜ, compound 74, K _f = 0.04 μΜ, compound 75, K- = 0.01 μΜ, compound 76, K ,. = 0,1 μΜ, compound 77, K, - = 6 μΜ, compound 78, Kj = 0,1 μΜ, compound 79, Κ, - = 1 μΜ, compound 84, K _i = 0,06 μΜ, compound 85, K, = 0.9 μΜ, compound 86, K ,. = 0.08 μΜ, compound 87, K- = 0.05 μΜ, compound 88, K. = 0.1 μΜ, compound 89, K ,. = 0.1 μΜ, compound 90, K _f = 1 μΜ, compound 91, K, - = 0.1 μΜ, compound 92, K ,. = 0.1 μΜ, compound 93, K, = 0.02 μΜ, compound 94, K _; = 0.007 μΜ, compound 95, K _i = 0.02 μΜ, compound 96, K _f = 0.02 μΜ, compound 97, K ,. = 0.0009 ·· ·· · · ·· ·

μΜ, compound 98,

compound 100, ^K i compound 102, ^K i compound 104, ^K i compound 106, ^K i compound 108, ^K i compound 110, ^K i compound 112, ^K i compound 114, ^K i

κ ,. = 0.03 μΜ, compound 99, K _i = 0.05 μΜ, = 0.009 μΜ, compound 101, Κ ,. = 0,04 μΜ, = 0,08 μΜ, compound 103, Κ, - = 0,001 μΜ, = 0,003 μΜ, compound 105, Κ, - = 0,04 μΜ, = 0,004 μΜ, compound 107, Κ, - = 0 , 0001 μΜ, = 0.0005 μΜ, compound 109, K _i = 0.0007 μΜ, = 0.0008 μΜ, compound 111, Κ _; = 0,3 μΜ, = 0,09 μΜ, compound 113, Κ, - = 0,005 μΜ, and = 0,058 μΜ.

Example 33

Vivoη vivo asthma test

Allergic sheep characterized by a dual response (ie showing early and late phase bronchoconstriction) are inoculated with an antigen (eg, Ascaris). Sheep are administered the test compound or diluent by aerosol inhalation 0.5 hours before and 4 and 24 hours after antigen administration. Specific lung resistance (SR _L ) is monitored by an esophagus balloon catheter from the time before administration of the first test compound or diluent and every 0.5 to 1 hour after administration.

In addition, airway responses are monitored 1 to 2 days before antigen administration and just after administration of test compound or diluent 24 hours after antigen administration. For the purposes of this application, the airway response is defined as the cumulative dose of carbachol needed to increase SR _L by 400% (PC ₄₀₀ ). PC ₄₀₀ values are obtained by administering 0 to 30 breath units of 1% carbachol (10 mg in 1 ml PBS) by aerosol inhalation until SR _L increases by 400%.

Solvent-treated sheep exhibit early bronchoconstriction from 0 to 4 hours after antigen administration and late bronchoconstriction from 4 to more than 8 hours after antigen administration. In addition, diluent treated sheep show a hyperresponsiveness to carbachol (i.e. a 60% increase in PC ₄₀₀ was observed).

• 4 4 4 4944 ·· 4 44 4 4 4 4 4 • »» 44 44 444 • 4 «4 4 44 44 44444 ·· 4 · 4 4 4 4 ···, ·· ·· ·· ··

Sheep treated with tryptase inhibitors did not show late phase bronchoconstriction (ie, 4-8 hours after antigen administration, SR _L remained at baseline). Moreover, sheep treated with tryptase inhibitors show no hyperresponsiveness to carbachol.

Example 34

Representative pharmaceutical compositions comprising a disubstituted cyclic compound of Formula I.

Oral preparation

a disubstituted cyclic compound of formula I citric acid monohydrate sodium hydroxide flavoring agent, water 10 to 100 mg 105 mg 18 mg q.s. to 100 ml Intravenous preparation a disubstituted cyclic compound 0.1 to 10 mg of formula I dextrose monohydrate q.s. for isotonicity citric acid monohydrate 1,05 mq sodium hydroxide 0.18 mg water for injection q.s. to 100 ml

Tablet preparation

a disubstituted cyclic compound 1 % (w / w) of formula I microcrystalline cellulose 73 % stearic acid 25 % colloidal silica 1 %

- ‘iy

Claims (43)

A disubstituted cyclic compound of formula I R ¹ -X ¹ -X ² -X ³ -X ^4, ₅ x ⁵ (i), r ² -x ⁹ -x®-x ⁷ -x ^ X ⁵ is C 3 -C 14 cycloalkylene, C 3 -C 14 heterocycloalkylene, C 6 -C 14 arylene or C 5 -C 14 heteroarylene, X ⁴ and X ⁶ independently represent alkylene of 0 to 2 carbon atoms, X ¹ and X ⁹ independently represent a covalent bond, -C (O) -, -C (O) O-, -OC (O) -, -C (O) N (R ³ ) -, -N (R ³⁾ )WHAT)-, -S (O ₂ ) N (R ³ ) -, -N (R ³ ) S (O) ₂ -, -OC (O) N (R ³ ) -, -N (R ³ ) C (O) O- , -N (R ³ ) C (O) N (R ³ ) - or -OC (O) O-, wherein each R ^{3 is} independently hydrogen, C 1 -C 3 alkyl or C 3 -C 8 cycloalkyl provided that both X ¹ and X ^{9 are} not covalent bonds, X ³ and X ⁷ independently represent -C (O) -, -C (O) O-, -OC (O) -, -C (O) N (R ³ ) -, -N (R ³ ) C ( O) -, -S (O ₂ ) N (R ³ ) -, a group -N (R ³ ) S (O) ₂ -, -OC (O) N (R ³ ) -, -N (R ³ ) C (O) O-, -N (R ³ ) C (O) N ( R ³ ) or -OC (O) O-, wherein R ³ is as defined above, X ² and X ⁸ independently represent C 1 -C 8 alkylene, C 1 -C 8 heteroalkylene, -X ¹⁰ -X ¹¹ - or -X ¹¹ -X ¹⁰ -, wherein X ¹⁰ is C 1-4 alkylene C 3 -C 4 heteroalkylene and X ¹¹ is C 3 -C 8 cycloalkylene or C 3 -C 8 heterocycloalkylene, R ¹ represents a group R ⁴ -X ¹² - or R ⁵ -X ¹³ -, wherein ^R4 is amino, amidino, guanidino, 1-iminoethyl or methylamine, X ¹² represents C 4 -C 6 alkylene, C 4 -C 6 heteroalkylene, heterooxoalkylene ·········· C 4 -C 6 oxoalkylene, C 4 -C 6 oxoalkylene or -X ¹⁴ -X ¹⁵ -X ¹⁶ -, wherein X ¹⁵ is C 3 -C 6 cycloalkylene, C 5 -C 6 heteroarylene, C 3 -C 6 heterocycloalkylene X ¹⁴ is alkylene with n 14 carbon atoms and X ¹⁶ is alkylene with n 16 carbon atoms, where the sum of n 14 and n 16 is 0, 1, 2, 3 or 4, R ⁵ represents a group selected from azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-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- ylu, 1,4,5,6-tetrahydropyrimidin-2-yl, 1,4,5,6-tetrahydropyrimidin-4-yl, 1,4,5,6-tetrahydropyrimidin-5-yl and any carbocyclic ketone or thioketone derivative thereof, the group of which is optionally substituted by one or more groups selected from halogen, hydroxyl, mercapto, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 14 carbon atoms, aryl of 6 to 14 carbon atoms, aryl (of 6 to 14 atoms) (C1 -C4) alkyl, (C1 -C8) alkanoyl, (C1 -C8) alkyloxy, (C6 -C14) aryloxy, (C3 -C14) cycloalkyloxy, (C1 -C4) alkyloxy carbon atoms, alkylthio having 1 to 8 carbon atoms, cycloalkyl lthioskupiny 3 to 14 carbon atoms, arylthio of 6 to 14 carbon atoms, and -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are independently selected from hydrogen alkyl of 1 to 8 carbon atoms, alkanoyl of 1 to 8 carbon atoms, cycloalkyl C 3 -C 14 carbon or C 6 -C 14 aryl, and X ¹³ is C 0 -C 6 alkylene, C 2 -C 6 heteroalkylene, C 3 -C 6 heterooxoalkylene, C 2 -C 6 oxoalkylene alkyl or -X ¹⁷ -X ¹⁸ -X ¹⁹ - in which X ¹⁸ is as defined above for X ^15, X ¹⁷ represents alkylene • · NL7 carbon atoms; and X ¹⁸ represents alkylene nl8 carbon atoms, wherein the sum NL7 and n 18 is 0, 1 or 2, and R ² represents a group R ⁸ -X ²⁰ - or R ⁹ -X ²¹ - in which R ⁸ represents an amino, 1-iminoethyl or methylamine group, X ²⁰ is C 4 -C 6 alkylene, C 4 -C 6 heteroalkylene, C 4 -C 6 heterooxoalkylene, C 4 -C 6 oxoalkylene or -X ²² -X ²³ -X ²⁴ - in which X ²³ is as defined above for X ¹⁵ , X ²² is alkylene with n 22 carbon atoms and X ²⁴ is alkylene with n 24 carbon atoms, wherein the sum of n 22 and n 24 is 0, 1, 2, 3 or 4, provided that if R ⁸ is amino, then X is not ²² alkylene having 4-6 carbon atoms or oxaalkylene having 4 to 6 carbon atoms and n22 is not 1, 2, 3 or 4, R ⁹ is as above for R ^5a X ²¹ represents alkylene of 0-6 carbon atoms, heteroalkylene of 2-6 carbon atoms, heterooxoalkylene of 3-6 carbon atoms, oxoalkylene of 2-6 carbon atoms, or a group -X ²⁵ -X ²⁶ -X ²⁷ - in which X ²⁶ is as previously defined for X ^15, X ²⁵ represents alkylene N25 carbon atoms, and X ²⁷ represents alkylene N27 carbon atoms, wherein the sum of n25 and n27 is 0, 1 or 2, wherein each of the above alkylene, cycloalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene is optionally substituted with one or more groups selected from halogen, hydroxyl, mercapto, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 14 carbon atoms, aryl of 6 to 14 carbon atoms, aryl ( (C 1 -C 4) alkyl (C 1 -C 4) alkyl, (C 1 -C 8) alkanoyl, (C 1 -C 8) alkyloxy, (C 6 -C 14) aryloxy, (C 3 -C 14) cycloalkyloxy, (C 1 -C 14) alkyloxy group up to 4 carbon atoms, alk (C 1 -C 8) ylthio, (C 3 -C 14) cycloalkylthio, (C 6 -C 14) arylthio, and -NR ⁶ R ⁷ in which R ⁶ and R ⁷ are as defined above, provided that between the heteroatoms contained in the R ¹ , X ² , X ⁴ , X ⁶ , X ⁸ and R ² and what • 99 • 99 The heteroatoms in X ³ , X ⁵ , X ⁷ and X ⁹ do not contain a covalent bond, and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. A disubstituted cyclic compound of formula I according to claim 1, wherein X ⁵ is cis-1,5-cyclooctylene and X ⁴ and X ⁶ are both covalent bond or X ⁵ is 1,4-phenylene and X ⁴ and X ⁶ are ethylene of 0 to 1 carbon atom, X ¹ and X ⁹ independently represent a covalent bond, -C (O) -, -NHC (O) -, -C (O) NH-, -N (CH ₃ ) C (O) - or -S (O) ₂ NH-, X ³ and X ⁷ independently represent -C (O) - or -C (O) O-, X ² and X ^{8 are} independently -X ¹⁰ -X ¹¹ -, wherein X ¹⁰ is a covalent bond or methylene and X ¹¹ is 4,1-piperidylene or 1,4-piperazinylene, R ¹ represents a group R ⁴ -X ¹² - or R ⁵ -X ¹³ -, wherein ^R4 is amidino, guanidino or methylamino 1aminovou group, X ¹² is -X ¹⁴ -X ¹⁵ -X ¹⁶ -, where X ¹⁵ is 1,4-phenylene or 1,4-piperidylene, ^X14 is alkylene I4 carbon atoms, and X ¹⁶ represents alkylene NL6 carbon atoms wherein the sum of NL4 and NL6 is 0, 1 or 2, R ⁵ is piperid-4-yl, X ¹³ is C 2 -C 3 alkylene, and R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ - in which: R ⁸ represents an amino group, a methylamino group or a 1-iminoethyl group, 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 ²² is alkylene N22 with the carbon atoms, and X ²⁴ represents alkylene n24 carbon atoms, 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; »4 4 4444 I 4 4 « 4 »·· 5-methylimidazol-1-yl, 1-methylpiperid-4-yl, piperid-4-yl, piperazin-1-yl, pyrid-3-yl, pyrid-4-yl, 1,4,5,6-tetrahydropyrimidine- 5-yl or 1,4,5,6-tetrahydro-2-dioxopyrimidin-5-yl, X ²¹ denotes alkylene of 1 to 6 carbon atoms, ω-azaalkylene of 2 to 5 carbon atoms, 2-aza-3-oxotrimethylene, 3-aza-2-oxotrimethylene, 3-oxotrimethylene, ω-thiaalkylene of 2 to 4 carbon atoms or the group -X ²⁵ -X ²⁶ -X ²⁷ - in which X ²⁶ is 1,4-phenylene, X ²⁵ is alkylene with N25 carbon atoms and X is alkylene having ²⁷ carbon atoms, N27, wherein N25 and N27 sum is 0 or 1, and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. A disubstituted cyclic compound of formula I according to claim 2, wherein X ⁵ is cis-1,5-cyclooctylene and X ⁴ and X ^{6 both} represent a covalent bond, X ¹ and X ⁹ independently represent a covalent bond, -C (O) -, -NHC (O) -, -C (O) NHor -S (O) ₂ NH, X ³ and X ⁷ independently represent -C (O) or -C (O) O-, R ¹ is R ^4- X ¹² -, wherein R ⁴ is an amidine or guanidine group, R ² is a group R ⁸ --X ²⁰ - or R ⁹ -X ²¹ - in which R ⁸ is an amino or methylamine group, X ²³ is trans-1, 4-cyclohexylene or 1,4-phenylene, R ⁹ is imidazol-1-yl, imidazol-4-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, piperid-4-yl or pyrid-4-yl, X ²¹ is C 1 -C 5 alkylene or 3-aza-trimethylene, and pharmaceutically acceptable salts thereof , N-oxides, prodrug derivatives and protected derivatives. A compound according to claim 3, wherein X ¹ and X ⁹ are independently -C (O) - or -NHC (O) -, both X ³ and X ⁷ are -C (O) O- X ² and X ⁸ are both -X ¹⁰ -X ¹¹ -, wherein X ¹⁰ is a covalent bond and X ^{11 is a} 1,4-piperazinylene group, R ¹ is a group R ⁴ -X ¹² -, wherein R ⁴ is an amidine or a guanidino group, and X ¹² represents a group -X ¹⁴ -X ¹⁵ -X ¹⁶ - in which X ¹⁵ represents 1,4-phenylene, X ¹⁴ represents a covalent bond and X ¹⁶ represents a methylene, R ² represents a group 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-1,4-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 pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. A compound according to claim 4, wherein X ¹ and X ⁹ are both -NHC (O) -, R ¹ is 4-amidinobenzyl and R ² is 2-piperid-4-ylethyl, in particular cis-1. 5-cyclooctylene 4- (4-amidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate, and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. A compound according to claim 4, wherein X ¹ is -NHC (O) -, X ⁹ is -C (O) -, R ¹ is 4-amidinobenzyl and R ² is 3-piperidino- 4-ylpropyl, particularly cis-1,5-cyclooctylene 4- (4-amidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate, and pharmaceutically acceptable salts, N-oxides, derivatives thereof prodrugs and protected derivatives. A compound according to claim 4, wherein X ¹ and X ⁹ are both -NHC (O) -, R ¹ is 4-guanidinobenzyl and R ² is trans -4-aminocyclohexylmethyl, in particular cis-1,5 -cyclooctylene trans 4- (4-aminocyclohexymethylcarbamoyl) -1-piperazinecarboxylate 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate, and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. A compound according to claim 4, wherein X ¹ and X ⁹ are both -C (O) -, R ¹ is 4-amidinobenzyl, and R ² is 3-piperid-4-ylpropyl. Specifically cis-1,5-cyclooctylene 4- (4-amidinophenylacetyl) -1-piperazinecarboxylate 4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate, and pharmaceutically acceptable salts thereof, N -oxides, prodrug derivatives and protected derivatives. A compound according to claim 4, wherein X ¹ and X ⁹ are both -NHC (O) -, R ¹ is 4-guanidinobenzyl and R ² is 2-piperid-4-ylethyl, in particular cis-1. 5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (2-piperidin-4-ylethylcarbamoyl) -1-piperazinecarboxylate, and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. 10th of a compound of formula I according to claim 4, wherein X ¹ is -NHC (O) -, ^X9 is -C (0) -, R ¹ is 4-guanidinobenzyl and ^R2 is 3-piperid 4-ylpropyl, particularly cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate, and pharmaceutically acceptable salts, N-oxides, derivatives thereof prodrugs and protected derivatives. A compound according to claim 4, wherein X ¹ is -C (O) -, X ⁹ is -NHC (O) -, R ¹ is 4-guanidinobenzyl and R ² is 2-piperidino- 4-ylethyl, in particular cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate, and pharmaceutically acceptable salts, N-oxides, derivatives thereof prodrugs and protected derivatives. A disubstituted cyclic compound of formula I according to claim 4, wherein X ¹ and X ⁹ are both -C (O) -, R ¹ is 4-guanidinobenzyl and R ² is 3-piperid-4-ylpropyl, in particular cis-1. 5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate, and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. A compound according to claim 4, wherein X ¹ is -C (O) -, X ⁹ is -NHC (O) -, R ¹ is 4-amidinobenzyl and R ² is 2-piperidino- 4-ylethyl, in particular cis-1,5-cyclooctylene 4- (4-amidinophenylacetyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate, and pharmaceutically acceptable salts thereof, N-oxides, prodrug derivatives and protected derivatives. 14. A pharmaceutical composition comprising a therapeutically effective amount of a disubstituted cyclic compound of formula (I) according to claim 1 in combination with a pharmaceutically acceptable excipient. 15. A method of treating an animal disease in which tryptase activity contributes to the pathology and / or symptomatology of the disease, which comprises administering to the animal a therapeutically effective amount of a disubstituted cyclic compound of formula I R ¹ -X ¹ -X ² -X ³ -X ^{4 X} x ⁵ (I), r ² -x ⁹ -x ⁸ -x ⁷ -x ^ X ⁵ is C 3 -C 14 cycloalkylene, C 3 -C 14 heterocycloalkylene, C 6 -C 14 arylene or C 5 -C 14 heteroarylene, X ⁴ and X ⁶ independently represent alkylene of 0 to 2 carbon atoms, X ¹ and X ⁹ independently represent a covalent bond, -C (O) -, -C (O) O-, -OC (O) -, -C (O) N (R ³ ) -, -N (R ³⁾ ) C (O) -, -S (O2) N (R ³⁾ -, -N (R ³⁾ S (O) 2-, -OC (O) N (R ³⁾ -, -N (R ³⁾ C (O) O-, -N (R ³ ) C (O) N (R ³ ) - or -OC (O) O-, wherein each R ³ independently represents a hydrogen atom, an alkyl of 1 to 3 carbon atoms or C 3 -C 8 cycloalkyl, both X ¹ and X ⁹ not being covalent bonds, X ⁷ and X ⁹ independently represent -C (O) -, -C (O) O-, -OC ( O) -, -C (O) N (R ³ ) -, a group -N (R ³ ) C (O) -, -S (O 2) N (R ³ ) -, -N (R ³ ) S (O) 2 -, -OC (O) N (R ³ ) -, -N (R ³ ) C (O) O-, -N (R ³ ) C (O) N (R ³ ) - or -OC (O) O-, wherein R ³ is as defined above, X ² and X ⁸ independently represent C 1 -C 8 alkylene, C 1 -C 8 heteroalkylene, -X ¹⁰ -X ¹¹ - or -X ¹¹ -X ¹⁰ -, wherein X ¹⁰ is C 1-4 alkylene C 3 -C 4 heteroalkylene and X ¹¹ is C 3 -C 8 cycloalkylene or C 3 -C 8 heterocycloalkylene, R ¹ represents a group R ⁴ -X ¹² - or R ⁵ -X ¹³ -, wherein ^R4 is amino, amidino, guanidino, 1-iminoethyl or methylamine, X ¹² is C 4 -C 6 alkylene, C 4 -C 6 heteroalkylene, C 4 -C 6 heterooxoalkylene, C 4 -C 6 oxoalkylene or -X ¹⁴ -X ¹⁵ -X ¹⁶ -, wherein X ¹⁵ means cycloalkylene having 3 to 6 carbon atoms and heteroarylene having 5-6 carbon atoms, heterocycloalkylene having 3 to 6 carbon atoms or phenylene, X ¹⁴ represents alkylene I4 carbon atoms; and X ¹⁶ represents alkylene NL6 carbon atoms wherein the sum of NL4 and NL6 stands for 0, 1, 2, 3 or 4 R ⁵ represents a group selected from azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 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, 1,4,5,6-tetrahydropyrimidin-4-yl, 1,4,5,6-tetrahydropyrimidin-5-yl and any carbocyclic ketone or thioketone derivative thereof, the group of which is optionally substituted with one or more groups selected from a halogen atom; Alkyl, hydroxyl, mercapto, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 14 carbon atoms, aryl of 6 to 14 carbon atoms, aryl (of 6 to 14 carbon atoms) of alkyl of 1 to 8 carbon atoms; C 1 -C 4, C 1 -C 8 alkanoyl, C 1 -C 8 alkyloxy, aryloxy C 6 -C 14 cycloalkyloxy, C 1 -C 4 alkyloxy, C 1 -C 8 alkylthio, C 3 -C 14 cycloalkylthio, C 6 -C 14 arylthio and - NR ⁶ R ⁷ , wherein R ⁶ and R ⁷ are independently selected from hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkanoyl, C 3 -C 14 cycloalkyl or C 6 -C 14 aryl carbon atoms, and X ¹³ represents a (C 1 -C 6) alkylene, (C 2 -C 6) heteroalkylene, (C 3 -C 6) heterooxoalkylene, (C 2 -C 6) oxoalkylene or -X ¹⁷ -X ¹⁸ -X ¹⁹ - group, wherein X ¹⁸ is as previously defined for X ^15, X ¹⁷ represents -alkylene with NL7 carbon atoms, and X ¹⁸ represents a nl8 -alkylene carbon atoms, wherein the sum NL7 nl8 and is 0, 1 or 2 and R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ - in which: R ⁸ represents an amino, 1-iminoethyl or methylamino group, X ²⁰ is C 4 -C 6 alkylene, C 4 -C 6 heteroalkylene, C 4 -C 6 heterooxoalkylene, C 4 -C 6 oxoalkylene or -X ²² -X ²³ -X ²⁴ - in which X ²³ is as defined above for X ^15, X ²² represents -alkylene with n22 carbon atoms, and X ²⁴ represents alkylene n24 carbon atoms, 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 is not ²² -alkylene with 4-6 carbon atoms or oxaalkylene having 4 to 6 carbon atoms and n22 is not 1, 2, 3 or 4, R ⁹ is as above for R ^5a X ²¹ represents a (C 1 -C 6) alkylene, a (C 2 -C 6) heteroarylene, (C 3 -C 6) heterooxoalkylene, (C 2 -C 6) oxoalkylene or a group -X ²⁵ -X ²⁶ -X ²⁷ - in which X ²⁶ is as previously defined for X ^15, X ²⁵ represents alkylene N25 carbon atoms, and X ²⁷ represents alkylene N27 carbon atoms, wherein the sum of n25 and n27 is 0, 1 or 2, wherein each of the above alkylene, cycloalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene is optionally substituted with one or more groups selected from halogen, hydroxyl, mercapto, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 14 carbon atoms, aryl of 6 to 14 carbon atoms, aryl (s) (C 1 -C 4) alkyl (C 1 -C 4) alkyl, (C 1 -C 8) alkanoyl, (C 1 -C 8) alkyloxy, (C 6 -C 14) aryloxy, (C 3 -C 14) cycloalkyloxy, (C 1 -C 4) alkyloxy group 4 carbon atoms ku, alkylthio of 1-8 carbon atoms, cycloalkylthio having 3 to 14 carbon atoms, arylthio of 6 to 14 carbon atoms, and -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are as defined above provided that the heteroatoms contained in R ¹ , X ² , X ⁴ , X ⁶ , X ⁸ and R ² and any heteroatoms in X ³ , X ⁵ , X ⁷ and X ⁹ do not present a covalent bond, or pharmaceutically acceptable salts, N-oxides, derivatives thereof prodrugs and protected derivatives. 16. The method of claim 15, wherein the disease is selected from asthma, allergic rhinitis, rheumatoid spondylitis, osteoarthritis, gout arthritis, arthritic conditions in general, urticaria, angioedema, eczematous dermatitis, anaphylaxis, hyperproliferative skin disease, peptic ulcer, peptic ulcer, intestinal diseases, ocular conjunctivitis, conjunctival janri and inflammatory conditions on the skin. 17. The method of claim 16, wherein the disease is asthma. 18. The method of claim 17, wherein the pharmaceutical composition comprises a therapeutically effective amount of a disubstituted cyclic compound of formula I in an aerosol pharmaceutically acceptable carrier suitable for administration as an inhalant. The method of claim 18, wherein the pharmaceutical composition further comprises a therapeutically effective amount of a β-adrenergic agonist, methylxanthine, cromoglycate, or a corticosteroid. The method of claim 19, wherein the β-adrenergic agonist is selected from albuterol, terbutaline, formoterol, phenoterol and prenalin, methylxanthine is selected from caffeine, theophylline, aminophylline and theobromine, the cromoglycate is selected from cromolyn and nedocromil and corticosteroid is selected from beclomethasone, triamcinolone, flurisolidone and dexamethasone. 21. The method of claim 16, wherein the disease is rheumatoid arthritis or conjunctivitis. The method of claim 21, wherein the pharmaceutical composition comprises a therapeutically effective amount of a disubstituted cyclic compound of Formula I in a pharmaceutically acceptable carrier suitable for topical administration. 23. A disubstituted cyclic compound of formula (I) R ¹ -X ¹ -X ² -X ³ -X ⁴ \ ₅ X ⁵ (I), r ² -x ⁹ -x ⁸ -x ⁷ -x ^ in which X ⁴ -X ⁵ -X ⁶ together represent alkylene of 2 to 12 carbon atoms or heteroalkylene of 3 to 12 carbon atoms, X ¹ and X ⁹ independently represent a covalent bond, a group · -C (O) -, -C (O) O-, -OC (O) -, -C (O) N (R ³ ) -, -N (R ³ ) C (O) -, -S (O 2) ) N (R ³⁾ -, -N (R ³⁾ S (O) 2-, -OC (O) N (R ³⁾ -, -N (R ³⁾ C (O) O-, -N (R ³ ) C (O) N (R ³ ) - or -OC (O) O-, wherein each R ^{3 is} independently hydrogen, C 1 -C 3 alkyl, or C 3 -C 8 cycloalkyl, both being X ¹ and X ^{9 are} not covalent bonds, X ³ and X ⁷ independently represent -C (O) -, -C (O) O-, -OC (O) -, -C (O) N (R ³ ) -, -N (R ³ ) C ( O) -, -S (O2) N (R ³ ) -, -N (R ³ ) S (O) 2 -, -OC (O) N (R ³ ) -, -N (R ³ ) C ( O) O-, -N (R ³ ) C (O) N (R ³ ) or -OC (O) O -, wherein R ³ is as defined above, X ² and X ⁸ independently represent C 1 -C 8 alkylene, C 1 -C 8 heteroalkylene, -X ¹⁰ -X ¹¹ - or -X ¹¹ -X ¹⁰ -, wherein X ¹⁰ is C 1-4 alkylene C 3 -C 4 heteroalkylene and X ¹¹ is C 3 -C 8 cycloalkylene or C 3 -C 8 heterocycloalkylene, R ¹ represents a group R ⁴ -X ¹² - or R ⁵ -X ¹³ -, wherein ^R4 is amino, amidino, guanidino, 1-iminoethyl or methylamine, X ¹² is C 4 -C 6 alkylene, C 4 -C 6 heteroalkylene, C 4 -C 6 heterooxoalkylene, C 4 -C 6 oxoalkylene or -X ¹⁴ -X ¹⁵ -X ¹⁶ -, wherein X ¹⁵ means cycloalkylene having 3 to 6 carbon atoms and heteroarylene having 5-6 carbon atoms, heterocycloalkylene having 3 to 6 carbon atoms or phenylene, X ¹⁴ represents alkylene I4 carbon atoms; and X ¹⁶ represents alkylene NL6 carbon atoms, wherein the sum of NL4 and n16 is 0, 1, 2, 3 or 4 R ⁵ represents a group selected from azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-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- ylu, 1,4,5,6-tetrahydropyrimidin-2-yl, 1,4,5,6-tetrahydropyrimidin-4-yl, 1,4,5,6-tetrahydropyrimidin-5-yl and any carbocyclic ketone or thioketone thereof a derivative whose group is optionally substituted by one or more groups selected from halogen, hydroxyl, mercapto, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 14 carbon atoms, aryl of 6 to 14 carbon atoms, aryl (of 6 to 6 carbon atoms) (C 1 -C 4) alkyl, (C 1 -C 4) alkanoyl, (C 1 -C 8) alkyloxy, (C 6 -C 14) aryloxy, (C 3 -C 14) cycloalkyloxy, (C 1 -C 4) alkyloxy group C 1 -C 8 alkylthio, C 3 -C 14 cycloalkylthio, C 6 -C 14 arylthio and -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are independently selected from hydrogen, alkyl C 1 -C 8 alkanoyl, C 1 -C 8 alkanoyl, cycloalkyl C 3 to C 14 or C 6 to C 14 aryl; and X ¹³ represents alkylene of 0-6 carbon atoms, heteroalkylene of 2-6 carbon atoms, heterooxoalkylene C 3 -C 6, C 2 -C 6 oxoalkylene or -X ¹⁷ -X ¹⁸ -X ¹⁹ - in which X ¹⁸ is as defined above for X ¹⁵ , X ¹⁷ is alkylene with n 17 carbon atoms and X ¹⁹ is alkylene having n18 carbon atoms, wherein the sum of n17 and n18 is 0, 1 or 2, and R ² is a group R ⁸ -X ²⁰ - or R ⁹ -X ²¹ - in which R ⁸ is as defined above for R ⁴ , X ²⁰ represents C 4 -C 6 alkylene, C 4 -C 6 heteroalkylene, heterooxoalkylene C 4 -C 6 oxoalkylene or C 4 -C 6 oxoalkylene or -X ²² -X ²³ -X ²⁴ - in which X ²³ is as above for X ¹⁵ , X ²² is alkylene with n 22 carbon atoms and X ²⁴ is alkylene with n24 carbon atoms, the sum of n22 and n24 being 0, 1, 2, 3 or 4, R ⁹ is as above for R ^5a X ²¹ represents alkylene of 0-6 carbon atoms, heteroalkylene of 2-6 carbon atoms, heterooxoalkylene of 3-6 carbon atoms, oxoalkylene of 2-6 carbon atoms and · ···· or -X ²⁵ -X ²⁶ -X ²⁷ - in which X ²⁶ is as defined above for X ^15, X ²⁵ represents alkylene N25 carbon atoms, and X ²⁷ represents alkylene N27 carbon atoms, wherein the sum of n25 and n27 is 0, 1 or 2, wherein each the aforementioned alkylene, cycloalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene is optionally substituted with one or more groups selected from halogen, hydroxyl, mercapto, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 14 carbon atoms, aryl of 6 (C 14-C 14) aryl (C až-C 14) aryl (C 1-C alky) alkyl, (C až-C alk) alkanoyl, (C až-C alky) alkyloxy, (Cx-Cry a) aryloxy, cycloalkyloxy C 3 -C 14 alkyloxy (C 4-C uhlíku) alkylthio, (C až-C alkyl) alkylthio, (C až-C cyk) cycloalkylthio, (C až-C 14 aryl) arylthio group, and -NR ⁶ R ⁷ in which R ⁶ and R ⁷ are as above by the absence of a covalent bond between the heteroatoms contained in R ¹ , X ² , X ⁴ , X ⁶ , X ⁸ and R ² and any heteroatoms in X ³ , X ⁵ , X ⁷ and X ⁹ , and pharmaceutically acceptable salts thereof, N-oxides, prodrug derivatives and protected derivatives. A disubstituted cyclic compound of formula I according to claim 23, wherein X ^{4 -} X ^{5 -} X ⁶ together represent alkylene of 2 to 12 carbon atoms or heteroalkylene of 3 to 12 carbon atoms, X ¹ and X ⁹ independently represent a covalent bond, -C (O) -, -NHC (O) -, -C (O) NH-, -N (CH ₃ ) C (O) -, or -S (O) ₂ NH, X ³ and X ⁷ independently represent -C (O) - or -C (O) O-, X ² and X ^{8 are} independently -X ¹⁰ -X ¹¹ -, wherein X ¹⁰ is a covalent bond or methylene and X ¹¹ is 4,1-piperidylene or 1,4-piperazinylene, R ¹ represents a group R ⁴ -X ¹² - or R ⁵ -X ¹³ -, wherein R ⁴ represents an amidine, guanidine or methylamine group; X ¹² is -X ¹⁴ -X ¹⁵ -X ¹⁶ -, where X ¹⁵ is 1,4-phenylene or 1,4-piperidylene, ^X14 is alkylene I4 carbon atoms, and X ¹⁶ represents alkylene NL6 carbon atoms wherein the sum of NL4 and NL6 is 0, 1 or 2, R ⁵ is piperid-4-yl, X ¹³ represents alkylene of 2 to 3 carbon atoms, R ² represents a group R ⁸ -X ²⁰ - or R ⁹ -X ²¹ - in which R ⁸ represents an amino, amidine, guanidine, methylamine or 1-iminoethyl group, 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 ²² is alkylene N22 with the carbon atoms, and X ²⁴ represents alkylene n24 carbon atoms, 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-yl, pyrid-3-yl, pyrid-4-yl, 1,4,5,6-tetrahydropyrimidin-5-yl or 1,4,5,6-tetrahydro -2-dioxo-pyrimidin-5-yl, a X ²¹ denotes alkylene of 1 to 6 carbon atoms, ω-azaalkylene of 2 to 5 carbon atoms, 2-aza-3-oxotrimethylene, 3-aza-2-oxotrimethylene, 3-oxotrimethylene, ω-thiaalkylene of 2 to 4 carbon atoms or -X ²⁵ -X ²⁶ -X ²⁷ - wherein X ²⁶ is 1,4-phenylene, X ²⁵ is alkylene of n 25 carbon atoms and X ²⁷ is alkylene of n 27 carbon atoms, wherein the sum of n25 and n27 is a number Or pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. A compound according to claim 24, wherein X ⁴ -X ⁵ -X ⁶ together represent C 4 -C 8 alkylene or C 4 -C 10 heteroalkylene, X ¹ and X ⁹ independently represent a covalent bond, -C (O) -, -NHC (O) -, -C (O) NH- or -S (O) ₂ NH, X ³ and X ⁷ independently represent -C (O) - or -C (O) ) O-, R ¹ represents a group R ⁴ -X ¹² -, wherein R ⁴ represents an amidine or gua nidin group, R ² represents a group R ⁸ -X ²⁰ - or R ⁹ -X ²¹ - in which R ⁸ is amino, amidino, guanidino or methylamino group, X ²³ is trans-1,4-cyclohexylene or 1,4-phenylene, ^R9 is imidazol-l-yl, imidazol-4-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, piperid-4-yl or pyrid-4-yl and X ²¹ is C 1 -C 5 alkylene or 3-azatrimethylene, and pharmaceutically acceptable salts thereof, N -oxides, prodrug derivatives and protected derivatives. A compound according to claim 25, wherein X ¹ and X ⁹ independently represent -C (O) - or -NHC (O) -, X ³ and X ⁷ independently represent -C (O) - or -C (O) O-, X ² and X ⁸ are both -X ¹⁰ -X ¹¹ -, wherein X ¹⁰ is a covalent bond and X ¹¹ is 1,4-piperazinylene, R ¹ is R ⁴ -X ¹² -, wherein R ⁴ represents an amidine or guanidine group and X ¹² represents a group -X ¹⁴ -X ¹⁵ -X ¹⁶ - in which X ¹⁵ represents 1,4-phenylene, X ¹⁴ represents a covalent bond and X ¹⁶ represents methylene, R ² represents a group R ⁸ -X ²⁰ - in which R ⁸ represents an amidine or guanidine group, X ²⁰ represents a group -X ²² -X ²³ -X ²⁴ - in which X ²³ represents 1,4-phenylene, X ²² represents a covalent bond and X ²⁴ represents methylene, and pharmaceutically acceptable salts, N-oxides, prodrug derivatives, and protected derivatives thereof. A compound according to claim 26, wherein X ⁴ -X ⁵ -X ⁶ together are hexamethylene, X ¹ and X ⁹ are both -NHC (O) -, X ³ and X ⁷ are both -C ( 0) - and R ¹ and R ² is 4-guanidinobenzyl, konkrétně4-guanidinobenzy1-4- {7 - [4 - (4-guanidinobenzylcarbamoyl) piperazin-ylkarbonylJheptanoyl} -1-piperazinecarboxamide, and pharmaceutically acceptable salts, N- oxides, prodrug derivatives and protected derivatives. A compound of formula I according to claim 26, wherein X ⁴ -X ⁵ -X ⁶ together are heptamethylene, X ¹ and X ⁹ are both -NHC (O) -, X ³ and X ^{7 respectively} . Φ 0000 00 0000 0 0 • 0 · ♦ -C (0) - and R ¹ and R ² is 4-guanidinobenzyl, namely 4-guanidinobenzyl 4- {8- [4- (4-guanidinobenzylcarbamoyl) piperazin-ylcarbonyl] octanoyl} -1-piperazinecarboxamide, and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. A compound according to claim 26, wherein X ⁴ -X ⁵ -X ⁶ together are octamethylene, X ¹ and X ⁹ are both -NHC (O) -, X ³ and X ⁷ are both -C ( O) - and R ¹ and R ² are 4-guanidinobenzyl, particularly 4-guanidinobenzyl-4- {9- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] nonanoyl} -1-piperazinecarboxamide, and pharmaceutically acceptable salts thereof , N-oxides, prodrug derivatives and protected derivatives. A compound according to claim 26, wherein X ⁴ -X ⁵ -X ⁶ together are hexamethylene, X ¹ and X ⁹ are both -NHC (O) -, X ³ and X ⁷ are both -C (O) - and R ¹ and R ² are 4-amidinobenzyl, particularly 4-amidinobenzyl-4- {7- [4- (4-amidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] heptanoyl} -1-piperazinecarboxamide, and pharmaceutically acceptable salts thereof salts, N-oxides, prodrug derivatives and protected derivatives. A compound according to claim 26, wherein X ⁴ -X ⁵ -X ⁶ together are pentamethylene, X ¹ and X ⁹ are both -NHC (O) -, X ³ and X ⁷ are both -C ( O) O- and R ¹ and R ² are both 4-guanidinobenzyl, in particular, 5-pentamethylene di [4- (4-guanidinobenzylcarbamoyl) piperazinecarboxylate], and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. A compound according to claim 26, wherein X ⁴ -X ⁵ -X ⁶ together are tetramethylene, X ¹ and X ⁹ are both -NHC (O) -, X ³ and X ⁷ are both -C ( O) O- and R ¹ and R ² are 4-guanidinobenzyl, in particular, 5-tetramethylene-di- [4- (4-guanidinobenzylcarbamoyl) piperazinecarboxylate], and a pharmaceutically acceptable salt thereof. acceptable salts, N-oxides, prodrug derivatives and protected derivatives. A compound according to claim 26, wherein X ⁴ -X ⁵ -X ⁶ together are pentamethylene, X ¹ and X ⁹ are both -NHC (O) -, X ³ and X ⁷ are both -C ( O) - and R ¹ and R ² are 4-guanidinobenzyl, in particular 4-guanidinobenzyl-4- {6 [4- (4-amidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] hexanoyl} -1-piperazincarboxamide, and pharmaceutically acceptable salts thereof, N-oxides, prodrug derivatives and protected derivatives. A compound according to claim 26, wherein X ⁴ -X ⁵ -X ⁶ together are oxatetramethylene, X ¹ and X ⁹ are both -C (O) -, X ³ and X ⁷ are both -C ( O) - and R ¹ and R ² are 4-amidinobenzyl, in particular 3-oxa-1,5-pentamethylene-di [4- (4-guanidinophenylacetyl) piperazin-1-ylcarbonyl], and pharmaceutically acceptable salts thereof, N-oxides , prodrug derivatives and protected derivatives. 35. A pharmaceutical composition comprising a therapeutically effective amount of a disubstituted cyclic compound of formula (I) according to claim 23 in combination with a pharmaceutically acceptable excipient. A method of treating an animal disease in which tryptase activity contributes to the pathology and / or symptomatology of the disease, comprising administering to the animal a therapeutically effective amount of a disubstituted cyclic compound of Formula I R ¹ -X ¹ -X ² -X ³ -X ⁴ X ⁵ (I), r ² -x ⁹ -x ⁸ -x ⁷ -x ^ in which X ⁴ -X ⁵ -X ⁶ together represent alkylene of 2 to 12 carbon atoms or heteroalkylene of 3 to 12 carbon atoms, X ¹ and X ⁹ , independently represent a covalent bond, -C (O) -, -C (O) O-, -OC (O) -, -C (O) N (R ³ ) -, -N (R ³ ) ³ ) C (O) -, -S (O 2) N (R ³ ) -, -N (R ³ ) S (O) 2 -, -OC (O) N (R ³ ) -, -N (R ³⁾ ) C (O) O-, -N (R ³ ) C (O) N (R ³ ) - or -OC (O) O-, wherein each R ^{3 is} independently hydrogen, C 1 -C 3 alkyl or C 3 -C 8 cycloalkyl; in that both X ¹ and X ^{9 are} not covalent bonds, X ³ and X ⁷ independently represent -C (O) -, -C (O) O-, -OC (O) -, -C (O) N (R ³ ) -, -N (R ³ ) C ( O) -, -S (O ₂ ) N (R ³ ) -, a group -N (R ³ ) S (O) ₂ -, -OC (O) N (R ³ ) -, -N (R ³ ) C (O) O-, -N (R ³ ) C (O) N ( R ³ ) or -OC (O) O-, wherein R ³ is as defined above, X ² and X ⁸ independently represent C 1 -C 8 alkylene, C 1 -C 8 heteroalkylene, -X ¹⁰ -X ¹¹ - or -X ¹¹ -X ¹⁰ -, wherein X ¹⁰ is C 1-4 alkylene C 3 -C 4 heteroalkylene and X ¹¹ is C 3 -C 8 cycloalkylene or C 3 -C 8 heterocycloalkylene, R ¹ represents a group R ⁴ -X ¹² - or R ⁵ -X ¹³ -, wherein ^R4 is amino, amidino, guanidino, 1-iminoethyl or methylamine, X ¹² is C 4 -C 6 alkylene, C 4 -C 6 heteroalkylene, C 4 -C 6 heterooxoalkylene, C 4 -C 6 oxoalkylene or -X ¹⁴ -X ¹⁵ -X ¹⁶ -, wherein X ¹⁵ means cycloalkylene having 3 to 6 carbon atoms, hteroarylen having 5-6 carbon atoms, heterocycloalkylene having 3 to 6 carbon atoms or phenylene, X ¹⁴ represents alkylene I4 carbon atoms; and X ¹⁶ represents alkylene NL6 carbon atoms wherein the sum of NL4 and NL6 is 0, 1, 2, 3 or 4 R ⁵ represents a group selected from azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-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, 9 · ·················· 9 9 9 999 9 pyrimidin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1,4,5,6-tetrahydropyrimidin-2-yl, 1,4,5,6-tetrahydropyrimidin-4-yl, 1,4,5,6-tetrahydropyrimidin-5-yl and any carbocyclic ketone or thioketone derivative thereof, wherein the group is optionally substituted with one or more groups selected from halogen, hydroxyl, mercapto, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 14 carbon atoms, aryl of 6 to 14 carbon atoms, aryl (of 6 to 14 carbon atoms) (C 1 -C 4) alkyl, (C 1 -C 8) alkanoyl, (C 1 -C 8) alkyloxy, (C 6 -C 14) aryloxy, (C 3 -C 14) cycloalkyloxy, (C 1 -C 4) alkyloxy C 1 -C 8 -cycloalkylthio, C 3 -C 14 -cycloalkylthio, C 6 -C 14 arylthio and -NR ⁶ R ⁷ in which R ⁶ and R ⁷ are independently selected from hydrogen, C ¹ -C ⁶ alkyl C 8 -C 8 alkanoyl, C 3 -C 8 cycloalkyl up to 14 carbon atoms or aryl of 6 to 14 carbon atoms, and X ¹³ represents alkylene of 0-6 carbon atoms, heteroalkylene of 2-6 carbon atoms, heterooxoalkylene C 3 -C 6, C 2 -C 6 oxoalkylene, or -X ¹⁷ -X ¹⁸ -X ¹⁹ - wherein X ¹⁸ is as defined above for X ¹⁵ , X ¹⁷ is alkylene with n 17 carbon atoms and X ¹⁸ is alkylene having n18 carbon atoms, wherein the sum of n17 and n18 is 0, 1 or 2, and R ² is a group R ⁸ -X ²⁰ - or R ⁹ -X ²¹ - in which R ⁸ is as defined above for R ⁴ , X ²⁰ represents C 4 -C 6 alkylene, C 4 -C 6 heteroalkylene, heterooxoalkylene C 4 -C 6 oxoalkylene or C 4 -C 6 oxoalkylene or -X ²² -X ²³ -X ²⁴ - in which X ²³ is as above for X ¹⁵ , X ²² is alkylene with n 22 carbon atoms and X ²⁴ is alkylene with n24 carbon atoms, the sum of n22 and n24 being 0, 1, 2, 3 or 4, R ⁹ is as above for R ^5a X ²¹ represents C 1 -C 6 alkylene, hete C 2 -C 6 roalkylene, C 3 -C 6 heterooxoalkylene, C 2 -C 6 oxoalkylene or -X ^25- X ²⁶ -X ²⁷ - wherein X ²⁶ is as above for X ¹⁵ , X ²⁵ is alkylene of n 25 carbon atoms and X ²⁷ is alkylene of n 27 carbon atoms, wherein the sum of n25 and n27 is 0, 1 or 2, wherein each of the above alkylene, cycloalkylene, heterolakylene, heterocycloalkylene, phenylene, arylene and heteroarylene is optionally substituted with one or more groups selected from halogen, hydroxyl, mercapto, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 14 carbon atoms, (C 6 -C 14) aryl, (C 1 -C 14) aryl (C 1 -C 4) alkyl, (C 1 -C 8) alkanoyl, (C 1 -C 8) alkyloxy, (C 6 -C 14) aryloxy group C 3 -C 14 cycloalkyloxy groups C 1-4 alkyl, (C 1 -C 8) alkylthio, (C 3 -C 14) cycloalkylthio, (C 6 -C 14) arylthio, and -NR ⁶ R ⁷ in which R ⁶ and R ⁷ are as above, provided that there is no covalent bond between the heteroatoms contained in R ¹ , X ² , X ⁴ , X ⁶ , X ⁸ and R ² and any heteroatoms in X ³ , X ⁵ , X ⁷ and X ⁹ , or pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives. 37. The method of claim 36, wherein the disease is selected from asthma, allergic rhinitis, rheumatoid spondylitis, osteoarthritis, gout arthritis, arthritic conditions in general, urticaria, angioedema, eczematous dermatitis, anaphylaxis, hyperproliferative skin disease, peptic ulcers, peptic ulcers. intestinal diseases, ocular conjunctivitis, conjunctival janri and inflammatory conditions on the skin. 38. The method of claim 37, wherein the disease is asthma. • · Λ Λ Λ Λ 100 ALIGN! 39. The method of claim 38, wherein the pharmaceutical composition comprises a therapeutically effective amount of a disubstituted cyclic compound of formula I in an aerosolized pharmaceutically acceptable carrier suitable for administration as an inhalation agent. The method of claim 39, wherein the pharmaceutical composition further comprises a therapeutically effective amount of a β-adrenergic agonist, methylxanthine, cromoglycate, or a corticosteroid. 41. The method of claim 40, wherein the [beta] -adrenergic agonist is selected from albuterol, terbutaline, formoterol, phenoterol, and prenalin, methylxanthine is selected from caffeine, theophylline, aminophylline and theobromine, the cromoglycate is selected from cromolino and necromilide, and corticosteroid is selected from beclomethasone, triamcinolone, flurisolidone and dexamethasone. 42. The method of claim 37, wherein the disease is rheumatoid arthritis or conjunctivitis. 43. The method of claim 42, wherein the pharmaceutical composition comprises a therapeutically effective amount of a disubstituted cyclic compound of Formula I in a pharmaceutically acceptable carrier suitable for topical administration. A process for the preparation of a disubstituted cyclic compound of formula (I) wherein: R ¹ -X ¹ -X ² -X ³ -X ^{4 X} x ⁵ (I), r ² -x'-x ⁸ -x ⁷ -x ^ 101 X ⁵ is C 3 -C 14 cycloalkylene, C 3 -C 14 heterocycloalkylene, C 6 -C 14 arylene or C 5 -C 14 heteroarylene and X ⁴ and X ⁶ independently represent C 0 -C 2 alkylene or X ⁴ -X ⁵ -X ⁶ - together represents an alkylene group having 2 to 12 carbon atoms or a heteroalkylene group having 3 to 12 carbon atoms, X ¹ and X ⁹ independently represent a covalent bond, -C (O) -, -C (O) O-, -OC (O) -, -C (O) N (R ³ ) -, -N (R ³⁾ ) C (O) -, -S (O2) N (R ³⁾ -, -N (R ³⁾ S (O) 2-, -OC (O) N (R ³⁾ -, -N (R ³⁾ C (O) O-, -N (R ³ ) C (O) N (R ³ ) - or -OC (O) O-, wherein each R ^{3 is} independently hydrogen, C 1 -C 3 alkyl, or cycloalkyl with 3 to 8 carbon atoms, both X ¹ and X ⁹ not being covalent bonds, X ³ and X ⁷ independently represent -C (O) -, -C (O) O-, -OC (O) -, -C (O) N (R ³ ) -, -N (R ³ ) C ( O) -, -S (O2) N (R ³ ) -, -N (R ³ ) S (O) 2 -, -OC (O) N (R ³ ) -, -N (R ³ ) C ( O) O-, -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 -C 8 alkylene, C 1 -C 8 heteroalkylene, -X ¹⁰ -X ¹¹ - or -X ¹¹ -X ¹⁰ -, wherein X ¹⁰ is C 1-4 alkylene C 3 -C 4 heteroalkylene and X ¹¹ is C 3 -C 8 cycloalkylene or C 3 -C 8 heterocycloalkylene, R ¹ represents a group R ⁴ -X ¹² - or R ⁵ -X ¹³ -, wherein R ⁴ represents an amino, amidine, guanidine, 1-iminoethyl or methylamine group, X ¹² is C 4 -C 6 alkylene, C 4 -C 6 heteroalkylene, C 4 -C 6 heterooxoalkylene, C 4 -C 6 oxoalkylene or -X ¹⁴ -X ¹⁵ -X ¹⁶ -, where X ¹⁵ represents cycloalkylene of 3 to 6 carbon atoms, heteroarylene of 5 to 6 carbon atoms, heterocycloalkylene of 3 to 6 carbon atoms or phenylene, ^X14 is -alkylene with I4 carbon atoms; and X ¹⁶ represents a NL6 -alkylene carbon atoms wherein the sum of NL4 and NL6 is 0, 1, 2, 3 or 4, R ⁵ represents a group selected from azetidin-3-yl, 102 benzoimidazol-4-yl, benzoimidazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazole 1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-methylpiperid-3-yl, 1-methylpiperid-4-yl, piperid-3-yl, piperid-4-yl, piperazine 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, 1,4,5,6-tetrahydropyrimidin-4-yl, 1,4,5,6-tetrahydropyrimidin-5-yl and any carbocyclic ketone or thioketone derivative thereof, the group of which is optionally substituted by one or more groups selected from halogen, hydroxyl, mercapto, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 14 carbon atoms, aryl of 6 to 14 carbon atoms, aryl (of 6 to 14 carbon atoms) (C 1 -C 4) alkyl, (C 1 -C 8) alkanoyl, (C 1 -C 8) alkyloxy, (C 6 -C 14) aryloxy, (C 3 -C 14) cycloalkyloxy, (C 1 -C 4) alkyloxy C 1 -C 8 -cycloalkylthio, C 3 -C 14 -cycloalkylthio, C 6 -C 14 arylthio and -NR ⁶ R ⁷ in which R ⁶ and R ⁷ are independently selected from hydrogen, C ¹ -C ⁶ alkyl C 8 -C 8 alkanoyl, cycloalkyl; C 3 to C 14 or C 6 to C 14 aryl; and X ¹³ represents alkylene of 0-6 carbon atoms, heteroalkylene of 2-6 carbon atoms, heterooxoalkylene of 3-6 carbon atoms, oxoalkylene of 2-6 carbon atoms, or a group -X ¹⁷ -X ¹⁸ -X ¹⁹ - in which X ¹⁸ is as previously defined for X ^15, X ¹⁷ represents alkylene NL7 carbon atoms, and X ¹⁸ represents alkylene nl8 carbon atoms, wherein the sum NL7 nl8 and is 0, 1 or 2 and R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ - in which: R ⁸ represents an amino, 1-iminoethyl or methylamine group, X ²⁰ represents C 4 -C 6 alkylene, C 4 -C 6 heteroalkylene, C 4 -C 6 heterooxoalkylene. 20 znamená · 20 20 hetero hetero hetero hetero hetero hetero hetero hetero · · · ················································ 103 6 carbon atoms, oxoalkylene of 4 to 6 atoms, or a group -X ²² -X ²³ -X ²⁴ - in which X ²³ is as above for X ¹⁵ , X ²² is alkylene with n 22 carbon atoms and X ²⁴ is alkylene with n 24 carbon atoms, 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 ²² is not an alkylene with 4-6 carbon atoms or oxaalkylene having 4 to 6 carbon atoms and n22 is not 1, 2, 3 or 4, R ⁹ is as above for R ^5a X ²¹ represents alkylene of 0-6 carbon atoms, heteroalkylene of 2-6 carbon atoms, heterooxoalkylene of 3-6 carbon atoms, oxoalkylene of 2-6 carbon atoms, or a group -X ²⁵ -X ²⁶ -X ²⁷ - in which X ²⁶ is as previously defined for X ^15, X ²⁵ represents alkylene N25 carbon atoms, and X ²⁷ represents alkylene N27 carbon atoms, wherein the sum of n25 and n27 is 0, 1 or 2, wherein each of the above alkylene, cycloalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene is optionally substituted with one or more groups selected from halogen, hydroxyl, mercapto, alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 14 carbon atoms, aryl of 6 to 14 carbon atoms, aryl (s) (C 1 -C 4) alkyl (C 1 -C 4) alkyl, (C 1 -C 8) alkanoyl, (C 1 -C 8) alkyloxy, (C 6 -C 14) aryloxy, (C 3 -C 14) cycloalkyloxy, (C 1 -C 4) alkyloxy group 4 carbon atoms, alkyl (C 1 -C 8) thio groups, (C 3 -C 14) cycloalkylthio groups, (C 6 -C 14) arylthio groups, and -NR ⁶ R ⁷ in which R ⁶ and R ⁷ are as defined above, provided that between the heteroatoms contained in the R ¹ , X ² , X ⁴ , X ⁶ , X ⁸ and R ² and any heteroatoms in X ³ , X ⁵ , X ⁷ and X ⁹ do not present a covalent bond, and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives, comprising: a) reacting a disubstituted cyclic compound of formula I 104 R ¹ -X ¹ -X ² -X ³ -X ⁴ X ³ (I) in 4 · 4 · 4 · 4 · 4 «4 · 44« 44 Y 0 -X'-X 'or a protected derivative thereof with a compound of the formula R ² -Y ⁹ -C (O) L or a protected derivative thereof, wherein L is a leaving group, Y ⁹ is a bond, -O- or -N (R ³ ) -, Y ⁸ is piperazin-1-yl, piperid-4-yl or HN (R ³ ) -alkyl of 1 to 8 carbon atoms and each R ¹ , R ² , R ³ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ and X ⁷ are as set forth in the Summary of the Invention, and then the protecting group is removed, if necessary, so as to obtain a disubstituted cyclic compound of formula I wherein X ⁸ is 1,4-piperazinylene or 1,4-piperidylene and X ⁹ is -C (O) -, -OC (O) - or -N (R ³ ) C (O) or wherein X ⁸ is C 1 -C 8 alkylene and X ⁹ is -C (O) N (R ³ ) -, -OC (O) N (R ³ ) - or -N (R ³ ) C (O) N (R) ³ ) -, b) reacting the disubstituted cyclic compound of formula I or a protected derivative thereof with an isocyanate of the formula R ² -NC (O) or a protected derivative thereof and after deprotection, if necessary, to obtain a disubstituted cyclic compound of formula I wherein: X ⁸ is 1,4-piperazinylene or 1,4-piperidylene and X ⁹ is -NHC (O) - or wherein X ⁸ is C 1 -C 8 alkylene and X ⁹ is -NHC (O) N ( R ³ ) -, c) reacting the disubstituted cyclic compound of formula II Y ^{2 -} X ^{3 -} X ⁴ X ³ (II) R ² -X ⁹ -X ⁸ -X ⁷ -X 'or a protected derivative thereof with a compound of the general formula ··· ·· · · · · · · 105 of the formula R ¹ -Y ¹ -C (O) L or a protected derivative thereof, wherein L is a leaving group; and Y ¹ is a bond, -O- or -N (R ³ ) -, Y ² is piperazin-1-yl, piperid-4-yl or HN (R ³ ) -alkyl of 1 to 8 carbon atoms and each R ¹ , R ² , R ³ , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ and X ⁹ is as set forth in the Summary of the Invention, and then the protecting group is removed, if necessary to form a disubstituted cyclic compound of formula I wherein X ² is 1,4-piperazinylene or 1,4-piperidylene and X ¹ is -C (O) -, -OC (O) - or -N (R 1) ³ ) C (O) - or wherein X ² is C 1 -C 8 alkylene and X ¹ is -C (O) N (R ³ ) -, -OC (O) N (R ³ ) -, or -N (R ³ ) C (O) N (R ³ ) -, d) reacting the disubstituted cyclic compound of formula II or a protected derivative thereof with an isocyanate of the formula R ¹ -NC (O) or a protected derivative thereof, and after deprotection, if necessary, to obtain a disubstituted cyclic compound of formula I wherein X ² is 1,4-piperazinylene or 1,4-piperidylene and X ¹ is -NHC (O) - or wherein X ² is C 1 -C 8 alkylene and X ¹ is -NHC (O) N (R ³ ) -, e) reacting the disubstituted cyclic compound of formula III Y ^{2 -} X ^{3 -} X ⁴ \ ₅ X ⁵ (III) Y ⁸ -X ⁷ -X 4 or a protected derivative thereof with two or more equivalents of a compound of the general formula R ¹ -Y ¹ -C (O) L or a protected derivative thereof, wherein L represents a leaving group, Y ¹ represents a bond, - O- or -N (R ³ ) -, Y ² and Y ⁸ independently represent piperazin-1-yl, piperid-4-yl or HN (R ³ ) -alkyl of 1 to 8 carbon atoms and each R ¹ , R ³ , X ³ , X ⁴ , X ⁵ , X ⁶ and X ⁷ are as set forth in the Summary of the Invention; ······ · * ········································ 106 and then deprotecting, if necessary, to give a disubstituted cyclic compound of formula I wherein R ¹ is R ² , X ² and / or X ⁸ is 1,4-piperazinylene or 1,4- piperidylene, X ¹ is -C (O) -, -OC (O) - or -N (R ³ ) C (O) -, X ⁹ is -C (O) -, -OC (O) -, or -N (R ³ ) C (O) - and / or wherein X ² and / or X ⁸ is C 1 -C 8 alkylene, X ¹ is -C (O) N (R ³ ) -, -OC (O) N (R ³ ) - or -N (R ³ ) C (O) N (R ³ ) - and X ⁹ is -C (O) N (R ³ ) -, -OC ( O) N (R ³ ) - or -N (R ³ ) C (O) N (R ³ ) -, f) reacting a disubstituted cyclic compound of formula III or a protected derivative thereof with two or more molar equivalents of an isocyanate of the formula R ¹ -NC (O) or a protected derivative thereof, and removing the protecting group, if necessary, to obtain a disubstituted cyclic compound of formula (I) wherein R ¹ is 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 (O) - and / or wherein X ² and / or X ⁸ is C 1 -C 8 alkylene, X ¹ is -NHC (O) N (R ³ ) - and / or X ⁹ is -NHC (0) N (R ³ ) -, g) reacting an amine of formula R ¹ -N (R ³ ) H or a protected derivative thereof with a disubstituted cyclic compound of formula IV LC (0) -Y ¹ -X ² -X ³ -X ⁴ \ ₅ X ⁵ (IV) r ² -x ⁹ -x ⁸ -x ⁷ -x ^ or a protected derivative thereof, wherein L is a leaving group, Y ¹ is a bond, -O- or -N (R ³ ) and each group R ¹ , R ² , R ³ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ and X ⁹ are as set forth in the Summary of the Invention, and then the protecting group is removed if necessary to form a disubstituted cyclic compound of formula I wherein X ¹ is -N (R ³ ) C (O) -, -N (R ³ ) C (O) O-, or 107 -N (R ³ ) C (O) N (R ³ ) -, h) reacting a compound of formula R ¹ -X ¹ -Y ² or a protected derivative thereof with a disubstituted cyclic compound of formula V LC (O) -Y ³ -X ⁴ \ ₅ X ⁵ (V) r ² -x ⁹ -x ⁸ -x ⁷ -x ^ or a protected derivative thereof in which L represents a leaving group, Y ³ represents a bond or a group -O- or -N (R ³ ) -, Y ² represents piperazin-1-yl, piperid-4-yl or HN (R ³ ) -alkyl of 1 to 8 carbon atoms 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 set forth in the Summary of the Invention, and then the protecting group is removed, if necessary, to yield a disubstituted cyclic compound of formula I wherein X ² is 1,4-piperazinylene or 1,4-piperidylene and X ³ is -C (O) -, -C (O) O- or -C (O) N (R ³ ) - or wherein X ² is alkylene with 1-8 carbon atoms and X ³ is -N (R ³ ) C (O) -, -N (R ³ ) C (O) O-, or -N (R ³ ) C (O) N (R 1) ³ ) -, i) reacting two or more molar equivalents of a compound of formula R ¹ -X ¹ -Y ² or a protected derivative thereof with a disubstituted cyclic compound of formula VI LC (O) -Y ³ -X ⁴ LC (O) Y ⁷ -X ⁶ X ³ (VI) or a protected derivative thereof in which L represents a leaving group, Y ³ and Y ⁷ independently represent a bond or an -O- or -N (R ³ ) - group, Y ² represents piperazin-1-yl, piperidine- 4-yl, HN (R ³ ) -alkyl of 1 to 8 carbon atoms or a and / or aa ······ • and aaaa · · • aa and aa ·· aaaa 108 is HN (R ³ ) -heteroalkyl of 1 to 8 carbon atoms and each R ¹ , X ¹ , X ⁴ , X ⁵ and X ⁶ is as set forth in the Summary of the Invention, and then deprotected if necessary to form a disubstituted cyclic compound of formula I wherein X ² and X ⁸ are both 1,4-piperazinylene or 1,4-piperidylene and X ³ and X ⁷ independently represent -C (O) -, -OC (O ) - or -C (O) N (R ³ ) - or wherein X ² and X ⁸ are both C 1 -C 8 alkylene or C 1 -C 8 heteroalkylene and X ³ and X ² independently represent -N ( R ³ ) C (O) -, -N (R ³ ) C (O) O-, or -N (R ³ ) C (O) N (R ³ ) -, j) optionally reacting a disubstituted cyclic compound of formula I wherein R ⁴ is an amino group with cyanamide to form a disubstituted cyclic compound of formula I wherein R ⁴ is a guanidine group, k) optionally further converting the disubstituted cyclic compound of Formula I to a pharmaceutically acceptable salt thereof, l) optionally further converting the salt of the disubstituted cyclic compound of formula I to a non-salt form; m) optionally further converting the non-oxidized form of the disubstituted cyclic compound of formula to a pharmaceutically acceptable N-oxide, n) optionally further converting the disubstituted compound of formula I in the N-oxide form to the non-oxidized form, o) optionally further converting the non-derivatized disubstituted compound of Formula I to a pharmaceutically acceptable prodrug derivative; and p) optionally further converting the prodrug derivative of the disubstituted cyclic compound of Formula I into its derivatized form.