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EP1189609A1 - Antagonistes du recepteur cxcr-4 et mimetiques de thrombopoietine - Google Patents

Antagonistes du recepteur cxcr-4 et mimetiques de thrombopoietine

Info

Publication number
EP1189609A1
EP1189609A1 EP00928735A EP00928735A EP1189609A1 EP 1189609 A1 EP1189609 A1 EP 1189609A1 EP 00928735 A EP00928735 A EP 00928735A EP 00928735 A EP00928735 A EP 00928735A EP 1189609 A1 EP1189609 A1 EP 1189609A1
Authority
EP
European Patent Office
Prior art keywords
tetraazacyclotetradecane
pentahydrochloride
imethy
pyrazol
compound according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00928735A
Other languages
German (de)
English (en)
Other versions
EP1189609A4 (fr
Inventor
Juan I. Luengo
Alan Thomas Price
Antony Shaw
Kenneth Wiggall
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP1189609A1 publication Critical patent/EP1189609A1/fr
Publication of EP1189609A4 publication Critical patent/EP1189609A4/fr
Withdrawn legal-status Critical Current

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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.

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Abstract

La présente invention concerne des dérivés du cyclam substitués, des compositions pharmaceutiques contenant ces composés, et l'utilisation de ces composés et tant qu'antagonistes du récepteur CXCR-4 et en tant que mimétiques de thrombopoïétine (TPO).
EP00928735A 1999-05-03 2000-05-03 Antagonistes du recepteur cxcr-4 et mimetiques de thrombopoietine Withdrawn EP1189609A4 (fr)

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