[go: up one dir, main page]

WO2008021788A2 - Composés de polyamine - Google Patents

Composés de polyamine Download PDF

Info

Publication number
WO2008021788A2
WO2008021788A2 PCT/US2007/075265 US2007075265W WO2008021788A2 WO 2008021788 A2 WO2008021788 A2 WO 2008021788A2 US 2007075265 W US2007075265 W US 2007075265W WO 2008021788 A2 WO2008021788 A2 WO 2008021788A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
deleted
heteroaryl
amino
pyridin
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.)
Ceased
Application number
PCT/US2007/075265
Other languages
English (en)
Other versions
WO2008021788A3 (fr
Inventor
Chi-Feng Yen
Chien-Huang Wu
Ying-Huey Huang
Chi-Hsin Richard King
Shu-Jen Chen
Hua-Chien Chen
Gholam Hossein Hakimelahi
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.)
TaiGen Biotechnology Co Ltd
Original Assignee
TaiGen Biotechnology Co Ltd
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 TaiGen Biotechnology Co Ltd filed Critical TaiGen Biotechnology Co Ltd
Publication of WO2008021788A2 publication Critical patent/WO2008021788A2/fr
Publication of WO2008021788A3 publication Critical patent/WO2008021788A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines

Definitions

  • Chemokines are a family of cytokines that regulate the adhesion and transendothelial migration of leukocytes during an immune or inflammatory reaction (Mackay C.R., Nat. Immunol., (2001) 2:95; Olson et al., Am. J. Physiol. Regul. Integr. Comp. Physiol., (2002) 283:R7). Chemokines also regulate T cells and B cells trafficking and homing, and contribute to the development of lymphopoietic and hematopoietic systems (Ajuebor et al., Biochem. Pharmacol., (2002) 63:1191). Approximately 50 chemokines have been identified in humans.
  • CXC CX3C
  • CC C chemokines
  • the biological functions of chemokines are mediated by their binding and activation of G protein-coupled receptors (GPCRs) on the cell surface.
  • GPCRs G protein-coupled receptors
  • CXCR4 receptor for example, it can be activated by Stromal-derived factor-1 or SDF-I, a member of CXC chemokines.
  • SDF-I was originally cloned from bone marrow stromal cell lines and found to act as a growth factor for progenitor B cells (Nishikawa et al., Eur. J. Immunol., (1988) 18:1767). SDF-I also induces bone marrow colonization of hematopoietic precursor cells during embryogenesis (Bleul et al., J. Exp. Med., (1996) 184:1101). The physiological function of SDF-I is mediated by CXCR4 receptor.
  • mice lacking SDF-I or CXCR4 receptor show lethal abnormality in bone marrow myelopoiesis, B cell lymphopoiesis, and cerebellar development (Nagasawa et al., Nature, (1996) 382:635; Ma et al., Proc. Natl. Acad. Sci., (1998) 95:9448; Zou et al., Nature (1998) 393:595; Lu et al., Proc. Natl. Acad. Sci. (2002) 99:7090).
  • CXCR4 receptor is expressed broadly in a variety of tissues, particularly in immune and central nervous systems, and has been described as the major co-receptor for HIV- 1/2 on T lymphocytes.
  • CXCR4 receptor and SDF-I are also involved in other pathological conditions such as rheumatoid arthritis, asthma, and tumor metastases (Buckley et al., J. Immunol., (2000) 165:3423).
  • CXCR4 receptor and SDF-I are also found widely expressed in many tissues during embryonic development.
  • the CXCR4/SDF-1 pathway has been shown to be critically involved in the regeneration of several tissue injury models. Specifically, it has been found that the SDF-I level is elevated at an injured site and CXCR4-positive cells actively participate in the tissue regenerating process.
  • this invention is based on the unexpected discovery that the polyamine compounds described below, either alone or in combination of granulocyte-colony stimulating factor (G- CSF), promote step/progenitor cell mobilization via blocking of the interaction between chemokine receptors (e.g., CXCR3 and CXCR4) and their ligands (e.g., SDF-I).
  • G- CSF granulocyte-colony stimulating factor
  • this invention features polyamine compounds of the formula:
  • Rj is H, Ci-Ci 0 alkyl, C 2 -Ci 0 alken
  • B 1 , B 2 , and B 3 independently, is -NR-, -CH 2 -, or deleted.
  • Each Of E 1 , E 2 , and E 3 is H, C 1 - C 1 O alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 8 cycloalkyl, Cs-C 8 cycloalkenyl, C 3 -C 8 heterocycloalkyl, C 5 -C 8 heterocycloalkenyl, aryl, or heteroaryl.
  • Each R independently, is H or C 1 -C 10 alkyl.
  • a subset of the just-described compounds are those in which X is -CH 2 - or -CH(CH 3 )-, Y is phenyl or 4,4'-biphenyl, Z 1 is -CH 2 - or -SO 2 -, Z 2 is -CH 2 - or -SO 2 -, or R 3 is deleted.
  • alkyl refers to a saturated, linear or branched, non-aromatic hydrocarbon moiety, such as CH 3 , -CH 2 -, or branched C 3 H 7 . Referring to the above formula, -C 2 H 4 - and -C 3 H 6 - can be either linear or branched.
  • alkynyl refers to a linear or branched, non-aromatic hydrocarbon moiety having at least one triple bond, such as -C ⁇ CH or -C ⁇ C-.
  • cycloalkyl refers to a saturated non- aromatic cyclic hydrocarbon moiety.
  • cycloalkenyl refers to a non-aromatic cyclic hydrocarbon moiety having at least one double bond in the ring.
  • heterocycloalkyl refers to a saturated non-aromatic cyclic moiety having at least one ring heteroatom (e.g., O, N, and S).
  • heterocycloalkenyl refers to a non-aromatic cyclic moiety having at least one ring heteroatom and at least one double bond in the ring.
  • aryl refers to a hydrocarbon moiety having at least one aromatic ring.
  • aryl moiety examples include phenyl, phenylene, biphenyl, naphthyl, naphthylene, pyrenyl, anthryl, and phenanthryl.
  • heteroaryl refers to a moiety having at least one aromatic ring which contains at least one heteroatom. Examples of a heteroaryl moiety include furyl, furylene, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, and indolyl.
  • Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl mentioned herein include both substituted and unsubstituted moieties.
  • substituents for cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl include C 1 -C 1O alkyl, C 2 -C 10 alkenyl, C 2 -C 1O alkynyl, C 3 -C 8 cycloalkyl, C 5 - C 8 cycloalkenyl, Ci-C 10 alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C 1 -Ci 0 alkylamino, C]-C 20 dialkylamino, arylamino, diarylamino, heteroarylamino, diheteroarylamino, Ci-Cio alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, Ci-Cio alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, hydroxy
  • substituents for alkyl, alkenyl, and alkynyl include all of the above substitutents except Ci-Ci 0 alkyl, C 2 -CiO alkenyl, and C 2 -Ci 0 alkynyl.
  • Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl also include fused groups.
  • this invention features polyamine compounds of the same formula shown above.
  • a subset of the just-described compounds are those in which X is -CH 2 - or -CH(CH 3 )-, Y is deleted, Zi is -CH 2 -, or Z 2 is -CH 2 -.
  • this invention features a method for treating an inflammatory or immune disease, a developmental or degenerative disease, or a tissue injury.
  • the method includes administering to a subject in need thereof an effective amount of one or more compounds of the same formula shown above.
  • Each of B 1 , B 2 , and B 3 is -NR-, -CH 2 -, or deleted.
  • Each of Ei, E 2 , and E 3 is H, C 1 -Ci 0 alkyl, C 2 -Ci 0 alkenyl, C 2 -Ci 0 alkynyl, C 3 -C 8 cycloalkyl, C 5 -C 8 cycloalkenyl, C 3 -C 8 heterocycloalkyl, C 5 -C 8 heterocycloalkenyl, aryl, or heteroaryl.
  • Each R independently, is H or Ci-C 10 alkyl.
  • E 3 can be phenyl optionally substituted with halo or OR', benzoimidazole optionally substituted with OR', indole optionally substituted with Ci-Ci 0 alkyl, cyclopentyl fused with phenyl, piperidinyl substituted with aryl or OR', piperidinyl fused with Ci-C 10 alkyl substituted indole, or pyrrolidinyl substituted with Ci-Ci 0 alkyl, in which R' is H or Ci-Ci 0 alkyl.
  • Treatment refers to administering one or more polyamine compounds to a subject, who has a disease described herein, a symptom of such a disease, or a predisposition toward such a disease, with the purpose to confer a therapeutic effect, e.g., to cure, relieve, alter, affect, ameliorate, or prevent the above-described disease, the symptom of it, or the predisposition toward it.
  • An inflammatory disease is characterized by a local or systemic, acute or chronic inflammation.
  • inflammatory retinopathy e.g., diabetic retinopathy
  • dermatoses e.g., dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria, necrotizing vasculitis, cutaneous vasculitis, hypersensitivity vasculitis, eosinophilic myositis, polymyositis, dermatomyositis, and eosinophilic fasciitis
  • inflammatory bowel diseases e.g., Crohn's disease and ulcerative colitis
  • hypersensitivity lung diseases e.g., hypersensitivity pneumonitis, eosinophilic pneumonia, delayed-type hypersensitivity, interstitial lung disease or ILD, idiopathic pulmonary fibrosis, and ILD associated with rheumatoid arthritis
  • asthma and allergic rhinitis.
  • the compounds are preferably administered to an eye of the subject.
  • a polyamine compound in a solution can be injected into an eye (e.g., into its vitreal space).
  • the compound can be topically administered to an eye, such as dropped into the eye in the form of an eye drop or applied to an area around the eye in the form of an ointment.
  • An immune disease is characterized by a hyper- or hypo-reaction of the immune system.
  • autoimmune diseases e.g., rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes, glomerulonephritis, autoimmune throiditis, ankylosing spondylitis, systemic sclerosis, and multiple sclerosis
  • acute and chronic inflammatory diseases e.g., systemic anaphylaxia or hypersensitivity responses, drug allergies, insect sting allergies, graft rejection, including allograft rejection, and graft- versus-host disease
  • Sjogren's syndrome human immunodeficiency virus infection, cancer (e.g., brain, breast, prostate, colon, kidney, ovary, thyroid, lung, and haematopoietic cancer), and tumor metastasis.
  • Degenerative diseases are growth or differentiation related disorders that lead to loss- of- function or gain-of- function.
  • Degenerative diseases generally refer to change of a tissue to a lower or less functional form. Examples of a developmental or degenerative disease include spinal muscular atrophy, Duchenne muscular dystrophy, Parkinson's disease, and Alzheimer's disease.
  • Tissue injuries can be caused by oxidative stress (e.g., ischemia-reperfusion in stroke or myocardial infarction), complement activation, graft rejection, chemicals (e.g., alcohol-induced liver damage or mucosal tissue injuries in cancer therapy), viral infection (e.g., glomerular injuries associated with hepatitis C infection), and mechanical forces (e.g., sports injury).
  • tissue injuries include brain injury, heart injury, liver damage, skeletal muscle injury, kidney damage, pancreatic injury, lung injury, skin injury, and gastrointestinal tract injury.
  • this invention features a method of treating retinopathy by administering to an eye of a subject in need thereof an effective amount of one or more compounds of the formula shown above.
  • Retinopathy a non-inflammatory disease of the retina, includes diabetic retinopathy, proliferative retinopathy, age-related macular degeneration, macular edema, corneal neovascularization, and iris neovascularization.
  • the one or more compounds can be applied to an eye, i.e., directly applied to an eye or applied near an eye and let them diffuse to the eye.
  • the polyamine compounds can be used to treat diseases associated with edema or angiogenesis.
  • tissue damage refers to a tissue or organ injury caused by loss of a certain type or types of cells (e.g., islet cells, neural lineage cells, hepatic cells, muscle cells, blood cells, and epithelial cells), resulting in dysfunction of the tissue or organ.
  • the term "repair tissue damage” refers to full or partial restoration of the function of the tissue/organ where damage has taken place.
  • Tissue damage can be caused by various diseases, including degenerative disease (e.g., Alzheimer's disease, Parkison's disease, osteoarthritis, and osteoporosis), tissue ischemia (e.g., cardiac ischemia, limb ischemia, nerve ischemia, liver ischemia, kidney ischemia, pancreatic ischemia, lung ischemia, and intestine ischemia), and autoimmune disease (e.g., type I diabetes, systemic lupus erythematosus, Sjogren's syndrome, Hashimoto's thyroiditis, Graves' disease, and rheumatoid arthritis.) These compounds can also be used to treat the just-mentioned underlining diseases themselves.
  • degenerative disease e.g., Alzheimer's disease, Parkison's disease, osteoarthritis, and osteoporosis
  • tissue ischemia e.g., cardiac ischemia, limb ischemia, nerve ischemia, liver ischemia, kidney ischemia,
  • a subject in need of treatment of an above-described disease or in need of repair of tissue damage can also be concurrently administered with a polyamine compound described above and one or more other therapeutic agents.
  • a therapeutic agent include a G-CSF growth factor, a steroidal or a non-steroidal anti-inflammatory drug, a COX2 inhibitor, a leukotriene receptor inhibitor, a prostaglandin modulator, a TNF modulator, and an immunosuppressive agent (e.g., cyclosporine A).
  • the term "concurrently administered” refers to administering a polyamine compound and one or more other therapeutic agents at the same time or at different times during the period of treatment.
  • this invention features a method for enhancing migration of bone marrow-derived cells to blood.
  • the method includes administering to a subject in need thereof an effective amount of one or more compounds of the same formula shown above. Referring to this formula, the same groups as those described above are assigned to each variable.
  • the term "bone marrow-derived cells” refers to cells originating from bone marrow. Examples of bone marrow-derived cells include, but are not limited to, CD34+ cells and CD133+ cells.
  • a pharmaceutical composition that contains an effective amount of at least one of the above-mentioned polyamine compounds and a pharmaceutically acceptable carrier.
  • the polyamine compounds described above include the compounds themselves, as well as their salts, prodrugs, and solvates, if applicable.
  • a salt for example, can be formed between an anion and a positively charged group (e.g., amino) on a polyamine compound. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate.
  • a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a polyamine compound.
  • Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion.
  • the polyamine compounds also include those salts containing quaternary nitrogen atoms.
  • prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing active polyamine compounds.
  • a solvate refers to a complex formed between an active polyamine compound and a pharmaceutically acceptable solvent.
  • pharmaceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine.
  • compositions containing one or more of the polyamine compounds described above for use in treating an above-described disease, and the use of such a composition for the manufacture of a medicament for the just-mentioned treatment.
  • polyamine compounds described in the summary section above can be prepared by methods well known in the art, including the synthetic routes disclosed herein.
  • compound 1-11 can be respectively prepared by reacting tris(2- aminoethyl)amine with three equivalent amounts of a corresponding aldehyde, and followed by a reduction reaction using sodium borohydride.
  • the reaction mixture is subsequently treated with hydrochloric acid to give an intermediate, l,4-di[bis(2-aminoethyl)aminomethyl]benzene.
  • This intermediate can react with four equivalent amounts of corresponding aldehyde compounds and sodium borohydride to give compounds 12-14.
  • this intermediate can react with two equivalent amounts of pyridine-2-carbaldehyde, and then with sodium borohydride to give compound 15.
  • Compounds 56-57, 65, 66, 68, 80, 86, 91, 93-95, 106-109, 141, and 142 can be prepared through this synthetic route, followed by sequential treatments with hydrochloric acid, two equivalent amounts of a corresponding aldehyde, and sodium borohydride.
  • compounds 49 can be prepared by reacting 1,4-dibromoxylene with one equivalent amount of tri-f- butoxycarbonyl protected cyclam and one equivalent amount of bis(2-pyridiyliminoethyl)amine, followed by a reduction reaction using sodium borohydride.
  • compounds 16-48, 58-64, 69-79, 81-85, 87-90, 92, 96-105, 115, 121, 122, and 125-141 can be synthesized using the following synthetic route.
  • This benzonitrile can then be treated sequentially with two equivalent amounts of an aldehyde, sodium borohydride, and diisobutylaluminum to form 4-[bis(2-substituted-aminoethyl)amino- methylj-benzaldehyde.
  • the just-mentioned compounds can then be prepared by treating this benzaldehyde sequentially with one equivalent amount of a corresponding amine, sodium borohydride, and hydrochloric acid.
  • Compounds 110, 111, 116, 117, 120, 123, and 124 can be prepared in a similar manner except that the benzonitrile is treated with one equivalent amount of an aldehyde and one equivalent amount of a ketone.
  • An intermediate is then obtained after treating the above reaction mixture with hydrochloric acid.
  • Compounds 51-55 can then be respectively prepared by treating this intermediate with a corresponding aldehyde and followed with sodium borohydride.
  • Compounds 50, 67, 112, and 113 can be prepared using the same procedure as that of compounds 51-55 except that 4-bromomethylbenzenesulfonyl chloride is treated with two equivalent amounts of bis(t-butoxycarbonylaminoethyl)amine.
  • the benzonitrile can be sequentially mesylated and treated with 2- aminomethylpyridine.
  • the benzonitrile can then be treated with diisobutylaluminum, one equivalent amount of a corresponding amine, sodium borohydride, triflic acid, and hydrochloric acid to obtain compounds 114, 118, and 119.
  • a polyamine compound thus synthesized can be further purified by a method such as column chromatography, high-pressure liquid chromatography, or recrystallization.
  • polyamine compounds can be prepared using other suitable starting materials through the above synthetic routes and others known in the art.
  • the methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the polyamine compounds.
  • various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
  • Synthetic chemistry transformations and protecting group methodologies useful in synthesizing applicable polyamine compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2 nd Ed., John Wiley and Sons (1991); L.
  • polyamine compounds mentioned herein may contain a non-aromatic double bond and one or more asymmetric centers. Thus, they can occur as racemates and racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans- isomeric forms. All such isomeric forms are contemplated.
  • a pharmaceutical composition contains an effective amount of at least one polyamine compound described above and a pharmaceutical acceptable carrier. Further, this invention covers a method of administering an effective amount of one or more of the polyamine compounds to a patient having a disease described in the summary section above. This invention also covers a method of administering an effective amount of one or more of the polyamine compounds for enhancing migration of bone marrow- derived cells to blood.
  • “An effective amount” refers to the amount of an active polyamine compound that is required to confer a therapeutic effect on the treated subject. Effective doses will vary, as recognized by those skilled in the art, depending on the types of diseases treated, route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatment.
  • a composition having one or more polyamine compounds can be administered parenterally, enterally (e.g., orally, nasally, and rectally), topically, or buccally.
  • parenteral refers to subcutaneous, intracutaneous, intravenous, intrmuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection, as well as any suitable infusion technique.
  • the compounds also can be administered intravitreally.
  • a sterile injectable composition can be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are mannitol, water, Ringer's solution, and isotonic sodium chloride solution.
  • fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or diglycerides).
  • Fatty acid, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions can also contain a long chain alcohol diluent or dispersant, carboxymethyl cellulose, or similar dispersing agents.
  • Other commonly used surfactants such as Tweens or Spans or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purpose of formulation.
  • a composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions.
  • commonly used carriers include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • a nasal aerosol or inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation.
  • such a composition can be prepared as a solution in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • a composition having one or more active polyamine compounds can also be administered in the form of suppositories for rectal administration.
  • the carrier in the pharmaceutical composition must be "acceptable” in the sense that it is compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject to be treated.
  • One or more solubilizing agents can be utilized as pharmaceutical excipients for delivery of an active polyamine compound.
  • examples of other carriers include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow # 10.
  • polyamine compounds described above can be preliminarily screened for their efficacy in treating above-described diseases by an in vitro assay (See Examples 144-146 below) and then confirmed by animal experiments and clinic trials. Other methods will also be apparent to those of ordinary skill in the art. Applicants have found that the polyamine compounds, acting as the antagonists of chemokine CXCR4, compete against its ligand SDF-I for binding to the receptor and thus block CXCR4/SDF-1 signaling, which is important in the mobilization/homing of stem and progenitor cells. Without being bound by theory, the polyamine compounds may act through the following mechanisms in treating and repairing tissue damage.
  • the polyamine compounds promote the mobilization of stem and progenitor cells from bone morrow, a reservoir of stem/progenitor cells, to the peripheral blood. More specifically, as SDF-I is highly expressed in bone marrow, stem and progenitor cells, expressing CXCR4, are trapped in bone morrow via CXCR4-SDF-1 interaction. By blocking this interaction, the polyamine compounds release stem and progenitor cells from bone marrow to the peripheral blood. While circulating in the blood, stem and progenitor cells home to tissues and organs where damage has occurred and repair the damage by differentiating into the type of cells, the loss of which has caused the damage.
  • SDF-I In the condition of retinopathy, SDF-I is highly expressed in vitreous. Binding to CXCR4 expressed in stem and progenitor cells, SDF-I facilitates these cells to migrate to the retina, resulting in neovascularization, which plays an essential role in retinopathy development and progression. Also by blocking CXCR4/SDF-1 signaling, the polyamine compounds prevent stem and progenitor cells homing to the retina, thus effectively treating retinopathy. The compounds can be applied topically to an eye of a retinopathy patient. Unlike systemic applications, topical application does not mobilize stem/progenitor cells out of bone marrow and therefore does not help the homing of these cells into retina.
  • Example 1 Preparation of compound 1: N-(4-fluoro-benzyl)-N',N'-bis-[2-(4-fluoro- benzylamino)-ethyl]-ethane-l,2-diamine Tris(2-aminoethyl)amine (0.01 mol) and 4-fluoro-benzaldehyde (0.03 mol) were dissolved in MeOH (50 mL). After stirring at 25 0 C for 15 h, NaBH 4 (1.90 g, 0.05 mol) was added to the above solution at O 0 C. The reaction mixture was stirred for 2 h at 25 0 C.
  • Example 2 Preparation of compound 2: N-(3-trifluoromethyl-benzyl)-N',N'-bis-[2-(3- trifluoromethyl-benzylamino)-ethyl] -ethane- 1 ,2-diamine Compound 2 was prepared in a manner similar to that described in Example 1.
  • Example 3 Preparation of compound 3: N-(3,4-difluoro-benzyl)-N',N'-bis-[2-(3,4-difluoro- benzylamino)-ethyl]-ethane-l,2-diamine Compound 3 was prepared in a manner similar to that described in Example 1.
  • Example 4 Preparation of compound 4: N-benzyl-N',N'-bis-(2-benzylamino-ethyl)-ethane-l,2- diamine Compound 4 was prepared in a manner similar to that described in Example 1.
  • Example 5 Preparation of compound 5: N-(2-chloro-4-fluoro-benzyl)-N',N'-bis-[2-(2-chloro-4- fluoro-benzylamino)-ethyl] -ethane- 1 ,2-diamine Compound 5 was prepared in a manner similar to that described in Example 1.
  • Example 6 Preparation of compound 6: N-(2-fluoro-benzyl)-N',N'-bis-[2-(2-fluoro- benzylamino)-ethyl] -ethane- 1 ,2-diamine Compound 6 was prepared in a manner similar to that described in Example 1.
  • Example 8 Preparation of compound 8: N-naphthalen-l-ylmethyl-N',N'-bis- ⁇ 2-[(naphthalen-l- ylmethyl)-amino]-ethyl ⁇ -ethane-l,2-diamine
  • Example 10 Preparation of compound 10: N-(lH-indol-6-ylmethyl)-N',N'-bis- ⁇ 2-[(lH-indol-6- ylmethyl)-amino]-ethyl ⁇ -ethane-l,2-diamine
  • Example 11 Preparation of compound 11: N-(l-methyl-lH-pyrrol-2-ylmethyl)-N',N'-bis- ⁇ 2-[(l- methyl-lH-pyrrol-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2-diamine
  • Example 12 Preparation of compound 12: N-[4-( ⁇ bis-[2-(2-fluoro-benzylamino)-ethyl]-amino ⁇ - methyl)-benzyl]-N'-(2-fluoro-benzyl)-N-[2-(2-fluoro-benzylamino)-ethyl]-ethane-l,2-diamine
  • 1,4-Dibromoxylene (0.012 mol) was treated with bis(tert-butoxyaminoethyl)amine (0.024mol) in the presence of K 2 CO 3 (0.5 mol) in CH 3 CN (60 mL) at 60 0 C. After stirring for 12 h, the solution was allowed to cool down to room temperature, filtered, and concentrated. The concentrate was then treated with HCl/ether and neutralized with K 2 CO 3 to afford 1,4- di[bis(2-aminoethyl)amino-methyl]benzene quantitatively.
  • Example 13 Preparation of compound 13: N-[4-( ⁇ bis-[2-(4-fluoro-benzylamino)-ethyl]-amino ⁇ - methyl)-benzyl]-N'-(4-fluoro-benzyl)-N-[2-(4-fluoro-benzylamino)-ethyl]-ethane-l,2-diamine Compound 13 was prepared in a manner similar to that described in Example 12.
  • Example 14 Preparation of compound 14: N- ⁇ 4-[(bis- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ - amino)-methyl]-benzyl ⁇ -N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ - ethane- 1,2-diamine
  • Compound 14 was prepared in a manner similar to that described in Example 12.
  • Example 15 Preparation of compound 15: N-(2-amino-ethyl)-N- ⁇ 4-[((2-amino-ethyl)- ⁇ 2- [(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -amino)-methyl]-benzyl ⁇ -N'-pyridin-2-ylmethyl-ethane-l,2- diamine l,4-Di[bis(2-aminoethyl)amino-methyl]benzene (0.01 mol) and pyridine-2-carbaldehyde (0.02 mol) were dissolved in MeOH (40 mL).
  • Example 16 Preparation of compound 16: N-(4-fluoro-benzyi)-N'-[2-(4-fluoro-benzylamino)- ethyl] -N'- ⁇ 4- [(4-fluoro-benzylamino)-methyl] -benzyl ⁇ -ethane- 1,2-diamine
  • Example 17 Preparation of compound 17: N- ⁇ 4-[(3-imidazol-l-yl-propylamino)-methyl]- benzyl ⁇ -N '-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino] -ethyl ⁇ -ethane- 1 ,2-diamine Compound 17 was prepared in a manner similar to that described in Example 16. LC/MS (M + +l): 513.
  • Example 18 Preparation of compound 18: l-( ⁇ 4-[(bis- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ - amino)-methyl]-benzylamino ⁇ -methyl)-cyclohexanol
  • Example 19 Preparation of compound 19: N- ⁇ 4-[(3-morpholin-4-yl-propylamino)-methyl]- benzyl ⁇ -N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2-diamine Compound 19 was prepared in a manner similar to that described in Example 16. LC/MS (M + +l): 532.
  • Example 20 Preparation of compound 20: N-(4- ⁇ [2-(2,5-dimethoxy-phenyl)-ethylamino]- methyl ⁇ -benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino] -ethyl ⁇ -ethane- 1,2- diamine
  • Compound 20 was prepared in a manner similar to that described in Example 16.
  • Example 21 Preparation of compound 21: N-(4- ⁇ [2-(4-fluoro-phenyl)-l,l-dimethyl- ethylamino]-methyl ⁇ -benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ - ethane- 1 ,2-diamine
  • Example 22 Preparation of compound 22: N-(4- ⁇ [2-(3-fluoro-phenyl)-ethylamino]-methyl ⁇ - benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2-diamine Compound 21 was prepared in a manner similar to that described in Example 16. LC/MS (M + +l): 527.
  • Example 23 Preparation of compound 23: N-(4- ⁇ [(lH-3-methoxybenzoimidazol-2-ylmethyl)- amino]-methyl ⁇ -benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ - ethane-l,2-diamine
  • Compound 23 was prepared in a manner similar to that described in Example 16.
  • Example 24 Preparation of compound 24: N-pyridin-2-ylmethyl-N'- ⁇ 2-[(pyridin-2-ylmethyl)- amino] -ethyl ⁇ -N'-(4- ⁇ [(pyridin-2-ylmethyl)-amino] -methyl ⁇ -benzyl)-ethane- 1 ,2-diamine
  • Compound 24 was prepared in a manner similar to that described in Example 16.
  • Example 26 Preparation of compound 26: N-(3,4-difluoro-benzyl)-N'-[2-(3,4-difluoro- benzylamino)-ethyl]-N'-(4- ⁇ [(pyridin-2-ylmethyl)-amino]-methyl ⁇ -benzyl)-ethane-l,2-diamine
  • Example 27 Preparation of compound 27: N-(4-fluoro-benzyl)-N'-[2-(4-fluoro-benzylamino)- ethyl]-N'-(4- ⁇ [(pyridin-2-ylmethyl)-amino]-methyl ⁇ -benzyl)-ethane-l,2-diamine
  • Example 28 Preparation of compound 28: N-(4-chloro-benzyl)-N'-[2-(4-chloro-benzylamino)- ethyl] -N'-(4- ⁇ [(pyridin-2-ylmethyl)-amino] -methyl ⁇ -benzyl)-ethane-l ,2-diamine
  • Example 29 Preparation of compound 29: N-(4- ⁇ [2-(3-chloro-phenyl)-ethylamino]-methyl ⁇ - benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2-diamine
  • Compound 29 was prepared in a manner similar to that described in Example 16.
  • Example 30 Preparation of compound 30: N-(4- ⁇ [2-(4-chloro-phenyl)-ethylamino] -methyl ⁇ - benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2-diamine
  • Compound 30 was prepared in a manner similar to that described in Example 16.
  • Compound 31 was prepared in a manner similar to that described in Example 16.
  • Example 32 Preparation of compound 32: N-(4- ⁇ [2-(lH-indol-3-yl)-ethylamino]-methyl ⁇ - benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2-diamine
  • Compound 32 was prepared in a manner similar to that described in Example 16.
  • Example 33 Preparation of compound 33: N-(4- ⁇ [2-(5-fluoro-lH-indol-3-yl)-ethylamino]- methyl ⁇ -benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2- diamine
  • Example 34 Preparation of compound 34: N-(4- ⁇ [2-(5-methoxy-lH-indol-3-yl)-ethylamino]- methyl ⁇ -benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2- diamine
  • Compound 34 was prepared in a manner similar to that described in Example 16.
  • Example 35 Preparation of compound 35: N-(4- ⁇ [2-(6-methoxy-lH-indol-3-yl)-ethylamino]- methyl ⁇ -benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2- diamine Compound 35 was prepared in a manner similar to that described in Example 16.
  • Example 36 Preparation of compound 36: N-(4- ⁇ [2-(7-methyl-lH-indol-3-yl)-ethylamino]- methyl ⁇ -benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridm-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2- diamine
  • Example 37 Preparation of compound 37: N- ⁇ 4-[(2-cyclohex-l-enyl-ethylamino)-methyl]- benzyl ⁇ -N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2-diamine Compound 37 was prepared in a manner similar to that described in Example 16.
  • Example 38 Preparation of compound 38: N- ⁇ 4-[(lH-indol-5-ylamino)-methyl]-benzyl ⁇ -N'- pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2-diamine Compound 38 was prepared in a manner similar to that described in Example 16.
  • Example 39 Preparation of compound 39: 2- ⁇ 4-[(bis- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ - amino)-methyl]-benzylamino ⁇ -4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester
  • Compound 39 was prepared in a manner similar to that described in Example 16.
  • Example 40 Preparation of compound 40: N-(4- ⁇ [2-(4-fluoro-phenyl)-ethylamino]-methyl ⁇ - benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2-diamine Compound 40 was prepared in a manner similar to that described in Example 16. LC/MS (M + +l): 527.
  • Example 41 Preparation of compound 41: N-(4- ⁇ [2-(4-chloro-phenyl)-propylamino]-methyl ⁇ - benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2-diamine Compound 41 was prepared in a manner similar to that described in Example 16. LC/MS (M + +l): 558.
  • Example 42 Preparation of compound 42: N-(4- ⁇ [2-(5-methyl-lH-indol-3-yl)-ethylamino]- methyl ⁇ -benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2- diamine
  • Compound 42 was prepared in a manner similar to that described in Example 16.
  • Example 43 Preparation of compound 43: N-(4-fluoro-benzyl)-N'-[2-(3-fluoro-benzylamino)- ethyl]-N'-(4- ⁇ [6-(pyridin-2-yloxy)-pyridin-3-ylamino]-methyl ⁇ -benzyl)-ethane-l,2-diamine
  • Compound 43 was prepared in a manner similar to that described in Example 16.
  • Example 44 Preparation of compound 44: 6-(5- ⁇ 4-[(bis- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ - amino)-methyl]-benzylamino ⁇ -pyridin-2-yloxy)-pyridine-2-carboxylic acid methyl ester
  • Example 45 Preparation of compound 45: N-(4- ⁇ [6-(5-chloro-pyridin-2-yloxy)-pyridin-3- ylamino]-methyl ⁇ -benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ - ethane- 1 ,2-diamine
  • Example 46 Preparation of compound 46: N-pyridin-2-ylmethyl-N'- ⁇ 2-[(pyridin-2-ylmethyl)- amino]-ethyl ⁇ -N'-(4- ⁇ [6-(pyridin-2-yloxy)-pyridin-3-ylamino]-methyl ⁇ -benzyl)-ethane-l,2- diamine
  • Example 47 Preparation of compound 47: N-(4- ⁇ [(lH-benzoimidazol-2-ylmethyl)-amino]- methyl ⁇ -benzyl)-N'-(4-fluoro-benzyl)-N-[2-(4-fluoro-benzylamino)-ethyl]-ethane-l,2-diamine
  • Example 49 Preparation of compound 49: N-pyridin-2-ylmethyl-N'- ⁇ 2-[(pyridin-2-ylmethyl)- amino]-ethyl ⁇ -N'-[4-(l,4,8,lltetraaza-cyclotetradec-l-ylmethyl)-benzyl]-ethane-l,2-diamine
  • Example 50 Preparation of compound 50: 4-[(bis- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ - amino)-methyl]-N,N-bis- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -benzenesulfonamide
  • Example 52 Preparation of compound 52: 4-( ⁇ bis-[2-(3,4-difluoro-benzylamino)-ethyl]-amino ⁇ - methyl)-N-pyridin-2-ylmethyl-benzenesulfonamide
  • Example 53 Preparation of compound 53: 4-( ⁇ bis-[2-(4-fluoro-benzylamino)-ethyl]-amino ⁇ - methyl)-N-pyridin-2-ylmethyl-benzenesulfonamide
  • Example 54 Preparation of compound 54: 4-( ⁇ bis-[2-(4-chloro-benzylamino)-ethyl]-amino ⁇ - methyl)-N-pyridin-2-ylrnethyl-benzenesulfonamide
  • Example 56 Preparation of compound 56: N-[4-(6-methoxy-l,3,4,9-tetrahydro-b-carbolin-2- ylmethyl)-benzyl]-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2- diamine
  • 1,4-Dibromoxylene 13.64 mmol was treated with bis(te?t-butoxyaminoethyl)amine (2.74 mmol) in the presence of Et 3 N (2.74 mmol) in CH 2 Cl 2 (50 mL) at 0 0 C. After stirring for 16 h, the solution was filtered, concentrated, and purified to afford a mono-substituted bromide.
  • Example 57 Preparation of compound 57: N-pyridin-2-ylmethyl-N'- ⁇ 2-[(pyridin-2-ylmethyl)- amino]-ethyl ⁇ -N'-[4-(l,3,4,9-tetrahydro-b-carbolin-2-ylmethyl)-benzyl]-ethane-l,2-diamine
  • Example 58 Preparation of compound 58: isonicotinic acid ⁇ 4-[(bis- ⁇ 2-[(pyridin-2-ylmethyl)- amino] -ethyl ⁇ -amino)-methyl] -benzylidene ⁇ -hydrazide
  • Example 59 Preparation of compound 59: thiophene-2-carboxylic acid ⁇ 4-[(bis- ⁇ 2-[(pyridin-2- ylmethyl)-amino]-ethyl ⁇ -amino)-methyl]-benzylidene ⁇ -hydrazide
  • Example 60 Preparation of compound 60: l-[bis[(2-(2-pyridinylmethyl)aminoethyi)]amino- methyl]-4-[2-(3-mdol)-l-((S)-hydroxymethyl)ethylaminomethyl]benzene
  • Example 61 Preparation of compound 61: l-[bis[(2-(2-pyridinyl-2-ethyl)aminoethyl)]amino- methyl]-4-[2-(3-indol)4-((S)-hydroxymethyl)ethylaminomethyl]benzene
  • Example 62 Preparation of compound 62: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- methyl]-4-[2-(phenyl)-l-((i?)-hydroxymethyl)ethylaminomethyl]benzene
  • Example 64 Preparation of compound 64: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- methyl]-4-[2-(3-indol)-l-((i?)-hydroxymethyl)ethylaminomethyl]benzene
  • Example 65 Preparation of compound 65: l-[bis[(2-(2-pyridinyl-2-ethyl)aminoethyl)]amino- methyl]-4-[(l,2,3,4-tetrahydro-9H-pyrido-6-methoxy[3,4-6]indol-2-methyl)benzene
  • Compound 65 was prepared by a similar manner to that described in Example 56.
  • Example 66 Preparation of compound 66: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- methyl]-4-[(l,2,3,4-tetrahydro-9H-pyrido-6-benzyloxy[3,4-b]indol-2-methyl)benzene
  • Example 67 Preparation of compound 67: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- sulfonyl]-4-(l,2,3,4-tetrahydro-9H-pyrido-6-methoxy[3,4-6]indol-2-methyl)benzene
  • Example 68 Preparation of compound 68: N-[4-(6-methoxy-l,3,4,9-tetrahydro-b-carbolin-2- ylmethyl)-benzyl]-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-2-hydroxyethylamino]- ethyl ⁇ -ethane-l,2-diamine
  • Example 69 Preparation of compound 69: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- methyl]-4-[2-(phenyl)-l-((/?)-hydroxycarbonyl)ethylaminomethyl]benzene
  • Example 70 Preparation of compound 70: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- methyl]-4-[2-(3-(5-hydroxyindol)-l-((i?)-hydroxycarbonyl)ethylaminomethyl]benzene
  • Compound 70 was prepared in a manner similar to that described in Example 16 (Yield: 75%).
  • Example 72 Preparation of compound 72: l-[bis[(2-(2-pyridinyl-2-ethyl)aminoethyl)]amino- methyl]-4-[2-(3-chlorophenyl)ethylaminomethyl]benzene
  • Example 73 Preparation of compound 73: l-[bis[(2-(2-pyridinyl-2-ethyl)aminoethyl)]amino- methyl] -4- ⁇ [(I H-benzoimidazol-2-ylmethyl)-amino] -methyljbenzene
  • Compound 73 was prepared in a manner similar to that described in Example 16 (Yield:
  • Example 74 Preparation of compound 74: l-[bis[(2-(2-pyridinylrnethyl)aminoethyl)]amino- methyl]-4-[(2-phenyl-2-hydroxy-l-methoxymethyl)ethylaminomethyl]benzene
  • Example 75 Preparation of compound 75: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- methyl]-4-[(2-(4-chlorophenyl)-l-hydroxymethyl)ethylaminomethyl]benzene
  • Compound 75 was prepared in a manner similar to that described in Example 16 (Yield: 70%).
  • Example 77 Preparation of compound 77: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- methyl]-4-[(2-phenyl-(2S)-hydroxy-(lS)-hydroxymethyl)ethylaminomethyl]benzene
  • Example 78 Preparation of compound 78: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- methyl]-4-[2-(4-bromophenyl)-l-((i?)-hydroxycarbonyl)ethylaminomethyl]benzene
  • Compound 78 was prepared in a manner similar to that described in Example 16 (Yield:
  • Example 79 Preparation of compound 79: 2-( ⁇ 4'-[(bis- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ - amino)-methyl]-biphenyl-4-ylmethyl ⁇ -pyridin-2-ylmethyl-amino)-3-phenyl-propan-l-ol
  • Example 80 Preparation of compound 80: N-pyridin-2-ylmethyl-N'- ⁇ 2-[(pyridin-2-ylmethyl)- amino] -ethyl ⁇ -N'- [4-(6-chloro- l,3,4,9-tetrahydro-b-carbolin-2-ylmethyl)-benzyl] -ethane- 1,2- diamine
  • Example 82 Preparation of compound 82: N-[4-( ⁇ [2-(3-chloro-phenyl)-ethyl]-ethyl-amino ⁇ - methyl)-benzyl]-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2- diamine
  • Compound 82 was prepared in a manner similar to that described in Example 56.
  • Example 83 Preparation of compound 83: l-[bis[(2-(2-pyridinylrnethyl)aminoethyl)]amino- methyl]-4-[(2S)-hydroxymethylpyrrolidme-N-methyl]benzene
  • Compound 83 was prepared in a manner similar to that described in Example 56 (Yield:
  • Example 84 Preparation of compound 84: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- methyl]-4-[(2i?)-hydroxymethylpyrrolidine-N-methyl]benzene
  • Example 85 Preparation of compound 85: 2-( ⁇ 4'-[(bis- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ - amino)-methyl] -biphenyl-4-ylmethyl ⁇ -amino)-3-phenyl-propan- 1 -ol
  • Example 87 Preparation of compound 87: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- methyl]-4-[2-(5-chloro-6-hydroxyphenyl-l-hydroxycarbonyl)ethylaminomethyl]benzene
  • Example 88 Preparation of compound 88: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- methyl]-4-[(2-thiophene-l-hydroxycarbonyl)ethylaminomethyl]benzene
  • Compound 88 was prepared in a manner similar to that described in Example 16 (Yield:
  • Example 89 Preparation of compound 89: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- methyl]-4- ⁇ [2-(4-chlorophenyl)-2-cyclopropyl]ethylaminomethyl ⁇ benzene
  • Example 90 Preparation of compound 90: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- methyl]-4- ⁇ [2-(3-chloro-6-methoxyphenyl)]ethylaminomethyl ⁇ benzene
  • Example 91 Preparation of compound 91: N-pyridin-2-yl-2-ethyl-N'- ⁇ 2-[(pyridin-2-ylmethyl)- amino]-ethyl ⁇ -N'-[4-(6-methoxy-l,3,4,9-tetrahydro-b-carbolin-2-ylmethyl)-benzyl]-ethane-l,2- diamine
  • Example 92 Preparation of compound 92: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- methyl]-4-[(2-thiophene-2-hydroxycarbonyl)ethylaminomethyl]benzene
  • Compound 92 was prepared in a manner similar to that described in Example 16 (Yield:
  • Example 93 Preparation of compound 93: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- methyl]-4-[3-hydroxymethyl-(5')-l,2,3,4-tetrahydroisoquinoline-N-ylmethyl]benzene
  • Example 94 Preparation of compound 94: l-[bis[(2-(2-pyridinylmethyl)aminoethyi)]amino- methyl]-4-(4-hydroxy-4-phenylpiperidine-N-ylmethyl)benzene
  • Example 95 Preparation of compound 95: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- methyl]-4-[4-hydroxy-4-(4-chlorophenylpiperidine)-N-ylmethyl]benzene
  • Example 96 Preparation of compound 96: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- methyl] -4-(l -indanaminomethyl)benzene
  • Compound 96 was prepared in a manner similar to that described in Example 16.
  • LC-MS C 33 H 4O N 6 -OHCl
  • M + +1-6HC1 521.
  • Example 97 Preparation of compound 97: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- methyl] -4-(3,4-dichlorophenylmethylaminomethyl)benzene
  • Example 98 Preparation of compound 98: l-[bis[(2-(2-pyridinylrnethyl)aminoethyl)]amino- methyl]-4-(3-chlorophenylmethylaminomethyl)benzene
  • Example 99 Preparation of compound 99: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- methyl]-4-[4-hydroxyphenyl(l-hydroxymethyl)ethylaminomethyl)benzene
  • Example 100 Preparation of compound 100: N-(4- ⁇ [2-(7-methyl-lH-indol-3-yl)-l- (hydroxycarbonylmethyl)ethylamino]-methyl ⁇ -benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2- ylmethyl)-amino]-ethyl ⁇ -ethane-l,2-diamine
  • Compound 100 was prepared in a manner similar to that described in Example 16.
  • Example 103 Preparation of compound 103: N-(4- ⁇ [2-(7-methyl-lH-indol-3-yl)ethylamino]- methyl ⁇ -benzyl)-N t -pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -propane-l,3- diamine Compound 103 was prepared in a manner similar to that described in Example 16.
  • Example 104 Preparation of compound 104: N-(4- ⁇ [2-(3-chlorophenyl)ethylamino]methyl ⁇ - benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -propane-l,3-diamine Compound 104 was prepared in a manner similar to that described in Example 16.
  • Example 105 Preparation of compound 105: N-(4- ⁇ [(lH-benzoimidazol-2-yl-methyl)amino]- methyl ⁇ -benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -propane-l,3- diamine
  • Example 106 Preparation of compound 106: N-pyridin-2-yl-hydroxyethyl-N'- ⁇ 2-[(pyridin-2- ylmethyl)-amino]-ethyl ⁇ -N'-[4-(6-methoxy-l,3,4,9-tetrahydro-b-carbolin-2-ylmethyl)-benzyl]- ethane-l,2-diamine
  • Example 108 Preparation of compound 108: N-pyridin-2-yl-hydroxyethyl-N'- ⁇ 2-[(pyridin-2- ylmethy ⁇ -aminoJ-ethylj-N'- ⁇ l-hydroxymethyl-o-methoxy-ljS ⁇ -tetrahydro-b-carbolin ⁇ -yl- methyl)-benzyl]-ethane-l,2-diamine Compound 108 was prepared in a manner similar to that described in Example 56.
  • Example 109 Preparation of compound 109: N-pyridin-2-yl-hydroxyethyl-N'- ⁇ 2-[(pyridin-2- ylmethyl)-amino]-ethyl ⁇ -N'-[4-(4-phenyl-l,2,3,6-tetrahydropyridine-l-methyl)-benzyl]-ethane- 1,2-diamine
  • Compound 109 was prepared in a manner similar to that described in Example 56.
  • Example 110 Preparation of compound 110: N-pyridin-2-yl-2-ethyl-N'- ⁇ 2-[(pyridin-2-yl-ethyl)- amino]-ethyl ⁇ -4-(cyanobenzyl]-ethane-l,2-diamine.5HCl
  • a mixture of bis(2-tert-butoxycarbonylaminoethyl)amine (0.01 mol), 4-cyanobenzyl- bromide (0.01 mol), K 2 CO 3 (0.05 mol), and CH 3 CN (70 mL) was heated at 60 0 C for 10 hours.
  • Example 111 Preparation of compound 111: N-pyridin-2-yl-2-ethyl-N'- ⁇ 2-[(pyridin-2- ylmethyl)-amino]-ethyl ⁇ -N'-[4-(lH-benzimidazol-2-yl-methyl)-aminomethyl]benzyl]-ethane- 1,2-diamine
  • a mixture of bis(2-te/t-butoxycarbonylaminoethyl)amine (0.01 mol), 4-cyanobenzyl- bromide (0.01 mol), K 2 CO 3 (0.05 mol), and CH 3 CN (70 mL) was heated at 60 0 C for 10 hours.
  • Example 112 Preparation of compound 112: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- methyl]-4-[4-hydroxy-4-(4-methoxyphenylpiperidine)-N-yl-methyl]benzene
  • Example 113 Preparation of compound 113: l-[bis[(2-(2-pyridinylmethyl)aminoethyl)]amino- methyl]-4-[4-hydroxy-4-(2-methoxyphenylpiperidine)-N-yl-methyl]benzene
  • Example 114 Preparation of compound 114: N-(4- ⁇ [2-(7-methyl-lH-indol-3-yl)ethylamino]- methyl ⁇ -benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -l- methylethane- 1 ,2-diamine 4-Cyanobenzaldehyde (0.01 mol) was treated with 2-methyl-2-aminoethanol (0.01 mol) in MeOH (20 mL) at 60 0 C for 12 hours. NaBH 4 (1.90 g, 0.05 mol) was then added to the above solution at 0 0 C.
  • the reaction mixture was stirred for another 2 hours at 25 0 C. It was then diluted with CH 2 Cl 2 (100 mL) and with an ammonium chloride aqueous solution (10%, 70 mL). The organic layer was separated, washed with water (100 mL), dried over MgSO 4 (s), and concentrated under reduced pressure to yield an oil intermediate. The oil intermediate was then condensed with 2-(2-bromo-ethoxy)-tetrahydro-pyran (0.01 mol) in the presence of K 2 CO 3 (0.05 mol) in refluxing CH 3 CN (30 mL). After deprotection, the resultant hydroxyl group was mesylated and was allowed to react with 2-aminomethylpyridine.
  • Example 115 Preparation of compound 115: 2- ⁇ 4-[(bis- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ - amino)-methyl] -benzylamino ⁇ - 1 -(3 -chloro -phenyl)-ethanol Compound 115 was prepared in a manner similar to that described in Example 16 (Yield:
  • Example 116 Preparation of compound 116: N-(4- ⁇ [(lH-benzoimidazol-2-ylmethyl)-amino]- methyl ⁇ -benzyl)-N'-piperidin-4-yl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2- diamine
  • Example 117 Preparation of compound 117: N-(4- ⁇ [2-(7-methyl-lH-indol-3-yl)-ethylamino]- methyl ⁇ -benzyl)-N'-(l-pyridin-2-yl-ethyl)-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2- diamine
  • Example 118 Preparation of compound 118: N2-(4- ⁇ [(lH-benzoimidazol-2-ylmethyl)-amino]- methyl ⁇ -benzyl)-Nl-pyridin-2-ylmethyl-N2- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -propane- 1,2-diamine Compound 118 was prepared in a manner similar to that described in Example 114 (Yield: 68%).
  • Example 119 Preparation of compound 119: N2-(4- ⁇ [2-(3-chloro-phenyl)-ethylamino]-methyl ⁇ - benzyl)-Nl-pyridin-2-ylmethyl-N2- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -propane-l,2-diamine
  • Example 120 Preparation of compound 120: N-ethyl-N'-(4- ⁇ [2-(7-methyl-lH-indol-3-yl)- ethylamino]-methyl ⁇ -benzyl)-N-pyridin-2-ylmethyl-N'- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ - ethane-l,2-diamine
  • Example 121 Preparation of compound 121: 3- ⁇ 4-[(bis- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ - amino)-methyl] -benzylamino ⁇ - 1 -(3 -chloro -phenyl)-propan- 1 -ol Compound 121 was prepared in a manner similar to that described in Example 16 (Yield:
  • Example 122 Preparation of compound 122: l-(3-benzyloxy-phenyl)-3- ⁇ 4-[(bis- ⁇ 2-[(pyridin-2- ylmethyl)-amino] -ethyl ⁇ -amino)-methyl] -benzylamino ⁇ -propan- 1 -ol
  • Example 123 Preparation of compound 123: 3-[2-((4- ⁇ [2-(7-methyl-lH-indol-3-yl)- ethylamino]-methyl ⁇ -benzyl)- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -amino)-ethylamino]-3- pyridin-2-yl-propan-l-ol
  • Example 124 Preparation of compound 124: 3-[2-((4- ⁇ [(lH-benzoimidazol-2-ylmethyl)-amino]- methyl ⁇ -benzyl)- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -amino)-ethylamino]-3-pyridin-2-yl- propan-1-ol
  • Example 125 Preparation of compound 125: N-(4- ⁇ [(lH-benzoimidazol-2-ylmethyl)-amino]- methyl ⁇ -benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2- diamine
  • Example 126 Preparation of compound 126: N-(4- ⁇ [3-(3-chloro-phenyl)-propylamino]-methyl ⁇ - benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2-diamine
  • Example 127 Preparation of compound 127: N-(4- ⁇ [2-(3-chloro-phenyl)-ethylamino]-methyl ⁇ - benzyl)-N'-pyridin-2-ylmethyl-N- ⁇ 2-[(pyridin-2-ylmethyl)-amino]-ethyl ⁇ -ethane-l,2-diamine.
  • Compound 127 was prepared in a manner similar to that described in Example 16 (Yield: 80%).
  • Example 128 Preparation of compound 128: (lR,2S)-2-(4-((bis(2-(pyridin-2-ylmethylamino)- ethyl)amino)methyl)benzylamino)-l-phenylpropane-l,3-diol
  • Example 129 Preparation of compound 129: (lS,2R)-2-(4-((bis(2-(pyridin-2-ylmethylamino)- ethyl)amino)methyl)benzylamino)-l-phenylpropane-l,3-diol
  • Example 130 Preparation of compound 130: 2-(4-((bis(2-(pyridin-2-ylmethylamino)ethyl)- amino)methyl)benzylamino)-3-(4-chlorophenyl)propan-l-ol
  • compound 130 was prepared in a manner similar to that described in Example 16 (Yield:
  • Example 131 Preparation of compound 131: (S)-4-(2-(4-((bis(2-(pyridin-2-ylmethylamino)- ethyl)amino)methyl)benzylamino)-3 -hydroxypropyl)phenol
  • Example 133 Preparation of compound 133: 2-(4-((bis(2-(pyridin-2-ylmethylamino)- ethyl)amino)methyl)benzylamino)-l-(3-chlorophenyl)ethanol Compound 133 was prepared in a manner similar to that described in Example 16 (Yield:
  • Example 134 Preparation of compound 134: l-(3-(benzyloxy)phenyl)-2-(4-((bis(2-(pyridin-2- ylmethylamino)ethyl)amino)methyl)benzylamino)ethanol
  • Example 135 Preparation of compound 135: 2-(4-((bis(2-(pyridin-2-ylmethylamino)- ethyl)amino)methyl)benzylamino)-l-(3-phenoxyphenyl)ethanol
  • Example 137 Preparation of compound 137: (S)-2-(4-((bis(2-(pyridin-2-ylmethylamino)- ethyl)amino)methyl)benzylamino)-3-(7-methyl-lH-indol-3-yl)propan-l-ol Compound 137 was prepared in a manner similar to that described in Example 16 (Yield:
  • Example 138 Preparation of compound 138: (R)-2-(4-((bis(2-(pyridin-2-ylmethylamino)- ethyl)amino)methyl)benzylamino)-3-(lH-indol-3-yl)propan-l-ol
  • Example 139 Preparation of compound 139: (S)-2-(4-((bis(2-(pyridin-2-ylmethylamino)- ethyl)amino)methyl)benzylamino)-3-(lH-indol-3-yl)propan-l-ol
  • Example 140 Preparation of compound 140: Nl-(4-((2-(7-methyl-lH-indol-3- yl)ethylamino)methyl)benzyl)-N2-(pyridin-2-ylmethyl)-Nl-(2-(pyridin-2-ylmethylamino)- ethyl)ethane- 1 ,2-diamine Compound 140 was prepared in a manner similar to that described in Example 16 (Yield: 80%).
  • Example 141 Preparation of compound 141: Nl-(4-((2,3-dihydro-lH-inden-l- ylamino)methyl)benzyl)-N2-(pyridin-2-ylmethyl)-Nl-(2-(pyridin-2-ylmethylamino)ethyl)ethane- 1,2-diamine
  • Example 142 Preparation of compound 142: Nl-(4-((6-methoxy-3,4-dihydro-lH-pyrido[3,4- b]indol-2(9H)-yl)methyl)benzyl)-N2-(pyridin-2-ylmethyl)-Nl-(2-(pyridin-2-ylmethylamino)- ethyl)ethane-l,2-diamine
  • 1,4-Dibromoxylene 13.64 mmol was treated with bis(te/t-butoxyaminoethyl)amine (2.74 mmol) in the presence of Et 3 N (2.74 mmol) in CH 2 Cl 2 (50 mL) at O 0 C. After stirring for 16 hours, the solution was filtered, concentrated, and purified to afford a mono-substituted bromide.
  • Example 143 Preparation of compound 143: (S)-(l-(4-((bis(2-(pyridin-2-ylmethylamino)- ethyl)amino)methyl)benzyl)pyrrolidin-2-yl)methanol Compound 143 was prepared in a manner similar to that described in Example 142 (Yield: 80%).
  • DELFIA GTP-binding kit (Wallac Oy, Turku, Finland).
  • the DELFIA GTP- binding assay is a time-resolved fluorometric assay based on GDP-GTP exchange on G-protein subunits followed by activation of a G protein-coupled receptor by its agonists.
  • Eu-GTP obtained from Wallac Oy, was used in this assay to allow monitoring of agonist-dependent activation of G-protein. Stimulation of CXCR4 receptor by SDF-I leads to the replacement of GDP by GTP on the ⁇ -subunit of G-protein.
  • This GTP-G ⁇ complex represents the activated form of G-protein.
  • Eu-GTP a non-hydrolysable analog of GTP, can be used to quantify the amount of activated G-protein.
  • Plasma membrane of CXCR4-expressing HEK293 cells was suspended in an assay buffer
  • Membranes of human CXCR4-transfected HEK293 cells (5-10 ⁇ g protein/well) in a 70 ⁇ l assay buffer (50 mM HEPES, pH 7.4, 0.5% bovine serum albumin, 90 rnM NaCl, 5 mM MgCl 2 , 1 mM CaCl 2 ) were incubated with 20 ⁇ l of each test compound and 10 ⁇ l of [ 125 I]-SDF-I (final concentration 150 pM) in U-bottom assay plates (Corning, Corning, NY).
  • a 70 ⁇ l assay buffer 50 mM HEPES, pH 7.4, 0.5% bovine serum albumin, 90 rnM NaCl, 5 mM MgCl 2 , 1 mM CaCl 2
  • Example 146 Synergistic effect of Compounds 125 and 136 with G-CSF in stem cell and endothelial progenitor cells (EPC) mobilization
  • G-CSF is a growth factor for stem cells and EPCs currently used in clinics to improve hematopoietic function in cancer patients after chemotherapy.
  • Compound 125 when used in combination with G-CSF, showed synergistic effect in stem cell and EPC mobilization. Specifically, a combination of compound 125 and G-CSF dramatically increased circulation of CD34 + cells up to 38 folds and circulation of CD133 + cells up to 64-folds. The results are summarized in Table 2 below.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne des procédés de traitement de la rétinopathie et de réparation de tissus endommagés. Les procédés comprennent l'administration à un sujet nécessitant celle-ci d'une quantité efficace d'un ou plusieurs composés de la formule suivante. Chaque variable de ladite formule est définie dans les spécifications.
PCT/US2007/075265 2006-08-08 2007-08-06 Composés de polyamine Ceased WO2008021788A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US83616806P 2006-08-08 2006-08-08
US60/836,168 2006-08-08

Publications (2)

Publication Number Publication Date
WO2008021788A2 true WO2008021788A2 (fr) 2008-02-21
WO2008021788A3 WO2008021788A3 (fr) 2008-12-04

Family

ID=39082891

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2007/075265 Ceased WO2008021788A2 (fr) 2006-08-08 2007-08-06 Composés de polyamine

Country Status (2)

Country Link
TW (1) TW200817365A (fr)
WO (1) WO2008021788A2 (fr)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2521416A1 (fr) * 2003-04-02 2004-10-21 Taigen Biotechnology Composes polyamine pour le traitement de maladies induites par le recepteur de la chemokine

Also Published As

Publication number Publication date
TW200817365A (en) 2008-04-16
WO2008021788A3 (fr) 2008-12-04

Similar Documents

Publication Publication Date Title
JP5118029B2 (ja) ピリミジン化合物
US8193206B2 (en) Pyrimidine compounds
SU1297728A3 (ru) Способ получени @ -гетероциклил-4-пиперидинаминов или их фармацевтически приемлемых солей
US7183413B2 (en) Aminoquinoline compounds
US8372849B2 (en) Heterocyclic compounds
JP6473420B2 (ja) 複素環スルホンアミド誘導体及びそれを含有する医薬
US20040229927A1 (en) Imidazole derivatives for treatment of allergic and hyperproliferative disorders
US20190023699A1 (en) Heterocyclic sulfonamide derivative and medicine containing same
US7399776B2 (en) Polyamine compounds for treating chemokine receptor mediated diseases
US20180162844A1 (en) Cyclopropane derivative and drug containing same
US7504422B2 (en) Polyamine compounds
US7501526B2 (en) Synthesis of polyamine compounds
WO2008021788A2 (fr) Composés de polyamine
AU2004227983B2 (en) Polyamine compounds for treating chemokine receptor mediated diseases
CN117355507A (zh) 用作lrrk2激酶抑制剂的嘧啶衍生物
DE10027514A1 (de) Liganden von Integrinrezeptoren
CN100566712C (zh) 用于治疗趋化因子受体介导的疾病的多胺化合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07813799

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

122 Ep: pct application non-entry in european phase

Ref document number: 07813799

Country of ref document: EP

Kind code of ref document: A2