WO2000066112A1 - Cxcr-4 receptor antagonists - thrombopoietin mimetics - Google Patents

Cxcr-4 receptor antagonists - thrombopoietin mimetics Download PDF

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WO2000066112A1
WO2000066112A1 PCT/US2000/011951 US0011951W WO0066112A1 WO 2000066112 A1 WO2000066112 A1 WO 2000066112A1 US 0011951 W US0011951 W US 0011951W WO 0066112 A1 WO0066112 A1 WO 0066112A1
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Prior art keywords
tetraazacyclotetradecane
pentahydrochloride
imethy
pyrazol
compound according
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PCT/US2000/011951
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French (fr)
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Juan I. Luengo
Alan Thomas Price
Antony Shaw
Kenneth Wiggall
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Smithkline Beecham Corporation
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Priority to EP00928735A priority Critical patent/EP1189609A4/en
Priority to JP2000614997A priority patent/JP2002543126A/en
Priority to AU46924/00A priority patent/AU4692400A/en
Publication of WO2000066112A1 publication Critical patent/WO2000066112A1/en

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Definitions

  • the present invention relates to cyclam derivatives, pharmaceutical compositions containing these compounds, the use of these compounds as CXCR-4 receptor antagonists and to use of these compounds as promoters of thrombopoiesis and megakaryocytopoiesis.
  • the CXCR-4 receptor originally known as LESTR/fusin, was shown to be the receptor for the ⁇ or CXC chemokine stromal cell-derived factor- 1 (SDF-1) in 1996 and renamed at this time. SDF- 1 appears to be specific for CXCR-4 and mediates its chemotactic effects via this receptor. The CXCR-4 receptor is widely expressed in a variety of cell types and is implicated in a range of inflammatory responses mediated by SDF- 1.
  • the widespread distribution of the receptor leads to its involvement in a number of disease areas including bacterial, fungal and protozoan infections, pain, cancer, diabetes, obesity, anorexia, bulimia, asthma, allergies, Parkinson's disease, acute heart failure, hypotension, hypertension, atherosclerosis, disease states involving angiogenesis. urinary retention, osteoporosis, angina pectoris, myocardial infarction, stroke, ulcers, benign prostatic hypertrophy, migraine, vomiting, psychotic and neurological disorders (e.g. anxiety, schizophrenia, manic depression, depression, delirium, dementia, mental retardation) and dyskinesias (Huntington's disease and Gilles de la Tourette's syndrome), injured or severed spinal cord and other injury related disease states.
  • angiogenesis urinary retention, osteoporosis, angina pectoris, myocardial infarction, stroke, ulcers, benign prostatic hypertrophy, migraine, vomiting, psychotic and neurological disorders (e.g. anxiety, schizophrenia, manic depression, depression,
  • CXCR-4 has been identified as the co-receptor used by T-tropic HIV- 1 viral strains to infect cells, and antagonists of the receptor may therefore be useful in the treatment of late stage HIV infection and AIDS.
  • CXCR-4 receptor antagonists offer a unique approach toward decreasing the pathophysiology associated with the aforementioned diseases.
  • Megakaryocytes are bone marrow-derived cells, which are responsible for producing circulating blood platelets. Although comprising ⁇ 0.25% of the bone marrow cells in most species, they have >10 times the volume of typical marrow cells. See Kuter et al. Proc. Natl. Acad. Aci. USA 91 : 1 1104-11108 (1994). Megakaryocytes undergo a process known as endomitosis whereby they replicate their nuclei but fail to undergo cell division and thereby give rise to polypoid cells. In response to a decreased platelet count, the endomitotic rate increases, higher pioidy megakaryocytes are formed, and the number of megakaryocytes may increase up to 3-fold. See Harker J. Gin. Invest. 47: 458-465 (1968). In contrast, in response to an elevated platelet count, the endomitotic rate decreases, lower pioidy megakaryocytes are formed, and the number of megakaryocytes may decrease by 50%.
  • TPO thrombopoietin
  • TPO is thought to affect megakaryocytopoiesis in several ways: (1) it produces increases in megakaryocyte size and number; (2) it produces an increase in DNA content, in the form of polyploidy, in megakaryocytes; (3) it increases megakaryocyte endomitosis; (4) it produces increased maturation of megakaryocytes; and (5) it produces an increase in the percentage of precursor cells, in the form of small acetylcholinesterase-positive cells, in the bone marrow.
  • TPO platelets
  • thrombocytes are necessary for blood clotting and when their numbers are very low a patient is at risk of death from catastrophic hemorrhage
  • TPO has potential useful application in both the diagnosis and the treatment of various hematological disorders, for example, diseases primarily due to platelet defects.
  • Ongoing clinical trials with TPO have indicated that TPO can be administered safely to patients.
  • recent studies have provided a basis for the projection of efficacy of TPO therapy in the treatment of thrombocytopenia, and particularly thrombocytopenia resulting from chemotherapy, radiation therapy, or bone marrow transplantation as treatment for cancer or lymphoma. See e.g., McDonald (1992) Am. J. Ped. Hematologv/Oncologv 14: 8-21 (1992).
  • Thrombopoietin is a glycoprotein with two distinct regions separated by a potential Arg-Arg cleavage site.
  • the amino-terminal region is highly conserved in man and mouse, and has some homology with erythropoietin and interferon-alpha and interferon-beta.
  • the carboxy-terminal region shows wide species divergence.
  • TPO-R human TPO receptor
  • c-mpl human TPO receptor
  • TPO-R as a key regulator of megakaryopoiesis
  • the present invention involves novel compounds represented by Formulas (I), and (II) hereinbelow, their use as CXCR-4 receptor antagonists and their use as agonist of the TPO receptor
  • the present invention further provides methods for antagonizing CXCR-4 receptors in an animal, including humans, which comp ⁇ ses administe ⁇ ng to a subject in need of treatment an effective amount of a compound of Formula (I), and (II) as indicated hereinbelow
  • compositions comp ⁇ sing a pharmaceutical carrier and compounds useful m the methods of the invention
  • Formula (I) wherein: the -CH2-Z substituent is meta or para to the tetraazacyclotetradecane substituent; Z represents a nitrogen-linked heteroaryl, a substituted nitrogen-linked heteroaryl, a cyclic amine moiety, a substituted cyclic amine moiety, or NY' Y ⁇ where ⁇ l and Y ⁇ are each independently selected from hydrogen, alkyl, substituted alkyl, C3- Ci2aryl, substituted C3-C[2 ryl, cycloalkyl, and substituted cycloalkyl; and
  • X is selected from the group consisting of hydrogen, alkyl, C3-C j 2aryl, substituted C3-Ci 2aryl, amino, alkylamino, mtro, hydroxy, alkoxy, halogen, carboxyl and carboxamido; and pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes thereof.
  • Preferred among the presently invented Formula (I) compounds are those in which the nitrogen-linked heteroaryl is selected form: benzimidazole, substituted benzimidazole, phe ⁇ othiazine, substituted phe ⁇ othiazine.
  • Particularly preferred among the presently invented Formula (I) compounds are those in which the nitrogen-linked heteroaryl is a substituted benzimidazole.
  • Preferred among the presently invented Formula (I) compounds are those in which cyclic amine mioety is selected form: piperazine, pipendme, azacycloheptane, diazacycloheptane, morpholine, azacyclotridecane, 5,6,14,15-dibenzo-l,4-dioxa-8,12- diazacyclopentadeca-5, 14-dien, 1 ,4,7-trioxa- 10-azacyclododecane, 1 ,4,1, 10,-tetraoxa- 13- azacyclopentadecane, 1,4,8,11 -tetraazacyclotetradecane, and diazacyclooctane.
  • Formula (I) compounds are those in which cyclic amine mioety is selected form: 1,4-d ⁇ azacycloheptane, azacyclotridecane, 5,6, 14, 15-d ⁇ benzo- 1 ,4-d ⁇ oxa-8, 12-d ⁇ azacyclopentadeca-5, 14-dien, 1,4,8, 1 1 -tetraazacyclotetradecane, and 1,5-d ⁇ azacyclooctane.
  • Preferred among the presently invented Formula (I) compounds are those in which C3-C j2aryl, when representing Y ' and or Y ⁇ , is independently selected form- phenyl. quino ne. thiazole, pyrazole and py ⁇ dine.
  • Particularly preferred among the presently invented Formula (I) compounds are those in which C3-C j 2aryl, when representing ⁇ l and or Y ⁇ is independently selected form- phenyl and pyrazole
  • Preferred among the presently invented Formula (I) compounds are those in which X is selected from hydrogen, mtro and halogen
  • heteroaryl as used herein, unless otherwise defined, is meant a cyclic or polycyclic aromatic ring containing from 3 to 16 carbon atoms and containing one to three heteroatoms, provided that one of the heteroatoms is nitrogen and provided that when the number of carbon atoms is 3 the aromatic ⁇ ng contains at least two heteroatoms
  • heteroaryl as used herein include benzimidazole and phenothiazine
  • cyclic amine moiety as used herein, unless otherwise defined, is meant a nitrogen-linked, non-aromatic, cyclic or polycyclic ring system containing from about 5 to 24 atoms; of which 1 to 4 are nitrogen atoms and 0 to 4 are oxygen atoms, which heteroatoms being separated by 2 or more carbon atoms, wherein the moiety comp ⁇ ses 0 to 2 fused aromatic rings
  • cyclic amine moiety examples include piperazme, pipe ⁇ dme, azacycloheptane, diazacycloheptane, morphohne, azacyclotridecane, 5,6,14,15-d ⁇ benzo- l,4-d ⁇ oxa-8,12-d ⁇ azacyclopentadeca-5,14-d ⁇ en, 1,4,7-t ⁇ oxa- l 0-azacyclododecane, 1,4,7,10,-tetraoxa- 13-azacyclopentadecane, 1,4,8,1 1 -tetraazacyclotetradecane, and 1,5- diazacyclooctane
  • C3-Ci 2aryl as used herein, unless otherwise defined, is meant a cyclic or polycyclic aromatic nng containing from 3 to 12 carbon atoms and optionally containing one to three heteroatoms, provided that when the number of carbon atoms is 3 the aromatic ring contains at least two heteroatoms and provided that when the number of carbon atoms is 4 the aromatic ⁇ ng contains at least one heteroatom
  • C3-C j 2aryl examples include phenyl, benzimidazole, phenothiazine, quinohne, thiazole, pyrazole, py ⁇ dine, py ⁇ midine, naphthyl, 3,4- methylenedioxyphenyl and biphenyl
  • heteroatom as used herein is meant oxygen, nitrogen or sulfur
  • halogen as used herein is meant a substituent selected from bromide, iodide, chlonde and fluo ⁇ de
  • cycloalkyl as used herein unless otherwise defined, is meant a nonaromatic, unsaturated or saturated, cyclic or polycyclic C3-C12
  • cycloalkyl and substituted cycloalkvl substituents as used herein include cyclohexyl, 4-hydroxy-cyclohexyl, 2-ethylcyclohexyl, propyl 4- methoxycyclohexyl, 4-methoxycyclohexyl, 4-carboxycyclohexyl and cyclopentyl
  • substituted as used herein, unless otherwise defined, is meant that the subject chemical moiety has one or more substituents selected from the group consisting of guanidmo, hydroxyalkyl, alkoxy, acyloxy, alkyl, py ⁇ dyl, py ⁇ midyl, ammo, alkylamino, dialkylammo, [( 1,4,8,1 l,-tetraazacyclotetradecan-l-ylmethyl)phenylmethyl], 3,4- methylenedioxyphenylmethyl, phenylalkyl, phenyl
  • alkoxy as used herein is meant -Oalkyl where alkyl is as described herein including -OCH3 and -OC(CH3) 2 CH3.
  • acyloxy as used herein is meant -OC(0)alkyl where alkyl is as described herein
  • Examples of acyloxy substituents as used herein include. -OC(0)CH3, - OC(0)CH(CH 3 ) 2 and -OC(0)(CH 2 )3CH 3 .
  • N-acylamino as used herein is meant -N(H)C(0)alkyl, where alkyl is as desc ⁇ bed herein.
  • Examples of N-acylammo substituents as used herein include- - N(H)C(0)CH 3 , -N(H)C(0)CH(CH 3 ) 2 and -N(H)C(0)(CH 2 )3CH 3 .
  • alkyl and de ⁇ vatives thereof and in all carbon chains as used herein is meant a linear or branched, saturated or unsaturated hydrocarbon chain having C j -C 12 carbon atoms
  • treating and de ⁇ vatives thereof as used herein, is meant prophylatic or therapeutic therapy.
  • Y' moiety can be optionally substituted by a substituent selected from the group consisting of alkyl, alkoxy, halogen and carboxy;
  • A represents an X -substituted aryl or heteroaryl ring wherein X' is selected from the group consisting of hydrogen, alkyl, aryl, amino, alkylammo, nitro, hydroxy, alkoxy, halogen, carboxyl, and carboxamido; provided that the YCH2 groups are arranged meta or para to each other.
  • Preferred compounds, having formula (I), useful in the present invention are selected from the group consisting of: l-[4-(4- Acetyl- l-piperazinomethyl)phenylmethyl]- 1 ,4,8, 11 -tetraazacyclotetradecane pentahydrochloride; l-[4-(l ,4-Diazacycloheptan- l-ylmethyl)phenylmethyl]- 1 ,4,8, 11 -tetraazacyclotetradecane hexahydrochloride; l-[4-(Azacycloheptan-l-ylmethyl)phenylmethyl]- l,4,8, l l-tetraazacyclotetradecane pentahydrochloride; l-[4-( 1 -Piperidinomethy phenylmethyl ]- 1 ,4,8, 1 1 -tetraazacyclotetradecane pentahydrochloride; 1 -[4
  • the most preferred compounds included in the present invention are selected from the group consisting of: l-[4-( 1 ,5-Diazacyclooctan- 1 -ylmethyOpheny Imethyl]- 1 ,4,8, 1 1 -tetraazacyclotetradecane hexahydrochloride; 1 -[4-(2-Guanidinobenzimidazol- 1 -y lmethyl)phenylmethy 1]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride; l-[4-(5,6,14,15-Dibenzo- l,4-dioxa-8,12-diazacyclopentadeca-5, 14-dien-8- ylmethyOpheny Imethyl]- 1,4,8, 11 -tetraazacyclotetradecane hexahydrochloride; l-[4-(Azacyclotridecan- l-yl
  • Preferred compounds of formula (II) are selected from the group consisting of: l,4-Bis[2-(2-benz ⁇ m ⁇ dazolylam ⁇ no)-5,5-di(2-py ⁇ dyI)-4-oxo-5H- ⁇ m ⁇ dazol ⁇ n-3- ylmethyl]benzene bis-t ⁇ fluoroacetic acid salt;
  • compositions of the present invention are pharmaceutically acceptable salts and complexes.
  • Preferred are the zinc, copper, nickel, cobalt and rhodium complexes, hydrochlonde, hydrobromide and t ⁇ fluoroacetate salts
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms All of these compounds and diastereomers are contemplated to be within the scope of the present invention
  • the compounds of Formulas (I) and (II) are prepared as shown in Schemes I to IV below wherein the pendent substituents (X, Z, A, Y', Y' , Y ⁇ and XO are as defined in formulas 1 and 2 and provided that the pendent substituents do not include any such substituents that render inoperative the processes of Schemes I the IV. All of the starting materials are commercially available or are readily made from commercially available starting materials by those of skill in the art.
  • the present compounds have been found to act as CXCR-4 receptor antagonist they are useful for the treatment of diseases including but not limited to bacterial, fungal and protozoan infections, pain, thrombocytopenia, cancer, diabetes, obesity, anorexia, bulimia, asthma, allergies, Parkinson s disease, acute heart failure, hypotension, hypertension, neural damage, atherosclerosis, urinary retention, osteoporosis, angina pecto ⁇ s, myocardial infarction, stroke, ulcers, benign prostatic hypertrophy, migraine, angiogenesis, vomiting, psychotic and neurological disorders (e g anxiety, schizophrenia, manic depression, depression, deh ⁇ um, dementia, mental retardation) and dyskmesias (Huntington's disease and Gilles de la Tourette's syndrome), viral infections, such as HIV infection in patients having clinical signs of AIDS and for the treatment of asymptomatic HIV- ⁇ nfected subjects
  • the present compounds are also useful for the treatment of an injured or severed spinal cord and other injury-related disease states
  • the treatment of thrombocytopenia is accomplished by enhancing the production of platelets
  • thrombocytopenia is accomplished by enhancing the production of platelets
  • 'co-administe ⁇ ng ' and derivatives thereof as used herein when directed to the TPO mimetic aspect of this invention is meant either simultaneous administration or any manner of separate sequential administration of a TPO mimetic compound, as described herein, and a further active ingredient or ingredients, known to treat thrombocytopenia, including chemotherapy-induced thrombocytopenia and bone marrow transplantation and other conditions with depressed platelet production
  • the compounds are administered in a close time proximity to each other
  • the compounds are administered in the same dosage form, e g one compound may be administered topicallv and another compound may be administered orally Because the compounds of the present invention have been found to be active as
  • TPO mimetics they exhibit therapeutic utility in treating thrombocytopenia and other conditions with depressed platelet production
  • TPO receptor in a Luciferase assay such as described in Lamb, et al , Nucleic Acids Research 23 3283-3289 (1995) and Seidel. et al . Proc Natl Acad Sci . USA 92 3041- 3045 (1995) by substituting a TPO-responsive BaF3 cell line (Vigon et al Proc Natl Acad Sci USA 1992, 89, 5640-5644) for the HepG2 cells utilized therein
  • the mu ⁇ ne BaF3 cells express TPO receptors and closely match the pattern of STAT (signal transducers and activators of transcription) activation observed in primary mu ⁇ ne and human bone marrow cells in response to TPO
  • UT-7/TPO leukemic megakaryoblastic cell line ( Komatsu, N et al , Blood, 1996, 87, 4552-4560) UT-7/TPO cells express TPO-R and are absolutely dependent on the presence of TPO for growth and survival Likewise, some of the most preferred compounds of this invention were also positive in stimulating the maturation of megakaryocytes from human bone marrow cells In this assay, purified human CD34+ progenitor cells were incubated in liquid culture with test compounds for 10 days and the number of cells expressing the transmembrane glycoprotein CD41 (gpllb), a megakaryocytic marker, was then measured by flow cytometry (see Cwirla, S E et al Science, 1997, 276, 1696-1699)
  • the pharmaceutically active compounds within the scope of this invention are useful as TPO mimetics in mammals, including humans, in need thereof
  • Some of the preferred compounds within the scope of the invention showed activation from about 5% to 100% of control (control is the maximal response to TPO) at a concentration of 0 1 -30 uM in the luciferase assay
  • the preferred compounds of the invention also promoted the proliferation of UT-7/TPO cells at a concentration of 0 1 to 30 uM.
  • the preferred compounds of the invention also showed activity in the CD41 megakaryocytic assay at a concentration of 0 1 to 30 uM
  • the activity of the compound of Example 46 in the luciferase assay is 86% of maximal TPO effect with an EC50 of 2.1 uM
  • One aspect of the present invention therefor provides a method of treating thrombocytopenia and other conditions with depressed platelet production, which comprises administering a compound of Formula (I) or (II), as described above, in a quantity effective to enhance platelet production
  • the compounds of Formulas (I) and (II) also provide for a method of treating the above indicated disease states because of their demonstrated ability to act as TPO mimetics
  • the drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal, and parenteral
  • the present invention therefor provides a method of treating thrombocytopenia and other conditions with depressed platelet production, which comprises administering a compound of Formula (I) or (II), as desc ⁇ bed above, in a quantity effective to enhance platelet production
  • the compounds of Formulas (I) and (II) also provide for a method of treating the above indicated disease states because of their demonstrated ability to act as TPO mimetics
  • the drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal, and parenteral
  • the pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products
  • Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0 001 - 100 mg/kg of active compound, preferably 0001 - 50 mg/kg
  • the selected dose is administered preferably from 1-6 times daily, orally or parenterally
  • Preferred forms of parenteral administration include topically, rectally, transdermally, by injection and continuously by infusion Oral dosage units for human administration preferably contain from 0 05 to 3500 mg of active compound Oral administration, which uses lower dosages is preferred
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular active in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration
  • the method of this invention of inducing TPO mimetic activity in mammals, including humans, comp ⁇ ses administe ⁇ ng to a subject in need of such activity an effective TPO mimetic amount of a pharmaceutically active compound of the present invention also provides for the use of a compound of Formula (I) or (II) in the manufacture of a medicament for use as a TPO mimetic
  • the invention also provides for the use of a compound of Formula (I) or (II) in the manufacture of a medicament for use in therapy
  • the invention also provides for the use of a compound of Formula (I) or (II) in the manufacture of a medicament for use in enhancing platelet production
  • the invention also provides for the use of a compound of Formula (I) or (II) in the manufacture of a medicament for use in treating thrombocytopenia
  • the invention also provides for a pharmaceutical composition for use as a TPO mimetic which comp ⁇ ses a compound of Formula (I) or (II) and a pharmaceutically acceptable earner
  • a pharmaceutical composition for use in the treatment of thrombocytopenia which comp ⁇ ses a compound of Formula (I) or (II) and a pharmaceutically acceptable carrier
  • the invention also provides for a pharmaceutical composition for use in enhancing platelet production which comprises a compound of Formula (I) or (II) and a pharmaceutically acceptable earner
  • the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to antagonize the CXCR-4 receptor or which exhibit a therapeutic effect on a disease state that is treatable with a CXCR-4 receptor antagonist; or such as other compounds known to treat thrombocytopenia, including chemotherapy-induced thrombocytopenia and bone marrow transplantation and other conditions with depressed platelet production, or compounds known to have utility when used in combination with a TPO mimetic
  • Assay plates were seeded with RBL transfected with the SDF- 1 receptor Dye loading buffer (EMEM w/Earl's salts w/ L-glutamine with IX Sulphinpyrozone and 10% BSA, 100 uL) was added to each well, and the plate incubated for 90 minutes at 37 "C The dye loading buffer was aspirated from the plates Hydrolysis buffer (EMEM w/Earl's salts w/ L-glutamine with IX Sulphinpyrozone, lOOuL) was added to each well, and the plate incubated for 10 minutes at 37 °C The cells were washed 3 times with wash buffer (IX Krebs Ringer, 15 mM HEPES, ImM MgCl, 1 mM CaCl with IX Sulphinpyrozone and
  • Example l(a)-(c) Following the procedure of Example l(a)-(c), except substituting homopiperazine for 1 -acetylpiperazine, the title compound was prepared (27% overall) H NMR (300MHz, d3-MeOD/D,0) ⁇ 7 67 (d, 2H), 7.50 (d, 2H), 4 52 (s, 2H), 3 98 (s, 2H), 3.90 (s, 2H), 3.62 (m, 2H), 3.53-3 20 (m, 8H), 3.15 (m, 2H), 2.95 (m, 4H), 2.35 (m, 2H), 2.19 ( , 4H), 2.09 ( , 2H), 1.26 (m, 4H).
  • Potassium carbonate (3.5 g, 25.3 mmol) was added, followed by the dropwise addition of a solution of l,4,8-t ⁇ -(r-butyloxycarbonyl)- 1 ,4,8, 1 1- tetraazacyclotetradecane (B Boitrel et. al., Tetrahedron Lett , 1995, 36, 4995) (6.0 g, 1 1 98 mmol) in acetonit ⁇ le (100 mL).
  • Example 18 l-(4-f(2-aminoethyl)(3-aminopropyl)aminomethyl1phenylmethyl ⁇ - l .4.8.1 1- tetraazacyclotetradecane heptahydrochloride a) (2-phthalimidoethyl)(3-phthalimidoprop- l-yl)amine
  • 1,4,8,1 1-tetraazacyclotetradecane pentahydrochloride 200 mg, 0.234 mmol
  • ethanol 5 L
  • hydrazine hydrate 2.0 mL, 64.2 mmol
  • the solvent was evaporated and the residue was slurried in diethyl ether with potassium carbonate.
  • the mixture was filtered and the filtrate treated with a 4M solution of
  • Example 19 l- ⁇ 4-fdi-(2-pyridyl)aminomethyl]phenylmethvU- 1.4,8.1 1-tetraazacyclotetradecane pentahydrochloride a) l- ⁇ 4-[di-(2-pyridyl)aminomethyljphenylmethyl ⁇ -4,8,l l-tri-(t-butoxycarbonyl)- 1,4,8,11- tetraazacyclotetradecane 2,2 -Dipyridylamine (77 mg, 0.500 mmol) was added to a suspension of sodium hydride (18.8 mg of a 60% dispersion in mineral oil, 0.470 mmol) in anhydrous DMF (10 mL) and the mixture stirred at 25 C for 1 hour under nitrogen.
  • sodium hydride 18.8 mg of a 60% dispersion in mineral oil, 0.470 mmol
  • Example 20 1 -r4-(2-th ⁇ azolylam ⁇ nomethyl)phenylmethv ⁇ - 1.4.8.1 1 -tetraazacyclotetradecane pentahvdrochlo ⁇ de
  • Example 21 1.4-b ⁇ sf2-(2-benz ⁇ m ⁇ dazolylam ⁇ no)-5.5-di(2-py ⁇ dyl)-4-oxo-5H- ⁇ m ⁇ dazol ⁇ n-3- ylmethyllbenzene bis-t ⁇ fluoroacetic acid salt a) 2-(2-benz ⁇ m ⁇ dazolylam ⁇ no)-5,5-d ⁇ (2-pyndyl)-5H- ⁇ m ⁇ dazol ⁇ n-4-one
  • Example 22 2.6-b ⁇ sf2-(2-benz ⁇ m ⁇ dazolylam ⁇ no)-5,5-d ⁇ (2-py ⁇ dvO-4-oxo-5H- ⁇ m ⁇ dazol ⁇ n- - ylmethyllpy ⁇ dine bis-t ⁇ fluoroacetic acid salt Following the procedure of Example 21 (a)- 1(b), except substituting 2,6- bis(bromomethyl)pyridine for ⁇ , ⁇ 'dibromo-p-xylene, the title compound was prepared (2% overall). MS (ES+) m/e 842 [M+H] + .
  • Potassium carbonate (2.0 g, 14.5 mmol) was added, followed by the dropwise addition of a solution of l,4,8-tri-(f-butyloxycarbonyl)- 1,4,8,11- tetraazacyclotetradecane (B. Boitrel et. al.. Tetrahedron Lett., 1995, 36, 4995) (4.0 g, 7.99 mmol) in acetonitrile (100 mL). The mixture was sti ⁇ ed for 6 hours, cooled and partially evaporated.
  • Potassium carbonate (3.5 g, 25.3 mmol) was added, followed by the dropwise addition of a solution of 1 , 4,8-tri-(r-butyloxycarbonyl)- 1,4,8, 11- tetraazacyclotetradecane (B. Boitrel et. al.. Tetrahedron Lett., 1995, 36, 4995) (6.0 g, 1 1.98 mmol) in acetonitrile (100 mL). The mixture was sti ⁇ ed for 6 hours, cooled and partially evaporated.
  • Example 26 l,8-bis-[4-( 1.4,8.1 1 -tetraazacyclotetradecan- l-ylmethvOphenylmethyll- 1.4.8.1 1- tetraazacvclotetradecane dodecahydrobromide a) 4, 1 1 -bis(p-toluenesulfony 0- 1 ,8-bis-[4-(4,8, 11 -tris ⁇ p-toluenesulfony 1 ⁇ -1,4,8, 11 - tetraazacyclotetradecan- l-ylmethyl)pheny Imethyl j- 1,4,8, 1 1-tetraazacyclotetradecane A mixture of slightly impure 4,8, l l-t ⁇ s-(p-toluenesulfonyl)- 1,4,8, 1 1- tetraazacyclotetradecane (590 mg, 0,890 mmol) (M.
  • Ciampolini et. al., Inorg. Chem., 1987, 26, 3527 a,a -dibromo-p-xylene ( 117 mg, 0.445 mmol), potassium carbonate (369 mg, 2.67 mmol) and acetonitrile (10 mL) was heated at 80 °C for 18h, then cooled and partitioned between water and dichloromethane. Extracts were washed (saturated aqueous NaCl), dried (MgS04) and solvent removed under vacuum.
  • Example 28 1 -f4-(N- ⁇ 3-(methylam ⁇ no)propyl l-N-methylam ⁇ nomethyl)phenylmethy 11- 1.4.8.1 1 - tetraazacyclotetradecane hexahydrochloride
  • Example 29 l-f4-(N-f 3.4-methylened ⁇ oxyphenylmethvUam ⁇ nomethyl)phenylmethyl1- 1.4.8.1 1 - tetraazacvclotetradecane pentahydrochloride
  • a mixture of l-[4-(bromomethyl)phenyimethyl]-4.8, l l-t ⁇ -(f-butoxycarbonyl)- 1,4,8,11-tetraazacyclotetradecane (61 mg, 0.089 mmol) and 3,4- methylenedioxybenzyiamine (40 mg, 0.267 mmol) in ethanol (3 mL) was heated at 80- 90°C for 3 hours The solvent was evaporated and the residue redissolved in DMSO and chromatographed by preparative HPLC (20-80 % acetonit ⁇ le/water + 0 1 % TFA) The resulting purified t ⁇ -(r-butoxycarbonyl) intermediate was dissolved in ethanol (2 5
  • Example 35 1 -[5-n ⁇ tro-3-(N- ⁇ 3-(2-th ⁇ enyl)pyrazol-5-yl ⁇ aminomethyOpheny Imethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochlo ⁇ de a) l-[3-(bromomethyl)-5-n ⁇ trophenylmethyl]-4,8, l l-t ⁇ -(r-butoxycarbonyl)- 1,4,8, 11- tetraazacy c lotetradecane
  • Example 40 1 -r5-bromo-3-(N- .3-(2-th ⁇ enyl)pyrazol-5-yl J aminomethvOphenylmethyll- 1.4.8.11 - tetraazacyclotetradecane pentahydrochloride a) l-[5-bromo-3-(bromomethyI)phenylmethyl]-4,8, l l-t ⁇ -(r-butoxycarbonyl)- 1,4,8, 1 1- tetraazacyclotetradecane
  • Example 47 l-f4-(N-( l-methyl-3-(2-th ⁇ enyl )pyrazol-5-yl )am ⁇ nomethvPphenylmethyl1- 1.4.8.1 1- tetraazacvclotetradecane pentahvdrochlo ⁇ de a) 1 -[4-(bromomethy Opheny Imethy 1]-4,8,1 l-t ⁇ -(r-butoxycarbonyl)-l, 4,8,11- tetraazacy c lotetradecane a,a -Dibromo-p-xylene (36.0 g, 136 mmol) was stirred at 60°C in acetonitrile (500 mL) until it dissolved.
  • Example 51 l-r3-(N- ⁇ 3-(4-methylphenvPpyrazol-5-vUaminomethyl)phenylmethyll- 1.4.8.1 1- tetraazacvclotetradecane pentahydrochloride a) l-[3-(bromomethyl)phenylmethylj-4,8,l l-tri-(f-butoxycarbonyl)- 1 ,4,8, 11- tetraazacyclotetradecane a,a -Dibromo-m-xylene (22.0 g, 83.3 mmol) was stirred at 60°C in acetonitrile (350 mL) until it dissolved.
  • Potassium carbonate (2.0 g, 14.5 mmol) was added, followed by the dropwise addition of a solution of l,4,8-tri-(r-butyloxycarbonyl)- 1,4,8,1 1- tetraazacyclotetradecane (B. Boitrel et. al., Tetrahedron Lett., 1995, 36, 4995) (4.0 g, 7.99 mmol) in acetonitrile ( 100 mL). The mixture was sti ⁇ ed for 6 hours, cooled and partially evaporated.
  • Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.
  • a compound of Formula I or II, (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
  • Example 57 A compound of Formula I or II, (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
  • Procedure for tablet formul ation Ingredients 1, 2, 3 and 4 are blended in a suitable mixer/blender. Sufficient water is added portion-wise to the blend with careful mixing after each addition until the mass is of a consistency to permit its conversion to wet granules. The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen. The wet granules are then dried in an oven at 140°F (60°C) until dry. The dry granules are lubricated with ingredient No. 5, and the lubricated granules are compressed on a suitable tablet press.
  • Example 58 Parenteral Formulation A pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of Formula I or II in polyethylene glycol with heating. This solution is then diluted with water for injections Ph Eur. (to 100 ml). The solution is then rendered sterile by filtration through a 0.22 micron membrane filter and sealed in sterile containers. Specific Examples of formulations for pharmaceutical use incorporating compounds of the present invention are given below.
  • Example 59 - Capsule Composition An oral dosage form for administering a presently invented compound is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table II, below.
  • Example 60 Iniectable Parenteral Composition
  • An injectable form for administering a presently invented agonist of the TPO receptor is produced by sti ⁇ ing 1.5% by weight of l-[3-(N- ⁇ 3-(2-guanidinothiazol-4- y Opheny l ⁇ aminomethyl)-5-nitrophenylmethyl]- 1,4,8, 1 1-tetraazacyclotetradecane pentahydrochloride (Compound of Example 39) in 10% by volume propylene glycol in water.
  • sucrose, calcium sulfate dihydrate and a presently invented agonist of the TPO receptor are mixed and granulated in the proportions shown with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.
  • Preferred among the compounds of the present invention are compounds of Examples 2 - CXCR4, 7 - CXCR4, 34 - TPO, 39 - TPO, 40 - TPO, 44 - TPO and 51 - TPO.

Abstract

Invented are substituted cyclam derivatives, pharmaceutical compositions containing these compounds, the use of these compounds as CXCR-4 receptor antagonists and to use of these compounds as thrombopoietin (TPO) mimetics.

Description

CXCR-4 RECEPTOR ANTAGONISTS - THROMBOPOIETIN MIMETICS
FIELD OF THE INVENTION
The present invention relates to cyclam derivatives, pharmaceutical compositions containing these compounds, the use of these compounds as CXCR-4 receptor antagonists and to use of these compounds as promoters of thrombopoiesis and megakaryocytopoiesis.
BACKGROUND OF THE INVENTION The CXCR-4 receptor, originally known as LESTR/fusin, was shown to be the receptor for the α or CXC chemokine stromal cell-derived factor- 1 (SDF-1) in 1996 and renamed at this time. SDF- 1 appears to be specific for CXCR-4 and mediates its chemotactic effects via this receptor. The CXCR-4 receptor is widely expressed in a variety of cell types and is implicated in a range of inflammatory responses mediated by SDF- 1.
The widespread distribution of the receptor leads to its involvement in a number of disease areas including bacterial, fungal and protozoan infections, pain, cancer, diabetes, obesity, anorexia, bulimia, asthma, allergies, Parkinson's disease, acute heart failure, hypotension, hypertension, atherosclerosis, disease states involving angiogenesis. urinary retention, osteoporosis, angina pectoris, myocardial infarction, stroke, ulcers, benign prostatic hypertrophy, migraine, vomiting, psychotic and neurological disorders (e.g. anxiety, schizophrenia, manic depression, depression, delirium, dementia, mental retardation) and dyskinesias (Huntington's disease and Gilles de la Tourette's syndrome), injured or severed spinal cord and other injury related disease states.
In addition, CXCR-4 has been identified as the co-receptor used by T-tropic HIV- 1 viral strains to infect cells, and antagonists of the receptor may therefore be useful in the treatment of late stage HIV infection and AIDS.
Based on the foregoing, CXCR-4 receptor antagonists offer a unique approach toward decreasing the pathophysiology associated with the aforementioned diseases.
As disclosed herein it has unexpectedly been discovered that certain cyclam derivatives are effective as CXCR-4 receptor antagonists.
Megakaryocytes are bone marrow-derived cells, which are responsible for producing circulating blood platelets. Although comprising <0.25% of the bone marrow cells in most species, they have >10 times the volume of typical marrow cells. See Kuter et al. Proc. Natl. Acad. Aci. USA 91 : 1 1104-11108 (1994). Megakaryocytes undergo a process known as endomitosis whereby they replicate their nuclei but fail to undergo cell division and thereby give rise to polypoid cells. In response to a decreased platelet count, the endomitotic rate increases, higher pioidy megakaryocytes are formed, and the number of megakaryocytes may increase up to 3-fold. See Harker J. Gin. Invest. 47: 458-465 (1968). In contrast, in response to an elevated platelet count, the endomitotic rate decreases, lower pioidy megakaryocytes are formed, and the number of megakaryocytes may decrease by 50%.
The exact physiological feedback mechanism by which the mass of circulating platelets regulates the endomitotic rate and number of bone marrow megakaryocytes is not known. The circulating thrombopoietic factor involved in mediating this feedback loop is now thought to be thrombopoietin (TPO). More specifically, TPO has been shown to be the main humoral regulator in situations involving thrombocytopenia. See, e.g., Metcalf Nature 369:519-520 (1994). TPO has been shown in several studies to increase platelet counts, increase platelet size. and increase isotope incorporation into platelets of recipient animals. Specifically, TPO is thought to affect megakaryocytopoiesis in several ways: (1) it produces increases in megakaryocyte size and number; (2) it produces an increase in DNA content, in the form of polyploidy, in megakaryocytes; (3) it increases megakaryocyte endomitosis; (4) it produces increased maturation of megakaryocytes; and (5) it produces an increase in the percentage of precursor cells, in the form of small acetylcholinesterase-positive cells, in the bone marrow. Because platelets (thrombocytes) are necessary for blood clotting and when their numbers are very low a patient is at risk of death from catastrophic hemorrhage, TPO has potential useful application in both the diagnosis and the treatment of various hematological disorders, for example, diseases primarily due to platelet defects. Ongoing clinical trials with TPO have indicated that TPO can be administered safely to patients. In addition, recent studies have provided a basis for the projection of efficacy of TPO therapy in the treatment of thrombocytopenia, and particularly thrombocytopenia resulting from chemotherapy, radiation therapy, or bone marrow transplantation as treatment for cancer or lymphoma. See e.g., McDonald (1992) Am. J. Ped. Hematologv/Oncologv 14: 8-21 (1992).
The gene encoding TPO has been cloned and characterized. See Kuter et al., Proc. Natl. Acad. Sci. USA 91 : 11104-11108 (1994); Barley et al., Cell 77:
1 117-1 124 (1994); Kaushansky et al., Nature 369:568-571 (1994); Wendling et al., Nature 369: 571-574 (1994); and Sauvage et al., Nature 369: 533-538 (1994). Thrombopoietin is a glycoprotein with two distinct regions separated by a potential Arg-Arg cleavage site. The amino-terminal region is highly conserved in man and mouse, and has some homology with erythropoietin and interferon-alpha and interferon-beta. The carboxy-terminal region shows wide species divergence.
The DNA sequences and encoded peptide sequences for human TPO receptor (TPO-R; also known as c-mpl) have been described. See, Vigon et al. Proc. Natl. Acad. Sci. USA 89: 5640-5644 (1992). TPO-R is a member of the haematopoietin growth factor receptor family, a family characterized by a common structural design of the extracellular domain, including for conserved C residues in the N-terminal portion and a WSXWS motif close to the transmembrane region. See Bazan Proc. Natl. Acad. Sci. USA 87: 6934-6938 ( 1990). Evidence that this receptor plays a functional role in hematopoiesis includes observations that its expression is restπcted to spleen, bone marrow, or fetal liver in mice (see Souyπ et al Cell 63 1 137-1 147 (1990)) and to megakaryocytes, platelets, and CD34+ cells in humans (see Methia et al Blood 82. 1395-1401 (1993)) Further evidence for TPO-R as a key regulator of megakaryopoiesis is the fact that exposure of CD34+ cells to synthetic o gonucleotides antisense to TPO-R RNA significantly inhibits the appearance of megakaryocyte colonies without affecting erythroid or myeloid colony formation Some workers postulate that the receptor functions as a homodimer, similar to the situation with the receptors for G-CSF and erythropoietin
The slow recovery of platelet levels in patients suffering from thrombocytopenia is a seπous problem, and has lent urgency to the search for a blood growth factor agonist able to accelerate platelet regeneration
It would be desirable to provide compounds which allow for the treatment of thrombocytopenia by acting as a TPO mimetic.
As disclosed herein it has unexpectedly been discovered that certain cyclam deπvatives are effective as agonists of the TPO receptor, they are potent TPO mimetics
SUMMARY OF THE INVENTION The present invention involves novel compounds represented by Formulas (I), and (II) hereinbelow, their use as CXCR-4 receptor antagonists and their use as agonist of the TPO receptor
The present invention further provides methods for antagonizing CXCR-4 receptors in an animal, including humans, which compπses administeπng to a subject in need of treatment an effective amount of a compound of Formula (I), and (II) as indicated hereinbelow
In a further aspect of the invention there is provided novel processes and novel intermediates useful in preparing the presently invented TPO mimetic - CXCR-4 receptor antagonist compounds
Included in the present invention are pharmaceutical compositions compπsing a pharmaceutical carrier and compounds useful m the methods of the invention
Also included in the present invention are methods of co-administeπng the presently invented TPO mimetic - - CXCR-4 receptor antagonist compounds with further active ingredients
DETAILED DESCRIPTION OF THE INVENTION The compounds useful in the present methods are selected from Formulas (I), and (II) hereinbelow
Compounds of formula (I) have the following structure
Figure imgf000006_0001
Formula (I) wherein: the -CH2-Z substituent is meta or para to the tetraazacyclotetradecane substituent; Z represents a nitrogen-linked heteroaryl, a substituted nitrogen-linked heteroaryl, a cyclic amine moiety, a substituted cyclic amine moiety, or NY' Y^ where γl and Y^ are each independently selected from hydrogen, alkyl, substituted alkyl, C3- Ci2aryl, substituted C3-C[2 ryl, cycloalkyl, and substituted cycloalkyl; and
X is selected from the group consisting of hydrogen, alkyl, C3-Cj2aryl, substituted C3-Ci 2aryl, amino, alkylamino, mtro, hydroxy, alkoxy, halogen, carboxyl and carboxamido; and pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes thereof.
Preferred among the presently invented Formula (I) compounds are those in which the nitrogen-linked heteroaryl is selected form: benzimidazole, substituted benzimidazole, pheπothiazine, substituted pheπothiazine.
Particularly preferred among the presently invented Formula (I) compounds are those in which the nitrogen-linked heteroaryl is a substituted benzimidazole. Preferred among the presently invented Formula (I) compounds are those in which cyclic amine mioety is selected form: piperazine, pipendme, azacycloheptane, diazacycloheptane, morpholine, azacyclotridecane, 5,6,14,15-dibenzo-l,4-dioxa-8,12- diazacyclopentadeca-5, 14-dien, 1 ,4,7-trioxa- 10-azacyclododecane, 1 ,4,1, 10,-tetraoxa- 13- azacyclopentadecane, 1,4,8,11 -tetraazacyclotetradecane, and diazacyclooctane. Particularly preferred among the presently invented Formula (I) compounds are those in which cyclic amine mioety is selected form: 1,4-dιazacycloheptane, azacyclotridecane, 5,6, 14, 15-dιbenzo- 1 ,4-dιoxa-8, 12-dιazacyclopentadeca-5, 14-dien, 1,4,8, 1 1 -tetraazacyclotetradecane, and 1,5-dιazacyclooctane.
Preferred among the presently invented Formula (I) compounds are those in which C3-C j2aryl, when representing Y ' and or Y^, is independently selected form- phenyl. quino ne. thiazole, pyrazole and pyπdine. Particularly preferred among the presently invented Formula (I) compounds are those in which C3-Cj2aryl, when representing γl and or Y^ is independently selected form- phenyl and pyrazole
Preferred among the presently invented Formula (I) compounds are those in which X is selected from hydrogen, mtro and halogen
By the term "heteroaryl" as used herein, unless otherwise defined, is meant a cyclic or polycyclic aromatic ring containing from 3 to 16 carbon atoms and containing one to three heteroatoms, provided that one of the heteroatoms is nitrogen and provided that when the number of carbon atoms is 3 the aromatic πng contains at least two heteroatoms Examples of heteroaryl as used herein include benzimidazole and phenothiazine
By the term "cyclic amine moiety" as used herein, unless otherwise defined, is meant a nitrogen-linked, non-aromatic, cyclic or polycyclic ring system containing from about 5 to 24 atoms; of which 1 to 4 are nitrogen atoms and 0 to 4 are oxygen atoms, which heteroatoms being separated by 2 or more carbon atoms, wherein the moiety compπses 0 to 2 fused aromatic rings
Examples of cyclic amine moiety as used herein include piperazme, pipeπdme, azacycloheptane, diazacycloheptane, morphohne, azacyclotridecane, 5,6,14,15-dιbenzo- l,4-dιoxa-8,12-dιazacyclopentadeca-5,14-dιen, 1,4,7-tπoxa- l 0-azacyclododecane, 1,4,7,10,-tetraoxa- 13-azacyclopentadecane, 1,4,8,1 1 -tetraazacyclotetradecane, and 1,5- diazacyclooctane
By the term "C3-Ci 2aryl" as used herein, unless otherwise defined, is meant a cyclic or polycyclic aromatic nng containing from 3 to 12 carbon atoms and optionally containing one to three heteroatoms, provided that when the number of carbon atoms is 3 the aromatic ring contains at least two heteroatoms and provided that when the number of carbon atoms is 4 the aromatic πng contains at least one heteroatom
Examples of C3-Cj2aryl as used herein include phenyl, benzimidazole, phenothiazine, quinohne, thiazole, pyrazole, pyπdine, pyπmidine, naphthyl, 3,4- methylenedioxyphenyl and biphenyl
By the term "heteroatom" as used herein is meant oxygen, nitrogen or sulfur By the term "halogen" as used herein is meant a substituent selected from bromide, iodide, chlonde and fluoπde
The term "cycloalkyl" as used herein unless otherwise defined, is meant a nonaromatic, unsaturated or saturated, cyclic or polycyclic C3-C12
Examples of cycloalkyl and substituted cycloalkvl substituents as used herein include cyclohexyl, 4-hydroxy-cyclohexyl, 2-ethylcyclohexyl, propyl 4- methoxycyclohexyl, 4-methoxycyclohexyl, 4-carboxycyclohexyl and cyclopentyl By the term "substituted" as used herein, unless otherwise defined, is meant that the subject chemical moiety has one or more substituents selected from the group consisting of guanidmo, hydroxyalkyl, alkoxy, acyloxy, alkyl, pyπdyl, pyπmidyl, ammo, alkylamino, dialkylammo, [( 1,4,8,1 l,-tetraazacyclotetradecan-l-ylmethyl)phenylmethyl], 3,4- methylenedioxyphenylmethyl, phenylalkyl, phenylmethyl, alkylphenyl, halogen substituted phenyl, dihalogen halogen substituted phenyl, thiazole, guanidmothiazole. thiophene. acetyl, N-acylamino, hydroxy, furan, phenyl, -(CH2) C(0)OR^, -S(0)nR^, mtro, cyano, halogen, tπfluoromethyl and protected -OH, where g is 0-6, R" is hydrogen or alkyl, n is 0- 2, and R^ is hydrogen or alkyl By the term "protected hydroxy" or "protected -OH" as used herein, is meant the alcoholic or carboxylic-OH groups which can be protected by conventional blocking groups in the art as described in "Protective Groups In Organic Synthesis" by Theodora W Greene, Wiley-Interscience, 1981, New York. Compounds containing protected hydroxy groups may also be useful as intermediates in the preparation of the pharmaceutically active compounds of the invention
By the term "alkoxy" as used herein is meant -Oalkyl where alkyl is as described herein including -OCH3 and -OC(CH3)2CH3.
By the term "acyloxy" as used herein is meant -OC(0)alkyl where alkyl is as described herein Examples of acyloxy substituents as used herein include. -OC(0)CH3, - OC(0)CH(CH3)2 and -OC(0)(CH2)3CH3.
By the term "N-acylamino" as used herein is meant -N(H)C(0)alkyl, where alkyl is as descπbed herein. Examples of N-acylammo substituents as used herein include- - N(H)C(0)CH3, -N(H)C(0)CH(CH3)2 and -N(H)C(0)(CH2)3CH3.
By the term "alkyl" and deπvatives thereof and in all carbon chains as used herein is meant a linear or branched, saturated or unsaturated hydrocarbon chain having Cj-C 12 carbon atoms Examples of alkyl substituents as used herein include -CH3, -CH2-CH3, -CH -CH2-CH3, -CH(CH )2, -C(CH3)3, -(CH2)3-CH , -CH2-CH(CH3)2 and -CH(CH3)- CH2-CH3, -CH=CH2.
By the term "treating" and deπvatives thereof as used herein, is meant prophylatic or therapeutic therapy.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as though fully set forth
Compound represented by formula (II) have the following structure Y'CH2ACH2Y'
Formula (II) wherein, Y' represents a moietv selected from
Figure imgf000009_0001
and
Figure imgf000009_0002
wherein the Y' moiety can be optionally substituted by a substituent selected from the group consisting of alkyl, alkoxy, halogen and carboxy; and
A represents an X -substituted aryl or heteroaryl ring wherein X' is selected from the group consisting of hydrogen, alkyl, aryl, amino, alkylammo, nitro, hydroxy, alkoxy, halogen, carboxyl, and carboxamido; provided that the YCH2 groups are arranged meta or para to each other. Preferred compounds, having formula (I), useful in the present invention are selected from the group consisting of: l-[4-(4- Acetyl- l-piperazinomethyl)phenylmethyl]- 1 ,4,8, 11 -tetraazacyclotetradecane pentahydrochloride; l-[4-(l ,4-Diazacycloheptan- l-ylmethyl)phenylmethyl]- 1 ,4,8, 11 -tetraazacyclotetradecane hexahydrochloride; l-[4-(Azacycloheptan-l-ylmethyl)phenylmethyl]- l,4,8, l l-tetraazacyclotetradecane pentahydrochloride; l-[4-( 1 -Piperidinomethy phenylmethyl ]- 1 ,4,8, 1 1 -tetraazacyclotetradecane pentahydrochloride; 1 -[4-( 1 -Morpholinomethy l)phenylmethyl ]- 1 ,4,8, 11 -tetraazacyclotetradecane pentahydrochloride; l-[4-(Azacyclotridecan-l-ylmethyl)phenylmethyl]- 1,4,8, 1 1 -tetraazacyclotetradecane pentahydrochloride;
1 -[4-(5,6, 14, 15-Dibenzo- 1 ,4-dioxa-8, 12-diazacyclopentadeca-5.14-dien-8- y lmethyl)phenylmethyl]- l , 4,8, 1 1 -tetraazacyclotetradecane hexahydrochloride; 1 - [4-( 1 ,4,7-Trioxa- 10-azacyclododecan- 10-y Imethy Opheny Imethy 1 ]- 1,4,8,11- tetraazacyclotetradecane pentahydrochloride; l-[4-( 1 ,4,7, 10-Tetraoxa- 13-azacyclopentadecan- 13-ylmethyl)pheny Imethyl]- 1 ,4,8, 11- tetraazacyclotetradecane pentahydrochloride; 1 -[4-( 1 ,4, 10-Trioxa-7, 13-diazacyclopentadecan-7-ylmethyl)phenylmethyl]- 1 ,4,8, 1 1- tetraazacyclotetradecane hexahydrochloride;
1 - { 4-[4-(2-Pyridy 1)- 1 -piperazinomethyljpheny Imethy 1 } - 1 ,4,8, 1 1 -tetraazacyclotetradecane hexahydrochloride; l-{4-[4-(2- Pyrimidyl)- l-piperazinomethyl]phenylmethyl }- 1,4,8, 1 1- tetraazacyclotetradecane hexahydrochloride;
1 -[4-(2-Guanidinobenzimidazol- 1 -y lmethyl)pheny Imethyl]- 1 ,4,8, 1 1 - tetraazacyclotetradecane pentahydrochloride;
1 -[4-( 1 -Piperazinomethy phenylmethyl]- 1 ,4,8, 1 1 -tetraazacyclotetradecane hexahydrochloride; 1, 4-Bis-[4-(l, 4,8, l l-tetraazacyclotetradecan-l-ylmethyl)pheny Imethy l]piperazine decahydrochloride; l-[4-(l,5-Diazacyclooctan-l-y Imethy l)pheny Imethyl]- 1 ,4,8, 11 -tetraazacyclotetradecane hexahydrochloride;.
1 -(4- { Bis[2-(diethylamino)ethyl]aminomethyl } phenylmethyl)- 1 ,4,8, 11 - tetraazacyclotetradecane heptahydrochloride; l-(4-{ [(2-AminoethyI)(3-aminopropyl)amino]methyl]}phenylmethyl)-l,4,8,l l- tetraazacyclotetradecane heptahydrochloride; l-{4-[Di-(2-pyridyl)aminomethyl]phenylmethyl }- l,4,8,l l-tetraazacyclotetradecane pentahydrochloride; l-[4-(2-Thiazolylaminomethyl)phenylmethyl]-l,4,8,l l-tetraazacyclotetradecane pentahydrochloride;
1 -[3-(2-guanidinobenzimidazol- 1 -y lmethyl)pheny Imethy 1]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride;
1 -[4-(2-aminobenzimidazol- 1 -ylmethyl)pheny Imethyl]- 1 ,4,8, 11 -tetraazacyclotetradecane pentahydrochloride; l ,8-bis-[4-( 1,4,8, 1 l-tetraazacyclotetradecan- l-ylmethyl)pheny Imethyl]- 1,4,8,1 1- tetraazacyclotetradecane dodecahydrobromide;
1 , 1 l-bis-[4-( 1 ,4,8, 1 1 -tetraazacyclotetradecan- 1 -y lmethyl)pheny Imethyl]- 1 ,4,8, 1 1 - tetraazacyclotetradecane dodecahydrobromide; 1 -[4-(N-{3-(methylamιno)propyl}-N-methylamιnomethyl)phenyimethyl]- 1 ,4,8, 1 1- tetraazacyclotetradecane hexahydrochloπde;
1 -[4-(N- { 3,4-methylenedιoxypheny Imethy 1 } aminomethy Opheny Imethy 1]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloπde: l-[4-(N-{ 3,5-difluorophenylmethyI }amιnomethy0pheny Imethyl]- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloπde,
1 -[4-(phenothιazιn- 10-y Imethy Ophenylmethy 1]- 1 ,4,8, 1 1 -tetraazacyclotetradecane pentahydrochloπde;
1 -[4-(N- { 4-amιno-2-methy lquιnohn-6-y 1 } aminomethy Opheny Imethy 1]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride; l-[4-(N-{4-(2-guanιdιnothιazol-4-yl)phenyl JaminomethyOphenylmethyl]- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloπde;
1 -[4-(N- { 3-(2-guanιdιnothιazol-4-yl)phenyl } aminomethy Opheny Imethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloπde; 1 -[5-nιtro-3-(N-{3-(2-thιenyl)pyrazol-5-yl} aminomethy Opheny Imethyl]- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloπde; l-[5-nιtro-3-(phenothιazιn-l 0-y Imethy Opheny Imethyl]- 1,4,8, 11 -tetraazacyclotetradecane pentahydrochloπde;
1 -[3-(N- { 4-amιno-2-methylquιnohn-6-y 1 } amιnomethyl)-5-nιtropheny Imethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloπde;
1 -[3-(N- ( 4-(2-guanιdιnothιazol-4-yl)phenyl } aminomethy l)-5-nιtropheny Imethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride;
1 -[3-(N-{3-(2-guanιdιnothιazol-4-yl)phenyl }amιnomethyl)-5-nιtrophenylmethyl]- 1,4,8, 1 1- tetraazacyclotetradecane pentahydrochloπde; 1 -[5-bromo-3-(N-{ 3-(2-thιenyl)pyrazol-5-yl } aminomethyl)phenylmethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloπde; l-[5-bromo-3-(phenothιazιn-10-ylmethyl)phenylmethyl]-l,4,8,l l-tetraazacyclotetradecane pentahydrochloride; l-[3-(N-{4-amιno-2-methylquιnolin-6-yl }amιnomethyl)-5-bromophenylmethyl]- 1 ,4,8, 1 1- tetraazacyclotetradecane pentahydrochloride, l-[5-bromo-3-(N-{4-(2-guanιdιnothιazol-4-yl)phenyl}amιnomethyl)phenylmethyI]-
1,4,8,1 1 -tetraazacyclotetradecane pentahydrochloride, l-[5-bromo-3-(N-{ 3-(2-guanιdιnothιazol-4-yl)phenyl }amιnomethyl)phenylmethyl]-
1 ,4,8,1 1 -tetraazacyclotetradecane pentahydrochloπde, 1 -[3-(N-{ 6-methyl-2-nitrophenyl } aminomethyOpheny Imethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride; and
1 -[3-(N-{ 3-(2-thienyl)pyrazol-5-yl }aminomethyI)phenylmethyl]- 1,4,8.1 1- tetraazacyclotetradecane pentahydrochloride; l-[4-(N-{ 1-methy l-3-(2-thienyl)pyrazol-5-yl} aminomethy Opheny Imethyl]- 1,4,8, 1 1- tetraazacyclotetradecane pentahydrochloride; l-[4-(N-{ 3-methylpyrazol-5-yl }aminomethyl)phenylmethyl]- 1,4,8,1 1- tetraazacyclotetradecane pentahydrochloride; l-[4-(N-{ 3-(4-methylphenyl)pyrazol-5-yl }aminomethyl)pheny Imethyl]- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloride; l-[4-(N-{3-(2-furyl)pyrazol-5-yl }aminomethyl)phenylmethyl]- 1 ,4,8, 1 1- tetraazacyclotetradecane pentahydrochloride;
1 -[3-(N-{3-(4-methylphenyl)pyrazol-5-yl }aminomethy0phenylmethyl]- 1 ,4,8, 1 1- tetraazacyclotetradecane pentahydrochloride; l-[3-(N-{ l-methyl-3-phenyipyrazol-5-yl}aminomethyl)phenylmethyl]-l,4,8,l l- tetraazacyclotetradecane; l-[3-(N-{ 3-(4-chlorophenyl)- 1-methy lpyrazol-5-yl }aminomethyl)pheny Imethyl]- 1 ,4,8, 11- tetraazacy c lotetradecane ;
1 -[3-(N- { 1 ,3-dipheny lpyrazol-5-yl } aminomethy Opheny Imethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane; and
1 -[3-(N- { 3-(4-f-butylphenyl)- 1 -methylpyrazol-5-yl } aminomethyOpheny Imethyl]- 1 ,4,8, 1 1 - tetraazacyclotetradecane; and further pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes thereof. More preferred compounds of the present invention are selected from the group consisting of:
1 -[4-( 1 ,4-Diazacycloheptan- 1 -ylmethy Ophenylmethy 1]- 1 ,4,8, 1 1 -tetraazacyclotetradecane hexahydrochloride;
1 - [4-(Azacycloheptan- 1 -ylmethy Ophenylmethy I]- 1 ,4,8, 11 -tetraazacyclotetradecane pentahydrochloride;
1 -[4-( 1 -PiperidinomethyOphenyimethyl]- 1 ,4,8, 1 1 -tetraazacyclotetradecane pentahydrochloride; l-[4-(Azacyclotridecan-l-ylrnethyl)phenylrnethyl]- 1 ,4,8,1 1 -tetraazacyclotetradecane pentahydrochloride; l-[4-(5,6,14,15-Dibenzo-l,4-dioxa-8.12-diazacyclopentadeca-5.14-dien-8- ylmethyl)phenylmethyl]-l,4,8,l l-tetraazacyclotetradecane hexahydrochloride:
1 -[4-( 1 ,4, 10-Trioxa-7, 13-diazacyclopentadecan-7-y l ethyOpheny Imethy 1]- 1 ,4,8, 1 1 - tetraazacyclotetradecane hexahydrochloride; 1 - { 4-[4-(2-Pyridy 1)- 1 -piperazinomethyljpheny Imethy 1 } - 1 ,4,8, 1 1 -tetraazacyclotetradecane hexahydrochloride;
1 - {4-[4-(2-Pyrimidy 1)- 1 -piperazinomethyljphenylmethy 1 } - 1 ,4,8, 1 1 - tetraazacyclotetradecane hexahydrochloride;
1 -[4-(2-Guanidinobenzimidazol- 1 -y lmethyOphenylmethy lj- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride;
1 ,4-Bis-[4-( 1 ,4,8, 11 -tetraazacyclotetradecan- 1 -ylmethyOpheny lmethyl]piperazine decahydrochloride;
1 -[4-( 1 ,5-Diazacyclooctan- 1-y lmethyOphenyimethyl]- 1 ,4,8, 1 1 -tetraazacyclotetradecane hexahydrochloride; 1 ,8-bis-[4-( 1 ,4,8, 11 -tetraazacyclotetradecan- 1 -ylmethy Opheny Imethyl]- 1 ,4,8, 1 1 - tetraazacyclotetradecane dodecahydrobromide;
1,1 l-bis-[4-(l, 4,8,1 1 -tetraazacyclotetradecan- 1-y Imethy Opheny Imethyl]- 1,4,8, 11- tetraazacyclotetradecane dodecahydrobromide;
1 -[4-(N- { 4-amino-2-methylquinolin-6-y 1 }aminomethy Opheny Imethy 1]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride;
1 -[4-(N- { 4-(2-guanidinothiazol-4-y Ophenyl } aminomethyOpheny Imethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride;
1 -[4-(N- { 3-(2-guanidinothiazol-4-y Opheny 1 } aminomethyOpheny Imethyl]- 1 ,4,8, 1 1 - tetraazacyclotetradecane pentahydrochloride; 1 -[5-nitro-3-(N- { 3-(2-thienyl)pyrazol-5-yl } aminomethy Opheny Imethyl]- 1 ,4,8, 1 1 - tetraazacyclotetradecane pentahydrochloride; l-[5-nitro-3-(phenothiazin-10-ylmethyl)phenylmethyl]- 1,4,8,1 1 -tetraazacyclotetradecane pentahydrochloride;
1 -[3-(N- { 4-(2-guanidinothiazol-4-y Ophenyl } aminomethyl)-5-nitropheny Imethy 1]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride;
1 -f 3-(N- { 3-(2-guanidinothiazoI-4-yl)phenyl } aminomethyl)-5-nitrophenylmethyl]- 1 ,4,8, 1 1 - tetraazacyclotetradecane pentahydrochloride;
1 -[5-bromo-3-(N- { 3-(2-thieny l)pyrazol-5-yl } aminomethyOphenylmethyl]- 1 ,4,8, 1 1 - tetraazacyclotetradecane pentahydrochloride; 1 -[3-(N-{4-amino-2-methylquinolin-6-yl } aminomethy l)-5-bromophenylmethyl j- 1 ,4,8, 1 1 - tetraazacyclotetradecane pentahydrochloride;
1 -[5-bromo-3-(N-{4-(2-guanidinothiazol-4-y Ophenyl }aminomethyl)phenylmethyl]-
1 ,4,8, 11 -tetraazacyclotetradecane pentahydrochloride; l-[5-bromo-3-(N-{3-(2-guanidinothiazol-4-yl)phenyl }aminomethyl)phenylmethyl]-
1,4.8,1 1 -tetraazacyclotetradecane pentahydrochloride:
1 -[3-(N-{ 3-(2-thienyl)pyrazol-5-yl }aminomethyl)phenylmethyl]- 1 ,4,8, 1 1 - tetraazacyclotetradecane pentahydrochloride;
1 -[4-(N- { 3-methylpyrazol-5-y 1 } aminomethy Opheny Imethy 1]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride;
1 -[4-(N- { 3-(4-methylpheny l)pyrazol-5-yl } aminomethyOpheny Imethy 1]- 1 ,4,8, 1 1 - tetraazacyclotetradecane pentahydrochloride; l-[3-(N-{3-(4-methylphenyl)pyrazol-5-yl }aminomethyl)phenylmethyl]- 1,4,8, 1 1- tetraazacyclotetradecane pentahydrochloride; 1 -[3-(N- { 3-(4-chlorophenyl)- 1 -methylpyrazol-5-y 1 } aminomethyOpheny Imethy 1]- 1 ,4,8, 11 - tetraazacyclotetradecane; and
1 -[3-(N- { 1 ,3-dipheny lpyrazol-5-y 1 } aminomethyOpheny Imethy 1 j- 1 ,4,8, 11 - tetraazacyclotetradecane; and further pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes thereof.
The most preferred compounds included in the present invention are selected from the group consisting of: l-[4-( 1 ,5-Diazacyclooctan- 1 -ylmethyOpheny Imethyl]- 1 ,4,8, 1 1 -tetraazacyclotetradecane hexahydrochloride; 1 -[4-(2-Guanidinobenzimidazol- 1 -y lmethyl)phenylmethy 1]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride; l-[4-(5,6,14,15-Dibenzo- l,4-dioxa-8,12-diazacyclopentadeca-5, 14-dien-8- ylmethyOpheny Imethyl]- 1,4,8, 11 -tetraazacyclotetradecane hexahydrochloride; l-[4-(Azacyclotridecan- l-ylmethyl)phenylmethyl]-l,4,8, l l-tetraazacyclotetradecane pentahydrochloride; l-[4-( 1 ,4-Diazacycloheptan- 1-y ImethyOphenylmethyl]- 1 ,4,8, 11 -tetraazacyclotetradecane hexahydrochloride; l-[4-(N-{4-(2-guanidinothiazol-4-yl)phenyl }aminomethy0phenylmethyl]- 1,4,8, 1 1- tetraazacyclotetradecane pentahydrochloride; 1 -[4-(N- { 3-(2-guanιdιnothιazol-4-yl)phenyl } aminomethy Opheny Imethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride; l-[5-nιtro-3-(N-{3-(2-thιenyl)pyrazol-5-yl }amιnomethyl)pheny Imethyl]- 1,4,8, 1 1- tetraazacyclotetradecane pentahydrochloride; l-[5-bromo-3-(N-{ 3-(2-thιenyl)pyrazol-5-yl }amιnomethyl)phenylmethyl]- 1,4,8, 1 1- tetraazacyclotetradecane pentahydrochloride.
1 -[5-bromo-3-(N-{4-(2-guanιdmothιazol-4-y Ophenyl (aminomethy Ophenylmethy 1]-
1,4,8,11 -tetraazacyclotetradecane pentahydrochloride; l-[3-(N- (3-(2-thιenyl)pyrazol-5-yl}amιnomethyl)phenylmethyl]- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloπde; l-[4-(N-{3-(4-methylphenyl)pyrazol-5-yl }amιnomethyl)pheny Imethyl]- 1,4,8, 1 1- tetraazacyclotetradecane pentahydrochloride; l-[3-(N-{3-(4-methylphenyl)pyrazol-5-yl }amιnomethyl)phenylmethyl]- 1,4,8, 1 1- tetraazacyclotetradecane pentahydrochloride; and 1 -[3-(N- { 3-(4-chloropheny I)- 1 -methy lpyrazol-5-y 1 } aminomethyOpheny Imethyl]- 1 ,4,8, 1 1 - tetraazacyclotetradecane; and further pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes thereof
Preferred compounds of formula (II) are selected from the group consisting of: l,4-Bis[2-(2-benzιmιdazolylamιno)-5,5-di(2-pyπdyI)-4-oxo-5H-ιmιdazolιn-3- ylmethyl]benzene bis-tπfluoroacetic acid salt;
2,6-Bιs[2-(2-benzιmιdazolylamιno)-5,5-di(2-pyπdyl)-4-oxo-5H-ιmιdazolιn-3- ylmethyljpyπdine bis-tπfluoroacetic acid salt; and
1 ,4-Bιs { [ 1 -(2-Benzιmιdazoly 1)- 1 -guanidmojmethy 1 } benzene, or further pharmaceutically acceptable salts, hydrates, solvates, esters or metal complexes thereof.
Also included in the present invention are pharmaceutically acceptable salts and complexes. Preferred are the zinc, copper, nickel, cobalt and rhodium complexes, hydrochlonde, hydrobromide and tπfluoroacetate salts The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms All of these compounds and diastereomers are contemplated to be within the scope of the present invention The compounds of Formulas (I) and (II) are prepared as shown in Schemes I to IV below wherein the pendent substituents (X, Z, A, Y', Y' , Y^ and XO are as defined in formulas 1 and 2 and provided that the pendent substituents do not include any such substituents that render inoperative the processes of Schemes I the IV. All of the starting materials are commercially available or are readily made from commercially available starting materials by those of skill in the art.
Compounds of formula I where X represents hydrogen are prepared by methods analogous to that shown in scheme 1.
Scheme 1
Figure imgf000016_0001
a) BOC2O, CH2CI2; b) ccα'-dibromo-p-xylene, K-2CO3, MeCN, 60°C; c) piperidine, K2C03, MeCN, 60°C; d) HCl, dioxane, CH2C12.
Compound \, available commercially, is protected as its tri-ferf-butylcarbamate derivative 2, which is alkylated on the free nitrogen to give compound 3. The benzylic bromide is displaced with the appropriate N nucleophile to give the protected precursor 4, which is deprotected with acid to furnish the final compound 5.
Compounds where the -CH2-Z substituent is in the "meta" position can be readily made by the skilled worker, using commercially available starting materials or using materials readily made from commercially available materials by analogous methods.
Compounds of formula I where X is other than hydrogen are prepared by methods analogous to that shown in scheme 2. Further, compounds of formula I where Z represents | jγlγ2 are prepared by methods analogous to that shown in scheme 2.
Scheme 2
Figure imgf000017_0001
(1) (2) (3)
t
Figure imgf000017_0002
(4)
Compound i, available commercially, is alkylated with dibromides 2, prepared by literature methods, in a suitable solvent in the presence of potassium carbonate to give the mono-bromide 3. 3 was heated with amines R1R2NH (as used in this Scheme, R1R2 is Y' Y^ of formula 1) in a suitable solvent with or without the addition of a base to give intermediates which were deprotected with HCl to furnish the final compounds 4.
Compounds where the -CH2-Z substituent is in the "meta" position can be readily made by the skilled worker, using commercially available starting materials or using materials readily made from commercially available materials by analogous methods.
Compounds of formula I where Z represents NY * Y^ are also prepared by methods analogous to that shown in scheme 3.
Scheme 3
Figure imgf000017_0003
a) BOC20, CH2C12; b) ocα'-dibromo-p-xylene, K2C03, MeCN, 60° C; c) 2- aminothiazole, K2C03, MeCN, 60 C; d) HCl, dioxane. CH C12. Compound I, available commercially, is protected as its tri-rerr-butylcarbamate derivative 2, which is alkylated on the free nitrogen to give compound 3. The benzyiic bromide is displaced with the appropriate N nucleophile to give the protected precursor 4, which is deprotected with acid to furnish the final compound 5.
Compounds where the -CH2-Z substituent is in the "meta" position can be readily made by the skilled worker, using commercially available starting materials or using materials readily made from commercially available materials by analogous methods.
Compounds of formula (II) are prepared by methods analogous to that shown in scheme 4.
Scheme 4
Figure imgf000018_0001
a) 2-Guanidinobenzimidazole, NaOH, rt; b) α,α -dibromo-p-xylene, DMF, rt Compound I, available commercially, condenses with 2-guanidinobenzimidazole to give the rearranged product 2, which is converted to its sodium salt and alkylated regioselectively with a bis- electrophile to give compound 3.
With appropriate manipulation and protection of any chemical functionality, synthesis of the remaining compounds of Formula (I) and (II) is accomplished by methods analogous to those above and to those described in the Experimental section.
Pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes of the presently invented compounds are readily prepared by those of skill in the art using readily available starting materials.
In order to use a compound of the Formula (I) or (II) or a pharmaceutically acceptable salt, hydrate, solvate, ester or metal complex thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Because the present compounds have been found to act as CXCR-4 receptor antagonist they are useful for the treatment of diseases including but not limited to bacterial, fungal and protozoan infections, pain, thrombocytopenia, cancer, diabetes, obesity, anorexia, bulimia, asthma, allergies, Parkinson s disease, acute heart failure, hypotension, hypertension, neural damage, atherosclerosis, urinary retention, osteoporosis, angina pectoπs, myocardial infarction, stroke, ulcers, benign prostatic hypertrophy, migraine, angiogenesis, vomiting, psychotic and neurological disorders (e g anxiety, schizophrenia, manic depression, depression, dehπum, dementia, mental retardation) and dyskmesias (Huntington's disease and Gilles de la Tourette's syndrome), viral infections, such as HIV infection in patients having clinical signs of AIDS and for the treatment of asymptomatic HIV-ιnfected subjects The present compounds are also useful for the treatment of an injured or severed spinal cord and other injury-related disease states
The treatment of thrombocytopenia, as described herein, is accomplished by enhancing the production of platelets By the term 'co-administeπng ' and derivatives thereof as used herein when directed to the TPO mimetic aspect of this invention is meant either simultaneous administration or any manner of separate sequential administration of a TPO mimetic compound, as described herein, and a further active ingredient or ingredients, known to treat thrombocytopenia, including chemotherapy-induced thrombocytopenia and bone marrow transplantation and other conditions with depressed platelet production
Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other Furthermore, it does not matter if the compounds are administered in the same dosage form, e g one compound may be administered topicallv and another compound may be administered orally Because the compounds of the present invention have been found to be active as
TPO mimetics they exhibit therapeutic utility in treating thrombocytopenia and other conditions with depressed platelet production
In determining potency as TPO mimetics, the following assays were employed Luciferase Assay Compounds of the present invention were tested for potency as mimetics of the
TPO receptor in a Luciferase assay such as described in Lamb, et al , Nucleic Acids Research 23 3283-3289 (1995) and Seidel. et al . Proc Natl Acad Sci . USA 92 3041- 3045 (1995) by substituting a TPO-responsive BaF3 cell line (Vigon et al Proc Natl Acad Sci USA 1992, 89, 5640-5644) for the HepG2 cells utilized therein The muπne BaF3 cells express TPO receptors and closely match the pattern of STAT (signal transducers and activators of transcription) activation observed in primary muπne and human bone marrow cells in response to TPO
Some of the most preferred compounds of this invention were also active in an in vitro proliferation assay using the human UT-7/TPO leukemic megakaryoblastic cell line (Komatsu, N et al , Blood, 1996, 87, 4552-4560) UT-7/TPO cells express TPO-R and are absolutely dependent on the presence of TPO for growth and survival Likewise, some of the most preferred compounds of this invention were also positive in stimulating the maturation of megakaryocytes from human bone marrow cells In this assay, purified human CD34+ progenitor cells were incubated in liquid culture with test compounds for 10 days and the number of cells expressing the transmembrane glycoprotein CD41 (gpllb), a megakaryocytic marker, was then measured by flow cytometry (see Cwirla, S E et al Science, 1997, 276, 1696-1699)
The pharmaceutically active compounds within the scope of this invention are useful as TPO mimetics in mammals, including humans, in need thereof Some of the preferred compounds within the scope of the invention showed activation from about 5% to 100% of control (control is the maximal response to TPO) at a concentration of 0 1 -30 uM in the luciferase assay The preferred compounds of the invention also promoted the proliferation of UT-7/TPO cells at a concentration of 0 1 to 30 uM. The preferred compounds of the invention also showed activity in the CD41 megakaryocytic assay at a concentration of 0 1 to 30 uM
The activity of the compound of Example 46 in the luciferase assay is 86% of maximal TPO effect with an EC50 of 2.1 uM
One aspect of the present invention therefor provides a method of treating thrombocytopenia and other conditions with depressed platelet production, which comprises administering a compound of Formula (I) or (II), as described above, in a quantity effective to enhance platelet production The compounds of Formulas (I) and (II) also provide for a method of treating the above indicated disease states because of their demonstrated ability to act as TPO mimetics The drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal, and parenteral
The present invention therefor provides a method of treating thrombocytopenia and other conditions with depressed platelet production, which comprises administering a compound of Formula (I) or (II), as descπbed above, in a quantity effective to enhance platelet production The compounds of Formulas (I) and (II) also provide for a method of treating the above indicated disease states because of their demonstrated ability to act as TPO mimetics The drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal, and parenteral
The pharmaceutical preparations are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products
Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0 001 - 100 mg/kg of active compound, preferably 0001 - 50 mg/kg When treating a human patient in need of a pharmaceutically active compound of this invention, the selected dose is administered preferably from 1-6 times daily, orally or parenterally Preferred forms of parenteral administration include topically, rectally, transdermally, by injection and continuously by infusion Oral dosage units for human administration preferably contain from 0 05 to 3500 mg of active compound Oral administration, which uses lower dosages is preferred Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient
Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular active in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration
The method of this invention of inducing TPO mimetic activity in mammals, including humans, compπses administeπng to a subject in need of such activity an effective TPO mimetic amount of a pharmaceutically active compound of the present invention The invention also provides for the use of a compound of Formula (I) or (II) in the manufacture of a medicament for use as a TPO mimetic
The invention also provides for the use of a compound of Formula (I) or (II) in the manufacture of a medicament for use in therapy
The invention also provides for the use of a compound of Formula (I) or (II) in the manufacture of a medicament for use in enhancing platelet production
The invention also provides for the use of a compound of Formula (I) or (II) in the manufacture of a medicament for use in treating thrombocytopenia
The invention also provides for a pharmaceutical composition for use as a TPO mimetic which compπses a compound of Formula (I) or (II) and a pharmaceutically acceptable earner The invention also provides for a pharmaceutical composition for use in the treatment of thrombocytopenia which compπses a compound of Formula (I) or (II) and a pharmaceutically acceptable carrier
The invention also provides for a pharmaceutical composition for use in enhancing platelet production which comprises a compound of Formula (I) or (II) and a pharmaceutically acceptable earner
In addition, the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to antagonize the CXCR-4 receptor or which exhibit a therapeutic effect on a disease state that is treatable with a CXCR-4 receptor antagonist; or such as other compounds known to treat thrombocytopenia, including chemotherapy-induced thrombocytopenia and bone marrow transplantation and other conditions with depressed platelet production, or compounds known to have utility when used in combination with a TPO mimetic
No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention
The activity of the compounds of Formula (I) and (II) as antagonists of the CXCR- 4 receptor are demonstrated by the following test CXCR-4/SDF-1 Assay Protocol
Assay plates were seeded with RBL transfected with the SDF- 1 receptor Dye loading buffer (EMEM w/Earl's salts w/ L-glutamine with IX Sulphinpyrozone and 10% BSA, 100 uL) was added to each well, and the plate incubated for 90 minutes at 37 "C The dye loading buffer was aspirated from the plates Hydrolysis buffer (EMEM w/Earl's salts w/ L-glutamine with IX Sulphinpyrozone, lOOuL) was added to each well, and the plate incubated for 10 minutes at 37 °C The cells were washed 3 times with wash buffer (IX Krebs Ringer, 15 mM HEPES, ImM MgCl, 1 mM CaCl with IX Sulphinpyrozone and
0 10% gelatin), then wash buffer was dispensed to each well (lOOuL/well) The plate was incubated for 10 minutes at 37 "C, then placed in FLIPR™ (Molecular Devices) Test compounds in gelatin buffer (IX Krebs Ringer, 15 M HEPES, ImM MgCl, 1 mM CaCl with 0 10% gelatin, 50uL) were preincubated with cells for 3 minutes, then ligand (SDF- lalpha PBSF, 15nM final concentration) was added The plate was incubated for 2 minutes while continually reading
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way Expeπmental Details
Example 1 Preparation of l-r4-(4-acetyl-l-pιperazιnomethyl)phenylmethvn-1.4.8.1 1- tetraazacyclotetradecane pentahydrochloride a) 1 -[4-(bromomethy Opheny Imethyl j-4,8,1 l-tπ-(r-butoxycarbonyl)- 1 ,4,8,1 1- tetraazacyclotetradecane a,a -Dibromo-p-xylene (36 0 g, 136 mmol) was stirred at 60 C in acetonitπle (500 mL) until it dissolved Potassium carbonate (3 5 g, 25 3 mmol) was added, followed by the dropwise addition of a solution of l,4,8-tπ-(r-butyloxycarbonyl)-l,4,8,l 1- tetraazacyclotetradecane (B Boitrel et al , Tetrahedron Lett , 1995, 36, 4995) (6 0 g, 1 1 98 mmol) in acetonitπle (100 L) The mixture was stirred for 6 hours, cooled and partially evaporated The excess dibromoxyiene was filtered off, the mother liquors evaporated under vacuum and chromatographed (silica gel, 50% dichloromethane/hexane to 2% methanol/dichloromethane) to afford the title compound as a foam (7 4 g, 90 %) MS
(ES+) m/e 683 and 685 [M+Hj+ b) 1 -[4-(4-acety 1- 1 -piperazmomethy Opheny Imethy l]-4,8, 1 1 -tπ-(f-butoxycarbonyl)-
1 ,4,8, 11 -tetraazacyclotetradecane
A mixture of l-[4-(bromomethyl)phenylmethyl]-4,8,l l-tπ-(r-butoxycarbonyl)- 1,4,8,11-tetraazacyclotetradecane (326 mg, 0 477 mmol), 1-acetylpιperazιne (95 mg, 0 741 mmol) and anhydrous potassium carbonate (350 mg, 2 53 mmol) in acetonitπle (30 mL) was vigorously stirred together at 50 C for 1 hour The solvent was evaporated and the residue was purified by flash chromatography (silica gel, 0-3% methanol/dichloromethane) to give the title compound as an oil (300 mg, 86%) MS (ES+) m/e 731 [M+H]+ c) l-[4-(4-acetyl-l-pιperazιnomethyl)phenylmethyl]- l,4,8,l 1-tetraazacyclotetradecane pentahydrochloride
To a solution of l-[4-(4-acetyl-l-pιperazιnomethyI)phenylmethyl]-4,8,l l-tπ-(f- butoxycarbonyl)- 1,4,8,1 1-tetraazacyclotetradecane (175 mg, 0 239 mmol) in 1,4-dιoxane
(1 0 mL) was added a solution of 4M hydrogen chloride in 1,4-dιoxane ( 1 0 L) The mixture was stood for 2 hours, the white solid collected and washed successively with 1,4- dioxane, diethyl ether and hexane
The hygroscopic solid was dried in vacuo (80°C) to give the title compound (35 mg, 34%)
MS (ES+) m/e 431 [M+H]+
Example 2 Preparation of l-f4-( l ,4-dιazacvcloheptan-l-ylmethyl)phenylmethyl1- 1.4.8.11- tetraazacvclotetradecane hexahvdrochloπde
Following the procedure of Example l(a)-(c), except substituting homopiperazine for 1 -acetylpiperazine, the title compound was prepared (27% overall) H NMR (300MHz, d3-MeOD/D,0) δ 7 67 (d, 2H), 7.50 (d, 2H), 4 52 (s, 2H), 3 98 (s, 2H), 3.90 (s, 2H), 3.62 (m, 2H), 3.53-3 20 (m, 8H), 3.15 (m, 2H), 2.95 (m, 4H), 2.35 (m, 2H), 2.19 ( , 4H), 2.09 ( , 2H), 1.26 (m, 4H).
Example 3 Preparation of l-r4-(azacvcloheptan-l-ylmethyl)phenylmethyll-1.4,8.11- tetraazacvclotetradecane pentahvdrochloπde
Following the procedure of Example l(a)-(c), except substituting hexamethyleneimine for 1 -acetylpiperazine, the title compound was prepared (45% overall). MS (ES+) m/e 402 [M+H]+. Example 4
Preparation of l-r4-(l-pιpeπdιnomethyl)phenylmethvn- 1 ,4,8.1 1 -tetraazacyclotetradecane pentahydrochloride
Following the procedure of Example l(a)-(c), except substituting pipeπdine for 1- acetylpiperazme, the title compound was prepared (75% overall). MS (ES+) m e 388 [M+H]+.
Example 5 Preparation of l-r4-(l-morpholιnomethyl)phenylmethyl1- 1.4.8.1 1-tetraazacyclotetradecane pentahvdrochloπde
Following the procedure of Example l(a)-(c), except substituting morphohne for 1- 1 acetylpiperazine, the title compound was prepared (60% overall). H NMR (300MHz,
D20) δ 7.7-7.5 (m, 4H), 4.5 (s, 2H), 4.1 (m, 4H), 3.8 (br m, 2H), 3 6-3.0 (br m, 16H), 2.2 (br s, 4H), 1.2 (s, 4H).
Example 6 Preparation of l-r4-(azacvclotπdecan- l-ylmethv0phenylmethvn- 1.4.8.1 1- tetraazacyclotetradecane pentahvdrochloπde
Following the procedure of Example l(a)-(c), except substituting azacyclotridecane for 1 -acetylpiperazine, the title compound was prepared ( 13% overall) MS (ES+) m/e 522
[M+H+HC1]+
Example 7 Preparation of l--"4-(5.6.14.15-dιbenzo- 1.4-dioxa-8.12-dιazacvclopentadeca-5.14-dιen-8- ylmethyl)phenylmethyl1-1.4.8.11-tetraazacvclotetradecane hexahydrochloride
Following the procedure of Example l(a)-(c), except substituting 5,6,14,15- dibenzo-l,4-dιoxa-8,12-dιazacyclopentadeca-5, 14-dιene for 1 -acetylpiperazine, the title compound was prepared (42% overall). ' H NMR (300MHz, d6-DMSO, D20) δ 7 90-
6.95(m, 12H), 4.7-4.1 (m, 14H), 3.5 (s, 2H), 3.45 (s, 2H), 3.5-3.0 (br m, 6H), 2.85-2.30 (br m, 2H), 2.3-2.0 (br m, 6H), 1.2 (br s, 6H,).
Example 8
Preparation of l-r4-(1.4.7-tπoxa-10-azacvclododecan- 10-ylmethyl)phenylmethyπ- l ,4.8.1 1- tetraazac vc lotetradecane pentahydrochloride
Following the procedure of Example l(a)-(c), except substituting l-aza-12-crown for 1 -acetylpiperazine, the title compound was prepared (86% overall). MS (ES+) m/e 478
[M+H]+.
Example 9 Preparation of l-T4-( 1.4.7.10-tetraoxa- l 3-azacvclopentadecan- 13-ylmethvPphenylmethyll-
1.4.8.1 1 -tetraazacyclotetradecane pentahydrochloride
Following the procedure of Example l(a)-(c), except substituting l-aza-15-crown-5 for 1 -acetylpiperazine, the title compound was prepared (50% overall). MS (ES+) m/e 522
[M+H]+. Example 10
Preparation of 1 -l~4-( 1.4.10-trioxa-7.13-diazacvclopentadecan-7-ylmethv phenylmethyll-
1.4.8.11 -tetraazacyclotetradecane hexahydrochloride
Following the procedure of Example l(a)-(c), except substituting 1,4,10-tπoxa-
7,13-dιaza-cyclopentadecane for 1 -acetylpiperazine, the title compound was prepared (21% overall). MS (ES+) m/e 261 [M+2H]2+, 557.
Example 1 1
Preparation of 1 - { 4-|"4-(2-pyπdvD- 1 -piperazinomethyllphenylmethy 11-1,4,8.11- tetraazacvclotetradecane hexahydrochloride
Following the procedure of Example l(a)-(c), except substituting l-(2- pyπdyOpiperazme for 1 -acetylpiperazine, the title compound was prepared (24% overall)
MS (ES+) m/e 466 [M+H]+, 502.
Example 12
Preparation of l -(4-f4-(2-pyπmιdyl)- l-pιperazιnomethvπphenylmethyl }- l ,4,8.1 1 - tetraazacvclotetradecane hexahydrochloride Following the procedure of Example l(a)-(c), except substituting l-(2- pynmidyOpiperaz e for 1 -acetylpiperazine, the title compound was prepared (25% overall) MS (ES+) m/e 467 [M+H]+, 503
Example 13 Preparation of l-r4-(2-guanιdιnobenzιmιdazol- l-ylmethyl)phenylmethyl1- 1.4.8.1 1 - tetraazacvclotetradecane pentahydrochloride a) l-t4-(2-guanιdιnobenzιmιdazol-l-ylmethyl)phenylmethyl]-4,8, l l-tπ-(f-butoxycarbonyl)-
1 ,4,8, 11 -tetraazacyclotetradecane
A mixture of l-[4-(bromomethyl)phenylmethyl]-4,8, l l-tπ-(f-butoxycarbonyl)-
1,4,8,1 1-tetraazacyclotetradecane (293 mg, 0 429 mmol) and 2-guamdιnobenzιmιdazole
(225 mg, 1.28 mmol) in acetonitπle (5 mL) was stirred and heated under reflux for 30 min
The solvent was evaporated and the residue was purified by flash chromatography (silica gel, 0-5 % methanol/dichloromethane) to give the title compound as a yellow gum. ( 1 15 mg, 34%) MS (ES+) m/e 778 [M+H]+ b) l-[4-(2-guanιdιnobenzιmιdazol-l-ylmethyl)phenylmethyl]-l,4,8,l 1- tetraazacyclotetradecane pentahydrochloπde
To a solution of l-[4-(2-guanιdmobenzιmιdazol- 1-y Imethy Opheny lmethyl]-4,8,l 1- tπ-(t-butoxycarbony 1)- 1 ,4,8, 11 -tetraazacyclotetradecane
(115 mg, 0.148 mmol) in 1,4-dioxane (2.0 mL) was added a 4M solution of hydrogen chloride in 1,4-dioxane (1 5 mL). The mixture was stood overnight, the red solid collected and washed successively with 1, 4,-dιoxane, diethyl ether and hexane The hygroscopic solid was dned in vacuo (80°C) to give the title compound (72 mg, 73%) MS (ES+) m/e 478 [M+H]+
Example 14 Preparation of l-r4-(l-pιperazιnomethyl)phenylmethyl]- 1.4.8.1 1 -tetraazacyclotetradecane hexahydrochloride
Following the procedure of Example l(a)-(c), except substituting piperazine for 1- acetylpiperazine, the title compound was prepared (32% overall) MS (ES+) m/e 389
[M+H]+ Example 15
Preparation of 1.4-bιs-f4-( 1 ,4.8.1 1 -tetraazacyclotetradecan- 1- ylmethvOphenylmethyllpiperazine decahvdrochloπde a) l,4-bιs-{4-[4,8,l l-tπ-(f-butoxycarbonyl)- 1 ,4,8,1 1-tetraazacvclotetradecan- l- ylmethyljphenylmethyl jpiperazine A mixture of l-[4-(bromomethyl)phenylmethyl]-4,8, l l-tπ-(f-butoxycarbonyl)- 1,4,8,11-tetraazacyclotetradecane (287 mg, 0.449 mmol), piperazine (92 mg, 1.07 mmol) and anhydrous potassium carbonate ( 100 mg, 0.724 mmol) in acetomtπle (5 mL) was vigorously stirred together at 50 C for 1 hour. The solvent was evaporated and the residue was punfied by flash chromatography (silica gel, 0-5 % methanol/dichloromethane) to give the title compound as an oil, ( 1 14 mg, 21 %) MS m/e 646 [M+2H]2+ b) l,4-bιs-[4-(l,4,8,l l-tetraazacyclotetradecan- l-ylmethyl)phenylmethyl]pιperazιne decahydrochloπde
Following the procedure of Example 1(c), except substituting l,4-bιs-{4-[4,8,l 1- tπ-(r-butoxycarbonyl)- 1 ,4,8, 11 -tetraazacyclotetradecan- 1 - ylmethyljphenylmethyl jpiperazine for l-[4-(4-acetyl- l-pιperazιnomethyl)phenylmethyl]- 4,8,1 l-tπ-(f-butoxycarbonyl)- 1,4,8,11-tetraazacyclotetradecane. the title compound was prepared (56%) MS (ES+) m/e 346 [M+2H]2+ Example 16
Preparation of l-r4-(1.5-dιazacvclooctan- l-ylmethyl)phenylmethyl1- 1.4.8.1 1- tetraazacvclotetradecane hexahydrochloride
Following the procedure of Example l(a)-(c), except substituting 1,5-dιazacyclooctane dihydrobromide (G. Ewm et al., J. Chem. Res., Synop., 1985, 11, 334) for 1- acetylpiperazine, the title compound was prepared (6% overall) H NMR (300MHz, d6-
DMSO/D20) δ 7.74 (s, 4H), 4.43 (br s, 4H), 3.6-3 0 (br m, 20H), 2.21 (br m, 12H)_
Example 17
1 -(4- ( bιsr2-(dιethylamιno)ethyl1amιnomethyl 1 phenylmethyl)- 1.4.8.1 1- tetraazacvclotetradecane heptahvdrochloπde a) 1 -[4-(bromomethy Opheny Imethy l]-4,8, 1 l-tn-(f-butoxycarbony 1)- 1, 4,8,11- tetraazacyclotetradecane a,a -Dibromo-p-xylene (36.0 g, 136 mmol) was stirred at 60 C in acetonitπle (500 mL) until it dissolved. Potassium carbonate (3.5 g, 25.3 mmol) was added, followed by the dropwise addition of a solution of l,4,8-tπ-(r-butyloxycarbonyl)- 1 ,4,8, 1 1- tetraazacyclotetradecane (B Boitrel et. al., Tetrahedron Lett , 1995, 36, 4995) (6.0 g, 1 1 98 mmol) in acetonitπle (100 mL). The mixture was stirred for 6 hours, cooled and partially evaporated The excess dibromoxylene was filtered off, the mother liquors evaporated under vacuum and chromatographed (silica gel, 50% dichloromethane/hexane to 2% methanol/dichloromethane) to afford the title compound as a foam (7.4 g, 90 %). MS (ES+) m/e 683 and 685 [M+H]+. b) l-(4-{bis[2-(diethylamino)ethyl]aminomethyl}pheny Imethy 0-4,8, 1 l-tri-(r- butoxycarbonyl)- 1,4,8,11-tetraazacyclotetradecane A mixture of l-[4-(bromomethyl)phenylmethyl]-4,8,l l-tri-(r-butoxycarbonyl)-
1,4,8, 1 l-_ tetraazacyclotetradecane (279 mg, 0.408 mmol), N,N,N\N - tetraethyldiethylenetriamine (211 uL, 0.820 mmol) and anhydrous potassium carbonate (100 mg, 0.724 mmol) in acetonitrile (5 mL) was vigorously stirred together at 50 C for 1 hour. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, 0-5% methanol/dichloromethane) to give the title compound as an oil, (210 mg, 63%) MS (ES+) m/e 818 [M+H]+. c) l-(4-{ bis[2-(diethylamino)ethyl]aminomethyl }phenyimethyl)- 1 ,4,8,1 1- tetraazacyclotetradecane heptahydrochloride To a solution of 1 -(4- {bis[2-(diethylamino)ethyl]aminomethyl }pheny Imethy 1)-4,8,1 l-tri-(r- butoxycarbony 1)- 1, 4,8,11-tetraazacyclotetradecane (200 mg, 0.244 mmol) in 1,4-dioxane (2.0 mL) was added a 4M solution of hydrogen chloride in diethyl ether ( 1.5 mL). The mixture was stood overnight, the solid collected and washed successively with diethyl ether and hexane. The hygroscopic solid was dried in vacuo (80 C) to give the title compound (100 mg,
53%). !H NMR (300MHz, d6-DMSO/D20) δ 7.6 (m, 4H), 4.0-2.9 (br m, 24H), 2.2 (br s,
4H), 1.1 1 (m, 12H), 1.07 (t, 12H).
Example 18 l-(4-f(2-aminoethyl)(3-aminopropyl)aminomethyl1phenylmethyl }- l .4.8.1 1- tetraazacyclotetradecane heptahydrochloride a) (2-phthalimidoethyl)(3-phthalimidoprop- l-yl)amine
A mixture of N-(2-aminoethyl)-l,3-propanediamine (10.0 mL, 79.2 mmol), phthalic anhydride (24.6 g, 166 mmol) and p-toluenesulfonic acid (1.0 g, 5.26 mmol) in toluene (500 L) was stiπed and heated under reflux, using a Dean & Stark head, for 5 hours. The mixture was cooled and diluted with hexane. The solid was collected, washed with ether and hexane, and dried to give the title compound as a pale yellow solid (21 g,
72%). MS (ES+) m e 378 [M+H]+. b) l-[4-{ [(2-phthalimidoethyl)(3-phthalimidoprop- l-yl)amino]methyl }phenylmethyl]-
1 ,4,8.1 1-tetraazacyclotetradecane pentahydrochloride Following the procedure of Example 1(a)- 1(c), except substituting (2- phthalimidoethyl)(3-phthalimidoprop- l-yI)amine for N,N,N',N - tetraethyldiethylenetriamine, the title compound was prepared (58% overall). MS (ES+) m/e 341 [M+2H]2+. c) l-(4-{ [(2-aminoethyl)(3-aminopropyl)amino]methyl }phenyimethyl)-l,4,8,l 1- tetraazacyclotetradecane heptahydrochloride l-[4-{[(2-phthalimidoethyl)(3-phthalimidoprop-l-yl)amino]methyl }phenylmethyl]-
1,4,8,1 1-tetraazacyclotetradecane pentahydrochloride (200 mg, 0.234 mmol) in ethanol (5 L) was treated with hydrazine hydrate (2.0 mL, 64.2 mmol) and stirred at 60 C for 4 hours. The solvent was evaporated and the residue was slurried in diethyl ether with potassium carbonate. The mixture was filtered and the filtrate treated with a 4M solution of
HCl in 1,4-dioxane and this mixture allowed to stand overnight. The solid was collected, washed with diethyl ether and hexane, then dried in vacuo (80 C) to give the title compound (150 mg, 95 %). MS (ES+) m/e 456 [M+HC1+H]+. Example 19 l-{4-fdi-(2-pyridyl)aminomethyl]phenylmethvU- 1.4,8.1 1-tetraazacyclotetradecane pentahydrochloride a) l-{4-[di-(2-pyridyl)aminomethyljphenylmethyl }-4,8,l l-tri-(t-butoxycarbonyl)- 1,4,8,11- tetraazacyclotetradecane 2,2 -Dipyridylamine (77 mg, 0.500 mmol) was added to a suspension of sodium hydride (18.8 mg of a 60% dispersion in mineral oil, 0.470 mmol) in anhydrous DMF (10 mL) and the mixture stirred at 25 C for 1 hour under nitrogen. A solution of l-[4- (bromomethyl)phenylmethyl]-4,8, l l-tri-(f-butoxycarbonyl)- 1,4,8, 11- tetraazacyclotetradecane (292 mg, 0.427 mmol) in anhydrous DMF was added and the mixture stirred overnight. Water was added and the mixture extracted twice with diethyl ether and once with ethyl acetate. The combined organic extracts were washed with water, dried (anhydrous potassium carbonate) and evaporated to a yellow gum, which was purified by flash chromatography (silica gel, 0-5% methanol/dichloromethane) to give the title compound as an oil, (100 mg 30%). MS (ES+) m/e 774 [M+H]+. b) l-{4-[di-(2-pyridyl)aminomethyl]phenylmethyl }- 1 ,4,8,1 1-tetraazacyclotetradecane pentahydrochloride
Following the procedure of Example 1(c), except substituting l-{4-fdi-(2- pyridyl)aminomethyI]phenylmethyl }-4,8, l l-tri-(-'-butoxycarbonyl)- 1 ,4,8, 1 1- tetraazacyclotetradecane for l -(4-{bis[2-(diethylamino)ethyl]aminomethyl }phenylmethyl)- 4,8,1 l-tπ-(r-butoxycarbony 1)-1, 4,8,11-tetraazacyclotetradecane, the title compound was prepared (94%) MS (ES+) m/e 474 [M+H]+
Example 20 1 -r4-(2-thιazolylamιnomethyl)phenylmethvπ- 1.4.8.1 1 -tetraazacyclotetradecane pentahvdrochloπde
Following the procedure of Example 17(a)- 1(c), except 2-amιnothιazole for N,N,N',N -tetraethyldiethylenetπamine, the title compound was prepared ( 19% overall) MS (ES+) m/e 202 [M+2H]2+
Example 21 1.4-bιsf2-(2-benzιmιdazolylamιno)-5.5-di(2-pyπdyl)-4-oxo-5H-ιmιdazolιn-3- ylmethyllbenzene bis-tπfluoroacetic acid salt a) 2-(2-benzιmιdazolylamιno)-5,5-dι(2-pyndyl)-5H-ιmιdazolιn-4-one
A mixture of 2,2'-pyπdιl (15.8 g, 74 4 mmol) and 2-guanιdιnobenzιmιdazole (19 5 g, 111 7 mmol) in methanol (440 mL) was treated with a solution of sodium hydroxide (2.97 g, 74.4 mmol) in water (74 mL) and the resulting mixture was left standing at room temperature for 4 days. A crystalline mateπal was filtered and the mother liquor allowed to stand for 3 weeks. The precipitated solid was filtered and dried under vacuum to give the title compound (10.5 g, 36%) as its sodium salt. !H NMR (300MHz, d^-DMSO) δ 1 1.55 (br s, IH), 10.05 (br s, IH), 8.47 (m, 2H), 7.76 (m, 2H), 7.68 (m, 2H), 7 25 (m, 4H), 6.90 (m, 2H) Further slow concentration of the mother liquor gave a third solid, which was filtered and dned under vacuum to give the title compound (1.25g, 5%) as a solid. Η NMR (300MHz, d6-DMSO) δ 1 1 8 (br s, 2H), 10.5 (br s, IH), 8 64 (m, 2H), 7 89 (m, 2H), 7 53 (d, J = 8 0 Hz, 2H), 7 44 (m, 4H), 7 07 (m, 2H). b) l,4-bιs[2-(2-benzιmιdazolylamιno)-5,5-dι(2-pyπdyI)-4-oxo-4H-ιmιdazolιn-3- ylmethyl]benzene bis-tπfluoroacetic acid salt
To a solution of 2-(2-benzιmιdazolylamιno)-5,5-dι(2-pyrιdyI)-5H-ιm,daZolιn-4-one (390 mg, 1.00 mmol) in DMF ( 1 mL) at room temperature was added α,α ' -dibromo-p- xylene (120 mg, 0.45 mmol) in one portion. The reaction was stiπed at room temperature for 12 hours then concentrated under reduced pressure. The residue was taken up in DMSO (5 L ) and purified by reverse phase HPLC [ODS, 0-90% CH,CN/H,0 (0 1 % TFA)] to give the title compound as a yellow solid (240 mg, 50%) MS (ES+) m/e 841 [M+H]+
Example 22 2.6-bιsf2-(2-benzιmιdazolylamιno)-5,5-dι(2-pyπdvO-4-oxo-5H-ιmιdazolιn- - ylmethyllpyπdine bis-tπfluoroacetic acid salt Following the procedure of Example 21 (a)- 1(b), except substituting 2,6- bis(bromomethyl)pyridine for α,α'dibromo-p-xylene, the title compound was prepared (2% overall). MS (ES+) m/e 842 [M+H]+.
Example 23 1.4-bis ( f 1 -(2-benzimidazolvO- 1 -euanidinolmethyl ) benzene
To a solution of 2-guanidinobenzimidazole (350 mg, 2.0 mmol) in DMF at 0°C was added NaH (88 mg of a 60 % dispersion in mineral oil, 2.2 mmol) in portions over five minutes. The solution was warmed to room temperature and allowed to stir for 45 minutes. The solution was cooled to 0°C and α,α'-dibromo-p-xylene (264 mg, 1.0 mmol) was added in portions over 1 hour. The solution was stirred an additional hour, concentrated under reduced pressure, and taken up in ethyl acetate. The organic solution was washed with aqueous NH4CI, NaCl, dried over anhydrous Na2Sθ4, and concentrated under reduced pressure. The residue was purified by flash chromotography (silica gel, ethyl acetate) to give the title compound as a white powder (350 mg, 77%). MS (ES+) m/e 453 [M+H]+. Example 24 l-f3-(2-guanidinobenzimidazol- l-ylmethyl)phenylmethyll- 1 ,4,8, 1 1- tetraazacvclotetradecane pentahydrochloride a) l-[3-(bromomethyl)phenylmethyl]-4,8,l l-tri-(t-butoxycarbonyl)- 1,4,8,1 1- tetraazacyclotetradecane a,a -Dibromo-m-xylene (22.0 g, 83.3 mmol) was stirred at 60°C in acetonitrile (350 mL) until it dissolved. Potassium carbonate (2.0 g, 14.5 mmol) was added, followed by the dropwise addition of a solution of l,4,8-tri-(f-butyloxycarbonyl)- 1,4,8,11- tetraazacyclotetradecane (B. Boitrel et. al.. Tetrahedron Lett., 1995, 36, 4995) (4.0 g, 7.99 mmol) in acetonitrile (100 mL). The mixture was stiπed for 6 hours, cooled and partially evaporated. The excess dibromoxylene was filtered off, the mother liquors evaporated under vacuum and chromatographed (silica gel, 50% dichloromethane/hexane to 2% methanol/dichloromethane) to afford the title compound as a foam (4.55 g, 83 %). 1H NMR (300MHz, CDC13) δ 7.30-7.19 (m, 4H), 4.49 (s, 2H), 3.51 (s, 2H), 3.45-3.20 (m, 12H), 2.62 (m, 2H), 2.38 (m, 2H), 1.91 (m, 2H), 1.68 (m, 2H), 1.47-1.43 (m, 27H). b) l-[3-(2-guanidinobenzimidazol- l-ylmethyI)phenylmethyl]-4,8,l l-tri(r-butoxycarbonyl)- 1,4,8, 1 1-tetraazacyclotetradecane
A mixture of l-[3-(bromomethyl)phenylmethyl]-4,8, l l-tri-(f-butoxycarbonyl)- 1,4,8,1 1-tetraazacyclotetradecane (293 mg, 0.43 mmol), 2-guanidinobenzimidazole (225 mg, 1.287 mmol) and potassium carbonate (100 mg, 0.724 mmol) were heated together under reflux with vigorous stirring in acetonitrile (5 mL) for 1 hr. Flash chromatography (silica gel, dichloromethane to 4% methanol/ dichloromethane) gave the title compound
(115 mg, 34%) as a yellow gum. MS (ES+) m/e 778 [M+Hj+. c) l-[3-(2-guanidinobenzimidazol- 1-ylmethyOphenylmethyl]- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloride A solution of l-[3-(2-guanidinobenzimidazol- l-ylmethyl)phenylmethyl]-4,8,l 1- tri( -butoxycarbonyl)- 1,4,8,1 1-tetraazacyclotetradecane (70 mg, 0.090 mmol) in ethanol (2 mL) was treated with HCl in dioxane (4M, 2.0 mL, 8.0 mmol) and stood overnight. The solid was filtered, washed with dioxane, ether and hexane to give the title compound (50 mg, 84%) as a red solid. MS (ES+) m e 478 [M+H]+. Example 25
1 -r4-(2-aminobenzimidazol- 1 -ylmethvDphenylmethyll- 1.4.8.11 -tetraazacyclotetradecane pentahydrochloride a) 1 -[4-(bromomethyl)pheny Imethy 1]-4,8,1 l-tri-(r-butoxycarbonyl)- 1,4,8,11- tetraazacyclotetradecane a,a -Dibromo-p-xylene (36.0 g, 136 mmol) was stirred at 60°C in acetonitrile (500 mL) until it dissolved. Potassium carbonate (3.5 g, 25.3 mmol) was added, followed by the dropwise addition of a solution of 1 , 4,8-tri-(r-butyloxycarbonyl)- 1,4,8, 11- tetraazacyclotetradecane (B. Boitrel et. al.. Tetrahedron Lett., 1995, 36, 4995) (6.0 g, 1 1.98 mmol) in acetonitrile (100 mL). The mixture was stiπed for 6 hours, cooled and partially evaporated. The excess dibromoxylene was filtered off, the mother liquors evaporated under vacuum and chromatographed (silica gel, 50% dichloromethane/hexane to 2% methanol/dichloromethane) to afford the title compound as a foam (7.4 g, 90 %). MS (ES+) m/e 683 and 685 [M+H]+. b) l-[4-(2-aminobenzimidazol- l-ylmethyl)phenylmethyl]- 1,4,8,11-tetraazacyclotetradecane pentahydrochloride
The procedure described in example 24b and lc was followed here, using 2- aminobenzimidazole in place of 2-guanidinobenzimidazole and l-[4- (bromomethyl)phenylmethyl]-4,8, 11 -tri-(f-butoxycarbony 1)- 1 ,4,8, 11 - tetraazacyclotetradecane in place of l-[3-(bromomethyl)phenylmethyl]-4,8,l l-tri-(f- butoxycarbonyl)- 1 ,4,8, 11-tetraazacyclotetradecane, to give the title compound as a solid. MS (ES+) m/e 219 [M+2H]2+.
Example 26 l,8-bis-[4-( 1.4,8.1 1 -tetraazacyclotetradecan- l-ylmethvOphenylmethyll- 1.4.8.1 1- tetraazacvclotetradecane dodecahydrobromide a) 4, 1 1 -bis(p-toluenesulfony 0- 1 ,8-bis-[4-(4,8, 11 -tris { p-toluenesulfony 1 } -1,4,8, 11 - tetraazacyclotetradecan- l-ylmethyl)pheny Imethyl j- 1,4,8, 1 1-tetraazacyclotetradecane A mixture of slightly impure 4,8, l l-tπs-(p-toluenesulfonyl)- 1,4,8, 1 1- tetraazacyclotetradecane (590 mg, 0,890 mmol) (M. Ciampolini et. al., Inorg. Chem., 1987, 26, 3527), a,a -dibromo-p-xylene ( 117 mg, 0.445 mmol), potassium carbonate (369 mg, 2.67 mmol) and acetonitrile (10 mL) was heated at 80 °C for 18h, then cooled and partitioned between water and dichloromethane. Extracts were washed (saturated aqueous NaCl), dried (MgS04) and solvent removed under vacuum. The crude material was chromatographed (silica gel, 50-100% ethyl acetate/ hexane then 5% methanol/dichloromethane) to give the title compound (35 mg, 8%) as an amorphous solid MS (ES+) m/e 1019 [M+2H]2+ b) 1, 8-bιs-[4-(l, 4,8, 1 1 -tetraazacyclotetradecan- l-ylmethyi)pheny imethyl]- 1 ,4,8, 1 1- tetraazacy c lotetradecane dodecahydrobromide
4, 11 -bis(p-toluenesulfonyl)- 1 ,8-bis-[4-(4,8, 1 1 -tπs { p-toluenesulfony 1 } - 1 ,4,8, 11 - tetraazacyclotetradecan- 1-y Imethy Ophenylmethyl]- 1,4,8,1 1-tetraazacyclotetradecane (35 mg, 0.017 mmol) was heated under reflux in 48% aqueous HBr/acetic acid (2:3, 2.5 mL) for 18h. After cooling, the solid was filtered, washed (acetic acid, dichloromethane. etner) and dned (60°C under vacuum) to give the title compound (26 mg, 87%) as a pink ,
MS (ES+) m e 403 [M+2H]2+.
Example 27
1.1 l-bιs-T4-( 1.4.8.11 -tetraazacyclotetradecan- 1-ylmethvPphenylmethyl]- 1.4.8.1 1- tetraazacyclotetradecane dodecahydrobromide
The procedure described in example 26 also gave the title compound (8 mg, 2%) as a solid. *H NMR (300MHz, D20) δ 7.57 (d, 4H, J = 1.9Hz), 7.47 (d, 4H, J = 7.9Hz), 4.29
(s, 4H), 4.03 (s, 4H), 3.39-2.94 (m, 48H), 2.13 (m, 8H), 1.97 (m, 4H).
Example 28 1 -f4-(N- { 3-(methylamιno)propyl l-N-methylamιnomethyl)phenylmethy 11- 1.4.8.1 1 - tetraazacyclotetradecane hexahydrochloride
The procedure described in example 24b and lc was followed here, using N,N'- dιmethyl-l,3-propanediamιne in place of 2-guanιdinobenzιmιdazole and l-[4-
(bromomethyl)pheny Imethyl j-4,8, 1 1 -tπ-(r-butoxycarbonyl)- 1 ,4,8, 1 1 - tetraazacyclotetradecane in place of l-[3-(bromomethyl)phenylmethyl]-4,8,l l-tπ-(r- butoxycarbony 1)-1 ,4,8,11-tetraazacyclotetradecane, to give the title compound as a solid.
!H NMR (300 MHz, DMSO/D20) δ 7 8 (m, 4H), 44 (m, 4H), 3.6 (s, 6H), 3.4-2.9 (m,
14H), 2.65 (m, 4H), 2.15 (m, 8H)
Example 29 l-f4-(N-f 3.4-methylenedιoxyphenylmethvUamιnomethyl)phenylmethyl1- 1.4.8.1 1 - tetraazacvclotetradecane pentahydrochloride A mixture of l-[4-(bromomethyl)phenyimethyl]-4.8, l l-tπ-(f-butoxycarbonyl)- 1,4,8,11-tetraazacyclotetradecane (61 mg, 0.089 mmol) and 3,4- methylenedioxybenzyiamine (40 mg, 0.267 mmol) in ethanol (3 mL) was heated at 80- 90°C for 3 hours The solvent was evaporated and the residue redissolved in DMSO and chromatographed by preparative HPLC (20-80 % acetonitπle/water + 0 1 % TFA) The resulting purified tπ-(r-butoxycarbonyl) intermediate was dissolved in ethanol (2 5 mL) and HCl in dioxane (4.0M, 2.0 mL, 8 mmol) added. The mixture was allowed to stand for 24 then evaporated to give the title compound. MS (ES+) m/e 454 [M+H]
Examples 30 to 34 The following compounds were prepared according to the procedure descπbed in example 29 using the appropriate amines:
l-[4-(N-{3,5-dιfluorophenylmethyl JaminomethyOphenylmethyl]- 1,4,8,11- tetraazacyclotetradecane pentahydrochloride. MS (ES+) m e 446 [M+H]
1 -[4-(phenothιazιn- l 0-y lmethyOphenylmethyl]- 1,4,8,1 1-tetraazacyclotetradecane pentahydrochloride. MS (ES+) m/e 502 [M+H]+
l-[4-(N-{4-amιno-2-methylquιnohn-6-yl JaminomethyOphenylmethyl]- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloπde. MS (ES+) m/e 476 [M+H]
l-[4-(N-{4-(2-guanιdιnothιazol-4-yl)phenyl JaminomethyOphenylmethyl]- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloπde. MS (ES+) m/e 536 [M+HJ
l-[4-(N-{3-(2-guanιdmothιazol-4-y Ophenyl JaminomethyOphenylmethyl]- 1,4,8, 1 1- tetraazacyclotetradecane pentahydrochloπde. MS (ES+) m/e 536 [M+H]
Example 35 1 -[5-nιtro-3-(N-{ 3-(2-thιenyl)pyrazol-5-yl } aminomethyOpheny Imethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloπde a) l-[3-(bromomethyl)-5-nιtrophenylmethyl]-4,8, l l-tπ-(r-butoxycarbonyl)- 1,4,8, 11- tetraazacy c lotetradecane
The procedure described in example la was followed here, using 1,3- bιs(bromomethyl)-5-nιtrobenzene in place of a,a -dibromo-m-xylene, to give the title compound as a foam !H NMR (300 MHz, CDC13) δ 8 12 ( , 2H), 7 65 (s, IH), 4 53 (s, 2H), 3 63 (s, 2H), 3 5-3 2 (m, 12H), 2.65 (m, 2H), 2 40 (m, 2H), 1 92 ( , 2H), 1 70 (m, 2H), 1 55- 1 30 (m. 27H) b) l-[5-nιtro-3-(N- (3-(2-thιenyl)pyrazol-5-yl JaminomethyOphenylmethyl]- 1,4,8.11- tetraazacyclotetradecane pentahydrochloride
The procedure described in example 29 was followed here, using l-[3-
(bromomethyl)-5-nιtrophenylmethy 1 J-4,8, 1 1 -tπ-(r-butoxycarbony 1)- 1.4,8, 1 1 - tetraazacyclotetradecane in place of l-[4-(bromomethyl)phenylmethyl]-4,8,l l-tπ-d*- butoxycarbony 1)-1, 4,8,11-tetraazacyclotetradecane and 5-amιno-3-(2-thιenyl)pyrazole in place of 3,4-methylenedιoxybenzylamιne, to give the title compound as a solid. MS (ES+) m/e 513 [M+H]+
Examples 36 to 39 The following compounds were prepared according to the procedure described in example
35 using the appropriate amines
1 -[5-nιtro-3-(phenothιazιn- 10-ylmethyl)pheny Imethy 1]- 1 ,4,8, 11 -tetraazacyclotetradecane
,+ pentahydrochloride MS (ES+) m/e 547 [M+H]
1 -[3-(N- { 4-amιno-2-methylquιnolιn-6-y 1 } amιnomethyl)-5-nιtrophenylmethy 1]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride. MS (ES+) m/e 521 [M+H]
1 -[3-(N- { 4-(2-guanιdmothιazol-4-y Ophenyl } aminomethy l)-5-nιtrophenylmethyl]- j 4^ j j . tetraazacyclotetradecane pentahydrochloπde. MS (ES+) m/e 581 [M+H]
1 -[3-(N- { 3-(2-guanιdιnothιazol-4-yl)phenyl } aminomethy l)-5-nιtrophenylmethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochlonde. MS (ES+) m e 581 [M+H]+
Example 40 1 -r5-bromo-3-(N- .3-(2-thιenyl)pyrazol-5-yl J aminomethvOphenylmethyll- 1.4.8.11 - tetraazacyclotetradecane pentahydrochloride a) l-[5-bromo-3-(bromomethyI)phenylmethyl]-4,8, l l-tπ-(r-butoxycarbonyl)- 1,4,8, 1 1- tetraazacyclotetradecane
The procedure descπbed in example la was followed here, using 5-bromo- l,3- bιs(bromomethyl)benzene in place of a,a -dibromo-w-xylene, to give the title compound a foam MS (ES+) m/e 761, 763, 765 [M+H]+ b) l-[5-bromo-3-(N-{3-(2-thιenyl)pyrazol-5-yl JaminomethyOphenylmethyl]- 1,4, 8,1 1- tetraazacyclotetradecane pentahydrochloride
The procedure described in example 29 was followed here, using l-[5-bromo-3- (bromomethyl)phenylmethyl]-4,8,l 1 -tπ-(r-butoxycarbonyl)-l, 4,8,1 1- tetraazacvclotetradecane in place of l -[4-(bromomethyI)phenylmethyl]-4,8.1 l-tπ-(/- butoxycarbonyl)- 1,4,8, 11-tetraazacyclotetradecane and 5-amιno-3-(2-thιenyl)pyrazole in place of 3,4-methylenedιoxybenzylamιne, to give the title compound as a solid MS (ES+) m/e 546, 548 [M+H]+
Examples 41 to 44 The following compounds were prepared according to the procedure descnbed in example
40 using the appropriate amines
l-[5-bromo-3-(phenothιazιn-10-ylmethyl)phenylmethyl]-l , 4,8,1 1-tetraazacyclotetradecane
.+ pentahydrochloride MS (ES+) m/e 580, 582 [M+H]
l-[3-(N-{4-amιno-2-methylquιnolιn-6-yl}amιnomethyl)-5-bromophenylmethyl]-l,4,8, l l- tetraazacyclotetradecane pentahydrochloride MS (ES+) m/e 554, 556 [M+H]
1 -[5-bromo-3-(N-{ 4-(2-guanιdιnothιazol-4-y Ophenyl } aminomethyOphenylmethyl]- 1 ,4,8,11- tetraazacyclotetradecane pentahydrochlonde MS (ES+) m/e 614, 616 [M+H]+
l-[5-bromo-3-(N-{3-(2-guanidinothiazol-4-y0phenyl}aminomethyl)phenylmethyl]-l ,4,8,l l- tetraazacyclotetradecane pentahydrochloπde MS (ES+) m/e 614, 616 [M+H]+
Example 45 l-[3-(N-{6-methyl-2-nιtrophenyl JaminomethyOphenylmethyl]- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloride
The procedure described in example 29 was followed here, using l-[3-
(bromomethyl)phenylmethyl]-4,8,l l-tπ-( t-butoxycarbonyl)- 1 ,4,8, 11- tetraazacyclotetradecane in place of l-[4-(bromomethyl)phenylmethyl]-4,8,l l-tπ-(r- butoxycarbonyl)- 1,4,8,1 1-tetraazacyclotetradecane and 6-methyl-2-nιtroanιlιne in place of
3,4-methylenedιoxybenzylamιne, to give the title compound as a solid MS (ES+) m/e 455
[M+H]+
Example 46
The following compounds were prepared according to the procedure described in example 45 using the appropnate amines
1 -[3-(N- { 3-(2-thιenyl)pyrazol-5-yl } aminomethyOphenylmethyl]- 1 ,4,8,1 1- tetraazacyclotetradecane pentahydrochloride. MS (ES+) m/e 468 [M+H]
Example 47 l-f4-(N-( l-methyl-3-(2-thιenyl )pyrazol-5-yl )amιnomethvPphenylmethyl1- 1.4.8.1 1- tetraazacvclotetradecane pentahvdrochloπde a) 1 -[4-(bromomethy Opheny Imethy 1]-4,8,1 l-tπ-(r-butoxycarbonyl)-l, 4,8,11- tetraazacy c lotetradecane a,a -Dibromo-p-xylene (36.0 g, 136 mmol) was stirred at 60°C in acetonitrile (500 mL) until it dissolved. Potassium carbonate (3.5 g, 25.3 mmol) was added, followed by the dropwise addition of a solution of l,4,8-tπ-(f-butyloxycarbonyl)- l,4,8,l l- tetraazacyclotetradecane (B. Boitrel et. al, Tetrahedron Lett., 1995, 36, 4995) (6 0 g, 11.98 mmol) in acetonitrile (100 mL). The mixture was stirred for 6 hours, cooled and partially evaporated. The excess dibromoxylene was filtered off, the mother liquors evaporated under vacuum and chromatographed (silica gel, 50% dichloromethane/hexane to 2% methanol/dichloromethane) to afford the title compound as a foam (7 4 g, 90 %) MS (ES+) m/e 683 and 685 [M+H]+ b) l-[4-(N-{ l-methyl-3-(2-thιenyl)pyrazol-5-yl }amιnomethyl)phenylmethyl]- l ,4,8,l 1- tetraazacyclotetradecane pentahydrochloride
A mixture of 5-ammo- 1-methy l-3-(2-thιenyl)pyrazole (300 mg, 1.67 mmol), l-[4- (bromomethyOpheny Imethy 1]-4,8,1 l-tπ-(r-butoxycarbonyl)- 1,4,8, 11- tetraazacyclotetradecane (379 mg, 0.555 mmol) and ethanol (3 mL) was heated under reflux for 3 h, then cooled. The solvent was removed under vacuum and the residue punfied by preparative HPLC (ODS, 10-90% acetonitπle/water + 0 1%TFA). A solution of the protected intermediate obtained in 4M HCl/dioxane (2 mL, 8 mmol) and dichloromethane (4 mL) was allowed to stand 18 h, then filtered. The residue was washed with dichloromethane and ether, then dned under high vacuum to give the title compound
(20 mg, 5%) as a solid. LCMS m/z 482 [M+H]+ Examples 48 to 50
The following compounds were prepared according to the procedure described in example
47 using the appropriate amines:
1 -[4-(N- { 3-methylpyrazol-5-y 1 } ammomethyOphenylmethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloπde. LCMS m/z 400 [M+H]+
1 -[4-(N- { 3-(4-methylphenyl)pyrazol-5-yl JaminomethyOphenylmethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride. LCMS m/z 476 [M+H]+
l-[4-(N- {3-(2-furyl)pyrazol-5-yl JaminomethyOphenylmethyl]- 1 ,4,8,1 1- tetraazacyclotetradecane pentahydrochloride LCMS m/z 452 [M+H]+
Example 51 l-r3-(N-{ 3-(4-methylphenvPpyrazol-5-vUaminomethyl)phenylmethyll- 1.4.8.1 1- tetraazacvclotetradecane pentahydrochloride a) l-[3-(bromomethyl)phenylmethylj-4,8,l l-tri-(f-butoxycarbonyl)- 1 ,4,8, 11- tetraazacyclotetradecane a,a -Dibromo-m-xylene (22.0 g, 83.3 mmol) was stirred at 60°C in acetonitrile (350 mL) until it dissolved. Potassium carbonate (2.0 g, 14.5 mmol) was added, followed by the dropwise addition of a solution of l,4,8-tri-(r-butyloxycarbonyl)- 1,4,8,1 1- tetraazacyclotetradecane (B. Boitrel et. al., Tetrahedron Lett., 1995, 36, 4995) (4.0 g, 7.99 mmol) in acetonitrile ( 100 mL). The mixture was stiπed for 6 hours, cooled and partially evaporated. The excess dibromoxylene was filtered off, the mother liquors evaporated under vacuum and chromatographed (silica gel, 50% dichloromethane/hexane to 2% methanol/dichloromethane) to afford the title compound as a foam (4.55 g, 83 %). *H NMR (300MHz, CDC13) δ 7.30-7.19 (m, 4H), 4.49 (s, 2H), 3.51 (s, 2H), 3.45-3.20 (m, 12H), 2.62 (m, 2H), 2.38 (m, 2H), 1.91 (m, 2H), 1.68 ( , 2H), 1.47-1.43 (m, 27H). b) l-[3-(N-{3-(4-methylphenyl)pyrazol-5-yl Jaminomethyl)phenylmethyl]-l,4,8,l 1- tetraazacyclotetradecane pentahydrochloride
A mixture of 5-amino-3-(4-methylphenyl)pyrazole (217 mg, 1.25 mmol), l-[3- (bromomethyl)phenylmethyl]-4,8, 11 -tri-(t-butoxycarbony 1)- 1 ,4,8, 11 - tetraazacyclotetradecane (779 mg, 1.14 mmol), potassium carbonate (473 mg, 3.42 mmol) and acetonitrile (11 mL) was stiπed at 60°C for 2.5 h, then cooled and partitioned between water and ethyl acetate. The extracts were washed with water, saturated aqueous NaCl, then dried (MgS04). The solvent was removed under reduced pressure and the residue chromatographed (silica gel, ethyl acetate, then 10% methanol/dichloromethane + Q 5% aqueous ammonia). A solution of 30 mg of the protected intermediate obtained in 4M HCl/dioxane (1 mL, 4 mmol) and dichloromethane (2 mL) was allowed to stand 18 h. then filtered. The residue was washed with dichloromethane and ether, then dried under high vacuum to give the title compound (25 mg, 26%) as a solid. MS (ES+) m/e 476 [M+H] .
Example 52 l-[3-(N-( l-methyl-3-phenylpyrazol-5-vUaminomethyl)phenylrnethvπ- 1.4.8.1 1- tetraazacyclotetradecane
A solution of 5-amino- l-methyl-3-phenylpyrazole (51 mg, 0.292 mmol) and l-[3- (bromomethyl)phenylmethyl]-4,8, 1 l-tri-(r-butoxycarbony 1)- 1 ,4,8, 1 1 - tetraazacyclotetradecane (100 mg, 0.146 mmol) in dimethylformamide (0.5 mL) was shaken for 18 h then partitioned between 0.1 M aqueous potassium carbonate and ethyl acetate. The organic extract was evaporated under reduced pressure and the residue purified by RP preparative HPLC (ODS, 10-90% acetonitrile/ water + 0.1 %TFA). A solution of the protected intermediate obtained in 4M HCl/dioxane (1 mL. 4 mmol) and dichloromethane (3 mL) was allowed to stand 72 h. then diluted with dichloromethane and water. The aqueous layer was partitioned between 1M aqueous NaOH and dichloromethane. The organic layer was dried (sodium sulfate) and evaporated under reduced pressure to give the title compound (3 mg, 4%) as an amorphous solid. LCMS m/z 476 [M+H]+.
Examples 53 to 55 The following compounds were prepared according to the procedure described in example
52 using the appropriate amines:
1 -[3-(N- { 3-(4-chloropheny 1)- 1 -methy lpyrazol-5-y 1 } aminomethy Opheny Imethyl]- j g j j _ tetraazacyclotetradecane. . LCMS m/z 510, 512 [M+H] .
l-[3-(N-{ l,3-diphenylpyrazol-5-yl JaminomethyOphenylmethyl]- 1,4,8, 11- tetraazacyclotetradecane.. LCMS m z 538 [M+H] .
1 -[3-(N- { 3-(4-f-butylpheny 1)- l-methylpyrazol-5-yl JaminomethyOphenylmethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane... LCMS m/z 532 [M+H]+.
Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.
Example 56 Inhalant Formulation
A compound of Formula I or II, (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use. Example 57
Tablet Formulation
Tablets/Ingredients Per Tablet
1. Active ingredient 40 mg
(Cpd of Form. I or ID 2 2.. C Coorrnn SSttaarrcchh 20 mg
3. Alginic acid 20 mg
4. Sodium Alginate 20 mg
5. Mg stearate 1.3 mg
Procedure for tablet formul ation: Ingredients 1, 2, 3 and 4 are blended in a suitable mixer/blender. Sufficient water is added portion-wise to the blend with careful mixing after each addition until the mass is of a consistency to permit its conversion to wet granules. The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen. The wet granules are then dried in an oven at 140°F (60°C) until dry. The dry granules are lubricated with ingredient No. 5, and the lubricated granules are compressed on a suitable tablet press.
Example 58 Parenteral Formulation A pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of Formula I or II in polyethylene glycol with heating. This solution is then diluted with water for injections Ph Eur. (to 100 ml). The solution is then rendered sterile by filtration through a 0.22 micron membrane filter and sealed in sterile containers. Specific Examples of formulations for pharmaceutical use incorporating compounds of the present invention are given below.
Example 59 - Capsule Composition An oral dosage form for administering a presently invented compound is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table II, below.
Table II
INGREDIENTS AMOUNTS l-[4-(Ν-{4-amino-2-methylquinolin-6- 25 mg yl JaminomethyOphenylmethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride
(Compound of Example 32)
Lactose 55 mg
Talc 16 mg
Magnesium Stearate 4 mg
Example 60 - Iniectable Parenteral Composition
An injectable form for administering a presently invented agonist of the TPO receptor is produced by stiπing 1.5% by weight of l-[3-(N-{ 3-(2-guanidinothiazol-4- y Opheny l }aminomethyl)-5-nitrophenylmethyl]- 1,4,8, 1 1-tetraazacyclotetradecane pentahydrochloride (Compound of Example 39) in 10% by volume propylene glycol in water.
Example 61 - Tablet Composition
The sucrose, calcium sulfate dihydrate and a presently invented agonist of the TPO receptor, as shown in Table III below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet. Table III
INGREDIENTS AMOUNTS l-[3-(N-{6-methyl-2- 20 mg nitrophenyl JaminomethyOphenylmethyl]- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloride
(Compound of Example 45) calcium sulfate dihydrate 30 mg sucrose 4 g starch 2 g talc 1 mg stearic acid 0.5 mg
Preferred among the compounds of the present invention are compounds of Examples 2 - CXCR4, 7 - CXCR4, 34 - TPO, 39 - TPO, 40 - TPO, 44 - TPO and 51 - TPO.
Most prefeπed among the compounds of the present invention are compounds of Examples 13 - CXCR4, 33 - TPO, 35 - TPO, 43 - TPO, 46 - TPO and 49 - TPO, 53 - TPO.
While the prefeπed embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved.

Claims

What is claimed is:
1. A compound according to formula (I):
Figure imgf000042_0001
Formula (I) wherein: the -CH2-Z substituent is eta or para to the tetraazacyclotetradecane substituent; Z represents a nitrogen-linked heteroaryl, a substituted nitrogen-linked heteroaryl, a cyclic amine moiety, a substituted cyclic amine moiety, or NY' Y2 where Y' and Y2 are each independently selected from hydrogen, alkyl, substituted alkyl, C3-
Cj2aryl, substituted C3-Ci 2 ryl, cycloalkyl, and substituted cycloalkyl; and X is selected from the group consisting of hydrogen, alkyl, C3-Ci2aryl, substituted C3-Cj2aryl- amino, alkylamino, nitro, hydroxy, alkoxy, halogen, carboxyl and carboxamido; and pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes thereof.
2. A compound according to formula (II): Y'CH2ACH2Y'
Formula (II) wherein, Y' represents a mo
Figure imgf000042_0002
and
Figure imgf000043_0001
wherein the Y' moiety can be optionally substituted by a substituent selected from the group consisting of alkyl, alkoxy, halogen and carboxy; and
A represents an X'-substituted aryl or heteroaryl ring wherein X' is selected from the group consisting of hydrogen, alkyl, aryl, amino, alkylamino. nitro, hydroxy, alkoxy, halogen, carboxyl, and carboxamido; provided that the YCH2 groups are aπanged eta or para to each other; and pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes thereof.
3. A compound according to claim 1 selected from the group consisting of : l-[4-(4- Acetyl- 1-piperazinomethy Opheny Imethyl]- 1 ,4,8, 11-tetraazacyclotetradecane pentahydrochloride;
1 -[4-( 1 ,4-Diazacycloheptan- 1 -ylmethy Ophenylmethy 1]- 1 ,4,8, 1 1 -tetraazacyclotetradecane hexahydrochloride; l-[4-(Azacycloheptan-l-ylmethyl)phenylmethyl]- 1,4,8,11-tetraazacyclotetradecane pentahydrochloride; l-[4-(l-Piperidinomethyl)phenylmethyl]- 1,4,8,11-tetraazacyclotetradecane pentahydrochloride;
1 -[4-( 1 -Mo holinomethy Ophenylmethy 1]- 1 ,4,8, 1 1 -tetraazacyclotetradecane pentahydrochloride; l-[4-(Azacyclotridecan-l-ylmethyl)phenylmethyl]- 1,4,8,11-tetraazacyclotetradecane pentahydrochloride; l-[4-(5,6, 14, 15-Dibenzo- 1 ,4-dioxa-8, 12-diazacyclopentadeca-5, 14-dien-8- y Imethy Ophenylmethyl]- 1,4,8,11-tetraazacyclotetradecane hexahydrochloride; 1 -[4-(l,4,7-Trioxa-10-azacyclododecan-10-ylmethy Opheny Imethyl]- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloride;
1 -[4-( 1 ,4,1, 10-Tetraoxa- 13-azacyclopentadecan- 13-ylmethyl)pheny Imethyl]- 1 ,4,8, 1 1 - tetraazacyclotetradecane pentahydrochloride;
1 -[4-( 1 ,4, 10-Trioxa-7, 13-diazacyclopentadecan-7-ylmethyl)phenylmethyl]- 1 ,4,8, 1 1 - tetraazacyclotetradecane hexahydrochloride; 1 - { 4-[4-(2-Pyridy I)- 1 -piperazinomethyljphenylmethy 1 }- 1 ,4,8, 11 -tetraazacyclotetradecane hexahydrochloride;
1 - { 4-[4-(2-Pyrimidyl)- 1 -piperazinomethyljphenylmethy 1 }- 1 ,4,8, 11 - tetraazacyclotetradecane hexahydrochloride; 1 -[4-(2-Guanidinobenzimidazol- 1 -ylmethyOphenylmethyl]- 1 ,4,8, 1 1- tetraazacyclotetradecane pentahydrochloride;
1 -[4-( 1 -PiperazinomethyOpheny Imethyl]- 1 ,4,8, 11 -tetraazacyclotetradecane hexahydrochloride;
1, 4-Bis-[4-( 1,4,8, 11 -tetraazacyclotetradecan- 1-y Imethy Opheny Imethy l]piperazine decahydrochloride; l-[4-( 1 ,5-Diazacyclooctan- 1 -ylmethyOphenylmethyl]- 1,4,8, 11-tetraazacyclotetradecane hexahydrochloride ; .
1 -(4- { Bis[2-(diethylamino)ethy l]aminomethyl J phenylmethyl)- 1 ,4,8, 1 1 - tetraazacyclotetradecane heptahydrochloride; 1 -(4- { [(2-Aminoethyl)(3-aminopropyl)amino]methyl] Jpheny Imethy 1)- 1,4,8,11- tetraazacyclotetradecane heptahydrochloride;
1 - { 4-[Di-(2-pyridy Oaminomethy ljphenylmethy 1 } - 1 ,4,8, 11 -tetraazacyclotetradecane pentahydrochloride; l-[4-(2-Thiazolylaminomethyl)phenylmethylj- 1 ,4,8, 11-tetraazacyclotetradecane pentahydrochloride;
1 -[3-(2-guanidinobenzimidazol- 1 -ylmethyOphenylmethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride;
1 -[4-(2-aminobenzimidazol- 1 -ylmethyOphenylmethyl]- 1 ,4,8, 11 -tetraazacyclotetradecane pentahydrochloride ; 1, 8-bis-[4-(l, 4,8, 1 1 -tetraazacyclotetradecan- 1-y ImethyOphenylmethyl]- 1, 4,8,11- tetraazacyclotetradecane dodecahydrobromide;
1,1 l-bis-[4-( 1,4,8,11 -tetraazacyclotetradecan- 1-y ImethyOphenylmethyl]- 1,4,8,11- tetraazacyclotetradecane dodecahydrobromide; l-[4-(N- { 3-(methy lamino)propy 1 }-N-methylaminomethyl)phenylmethyI]- 1,4,8,11- tetraazacyclotetradecane hexahydrochloride;
1 -[4-(N- { 3,4-methyienedioxyphenylmethyl } aminomethyl)phenylmethy 1]- 1 ,4,8, 1 1 - tetraazacyclotetradecane pentahydrochloride;
1 -[4-(N- { 3,5-difluorophenylmethyl JaminomethyOphenylmethyl]- 1 ,4,8, 1 1 - tetraazacyclotetradecane pentahydrochloride; 1 -[4-(phenothiazin- 10-ylmethyl)phenylmethy 1J- 1 ,4,8, 11 -tetraazacyclotetradecane pentahydrochloride;
1 -[4-(N- {4-amino-2-methylquinolin-6-yl JaminomethyOphenylmethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride; 1 -[4-(N- { 4-(2-guanidinothiazol-4-y Opheny 1 } aminomethyOpheny Imethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride;
1 -[4-(N- { 3-(2-guanidinothiazol-4-yl)phenyl } aminomethyOpheny Imethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride; l-[5-nitro-3-(N-{ 3-(2-thienyl)pyrazol-5-yl JaminomethyOphenylmethyl]- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloride; l-[5-nitro-3-(phenothiazin- 10-ylmethy Ophenylmethy 1]- 1 ,4,8, 1 1-tetraazacyclotetradecane pentahydrochloride;
1 -[3-(N- { 4-amino-2- methy lquinolin-6-y 1 } aminomethyl)-5-nitropheny Imethy 1]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride; 1 -[3-(N- { 4-(2-guanidinothiazol-4-yl)phenyl } aminomethy l)-5-nitrophenylmethyl]- 1 ,4,8, 11- tetraazacyclotetradecane pentahydrochloride; l-[3-(N-{3-(2-guanidinothiazol-4-yl)phenyl}aminomethyl)-5-nitrophenylmethylj- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloride;
1 -[5-bromo-3-(N- { 3-(2-thienyl)pyrazol-5-yl } aminomethyOpheny Imethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride; l-[5-bromo-3-(phenothiazin-10-ylmethyl)pheny Imethyl]- 1,4,8,11-tetraazacyclotetradecane pentahydrochloride;
1 -[3-(N- { 4-amino-2-methylquinolin-6-yl Jaminomethy l)-5-bromophenylmethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride; 1 -[5-bromo-3-(N-{4-(2-guanidinothiazol-4-yl)phenyl Jaminomethy Ophenylmethyl]-
1,4,8,11-tetraazacyclotetradecane pentahydrochloride;
1 -[5-bromo-3-(N-{3-(2-guanidinothiazol-4-yl)phenylJ aminomethyOpheny Imethy 1]-
1,4,8,11-tetraazacyclotetradecane pentahydrochloride;
1 -[3-(N- { 6-methyI-2-nitropheny 1 } aminomethyOpheny Imethy 1]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride; and
1 -[3-(N- { 3-(2-thienyl)pyrazol-5-yI JaminomethyOphenylmethyl]- 1 ,4,8, 1 1 - tetraazacyclotetradecane pentahydrochloride; l-[4-(N-{ l-methyl-3-(2-thienyl)pyrazol-5-yl JaminomethyOphenylmethyl]- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloride; l-[4-(N-{3-methylpyrazol-5-yl JaminomethyOphenylmethyl]- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloride;
1 -[4-(N- { 3-(4-methylphenyl)pyrazol-5-yl } aminomethyOpheny Imethy 1]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride; l-[4-(N-{3-(2-furyl)pyrazol-5-yl JaminomethyOphenylmethyl]- 1 ,4,8,11- tetraazacyclotetradecane pentahydrochloride;
1 -[3-(N- { 3-(4-methy lpheny l)pyrazol-5-yl } aminomethy Opheny Imethy 1]- 1 ,4,8, 1 1 - tetraazacyclotetradecane pentahydrochloride; l-[3-(N-{ l-methyl-3-phenylpyrazol-5-yl}aminomethyl)pheny Imethyl]- 1, 4,8,11- tetraazacyclotetradecane;
1 -[3-(N- { 3-(4-chloropheny 1)- 1 -methylpyrazol-5-y 1 } aminomethy Opheny Imethy I]- 1 ,4,8, 1 1 - tetraazacyclotetradecane;
1 -[3-(N- { 1 ,3-diphenylpyrazol-5-yl JaminomethyOphenylmethyl]- 1 ,4,8, 1 1 - tetraazacyclotetradecane; and 1 -[3-(N- { 3-(4-f-butylpheny 1)- 1 -methylpyrazol-5-y 1 Jaminomethy Ophenylmethyl]- 1 ,4,8, 1 1 - tetraazacyclotetradecane; and further pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes thereof.
4. A compound according to claim 3 selected from the group consisting of:
1, 8-bis-[4-(l, 4,8, 11 -tetraazacyclotetradecan- 1 -ylmethy Opheny Imethyl]- 1,4,8, 11- tetraazacyclotetradecane dodecahydrobromide;
1,1 l-bis-[4-( 1,4,8,11 -tetraazacyclotetradecan- 1 -ylmethy Opheny Imethy 1]-1 , 4,8,11- tetraazacyclotetradecane dodecahydrobromide ; 1 -[4-(N- { 4-amino-2-methy lquinolin-6-y 1 } aminomethy Opheny Imethy 1]- 1,4,8,11- tetraazacyclotetradecane pentahydrochloride;
1 -[4-(N- { 4-(2-guanidinothiazol-4-yl)pheny 1 } aminomethy Opheny Imethyl]- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloride;
1 -[4-(N- { 3-(2-guanidinothiazol-4-yl)pheny 1 } aminomethyOpheny Imethy I]- 1 ,4,8, 1 1 - tetraazacyclotetradecane pentahydrochloride;
1 -[5-nitro-3-(N- { 3-(2-thieny l)pyrazol-5-yl } aminomethyOpheny Imethy 1]- 1 ,4,8, 1 1 - tetraazacyclotetradecane pentahydrochloride;
1 -[5-nitro-3-(phenothiazin- 10-ylmethyl)phenylmethyl]- 1 ,4,8, 1 1 -tetraazacyclotetradecane pentahydrochloride; l-[3-(N-{ 4-(2-guanιdιnothιazol-4-yl)phenyl}amιnomethyl)-5-nιtrophenylmethylj- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloride; l-[3-(N-{ 3-(2-guanιdιnothιazol-4-yl)phenylJamιnomethyl)-5-nιtrophenylmethyl]- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloride; 1 -[5-bromo-3-(N- { 3-(2-thιeny i)pyrazol-5-y 1 JaminomethyOphenylmethyl]- 1 ,4,8, 1 1 - tetraazacyclotetradecane pentahydrochlonde,
1 -[3-(N- { 4-amιno-2-methylquιnolιn-6-yl Jaminomethy l)-5-bromophenylmethy 1]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride;
1 -[5-bromo-3-(N- { 4-(2-guanιdιnothιazol-4-y Ophenyl } aminomethy Ophenylmethyl]- 1,4,8,11-tetraazacyclotetradecane pentahydrochlonde;
1 -[5-bromo-3-(N- { 3-(2-guanιdιnothιazol-4-yl)phenyl } aminomethy Opheny lmethyl]-
1,4,8,11-tetraazacyclotetradecane pentahydrochlonde;
1 -[3-(N- { 3-(2-thιenyl)pyrazol-5-yl JaminomethyOphenylmethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloπde; 1 -[4-(N- { 3-methylpyrazol-5-yl Jaminomethy Ophenylmethy 1]- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochlonde;
1 -[4-(N- { 3-(4-methylphenyl)pyrazol-5-yl } aminomethyOpheny Imethy lj- 1,4,8, 1 1- tetraazacyclotetradecane pentahydrochlonde;
1 -[3-(N- { 3-(4-methy lpheny l)pyrazol-5-y 1 } aminomethy Opheny Imethy 1]- 1,4,8,11- tetraazacyclotetradecane pentahydrochlonde; l-[3-(N- { 3-(4-chloropheny 1)- 1 -methylpyrazol-5-yl } aminomethyOphenylmethyl]- 1 ,4,8, 11 - tetraazacyclotetradecane; and
1 -[3-(N- { 1 ,3-dιpheny lpyrazol-5-yl JaminomethyOphenylmethyl]- 1,4,8,11- tetraazacyclotetradecane; and further pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes thereof.
5. A compound according to claim 2 selected from the group consisting of l,4-Bis[2-(2-benzιmιdazolylamιno)-5,5-di(2-pyπdyl)-4-oxo-5H-ιmιdazolιn-3- ylmethyljbenzene bis-tπfluoroacetic acid salt,
2,6-Bιs[2-(2-benzιmιdazolylamιno)-5,5-dι(2-pyπdyl)-4-oxo-5H-ιmιdazolιn-3- ylmethyljpyπdine bis-tπfluoroacetic acid salt; and
1 ,4-Bιs { [ 1 -(2-Benzιmιdazolyl)- 1 -guanidinojmethyl } benzene, and further pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes thereof.
6. A compound according to claim 3 selected from the group consisting of: 1 -[4-(N- { 4-(2-guanidinothiazol-4-y Ophenyl } aminomethyOpheny Imethy 1]- 1 ,4,8, 1 1 - tetraazacyclotetradecane pentahydrochloride;
1 -[4-(N- { 3-(2-guanidinothiazol-4-y Opheny 1 } aminomethyOphenylmethy 1 J- 1 ,4,8, 11 - tetraazacyclotetradecane pentahydrochloride;
1 -[5-nitro-3-(N-{3-(2-thienyl)pyrazol-5-ylJ aminomethyOpheny Imethyl]- 1,4,8,1 1- tetraazacyclotetradecane pentahydrochloride;
1 -[5-bromo-3-(N- { 3-(2-thienyl)pyrazol-5-y 1 JaminomethyOphenylmethyl]- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloride; l-[5-bromo-3-(N-{4-(2-guanidinothiazol-4-yl)phenyl Jaminomethyl)phenylmethyI]-
1,4,8,11-tetraazacyclotetradecane pentahydrochloride; l-[3-(N-{3-(2-thienyl)pyrazol-5-yl JaminomethyOphenylmethyl]- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloride; l-[4-(N- { 3-(4-methylphenyl)pyrazol-5-y 1 } aminomethyOpheny Imethyl]- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloride; l-[3-(N-{3-(4-methylphenyl)pyrazol-5-yl JaminomethyOphenylmethyl]- 1,4,8, 11- tetraazacyclotetradecane pentahydrochloride; and l-[3-(N-{ 3-(4-chlorophenyl)-l-methylpyrazol-5-yl JaminomethyOphenylmethyl]- 1,4,8, 11- tetraazacyclotetradecane; and further pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes thereof.
7. A compound according to claim 6 selected from the group consisting of: 1 -[4-( 1 ,5-Diazacyclooctan- 1 -ylmethyOphenylmethyl]- 1 ,4,8, 1 1 -tetraazacyclotetradecane hexahydrochloride; l-[4-(2-GuanidinobenzimidazoI- 1 -ylmethyOphenylmethyl]- 1 ,4,8, 11- tetraazacyclotetradecane pentahydrochloride;
1 -[4-(5,6, 14, 15-Dibenzo- 1 ,4-dioxa-8, 12-diazacyclopentadeca-5, 14-dien-8- y ImethyOphenylmethyl]- 1,4,8,11-tetraazacyclotetradecane hexahydrochloride; 1 -[4-(Azacyclotridecan- 1 -ylmethyOphenylmethyl]- 1 ,4,8, 1 1 -tetraazacyclotetradecane pentahydrochloride; and
1 -[4-( 1 ,4-Diazacycloheptan- 1 - lmethyOphenylmethyl]- 1 ,4,8, 11 -tetraazacyclotetradecane hexahydrochloride; and further pharmaceutically acceptable salts, hydrates, solvates. esters and metal complexes thereof.
8. A method of antagonizing a CXCR-4 receptor by administering a compound according to claim 1.
9. A method of antagonizing a CXCR-4 receptor by administering a compound according to claim 2.
10. A pharmaceutical composition comprising a suitable pharmaceutical caπier and a compound according to claim 1.
11. A pharmaceutical composition comprising a suitable pharmaceutical carrier and a compound according to claim 2.
12. A compound according to any one of claims 1 to 7 for use as an active therapeutic substance.
13. Use of a compound according to claim 1 in the manufacture of a medicament for use in treating thrombocytopenia.
14. Use of a compound according to claim 2 in the manufacture of a medicament for use in treating thrombocytopenia.
15. A method of agonizing the TPO receptor in a subject which comprises administering an effective amount of a compound according to claim 1.
16. A method of agonizing the TPO receptor in a subject which comprises administering an effective amount of a compound according to claim 2.
17. Use of a compound according to claim 1 in the manufacture of a medicament for use in antagonizing the CXCR-4 receptor.
18. Use of a compound according to claim 2 in the manufacture of a medicament for use in antagonizing the CXCR-4 receptor.
19. A method of treating a CXCR-4-mediated disease comprising administering to a patient in need of treatment a safe and effective amount of a compound according to claim 1 or claim 2.
20. A method according to claim 8 or claim 9 wherein the disease is selected from the group consisting of bacterial, fungal and protozoan infections, pain, cancer, thrombocytopenia, diabetes, obesity, anorexia, bulimia, asthma, allergies, Parkinson's disease, acute heart failure, hypotension, hypertension, neural damage, atherosclerosis, urinary retention, osteoporosis, angina pectoris, myocardial infarction, stroke, ulcers, benign prostatic hypertrophy, migraine, angiogenesis, vomiting, psychotic and neurological disorders, dyskinesias, viral infections, and spinal cord-related injury.
21. A method according to claim 19 wherein the disease is a neurological disease selected from the group consisting of anxiety, schizophrenia, manic depression, depression, delirium, dementia, mental retardation, Huntington's disease and Gilles de la Tourette's syndrome.
22. A method according to claim 19 wherein the disease is a viral infection selected from HIV infection exhibiting clinical signs of AIDS and asymptomatic HIV infection.
23. A method according to claim 19 wherein the disease is an injury to the spinal cord.
PCT/US2000/011951 1999-05-03 2000-05-03 Cxcr-4 receptor antagonists - thrombopoietin mimetics WO2000066112A1 (en)

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