JP2002543126A - CXCR-4 receptor antagonist-thrombopoietin mimic - Google Patents

Abstract

  (57) [Summary] Substituted cyclam derivatives, pharmaceutical compositions containing these compounds, the use of these compositions as CXCR-4 receptor antagonists, and the use of these compounds as thrombopoietin (TPO) mimetics have been invented.

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION The present invention relates to cyclam derivatives, pharmaceutical compositions containing these compounds, C
It relates to the use of these compounds as XCR-4 receptor antagonists and to the use of these compounds as promoters of thrombopoiesis and megakaryopoiesis.

BACKGROUND OF THE INVENTION The CXCR-4 receptor, initially known as LESTR / fusin,
Α1 or CXC chemokine stromal cell derived factor 1 (SDF-1) in 996
And has been renamed at this time. SDF-1 is thought to be specific for CXCR-4 and mediates its chemotactic effect via this receptor. The CXCR-4 receptor is widely expressed on various cell types and is involved in a series of inflammatory responses mediated by SDF-1.

[0003] The widespread distribution of the receptor includes bacterial, fungal and protozoal infections, pain, cancer, diabetes, obesity, anorexia, morbid hunger, asthma, allergies, Parkinson's disease,
Acute heart failure, hypotension, hypertension, atherosclerosis, pathologies including angiogenesis, urinary retention, osteoporosis, angina, myocardial infarction, stroke, ulcer, benign prostatic hyperplasia, migraine, vomiting, psychotic And neurological disorders (eg, anxiety, schizophrenia, manic depression, depression, delirium, dementia, mental retardation) and dyskinesia (Huntington's disease and Jill de la Tourette syndrome), damaged or amputated It has implications for many disease areas, including spinal cord and other injury-related conditions.

In addition, CXCR-4 has been defined as a co-receptor used by the T-stimulatory HIV-1 virus strain to infect cells, and thus antagonists of the receptor are , May be useful in the treatment of terminal HIV infection and AIDS.

[0005] Based on the above, CXCR-4 receptor antagonists provide a unique approach to reduce the pathophysiology associated with the above diseases.

As described herein, surprisingly, certain cyclam derivatives are CXC
We have found that it is effective as an R-4 receptor antagonist.

[0007] Megakaryocytes are bone marrow-derived cells that cause the production of circulating platelets. They make up <0.25% of bone marrow cells in most species, but> 10 times the typical bone marrow cell volume. Kuter et al. Proc. Natl. Acad. Aci. USA 91: 11104-
See 11108 (1994). Megakaryocytes undergo a process known as nuclear division in which they replicate their nuclei but do not undergo cell division, thereby giving rise to polyploid cells. In response to a decrease in platelet count, the rate of nuclear division increases, hyperploid megakaryocytes are formed, and the number of megakaryocytes increases up to 3-fold. Harker J. Clin. Invest
47: 458-465 (1968). In contrast, in response to an increase in platelet count,
The rate of fission is reduced, hypoploid megakaryocytes are formed, and the number of megakaryocytes is reduced by 50%.

[0008] The exact physiological feedback mechanism by which the mass of circulating platelets regulates the rate and number of nuclear division of megakaryocytes in the bone marrow is unknown. Circulating thrombopoietic factors involved in mediating this feedback loop are currently thrombopoietin (TP
O). More specifically, TPO has proven to be the primary humoral regulator in situations involving thrombocytopenia. For example, Metcal
f See Nature 369: 519-520 (1994). TPO has been shown in several studies to increase platelet numbers, increase platelet size, and increase isotope uptake into platelets of recipient animals. Specifically, TPO
Is thought to affect megakaryopoiesis in several ways: (1) causing an increase in the size and number of megakaryocytes; (2) in megakaryocytes, in the form of polyploids, DNA Causes increased content; (3) increases megakaryocytic fission; (
4) Causes increased maturation of megakaryocytes; (5) Causes an increase in the percentage of progenitor cells in the bone marrow, in the form of small acetylcholinesterase positive cells.

Platelets (thrombocytes) are required for blood clotting, so if their number is very low, patients can die from catastrophic bleeding, and T
PO may have useful applications in both the diagnosis and treatment of various blood disorders, for example, mainly due to platelet deficiency. Ongoing clinical trials with TPO have demonstrated that TPO can be safely administered to patients. In addition, recent studies have provided a basis for estimating the efficacy of TPO therapy in treating thrombocytopenia, particularly thrombocytopenia caused by chemotherapy, radiation therapy or bone marrow transplantation as a treatment for cancer or lymphoma. . For example, McDonald (
1992) Am. J. Ped. Hematology / Oncology 14: 8-21 (1992).

[0010] The gene encoding TPO has been cloned and characterized. Kute
Natl. Acad. Sci. USA 91: 11104-11108 (1994); Barley et a.
l., Cell 77: 1117-1124 (1994); Kaushansky et al., Nature 369: 568-571 (1
994); Wendling et al., Nature 369: 571-574 (1994); and Sauvage et al.,
See Nature 369: 533-538 (1994). Thrombopoietin is a potential A
A glycoprotein with two different regions separated by an rg-Arg cleavage site. The amino-terminal region is very well conserved in humans and mice and has some homology with erythropoietin and interferon-alpha and interferon-beta. The carboxy terminal region shows extensive species diversity.

[0011] The DNA and encoded peptide sequences for the human TPO receptor (TPO-R; also known as c-mpl) have been disclosed. Vigon et al.
Proc. Natl. Acad. Sci. USA 89: 5640-5644 (1992). TPO-
R is a conserved C residue in the N-terminal part and WSXWS close to the transmembrane region
It is a member of the hematopoietin growth factor receptor family characterized by the general structural design of the extracellular domain encompassing the motif. Bazan Proc. Natl. Acad
Sci. USA 87: 6934-6938 (1990). The evidence that this receptor plays a functional role in hematopoiesis includes the observation that its expression is restricted to spleen, bone marrow or fetal liver in mice (Souyri et al. Cell 63: 1137-11
47 (1990)) and the observation that it is restricted to megakaryocytes, platelets and CD34 ⁺ cells in humans (Methia et al. Blood 82: 1395-1401 (1993)).
). TPO- as an important regulator of megakaryopoiesis
In addition, exposure of CD34 ⁺ cells to synthetic oligonucleotides antisense to TPO-R RNA significantly increased the appearance of megakaryocyte colonies without affecting erythroid or myeloid colony formation for R. It has been shown to inhibit. Some investigators have claimed that the receptor functions as a homodimer, similar to that for the receptor for G-CSF and erythropoietin.

[0012] The slow recovery of platelet levels in patients suffering from thrombocytopenia is a serious problem and has added urgency to studies on blood growth factor agonists that can promote platelet regeneration.

[0013] It is desirable to provide compounds that can treat thrombocytopenia by acting as a TPO mimetic.

[0014] As noted herein, surprisingly, certain cyclam derivatives have been found to be effective as agonists of the TPO receptor.
It is an imitation.

(Summary of the Invention) The present invention provides a novel compound, CXCR-4, represented by the following formulas (I) and (II):
Includes their use as receptor antagonists and their use as agonists of the TPO receptor.

The invention further provides a method of antagonizing the CXCR-4 receptor in an animal, including a human, comprising administering to a subject in need of such treatment an effective amount of the following formula (I)
) And (II).

In a further aspect of the present invention, there are provided novel methods and novel intermediates useful for preparing the TPO mimetic-CXCR-4 receptor antagonist compounds of the present invention.

The present invention includes a pharmaceutical composition comprising a pharmaceutical carrier and a compound useful in the methods of the present invention.

The present invention also includes a method of co-administering a TPO mimetic-CXCR-4 receptor antagonist compound of the present invention with an additional active ingredient.

DETAILED DESCRIPTION OF THE INVENTION Compounds useful in the method of the present invention are selected from Formulas (I) and (II) below.

The compound represented by the formula (I) has the following structural formula:

Embedded image Wherein, -CH 2 _-Z substituent is in the meta or para position with respect tetraazacyclotetradecane substituent; Z is nitrogen binding heteroaryl, substituted nitrogen linked heteroaryl, cyclic amine groups, substituted cyclic amine or represents ^NY 1 ^{Y 2} (where,, ^{Y 1} and ^{Y 2} are each independently hydrogen, alkyl, substituted _alkyl, C 3 _{-C 1 2} aryl, substituted X is hydrogen, alkyl, C ₃ -C ₁₂ aryl, substituted C ₃ -C ₁₂ aryl, amino, alkylamino, nitro, C ₃ -C ₁₂ aryl, cycloalkyl and substituted cycloalkyl). , Hydroxy, alkoxy, halogen,
Selected from the group consisting of carboxyl and carboxamide], and pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes thereof.

Among the compounds of the formula (I) of the present invention, compounds wherein the nitrogen-bonded heteroaryl is selected from benzimidazole, substituted benzimidazole, phenothiazine, substituted phenothiazine are preferred.

Among the compounds of the present invention represented by the formula (I), those compounds in which the nitrogen-bonded heteroaryl is substituted benzimidazole are particularly preferred.

In the compound of the formula (I) of the present invention, the cyclic amine moiety is piperazine, piperidine, azacycloheptane, diazacycloheptane, morpholine, azacyclotridecane, 5,6,14,15-dibenzo -1,4-Dioxa-8,12-diazacyclopentadeca-5,14-diene, 1,4,7-trioxa-10-azacyclododecane, 1,4,7,10-tetraoxa-13-aza Compounds selected from cyclopentadecane, 1,4,8,11-tetraazacyclotetradecane, and diazacyclooctane are preferred.

In the compound of the present invention represented by the formula (I), the cyclic amine moiety is 1,4-diazacycloheptane, azacyclotridecane, 5,6,14,15-dibenzo-1,4-
Dioxa-8,12-diazacyclopentadeca-5,14-diene, 1,4,8,1
Compounds selected from 1-tetraazacyclotetradecane and 1,5-diazacyclooctane are particularly preferred.

In the compounds of the formula (I) of the present invention, C ₃ -C ₁₂ aryl when represented by Y ¹ and / or Y ² is independently selected from phenyl, quinoline, thiazole, pyrazole and pyridine The selected compound is preferred.

Among the compounds of the formula (I) of the present invention, those in which the C ₃ -C ₁₂ aryl when represented by Y ¹ and / or Y ² are independently selected from phenyl and pyrazole are particularly preferred. preferable.

Among the compounds represented by formula (I) of the present invention, those compounds wherein X is selected from hydrogen, nitro and halogen are preferred.

As used herein, the term “heteroaryl,” unless otherwise defined, includes a monocyclic or polycyclic aromatic ring containing from 3 to 16 carbon atoms and containing from 1 to 3 heteroatoms ( However, one of the hetero atoms is nitrogen, and when the number of carbon atoms is three, the aromatic ring contains at least two hetero atoms.

As used herein, examples of heteroaryl include benzimidazole and phenothiazine.

As used herein, the term “cyclic amine moiety”, unless otherwise specified, includes a nitrogen-bonded non-aromatic monocyclic or polycyclic ring system containing about 5 to 24 atoms, including 1-4 of the atoms are nitrogen atoms, 0-4 are oxygen atoms, and the heteroatoms are separated by two or more carbon atoms). , 0 to 2 fused aromatic rings.

As used herein, examples of cyclic amine moieties include piperazine, piperidine, azacycloheptane, diazacycloheptane, morpholine, azacyclotridecane, 5,6,14,15-dibenzo-1, 4-dioxa-8,12-diazacyclopentadeca-5,14-diene, 1,4,7-trioxa-10-azacyclododecane, 1,4,7,10-tetraoxa-13-azacyclopentadecane, 1,4
, 8,11-tetraazacyclotetradecane, and 1,5-diazacyclooctane.

As used herein, the term “C ₃ -C ₁₂ aryl,” unless otherwise defined, is a single atom containing from 3 to 12 carbon atoms and optionally containing from 1 to 3 heteroatoms. A cyclic or polycyclic aromatic ring (provided that the aromatic ring contains at least 2 heteroatoms when it has 3 carbon atoms, and that the aromatic ring contains at least 1 heteroatom when it has 4 carbon atoms) Including heteroatoms).

As used herein, examples of C ₃ -C ₁₂ aryl include phenyl, benzimidazole, phenothiazine, quinoline, thiazole, pyrazole, pyridine, pyrimidine, naphthyl, 3,4-methylenedioxyphenyl and biphenyl Is mentioned.

As used herein, the term “heteroatom” means oxygen, nitrogen or sulfur.

As used herein, the term “halogen” refers to a substituent selected from bromine, iodine, chlorine and fluorine.

As used herein, the term “cycloalkyl,” unless otherwise defined, means a non-aromatic, unsaturated or saturated, monocyclic or polycyclic C ₃ -C ₁₂ .

As used herein, examples of cycloalkyl and substituted cycloalkyl substituents include cyclohexyl, 4-hydroxy-cyclohexyl, 2-ethylcyclohexyl, propyl 4-methoxycyclohexyl, 4-methoxycyclohexyl, -Carboxycyclohexyl and cyclopentyl.

As used herein, the term “substituted,” unless otherwise defined, refers to
Elephant chemical moieties are guanidino, hydroxyalkyl, alkoxy, acyl
Oxy, alkyl, pyridyl, pyrimidyl, amino, alkylamino, dialky
Ruamino, [(1,4,8,11-tetraazacyclotetradecane-1-ylmethyl)
Phenylmethyl], 3,4-methylenedioxyphenylmethyl, phenylalkyl
, Phenylmethyl, alkylphenyl, halogen-substituted phenyl, dihalogen
Halogen-substituted phenyl, thiazole, guanidinothiazole, thiof
Ene, acetyl, N-acylamino, hydroxy, furan, phenyl,-(CH
₂)_gC (O) OR⁶, -S (O)_nR⁷, Nitro, cyano, halogen, trifluoro
Methyl and protected -OH (where g is 0-6,⁶Is hydrogen
Or alkyl, n is 0-2, R⁷Is hydrogen or alkyl
Has one or more substituents selected from the group consisting of
I do.

As used herein, the term “protected hydroxy” or “protected —OH” refers to “Protective Groups In Organic Synthesis” by Theodora W. Greene,
Alcoholic or carboxylic acid --OH which can be protected by conventional protecting groups in the art as disclosed in Wiley-Interscience, 1981, New York.
Means a group. Compounds containing a protected hydroxy group are also useful as intermediates in preparing the pharmaceutically active compounds of the present invention.

As used herein, the term “alkoxy” means —Oalkyl where alkyl is as described herein, including —OCH ₃ and —OC (CH ₃ ) ₂ CH _3. Can be

As used herein, the term “acyloxy” refers to an alkyl as defined herein.
Means -OC (O) alkyl as described. As used herein,
Examples of acyloxy substituents include -OC (O) CH₃, -OC (O) CH (CH₃) ₂ And -OC (O) (CH₂)₃CH₃Is mentioned.

As used herein, the term “N-acylamino” refers to an —N (H) C (O) alkyl where alkyl is as described herein. As used herein, examples of N- acylamino substituent, -N (H) C (O ) CH 3, -N (
H) C (O) CH ( CH 3) 2 and -N (H) C (O) (CH 2) 3 CH 3 and the like.

As used herein, the term “alkyl” and all and all carbon atoms
The derivative in the chain is C₁-C₁₂Straight or branched chain saturated with carbon atoms
Means a sum or unsaturated hydrocarbon chain. As used herein, an alkyl substituent
Examples of -CH₃, -CH₂-CH₃, -CH₂-CH₂-CH₃, -C
H (CH₃)₂, -C (CH₃)₃,-(CH₂)₃-CH₃, -CH₂-CH (CH
₃)₂And -CH (CH₃) -CH₂-CH₃, -CH = CH₂Is mentioned.

As used herein, the term “treatment” and its derivatives refer to prophylactic or therapeutic treatment.

All publications, including but not limited to patents and patent applications, cited herein are hereby incorporated by reference as if fully set forth.

The compound represented by the formula (II) has the following structural formula: Y′CH ₂ ACH ₂ Y ′ Formula (II) wherein Y ′ is

Embedded image and

Embedded image Wherein Y 'is optionally substituted by a substituent selected from the group consisting of alkyl, alkoxy, halogen and carboxy, wherein A is X'-substituted Represents an aryl or heteroaryl ring (where X ′
Is selected from the group consisting of hydrogen, alkyl, aryl, amino, alkylamino, nitro, hydroxy, alkoxy, halogen, carboxyl, and carboxamide); provided that the Y′CH ₂ groups are in the meta or para position to each other. Is disposed].

Preferred compounds of formula (I) useful in the present invention are selected from the group consisting of the following compounds: 1- [4- (4-acetyl-1-piperazinomethyl) phenylmethyl] -1, 4,8
, 11-Tetraazacyclotetradecane pentahydrochloride; 1- [4- (1,4-diazacycloheptan-1-ylmethyl) phenylmethyl]
-1,4,8,11-tetraazacyclotetradecane hexahydrochloride; 1- [4- (azacycloheptane-1-ylmethyl) phenylmethyl] -1,4,8
1,11-Tetraazacyclotetradecane pentahydrochloride; 1- [4- (1-piperidinomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (1 -Morpholinomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (azacyclotridecane-1-ylmethyl) phenylmethyl] -1,4,
8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (5,6,14,15-dibenzo-1,4-dioxa-8,12-diazacyclopentadeca-5,14-diene -8-ylmethyl) phenylmethyl] -1,4
, 8,11-tetraazacyclotetradecane hexahydrochloride;

1- [4- (1,4,7-trioxa-10-azacyclododecane-10-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; [4- (1,4,7,10-tetraoxa-13-azacyclopentadecane-
13-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (1,4,10-trioxa-7,13-diazacyclopentadecane-
7-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane hexahydrochloride; 1- {4- [4- (2-pyridyl) -1-piperazinomethyl] phenylmethyl} -1
, 4,8,11-Tetraazacyclotetradecane hexahydrochloride; 1- {4- [4- (2-pyrimidyl) -1-piperazinomethyl] phenylmethyl}-
1,4,8,11-tetraazacyclotetradecane hexahydrochloride; 1- [4- (2-guanidinobenzimidazol-1-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane Pentahydrochloride; 1- [4- (1-piperazinomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane hexahydrochloride; 1,4-bis- [4- (1,4,8 , 11-Tetraazacyclotetradecane-1-ylmethyl) phenylmethyl] piperazine decahydrate; 1- [4- (1,5-diazacyclooctane-1-ylmethyl) phenylmethyl]
-1,4,8,11-tetraazacyclotetradecane hexahydrochloride; 1- (4- {bis [2- (diethylamino) ethyl] aminomethyl} phenylmethyl)
-1,4,8,11-tetraazacyclotetradecane heptahydrochloride; 1- (4-{[(2-aminoethyl) (3-aminopropyl) amino] methyl]} phenylmethyl) -1,4, 8,11-tetraazacyclotetradecane heptahydrochloride; 1- {4- [di- (2-pyridyl) aminomethyl] phenylmethyl} -1,4,8,1
1-tetraazacyclotetradecane pentahydrochloride; 1- [4- (2-thiazolylaminomethyl) phenylmethyl] -1,4,8,11-
1- [3- (2-guanidinobenzimidazol-1-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4 -(2-aminobenzimidazol-1-ylmethyl) phenylmethyl]
-1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1,8-bis- [4- (1,4,8,11-tetraazacyclotetradecane-1-ylmethyl) phenylmethyl] -1 , 4,8,11-tetraazacyclotetradecane
Dihydrobromide; 1,11-bis- [4- (1,4,8,11-tetraazacyclotetradecane-1-
Ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane / 12 hydrobromide;

1- [4- (N- {3- (methylamino) propyl} -N-methylaminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane hexahydrochloride; [4- (N- {3,4-methylenedioxyphenylmethyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (N- { 3,5-difluorophenylmethyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (phenothiazin-10-ylmethyl) phenylmethyl] -1, 4,8,
11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (N- {4-amino-2-methylquinolin-6-yl} aminomethyl)
Phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (N- {4- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (N- {3- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) phenylmethyl] -1, 4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [5-nitro-3- (N- {3- (2-thienyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1, 4,8,11-tetraazacyclotetradecane
Pentahydrochloride; 1- [5-nitro-3- (phenothiazin-10-ylmethyl) phenylmethyl]
-1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {4-amino-2-methylquinolin-6-yl} aminomethyl)
-5-nitrophenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {4- (2-guanidinothiazol-4-yl) phenyl} aminomethyl ) -5-Nitrophenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {3- (2-guanidinothiazol-4-yl) phenyl} amino Methyl) -5-nitrophenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [5-bromo-3- (N- {3- (2-thienyl) pyrazole-5 -Yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane.
Pentahydrochloride; 1- [5-bromo-3- (phenothiazin-10-ylmethyl) phenylmethyl]
-1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {4-amino-2-methylquinolin-6-yl} aminomethyl)
-5-bromophenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [5-bromo-3- (N- {4- (2-guanidinothiazol-4-yl) Phenyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [5-bromo-3- (N- {3- (2-guanidinothiazol-4-yl) ) Phenyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride;

1- [3- (N- {6-methyl-2-nitrophenyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; and 1- [3 -(N- {3- (2-thienyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (N- {1-methyl-3- (2-thienyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane.
1- [4- (N- {3-methylpyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4 -(N- {3- (4-methylphenyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (N -{3- (2-furyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {3- (4-methylphenyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {1-methyl-3 -Phenylpyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetra 1- [3- (N- {3- (4-chlorophenyl) -1-methylpyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane; 1- [3- (N- {1,3-diphenylpyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane; and 1- [3- (N- { 3- (4-t-butylphenyl) -1-methylpyrazole-5
-Yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane; and their further pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes.

Further preferred compounds of the present invention are selected from the group consisting of the following compounds: 1- [4- (1,4-diazacycloheptane-1-ylmethyl) phenylmethyl]
-1,4,8,11-tetraazacyclotetradecane hexahydrochloride; 1- [4- (azacycloheptane-1-ylmethyl) phenylmethyl] -1,4,8
, 11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (1-piperidinomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (aza Cyclotridecane-1-ylmethyl) phenylmethyl] -1,4,
8,11-tetraazacyclotetradecane pentahydrochloride;

1- [4- (5,6,14,15-dibenzo-1,4-dioxa-8,12-diazacyclopentadeca-5,14-dien-8-ylmethyl) phenylmethyl] -1 , 4
1,8,11-tetraazacyclotetradecane hexahydrochloride; 1- [4- (1,4,10-trioxa-7,13-diazacyclopentadecane-
7-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane hexahydrochloride; 1- {4- [4- (2-pyridyl) -1-piperazinomethyl] phenylmethyl} -1
, 4,8,11-Tetraazacyclotetradecane hexahydrochloride; 1- {4- [4- (2-pyrimidyl) -1-piperazinomethyl] phenylmethyl}-
1,4,8,11-tetraazacyclotetradecane hexahydrochloride; 1- [4- (2-guanidinobenzimidazol-1-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane Pentahydrochloride; 1,4-bis- [4- (1,4,8,11-tetraazacyclotetradecane-1-ylmethyl) phenylmethyl] piperazine decahydrochloride; 1- [4- (1,5- Diazacyclooctane-1-ylmethyl) phenylmethyl]
-1,4,8,11-tetraazacyclotetradecane hexahydrochloride; 1,8-bis- [4- (1,4,8,11-tetraazacyclotetradecane-1-ylmethyl) phenylmethyl] -1 , 4,8,11-tetraazacyclotetradecane
Dihydrobromide; 1,11-bis- [4- (1,4,8,11-tetraazacyclotetradecane-1-
Ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane / 12 hydrobromide; 1- [4- (N- {4-amino-2-methylquinolin-6-yl} amino Methyl)
Phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (N- {4- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (N- {3- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) phenylmethyl] -1, 4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [5-nitro-3- (N- {3- (2-thienyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1, 4,8,11-tetraazacyclotetradecane
Pentahydrochloride; 1- [5-nitro-3- (phenothiazin-10-ylmethyl) phenylmethyl]
-1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {4- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) -5-nitrophenylmethyl ] -1,4,8,11-Tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {3- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) -5-nitrophenyl Methyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [5-bromo-3- (N- {3- (2-thienyl) pyrazol-5-yl} aminomethyl) phenyl Methyl] -1,4,8,11-tetraazacyclotetradecane
Pentahydrochloride;

1- [3- (N- {4-amino-2-methylquinolin-6-yl} aminomethyl)
-5-bromophenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [5-bromo-3- (N- {4- (2-guanidinothiazol-4-yl) Phenyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [5-bromo-3- (N- {3- (2-guanidinothiazol-4-yl) ) Phenyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {3- (2-thienyl) pyrazol-5-yl} amino Methyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (N- {3-methylpyrazol-5-yl} aminomethyl) phenylmethyl] -1, 4,8,11-tetraazacyclotetradecane pentahydrochloride; 1 [4- (N- {3- (4-methylphenyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {3- (4-methylphenyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {3- (4-chlorophenyl) -1-methylpyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane; and 1- [3- (N- {1, 3-diphenylpyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane; and their further pharmaceutically acceptable salts, hydrates, solvates, esters and Metal complex.

The most preferred compounds encompassed by the present invention are selected from the group consisting of: 1- [4- (1,5-diazacyclooctan-1-ylmethyl) phenylmethyl]
-1,4,8,11-tetraazacyclotetradecane hexahydrochloride; 1- [4- (2-guanidinobenzimidazol-1-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane Pentahydrochloride; 1- [4- (5,6,14,15-dibenzo-1,4-dioxa-8,12-diazacyclopentadeca-5,14-dien-8-ylmethyl) phenylmethyl] -1,4
, 8,11-Tetraazacyclotetradecane hexahydrochloride; 1- [4- (azacyclotridecane-1-ylmethyl) phenylmethyl] -1,4,
8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (1,4-diazacycloheptan-1-ylmethyl) phenylmethyl]
-1,4,8,11-tetraazacyclotetradecane hexahydrochloride; 1- [4- (N- {4- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) phenylmethyl] -1, 4,8,11-tetraazacyclotetradecane pentahydrochloride;

1- [4- (N- {3- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [5-nitro-3- (N- {3- (2-thienyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane.
Pentahydrochloride; 1- [5-bromo-3- (N- {3- (2-thienyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane.
Pentahydrochloride; 1- [5-bromo-3- (N- {4- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane Pentahydrochloride; 1- [3- (N- {3- (2-thienyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride 1- [4- (N- {3- (4-methylphenyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; [3- (N- {3- (4-methylphenyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; and 1- [3 -(N- {3- (4-chlorophenyl) -1-methylpyrazol-5-yl} a Minomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane; and further pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes thereof.

Preferred compounds of formula (II) are selected from the group consisting of: 1,4-bis [2- (2-benzimidazolylamino) -5,5-di (2-pyridyl)
) -4-oxo-5H-imidazolin-3-ylmethyl] benzene, bis-trifluoroacetate; 2,6-bis [2- (2-benzimidazolylamino) -5,5-di (2-pyridyl)
) -4-oxo-5H-imidazolin-3-ylmethyl] pyridine, bis-trifluoroacetate; and 1,4-bis {[1- (2-benzimidazolyl) -1-guanidino] methyl} benzene; Further pharmaceutically acceptable salts, hydrates, solvates, esters or metal complexes.

[0058] Pharmaceutically acceptable salts and complexes are also encompassed by the present invention. Preference is given to zinc, copper, nickel, cobalt and rhodium complexes, hydrochlorides, hydrobromides and trifluoroacetates. Some of the compounds of the present invention contain one or more asymmetric carbons and may exist in racemic and optically active forms. All of these compounds and diastereomers are intended to be within the scope of the present invention.

Compounds of formulas (I) and (II) can be prepared by reacting the following schemes I-IV wherein the hanging substituents (X, Z, A, Y ′, Y ¹ , Y ² and X ′) As defined in formulas 1 and 2, except that the dangling substituent is
No substituents that render the IV process inoperable]. All starting materials are either commercially available or are readily prepared by those skilled in the art from commercially available starting materials.

Compounds of formula I wherein X represents hydrogen are prepared by methods analogous to those shown in Scheme 1.

[0061]

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Commercially available compound 1 is protected as its tri-tert-butyl carbamate derivative 2 and alkylated on free nitrogen to give compound 3. Benzyl bromine to a suitable N
Displacement with a nucleophile gives protected precursor 4, which is deprotected with acid to give final compound 5.

Compounds in which the —CH ₂ —Z substituent is in the “meta” position can be prepared in a similar manner using commercially available starting materials or using materials readily prepared from commercially available materials. Can be readily prepared by those skilled in the art.

Compounds of formula I wherein X is other than hydrogen are prepared by methods analogous to those shown in Scheme 2. Also, compounds of formula I wherein Z represents NY ¹ Y ² are prepared by methods analogous to those shown in Scheme 2.

[0065]

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Commercially available compound 1 was alkylated with dibromide 2 prepared by literature methods in the presence of potassium carbonate in a suitable solvent to give monobromide 3. Base without either or additives added in a suitable solvent, (when used in this scheme, R1R2 is Y ¹ Y ² of Formula 1) 3 amine R1R2NH the intermediate is heated with This was deprotected with HCl to give final compound 4.

Compounds in which the —CH ₂ —Z substituent is in the “meta” position can be prepared in a similar manner using commercially available starting materials or using materials readily prepared from commercially available materials. Can be readily prepared by those skilled in the art.

Compounds of formula I wherein Z represents NY ¹ Y ² are also prepared by methods analogous to those shown in Scheme 3.

[0069]

Embedded image

The commercially available compound 1 was protected as a tri-tert-butyl carbamate derivative 2, which was alkylated on free nitrogen to give compound 3. Displacement of the benzyl bromine with the appropriate N nucleophile gives the protected precursor 4, which is deprotected with acid to give the final compound 5
I got

Compounds in which the —CH ₂ —Z substituent is in the “meta” position can be prepared in an analogous manner using commercially available starting materials or using materials readily prepared from commercially available materials. Can be readily prepared by those skilled in the art.

The compound of formula (II) is prepared by a method similar to that shown in Scheme 4.

[0073]

Embedded image

The commercially available compound 1 is condensed with 2-guanidinobenzimidazole to give the rearranged product 2
Which is converted to its sodium salt and regioselectively alkylated with a divalent electrophile to give compound 3.

Using appropriate manipulations and protection of any chemical functional groups, the compounds of formulas (I) and (I
The synthesis of the remaining compounds of I) is carried out by methods analogous to those described above and in the experimental section.

Pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes of the compounds of the present invention are readily prepared by those skilled in the art using readily available starting materials.

To use a compound of formula (I) or (II) or a pharmaceutically acceptable salt, hydrate, solvate, ester or metal complex thereof for the treatment of humans and other mammals Is usually formulated as a pharmaceutical composition according to standard pharmaceutical practice.

Since the compounds of the present invention have been found to act as CXCR-4 receptor antagonists, they are useful for bacterial, fungal and protozoal infections, pain, thrombocytopenia, cancer, diabetes, obesity, appetite Depression, pathological starvation, asthma, allergy, Parkinson's disease, acute heart failure, hypotension, hypertension, nerve damage, atherosclerosis,
Urinary retention, osteoporosis, angina, myocardial infarction, stroke, ulcer, benign prostatic hyperplasia, migraine,
Angiogenesis, vomiting, psychotic and neurological disorders (eg, anxiety, schizophrenia,
Manic depression, depression, delirium, dementia, mental retardation) and dyskinesia (Huntington's disease and Jill de la Tourette syndrome), viral infections, including HIV infection in patients with clinical signs of AIDS It is useful for the treatment of diseases without limitation, as well as for the treatment of asymptomatic HIV-infected patients. The compounds of the present invention are also useful in treating injured or amputated spinal cord and other injury-related conditions.

The treatment of thrombocytopenia described herein is achieved by enhancing the production of platelets.

As used herein, the term “co-administration” and its derivatives are defined by the term T
In the context of PO mimetic embodiments, treating TPO mimetic compounds described herein and thrombocytopenia, including chemotherapy-induced thrombocytopenia and other conditions involving bone marrow transplantation and inhibition of platelet production may be used. It refers to the simultaneous administration of the additional active ingredient (s) known or any independent sequential administration method. Preferably, if the administration is not simultaneous, the compounds are administered within close time of each other. Furthermore, it does not matter if the compounds are administered in the same dosage form,
For example, one compound may be administered topically, and another compound may be administered orally.

As the compounds of the present invention have been found to be active as TPO mimetics, they show therapeutic utility in treating thrombocytopenia and other conditions involving suppression of platelet production.

The following assays were used in determining potency as a TPO mimetic:

Luciferase Assay Compounds of the present invention were assayed using Lamb, et al., Nucleic Acids Research 23: 3283-3289 (
1995) and Seidel, et al., Proc. Natl. Acad. Sci., USA 92: 3041-3045 (
1995), in place of the HepG2 cells used therefor in place of the TPO-responsive BaF3 cell line (Vigon et al.
Proc. Natl. Acad. Sci. USA 1992, 89, 5640-5644).
The PO receptor was tested for potency as a mimetic. Murine BaF3 cells contain T
It expresses the PO receptor and, in response to TPO, closely mimics the pattern of STAT (signal transducer and activator) activation observed primarily in murine and human bone marrow cells.

Some of the most preferred compounds of the present invention also include human UT-7 / TPO
It was also active in an in vitro proliferation assay using a leukemic megakaryocyte 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. Similarly, some of the most preferred compounds of the present invention were also positive in stimulating the maturation of megakaryocytes from human bone marrow cells.
In this assay, purified human CD34 + progenitor cells are incubated with the test compound in culture for 10 days, and then the number of cells expressing the megakaryocyte marker transmembrane glycoprotein CD41 (gpIIb) is determined by flow cytometry. (See Cwirla, SE et al Science, 1997, 276, 1696-1699).

The pharmaceutically active compounds within the scope of the present invention are useful as TPO mimetics in mammals, including humans, in need thereof.

Some of the preferred compounds within the scope of the present invention activate about 5% to 100% of the control (control is the maximal response to TPO) at a concentration of 0.1 to 30 uM in the luciferase assay. showed that. Preferred compounds of the present invention also include
The concentration of 0.1 to 30 uM promoted the growth of UT-7 / TPO cells. Preferred compounds of the invention also showed activity in the CD41 megakaryocyte assay at a concentration of 0.1-30 uM.

The activity of the compound of Example 46 in the luciferase assay is 86% of the maximal TPO effect with an EC50 of 2.7 uM.

One embodiment of the present invention provides for suppressing thrombocytopenia and platelet production, comprising administering an effective amount of a compound represented by the above formula (I) or (II) to enhance platelet production. And methods for treating other conditions associated with The compounds of formulas (I) and (II) also provide a method of treating the above conditions due to their proven ability to act as TPO mimetics. The drug can be administered to a patient in need thereof by conventional routes of administration including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intradermal, and parenteral administration.

Treating thrombocytopenia and other conditions associated with suppression of platelet production, including administering an effective amount of a compound of Formula (I) or (II) above to enhance platelet production. Provide a way. Compounds of formula (I) and (II)
Also, because of their proven ability to act as TPO mimetics, they provide a method of treating the above conditions. The drugs may be administered to a patient in need thereof by conventional routes of administration including, but not limited to, intravenous, intramuscular, oral, subcutaneous, transdermal and parenteral administration.

Pharmaceutical formulations may be mixed, granulated, and compressed (if necessary for tablet form) or mixed, filled and dissolved as appropriate to obtain the desired oral or parenteral product. And prepared according to conventional techniques of medicinal chemists, including

The dosage of the pharmaceutically active compound of the present invention in the above pharmaceutical dosage unit is an effective non-toxic amount, preferably selected from the range of 0.001 to 100 mg / kg of the active compound, and is preferably 0. 0.0001 to 50 mg / kg. When treating a human patient in need of a pharmaceutically active compound of the present invention, the selected dose is preferably administered orally or parenterally 1 to 6 times daily. Preferred methods of parenteral administration include topical, rectal, transdermal, injection, or continuous administration by infusion. Oral dosage units for human administration are preferably from 0.05 to 35 active compounds.
Contains 00mg. Oral administration, which administers low doses, is preferred. However, parenteral administration at high doses can also be used if it is safe and convenient for the patient.

The optimal dosage to be administered can be readily determined by one skilled in the art, and will vary with the particular activity in use, the strength of the formulation, the mode of administration, and the progress of the condition. Additional factors dependent on the particular patient being treated, including patient age, weight, diet, and time of administration, require adjustment of the dosage.

The method of the present invention for inducing TPO mimetic activity in mammals, including humans, comprises:
Administering to a subject in need of such activity an effective TPO mimetic amount of a pharmaceutically active compound of the present invention.

The present invention also provides a method for preparing a medicament for use as a TPO mimetic,
There is provided the use of a compound according to I) or (II).

The present invention also provides for the use of a compound of Formula (I) or (II) in the preparation of a therapeutic medicament.

The present invention also relates to a method for preparing a medicament for enhancing platelet production, comprising formula (I) or (I)
There is provided the use of a compound according to I).

The present invention also relates to the preparation of a medicament for the treatment of thrombocytopenia.
There is provided the use of a compound according to II).

The present invention also provides a pharmaceutical composition for use as a TPO mimetic comprising a compound of formula (I) or (II) and a pharmaceutically acceptable carrier.

The present invention also provides a pharmaceutical composition for treating thrombocytopenia, comprising a compound of formula (I) or (II) and a pharmaceutically acceptable carrier.

The present invention also provides a pharmaceutical composition for enhancing platelet production, comprising a compound of formula (I) or (II) and a pharmaceutically acceptable carrier.

Furthermore, the pharmaceutically active compounds of the present invention are known to antagonize the CXCR-4 receptor or have a therapeutic effect on conditions treatable with a CXCR-4 receptor antagonist. Other compounds that exhibit or are known to treat thrombocytopenia, including chemotherapy-induced thrombocytopenia and other conditions involving bone marrow transplantation and suppression of platelet production, or TPO mimics Can be co-administered with additional active ingredients such as compounds that are known to have utility when used in combination with an active ingredient.

No unacceptable toxicological effects are expected when a compound of the present invention is administered in accordance with the present invention.

The activity of the compounds of formulas (I) and (II) as antagonists of the CXCR-4 receptor is demonstrated by the following tests.

CXCR-4 / SDF-1 Assay Protocol RBLs transfected with the SDF-1 receptor were plated on assay plates. Dye loading buffer (EMEM w / Earl salt w / L-glutamine and 1X Sulfinpyrozone) and 10% BSA,
100 uL) was added to each well and the plate was incubated at 37 ° C. for 90 minutes. The dye loading buffer was aspirated from the plate. Hydrolysis buffer (EMEM
w / Earl salt w / L-glutamine and 1X sulfinpyrozone, 100 uL
) Was added to each well and the plate was incubated at 37 ° C. for 10 minutes. The cells were washed with washing buffer (1 × Krebs Ringer, 15 mM HEPES, 1 mM M
Washed three times with gCl, 1 mM CaCl and 1X sulfinpyrazone and 0.10% gelatin), then the wash buffer was dispensed into each well (100 uL / well). The plate was incubated 37 ° C. for 10 minutes and then placed in a FLIPR ^{T M} (Molecular Debaishizu (Molecular Devices)). Gelatin buffer (1X Krebs Ringer, 15 mM HEPES, 1 mM MgCl, 1 m
Test compounds in M CaCl and 0.10% gelatin, 50 uL) were pre-incubated with the cells for 3 minutes and then ligand (SDF-1 alpha / PBS)
F, 15 nM final concentration). The plate was incubated for 2 minutes with constant measurement.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Accordingly, the following examples are intended merely to illustrate, and do not limit the scope of the invention in any way.

Experimental Details Example 1 1- [4- (4-Acetyl-1-piperazinomethyl) phenylmethyl] -1,4,8
Preparation of 1,11-tetraazacyclotetradecane pentahydrochloride a) 1- [4- (Bromomethyl) phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl) -1,4,8,11- Α, α′-Dibromo-p-xylene (36.0 g, 136 mmol) was stirred in tetraazacyclotetradecane acetonitrile (500 mL) at 60 ° C. until dissolved. Potassium carbonate (
3.5 g, 25.3 mmol) were added and then 1,4,8-tri- (t-butyloxycarbonyl) -1,4,8,11-tetraazacyclotetradecane (B. Boitr
el et. al., Tetrahedron Lett., 1995, 36, 4995) (6.0 g, 11.98 mm)
ol) in acetonitrile (100 mL) was added dropwise. The mixture was stirred for 6 hours, cooled and partially evaporated. Excess dibromoxylene was filtered off, the mother liquor was evaporated in vacuo and chromatographed (silica gel, 50% dichloromethane / hexane to 2% methanol / dichloromethane) to give the title compound as a foam (
7.4 g, 90%). MS (ES +) m / e 683 and 685 [M + H] ^< +>.

B) 1- [4- (4-acetyl-1-piperazinomethyl) phenylmethyl] -4,
8,11-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane 1- [4- (bromomethyl) phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl ) -1,4,8,11-Tetraazacyclotetradecane (326 mg,
0.477 mmol), 1-acetylpiperazine (95 mg, 0.741 mmol)
) And anhydrous potassium carbonate (350 mg, 2.53 mmol) in acetonitrile (30 mL) were stirred together at 50 ° C for 1 hour. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, 0-3% methanol / dichloromethane) to give the title compound as an oil (300
mg, 86%). MS (ES +) m / e 731 [M + H] ^< +>.

C) 1- [4- (4-acetyl-1-piperazinomethyl) phenylmethyl] -1,
4,8,11-Tetraazacyclotetradecane pentahydrochloride 1- [4- (4-acetyl-1-piperazinomethyl) phenylmethyl] -4,8,1
1-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane (175 mg, 0.239 mmol) in 1,4-dioxane (1.0 mL)
)), A 4 M solution of hydrogen chloride in 1,4-dioxane (1.0 mL) was added. The mixture was left for 2 hours and the white solid was collected and washed successively with 1,4-dioxane, diethyl ether and hexane. The hygroscopic solid was dried under vacuum (80 ° C.) to give the title compound (35 mg, 34%). MS (ES +) m / e 431 [M + H] ^< +>.

Example 2 1- [4- (1,4-Diazacycloheptane-1-ylmethyl) phenylmethyl]
Preparation of -1,4,8,11-tetraazacyclotetradecane hexahydrochloride Example 1 except that homopiperazine was used instead of 1-acetylpiperazine.
The title compound was prepared according to the method of (a)-(c) (total yield 27%). ¹ H
_{NMR (300MHz, d3-MeOD /} D 2 O) δ 7.67 (d, 2H), 7
.50 (d, 2H), 4.52 (s, 2H), 3.98 (s, 2H), 3.90 (s
, 2H), 3.62 (m, 2H), 3.53-3.20 (m, 8H), 3.15 (m
, 2H), 2.95 (m, 4H), 2.35 (m, 2H), 2.19 (m, 4H)
, 2.09 (m, 2H), 1.26 (m, 4H).

Example 3 1- [4- (azacycloheptane-1-ylmethyl) phenylmethyl] -1,4,8
Preparation of 1,11-tetraazacyclotetradecane pentahydrochloride The title compound was prepared according to the method of Example 1 (a)-(c) except that hexamethyleneimine was used instead of 1-acetylpiperazine (total yield). Rate 45%)
. MS (ES +) m / e 402 [M + H] ^< +>.

Example 4 Preparation of 1- [4- (1-piperidinomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride Except that piperidine was used instead of 1-acetylpiperazine In Example 1 (a
)-(C) to give the title compound (total yield 75%). MS (E
S +) m / e 388 [M + H] ^< +>.

Example 5 Preparation of 1- [4- (1-morpholinomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride Using morpholine instead of 1-acetylpiperazine Other than Example 1 (a
)-(C) to give the title compound (total yield 60%). ¹ H N
MR (300 MHz, D ₂ O) δ 7.7-7.5 (m, 4H), 4.5 (s, 2H)
), 4.1 (m, 4H), 3.8 (br m, 2H), 3.6-3.0 (br m, 1
6H), 2.2 (brs, 4H), 1.2 (s, 4H).

Example 6 1- [4- (azacyclotridecane-1-ylmethyl) phenylmethyl] -1,4,
Preparation of 8,11-tetraazacyclotetradecane pentahydrochloride The title compound was prepared according to the method of Example 1 (a)-(c) except that azacyclotridecane was used instead of 1-acetylpiperazine ( (13% overall yield)
. MS (ES +) m / e 522 [M + H + HCl] ⁺ .

Example 7 1- [4- (5,6,14,15-dibenzo-1,4-dioxa-8,12-diazacyclopentadeca-5,14-dien-8-ylmethyl) phenylmethyl ] -1,4
Preparation of 8,8,11-Tetraazacyclotetradecane hexahydrochloride 5,6,14,15-Dibenzo-1,4-dioxa-8,12-diazacyclopentadeca-5, instead of 1-acetylpiperazine The title compound was prepared according to the method of Example 1 (a)-(c) except that 14-diene was used (total yield 42%).
. ^{1 H NMR (300MHz, d6-} DMSO, D 2 O) δ 7.90-6.95
(M, 12H), 4.7-4.1 (m, 14H), 3.5 (s, 2H), 3.45 (
s, 2H), 3.5-3.0 (br m, 6H), 2.85-2.30 (br m, 2
H) 2.3-2.0 (br m, 6H), 1.2 (br s, 6H,).

Example 8 1- [4- (1,4,7-Trioxa-10-azacyclododecane-10-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride Preparation of The title compound was prepared according to the method of Example 1 (a)-(c) except that 1-aza-12-crown was used instead of 1-acetylpiperazine (total yield: 86).
%). MS (ES +) m / e 478 [M + H] ^< +>.

Example 9 1- [4- (1,4,7,10-tetraoxa-13-azacyclopentadecane-
Preparation of 13-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride Example 1 except that 1-aza-15-crown-5 was used instead of 1-acetylpiperazine. The title compound was prepared according to the method of (a)-(c) (total yield: 50%). MS (ES +) m / e 522 [M + H] ^< +>.

Example 10 1- [4- (1,4,10-Trioxa-7,13-diazacyclopentadecane-
7-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane hexahydrochloride Preparation of 1,4,10-trioxa-7,13-diaza-cyclopentadecane in place of 1-acetylpiperazine The title compound was prepared according to the method of Example 1 (a)-(c) except that it was used (total yield: 21%). MS (ES +) m / e 261 [
M + 2H] ²⁺ , 557.

Example 11 1- {4- [4- (2-pyridyl) -1-piperazinomethyl] phenylmethyl} -1
Preparation of 4,8,11-tetraazacyclotetradecane hexahydrochloride According to the method of Example 1 (a)-(c) except that 1- (2-pyridyl) piperazine was used instead of 1-acetylpiperazine. The title compound was prepared (24% overall yield). MS (ES +) m / e 466 [M + H] ⁺ , 502.

Example 12 1- {4- [4- (2-Pyrimidyl) -1-piperazinomethyl] phenylmethyl}-
Preparation of 1,4,8,11-tetraazacyclotetradecane hexahydrochloride The method of Example 1 (a)-(c) except that 1- (2-pyrimidyl) piperazine was used instead of 1-acetylpiperazine. The title compound was prepared according to (total yield 25%). MS (ES +) m / e 467 [M + H] ⁺ , 503.

Example 13 Preparation of 1- [4- (2-guanidinobenzimidazol-1-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride a) 1- [4 -(2-guanidinobenzimidazol-1-ylmethyl) phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane 1- [4- (bromomethyl ) Phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane (293 mg,
0.429 mmol) and 2-guanidinobenzimidazole (225 mg,
(1.28 mmol) in acetonitrile (5 mL) was stirred and heated at reflux for 30 minutes. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, 0-5% methanol / dichloromethane) to give the title compound as a yellow gum (115 mg, 34%). MS (ES +) m / e
778 [M + H] ⁺ .

B) 1- [4- (2-Guanidinobenzimidazol-1-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride 1- [4- (2-guanidino Benzimidazol-1-ylmethyl) phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane (115 mg, 0.148 mmol) in 1,4- To a solution in dioxane (2.0 mL) was added a 4M solution of hydrogen chloride in 1,4-dioxane (1.5 mL).
) Was added. The mixture was left overnight and the red solid was collected and washed successively with 1,4-dioxane, diethyl ether and hexane. The hygroscopic solid was dried under vacuum (80 ° C.) to give the title compound (72 mg, 73%). MS (ES +) m / e 478 [M + H] ^< +>.

Example 14 Preparation of 1- [4- (1-piperazinomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane hexahydrochloride Except that piperazine was used instead of 1-acetylpiperazine In Example 1 (a
)-(C) to give the title compound (32% overall yield). MS (E
S +) m / e 389 [M + H] ^< +>.

Example 15 Preparation of 1,4-bis- [4- (1,4,8,11-tetraazacyclotetradecane-1-ylmethyl) phenylmethyl] piperazine decahydrochloride a) 1,4-bis -{4- [4,8,11-tri- (t-butoxycarbonyl) -1,
4,8,11-Tetraazacyclotetradecane-1-ylmethyl] phenylmethyl}
Piperazine 1- [4- (bromomethyl) phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane (287 mg,
0.449 mmol), piperazine (92 mg, 1.07 mmol) and anhydrous potassium carbonate (100 mg, 0.724 mmol) in acetonitrile (5 mL) were stirred together vigorously at 50 ° C. for 1 hour. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, 0-5% methanol / dichloromethane) to give the title compound as an oil (114 mg, 21%). MS m / e 646 [M + 2H] ²⁺ .

B) 1,4-bis- [4- (1,4,8,11-tetraazacyclotetradecane-1
-Ylmethyl) phenylmethyl] piperazine decahydrate 1- [4- (4-acetyl-1-piperazinomethyl) phenylmethyl] -4,8,
1,4-bis- {4- [4,8,11-tri- (t-butoxycarbonyl) instead of 11-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane -1,4,8,11-tetraazacyclotetradecane-1-ylmethyl]
According to the method of Example 1 (c) except that phenylmethyl} piperazine was used,
The title compound was prepared (56% overall yield). MS (ES +) m / e 346 [M +
2H] ²⁺ .

Example 16 1- [4- (1,5-Diazacyclooctan-1-ylmethyl) phenylmethyl]
Preparation of -1,4,8,11-tetraazacyclotetradecane hexahydrochloride 1,5-diazacyclooctane dihydrobromide (G. Ewin et al., J.) instead of 1-acetylpiperazine Chem. Res., Synop., 1985, 11, 334), but the title compound was prepared according to the method of Example 1 (a)-(c) (total yield: 6%). ¹ H NMR (300 MHz, d6-DMSO / D ₂ O) δ 7.74 (
s, 4H), 4.43 (br s, 4H), 3.6-3.0 (br m, 20H),
2.21 (br m, 12H).

Example 17 1- (4- {bis [2- (diethylamino) ethyl] aminomethyl} phenylmethyl)
-1,4,8,11-Tetraazacyclotetradecane heptahydrochloride a) 1- [4- (bromomethyl) phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl) -1,4, Α, α′-Dibromo-p-xylene (36.0 g, 136 mmol) was stirred in 8,11-tetraazacyclotetradecane acetonitrile (500 mL) at 60 ° C. until dissolved. Potassium carbonate (
3.5 g, 25.3 mmol) were added and then 1,4,8-tri- (t-butyloxycarbonyl) -1,4,8,11-tetraazacyclotetradecane (B. Boitr
el et al., Tetrahedron Lett., 1995, 36, 4995) (6.0 g, 11.98 mmo)
A solution of l) in acetonitrile (100 mL) was added dropwise. The mixture was stirred for 6 hours, cooled and partially evaporated. Excess dibromoxylene is filtered off, the mother liquor is evaporated in vacuo and chromatographed (silica gel, 50% dichloromethane / hexane to 50%).
2% methanol / dichloromethane) to give the title compound as a foam (7
.4 g, 90%). MS (ES +) m / e 683 and 685 [M + H] ^< +>.

B) 1- (4- {bis [2- (diethylamino) ethyl] aminomethyl} phenylmethyl) -4,8,11-tri- (t-butoxycarbonyl) -1,4,8,11- Tetraazacyclotetradecane 1- [4- (bromomethyl) phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane (279 mg,
0.408 mmol), N, N, N ', N'-tetraethyldiethylenetriamine (2
11 uL, 0.820 mmol) and anhydrous potassium carbonate (100 mg, 0.72).
4 mmol) in acetonitrile (5 mL) together at 50 ° C. for 1 hour,
Stir vigorously. The solvent was evaporated and the residue was purified by flash chromatography (silica gel, 0-5% methanol / dichloromethane) to give the title compound as an oil (210 mg, 63%). MS (ES +) m / e 818 [M + H] ^< +>.

C) 1- (4- {bis [2- (diethylamino) ethyl] aminomethyl} phenylmethyl) -1,4,8,11-tetraazacyclotetradecane heptahydrochloride 1- (4- {bis [2- (diethylamino) ethyl] aminomethyl} phenylmethyl)
-4,8,11-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane (200 mg, 0.244 mmol) in 1,4-dioxane (
(2.0 mL) was added a 4 M solution of hydrogen chloride in diethyl ether (1.5 mL). The mixture was left overnight and the solid was collected and washed successively with diethyl ether and hexane. Dry the hygroscopic solid in vacuo (80 ° C.) to give the title compound (100 mg, 53%)
I got ¹ H NMR (300 MHz, d6-DMSO / D ₂ O) δ 7.6 (m
, 4H), 4.0-2.9 (br m, 24H), 2.2 (br s, 4H), 1.1
1 (m, 12H), 1.07 (t, 12H).

Example 18 1- {4-[(2-aminoethyl) (3-aminopropyl) aminomethyl] phenylmethyl} -1,4,8,11-tetraazacyclotetradecane heptahydrochloride a) ( 2-phthalimidoethyl) (3-phthalimidoprop-1-yl) amine N- (2-aminoethyl) -1,3-propanediamine (10.0 mL, 79.2)
mmol), a mixture of phthalic anhydride (24.6 g, 166 mmol) and p-toluenesulfonic acid (1.0 g, 5.26 mmol) in toluene (500 mL) was stirred, and the mixture was mixed with Dean & Stark head. Heated at reflux for 5 hours. The mixture was cooled and diluted with hexane. The solid was collected, washed with ether and hexane, and dried to give the title compound as a pale yellow solid (21 g, 72%). MS (ES +) m / e 378 [
M + H] ⁺ .

B) 1- [4-{[(2-phthalimidoethyl) (3-phthalimidoprop-1-yl) amino] methyl} phenylmethyl] -1,4,8,11-tetraazacyclotetradecane / 5 Example 1 (a) -1 (c) Except that (2-phthalimidoethyl) (3-phthalimidoprop-1-yl) amine was used instead of N, N, N ', N'-tetraethyldiethylenetriamine hydrochloride The title compound was prepared according to the method of (a total yield of 58%).
. MS (ES +) m / e 341 [M + 2H] ²⁺ .

C) 1- (4-{[(2-aminoethyl) (3-aminopropyl) amino] methyl} phenylmethyl) -1,4,8,11-tetraazacyclotetradecane heptahydrochloride ethanol ( 1- [4-{[(2-phthalimidoethyl) (3-phthalimidoprop-1-yl) amino] methyl} phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride in 5 mL). The salt (200 mg, 0.234 mmol) was treated with hydrazine hydrate (2.0 mL, 64.2 mmol) and stirred at 60 ° C. for 4 hours. The solvent was evaporated and the residue was slurried in diethyl ether containing potassium carbonate. The mixture was filtered and the filtrate was filtered with HCl in 4 in 1,4-dioxane.
M solution and the mixture was left overnight. The solid was collected, washed with diethyl ether and hexane, then dried in vacuo (80 ° C.) to give the title compound (150 mg, 95%). MS (ES +) m / e 456 [M + HCl + H] ⁺
.

Example 19 1- {4- [di- (2-pyridyl) aminomethyl] phenylmethyl} -1,4,8,1
1-tetraazacyclotetradecane pentahydrochloride a) 1- {4- [di- (2-pyridyl) aminomethyl] phenylmethyl} -4,8,1
1-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane 2,2'-dipyridylamine (77 mg, 0.500 mmol) in sodium hydride (60% dispersion in mineral oil 18. 8 mg, 0.470 mmol) of anhydrous DMF (1
0 mL) and the mixture was stirred at 25 ° C. under nitrogen for 1 hour. 1
-[4- (Bromomethyl) phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane (292 mg, 0.1%).
(427 mmol) in anhydrous DMF was added and the mixture was stirred overnight. Water was added and the mixture was extracted twice with diethyl ether and then once with ethyl acetate. The combined organic extracts were washed with water, dried (anhydrous potassium carbonate) and evaporated to a yellow gum, which was flash chromatographed (silica gel, 0%).
Purification by ５5% methanol / dichloromethane) provided the title compound as an oil (100 mg, 30%). MS (ES +) m / e 774 [M + H] ^< +>.

B) 1- {4- [di- (2-pyridyl) aminomethyl] phenylmethyl} -1,4,8
, 11-Tetraazacyclotetradecane pentahydrochloride 1- (4- {bis [2- (diethylamino) ethyl] aminomethyl} phenylmethyl)
1- {4- [di- (2-pyridyl) aminomethyl] phenylmethyl} instead of -4,8,11-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane -4,8,11-tri- (t-butoxycarbonyl) -1,4,8,11
-The title compound was prepared according to the method of Example 1 (c) except that tetraazacyclotetradecane was used (94% overall yield). MS (ES +) m / e 474 [
M + H] ⁺ .

Example 20 1- [4- (2-Thiazolylaminomethyl) phenylmethyl] -1,4,8,11-
Tetraazacyclotetradecane pentahydrochloride The title compound was prepared according to the method of Example 17 (a) -1 (c) except that 2-aminothiazole was used instead of N, N, N ', N'-tetraethyldiethylenetriamine. Prepared (19% overall yield). MS (ES +) m / e 202 [M + 2H] 2 +.

Example 21 1,4-bis [2- (2-benzimidazolylamino) -5,5-di (2-pyridyl)
) -4-Oxo-5H-imidazolin-3-ylmethyl] benzene, bis-trifluoroacetate a) 2- (2-benzimidazolylamino) -5,5-di (2-pyridyl) -5H
-Imidazolin-4-one 2,2'-pyridyl (15.8 g, 74.4 mmol) and 2-guanidinobenzimidazole (19.5 g, 111.7 mmol) in methanol (440 mL)
The aqueous mixture was treated with sodium hydroxide (2.97 g, 74.4 mmol) in water (74 mL)
The mixture was treated with a medium solution and the resulting mixture was left at room temperature for 4 hours. Filtering the crystalline material,
The mother liquor was left for 3 weeks. The precipitated solid was filtered and dried under vacuum to give the title compound as its sodium salt (10.5 g, 36%). ¹ H NMR (300 MHz
, D ₆ -DMSO) δ 11.55 (br s, 1H), 10.05 (br s, 1
H), 8.47 (m, 2H), 7.76 (m, 2H), 7.68 (m, 2H), 7.
25 (m, 4H), 6.90 (m, 2H). Further concentration of the mother liquor slowly yielded a third solid, which was filtered and dried in vacuo to give the title compound as a solid (1
.25 g, 5%). ¹ H NMR (300 MHz, d ₆ -DMSO) δ 11.8 (
br s, 2H), 10.5 (br s, 1H), 8.64 (m, 2H), 7.89
(M, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.44 (m, 4H),
7.07 (m, 2H).

B) 1,4-bis [2- (2-benzimidazolylamino) -5,5-di (2-pyridyl) -4-oxo-4H-imidazolin-3-ylmethyl] benzene, bis-trifluoroacetic acid Salt 2- (2-benzimidazolylamino) -5,5-di (2-pyridyl)-at room temperature
5H-imidazolin-4-one (390 mg, 1.00 mmol) in DMF (1
α, α′-Dibromo-p-xylene (120 mg, 0.45 mmol)
l) was added all at once. The reaction was stirred at room temperature for 12 hours, then concentrated in vacuo. The residue was dissolved in DMSO (5 mL) and reverse phase HPLC [ODS, 0-90%
CH ₃ CN / H ₂ O (0.1% TFA)] to give the title compound as a yellow solid (240 mg, 50%). MS (ES +) m / e 841 [M + H] ^< +>.

Example 22 2,6-Bis [2- (2-benzimidazolylamino) -5,5-di (2-pyridyl)
) -4-Oxo-5H-imidazolin-3-ylmethyl] pyridine, bis-trifluoroacetate The procedure was carried out except that 2,6-bis (bromomethyl) pyridine was used in place of α, α′-dibromo-p-xylene. The title compound was prepared according to the method of Example 21 (a) -1 (b) (total yield 2%). MS (ES +) m / e 842 [M + H] ^< +>.

Example 23 1,4-Bis {[1- (2-benzimidazolyl) -1-guanidino] methyl} benzene 2-guanidinobenzimidazole (350 mg, 2.0 mmol) at 0 ° C.
NaH (88 mg of a 60% dispersion in mineral oil, 2.2 mmol) was added in portions to a solution of DMF over 5 minutes. The solution was warmed to room temperature and stirred for 45 minutes. The solution was cooled to 0 ° C. and α, α′-dibromo-p-xylene (264 mg, 1.
0 mmol) was added in several portions over 1 hour. The solution was stirred for another hour, concentrated under reduced pressure and dissolved in ethyl acetate. The organic solution was diluted with aqueous NH ₄ Cl, Na
Washed with Cl, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate) to give the title compound as a white powder (350mg, 77%). MS (ES +) m / e 453 [M
+ H] ⁺ .

Example 24 Preparation of 1- [3- (2-guanidinobenzimidazol-1-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride a) 1- [3 -(Bromomethyl) phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane acetonitrile (350 mL) at 60 ° C. at α, α′- Dibromo-m-xylene (22.0 g, 83.3 mmol) was stirred until dissolved. Potassium carbonate (
2.0 g, 14.5 mmol) were added, followed by 1,4,8-tri- (t-butyloxycarbonyl) -1,4,8,11-tetraazacyclotetradecane (B. Boitr
el et al., Tetrahedron Lett., 1995, 36, 4995) (4.0 g, 7.99 mmol)
) In acetonitrile (100 mL) was added dropwise. The mixture was stirred for 6 hours, cooled and partially evaporated. Excess dibromoxylene is filtered off, the mother liquor is evaporated under reduced pressure and chromatographed (silica gel, 50% dichloromethane / hexane to 2%).
% Methanol / dichloromethane) to give the title compound as a foam (4.
55 g, 83%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.30-7.
19 (m, 4H), 4.49 (s, 2H), 3.51 (s, 2H), 3.45-3.
20 (m, 12H), 2.62 (m, 2H), 2.38 (m, 2H), 1.91 (
m, 2H), 1.68 (m, 2H), 1.47-1.43 (m, 27H).

B) 1- [3- (2-Guanidinobenzimidazol-1-ylmethyl) phenylmethyl] -4,8,11-tri (t-butoxycarbonyl) -1,4,8,11-tetraazacyclo Tetradecane 1- [3- (bromomethyl) phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane (293 mg,
0.43 mmol), 2-guanidinobenzimidazole (225 mg, 1.28
A mixture of 7 mmol) and potassium carbonate (100 mg, 0.724 mmol) was heated together in acetonitrile (5 mL) at reflux with vigorous stirring for 1 hour. Flash chromatography (silica gel, dichloromethane to
4% methanol / dichloromethane) to give the title compound as a yellow gum (115 mg, 34%). MS (ES +) m / e 778 [M + H] ^< +>.

C) 1- [3- (2-Guanidinobenzimidazol-1-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride 1- [3- (2-guanidino Benzimidazol-1-ylmethyl) phenylmethyl] -4,8,11-tri (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane (70 mg, 0.090 mmol) in ethanol (2 mL
)) Was treated with HCl in dioxane (4M, 2.0 mL, 8.0 mmol) and left overnight. The solid was filtered and washed with dioxane, ether and hexane to give the title compound as a red solid (50mg, 84%). MS (ES +) m /
e 478 [M + H] ⁺ .

Example 25 1- [4- (2-Aminobenzimidazol-1-ylmethyl) phenylmethyl]
-1,4,8,11-tetraazacyclotetradecane pentahydrochloride a) 1- [4- (Bromomethyl) phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl) -1,4, Α, α′-Dibromo-p-xylene (36.0 g, 136 mmol) was stirred in 8,11-tetraazacyclotetradecane acetonitrile (500 mL) at 60 ° C. until dissolved. Potassium carbonate (
3.5 g, 25.3 mmol) were added and then 1,4,8-tri- (t-butyloxycarbonyl) -1,4,8,11-tetraazacyclotetradecane (B. Boitr
el et al., Tetrahedron Lett., 1995, 36, 4995) (6.0 g, 11.98 mmo)
A solution of l) in acetonitrile (100 mL) was added dropwise. The mixture was stirred for 6 hours, cooled and partially evaporated. Excess dibromoxylene is filtered off, the mother liquor is evaporated in vacuo and chromatographed (silica gel, 50% dichloromethane / hexane to 50%).
2% methanol / dichloromethane) to give the title compound as a foam (7
.4 g, 90%). MS (ES +) m / e 683 and 685 [M + H] ^< +>.

B) 1- [4- (2-aminobenzimidazol-1-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride 2 in place of 2-guanidinobenzimidazole Using -aminobenzimidazole, 1- [3- (bromomethyl) phenylmethyl] -4,8,11-tri- (t
1- [4- (bromomethyl) phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl) -1,4 in place of -butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane Using 8,11-tetraazacyclotetradecane,
The procedure described in Examples 24b and 1c was performed to give the title compound as a solid. MS (ES +) m / e 219 [M + 2H] ²⁺ .

Example 26 1,8-bis- [4- (1,4,8,11-tetraazacyclotetradecane-1-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane.
Twelve hydrobromide salts a) 4,11-bis (p-toluenesulfonyl) -1,8-bis- [4- (4,8,
11-tris {p-toluenesulfonyl} -1,4,8,11-tetraazacyclotetradecane-1-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane 8,11-tris- (p-toluenesulfonyl) -1,4,
8,11-tetraazacyclotetradecane (590 mg, 0.890 mmol) (
M. Ciampolini et al., Inorg. Chem., 1987, 26, 3527), α, α'-dibromo-
p-xylene (117 mg, 0.445 mmol), potassium carbonate (369 mg)
, 2.67 mmol) and acetonitrile (10 mL) at 80 ° C. for 1 hour.
Heated for 8 hours, then cooled and partitioned between water and dichloromethane. The extracts were washed (sat. Aq. NaCl), dried (MgSO ₄ ) and the solvent was removed in vacuo. The crude material is chromatographed (silica gel, 50-100% ethyl acetate /
Hexane followed by 5% methanol / dichloromethane) gave the title compound as an amorphous solid (35 mg, 8%). MS (ES +) m / e 1019 [M
+ 2H] ²⁺ .

B) 1,8-bis- [4- (1,4,8,11-tetraazacyclotetradecane-1
-Ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane / 12 hydrobromide 4,11-bis (p-toluenesulfonyl) -1,8-bis- [4- (4 , 8,11-
Tris {p-toluenesulfonyl} -1,4,8,11-tetraazacyclotetradecane-1-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane (35 mg, 0.017 mmol) is added to 48 % Aqueous HBr / acetic acid (2: 3
(2.5 mL) at reflux for 18 h. After cooling, the solid is filtered, washed (acetic acid, dichloromethane, ether) and dried (60 ° C. under vacuum)
), To give the title compound as a pink solid (26 mg, 87%). MS (ES
+) M / e 403 [M + 2H] ²⁺ .

Example 27 1,11-bis- [4- (1,4,8,11-tetraazacyclotetradecane-1-
Ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane / 12 hydrobromide The title compound was obtained as a solid by the method described in Example 26 (8 mg, 2%
). ¹ H NMR (300 MHz, D ₂ O) δ 7.57 (d, 4H, J = 7.9H)
z), 7.47 (d, 4H, J = 7.9 Hz), 4.29 (s, 4H), 4.03 (s
, 4H), 3.39-2.94 (m, 48H), 2.13 (m, 8H), 1.97 (
m, 4H).

Example 28 1- [4- (N- {3- (methylamino) propyl} -N-methylaminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane hexahydrochloride Using N, N'-dimethyl-1,3-propanediamine instead of 2-guanidinobenzimidazole, 1- [3- (bromomethyl) phenylmethyl] -4,8,1
1- [4- (bromomethyl) phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl) in place of 1-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane The procedure described in Examples 24b and 1c was performed using (carbonyl) -1,4,8,11-tetraazacyclotetradecane to give the title compound as a solid. ¹ H NMR (300 MHz, DMSO / D ₂ O) δ 7.8
(M, 4H), 4.4 (m, 4H), 3.6 (s, 6H), 3.4-2.9 (m, 1
4H), 2.65 (m, 4H), 2.15 (m, 8H).

Example 29 1- [4- (N- {3,4-methylenedioxyphenylmethyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride 1- [4- (bromomethyl) phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane (61 mg, 0
0.089 mmol) and 3,4-methylenedioxybenzylamine (40 mg,
(0.267 mmol) in ethanol (3 mL) was heated at 80-90 ° C. for 3 hours. The solvent was evaporated, the residue was redissolved in DMSO and purified by preparative HPLC (20
(-80% acetonitrile / water + 0.1% TFA). The resulting purified tri- (t-butoxycarbonyl) intermediate was converted to ethanol (2.
5 mL) and HCl in dioxane (4.0 M, 2.0 mL, 8 mmol)
Was added. The mixture was left for 24 hours and then evaporated to give the title compound. MS (ES +) m / e 454 [M + H] ^< +>.

Examples 30-34 The following compounds were prepared according to the method described in Example 29 using the appropriate amine.

1- [4- (N- {3,5-difluorophenylmethyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride. MS (ES
+) M / e 446 [M + H] ⁺ . 1- [4- (phenothiazin-10-ylmethyl) phenylmethyl] -1,4,8,
11-tetraazacyclotetradecane pentahydrochloride. MS (ES +) m / e 50
2 [M + H] ⁺ . 1- [4- (N- {4-amino-2-methylquinolin-6-yl} aminomethyl)
Phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride.
MS (ES +) m / e 476 [M + H] ^< +>. 1- [4- (N- {4- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride. MS (ES +) m / e 536 [M + H] ^< +>. 1- [4- (N- {3- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride. MS (ES +) m / e 536 [M + H] ^< +>.

Example 35 1- [5-Nitro-3- (N- {3- (2-thienyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclo Tetradecane
Pentahydrochloride a) 1- [3- (bromomethyl) -5-nitrophenylmethyl] -4,8,11-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane α, 1,3-bis (bromomethyl) -5 in place of α'-dibromo-m-xylene
The title compound was obtained as a foam following the procedure described in Example 1 using -nitrobenzene. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.12 (m,
2H), 7.65 (s, 1H), 4.53 (s, 2H), 3.63 (s, 2H),
3.5-3.2 (m, 12H), 2.65 (m, 2H), 2.40 (m, 2H), 1
.92 (m, 2H), 1.70 (m, 2H), 1.55-1.30 (m, 27H).

B) 1- [5-Nitro-3- (N- {3- (2-thienyl) pyrazol-5-yl}
Aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride 1- [4- (bromomethyl) phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl)- 1,1-, 8,11-tetraazacyclotetradecane
[3- (bromomethyl) -5-nitrophenylmethyl] -4,8,11-tri- (t-
(Butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane using 5-amino-3- (2-thienyl) pyrazole instead of 3,4-methylenedioxybenzylamine The procedure described in Example 29 was performed to give the title compound as a solid. MS (ES +) m / e 513 [M + H] ^< +>.

Examples 36-39 The following compounds were prepared according to the method described in Example 35 using the appropriate amine. 1- [5-nitro-3- (phenothiazin-10-ylmethyl) phenylmethyl]
-1,4,8,11-tetraazacyclotetradecane pentahydrochloride. MS (ES +)
m / e 547 [M + H] ⁺ . 1- [3- (N- {4-amino-2-methylquinolin-6-yl} aminomethyl)
-5-nitrophenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride. MS (ES +) m / e 521 [M + H] ^< +>. 1- [3- (N- {4- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) -5-nitrophenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride . MS (ES +) m / e 581 [M + H] ^< +>. 1- [3- (N- {3- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) -5-nitrophenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride . MS (ES +) m / e 581 [M + H] ^< +>.

Example 40 1- [5-Bromo-3- (N- {3- (2-thienyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclo Tetradecane
Pentahydrochloride a) 1- [5-Bromo-3- (bromomethyl) phenylmethyl] -4,8,11-
Using 5-bromo-1,3-bis (bromomethyl) benzene in place of tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane α, α'-dibromo-m-xylene The title compound was obtained as a foam by performing the procedure described in Example 1a. MS (ES +) m / e 761, 763, 765 [M + H] ⁺ .

B) 1- [5-Bromo-3- (N- {3- (2-thienyl) pyrazol-5-yl}
Aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride 1- [4- (bromomethyl) phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl)- 1,1-, 8,11-tetraazacyclotetradecane
[5-Bromo-3- (bromomethyl) phenylmethyl] -4,8,11-tri- (t-
(Butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane using 5-amino-3- (2-thienyl) pyrazole instead of 3,4-methylenedioxybenzylamine The procedure described in Example 29 was performed to give the title compound as a solid. MS (ES +) m / e 546, 548 [M + H] ^< +>.

Examples 41-44 The following compounds were prepared according to the method described in Example 40 using the appropriate amine. 1- [5-bromo-3- (phenothiazin-10-ylmethyl) phenylmethyl]
-1,4,8,11-tetraazacyclotetradecane pentahydrochloride. MS (ES +)
m / e 580, 582 [M + H] ⁺ . 1- [3- (N- {4-amino-2-methylquinolin-6-yl} aminomethyl)
-5-bromophenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride. MS (ES +) m / e 554, 556 [M + H] ^< +>. 1- [5-bromo-3- (N- {4- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride . MS (ES +) m / e 614, 616 [M + H] ^< +>. 1- [5-bromo-3- (N- {3- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride . MS (ES +) m / e 614, 616 [M + H] ^< +>.

Example 45 1- [3- (N- {6-methyl-2-nitrophenyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride 1- [ 4- (bromomethyl) phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane
Using [3- (bromomethyl) phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane, 3,4-methylenedioxybenzylamine The title compound was obtained as a solid by following the procedure described in Example 29 using 6-methyl-2-nitroaniline instead of M
S (ES +) m / e 455 [M + H] ^< +>.

Example 46 The following compounds were prepared according to the method described in Example 45 using the appropriate amine. 1- [3- (N- {3- (2-thienyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride. M
S (ES +) m / e 468 [M + H] ⁺ .

Example 47 1- [4- (N- {1-methyl-3- (2-thienyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclo Tetradecane
Pentahydrochloride a) In 1- [4- (bromomethyl) phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane acetonitrile (500 mL) At 60 ° C., α, α′-dibromo-p-xylene (36.0 g, 136 mmol) was stirred until dissolved. Potassium carbonate (
3.5 g, 25.3 mmol) were added and then 1,4,8-tri- (t-butyloxycarbonyl) -1,4,8,11-tetraazacyclotetradecane (B. Boitr
el et al., Tetrahedron Lett., 1995, 36, 4995) (6.0 g, 11.98 mmo)
A solution of l) in acetonitrile (100 mL) was added dropwise. The mixture was stirred for 6 hours, cooled and partially evaporated. Excess dibromoxylene is filtered off, the mother liquor is evaporated under reduced pressure and chromatographed (silica gel, 50% dichloromethane / hexane to 50%).
2% methanol / dichloromethane) to give the title compound as a foam (7
.4 g, 90%). MS (ES +) m / e 683 and 685 [M + H] ^< +>.

B) 1- [4- (N- {1-methyl-3- (2-thienyl) pyrazol-5-yl}
Aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride 5-amino-1-methyl-3- (2-thienyl) pyrazole (300 mg, 1.
67 mmol), 1- [4- (bromomethyl) phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane (379 mg, 0.555 mmol) and A mixture of ethanol (3 mL) was heated at reflux for 3 hours, then cooled. The solvent was removed in vacuo and the residue was purified by preparative HPLC (ODS, 10-90% acetonitrile / water + 0.1% TFA). The resulting protected intermediate, 4M HCl / dioxane (2 mL, 8 mmol)
l) and the solution in dichloromethane (4 mL) was allowed to stand for 18 hours, then filtered. The residue was washed with dichloromethane and ether, then dried under high vacuum to give the title compound as a solid (20mg, 5%). LCMS m / z 48
2 [M + H] ⁺ .

Examples 48-50 The following compounds were prepared according to the method described in Example 47 using the appropriate amine. 1- [4- (N- {3-methylpyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride. LCMS
m / z 400 [M + H] ⁺ . 1- [4- (N- {3- (4-methylphenyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride. LCMS m / z 476 [M + H] ^< +>. 1- [4- (N- {3- (2-furyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride. LC
MS m / z 452 [M + H] ^< +>.

Example 51 1- [3- (N- {3- (4-methylphenyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane / 5 Hydrochloride a) 60% in 1- [3- (bromomethyl) phenylmethyl] -4,8,11-tri- (t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane acetonitrile (350 mL). Stirred at 0 ° C. until α, α′-dibromo-m-xylene (22.0 g, 83.3 mmol) was dissolved. Potassium carbonate (2
2.0 g, 14.5 mmol) was added, followed by 1,4,8-tri- (t-butyloxycarbonyl) -1,4,8,11-tetraazacyclotetradecane (B. Boitrel).
et al., Tetrahedron Lett., 1995, 36, 4995) (4.0 g, 7.99 mmol)
A solution of in acetonitrile (100 mL) was added dropwise. The mixture is stirred for 6 hours,
Cooled and partially evaporated. Excess dibromoxylene is filtered off, the mother liquor is evaporated in vacuo and chromatographed (silica gel, 50% dichloromethane / hexane to 2%
Methanol / dichloromethane) gave the title compound as a foam (4.5).
5 g, 83%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.30-7.1
9 (m, 4H), 4.49 (s, 2H), 3.51 (s, 2H), 3.45-3.2
0 (m, 12H), 2.62 (m, 2H), 2.38 (m, 2H), 1.91 (m
, 2H), 1.68 (m, 2H), 1.47-1.43 (m, 27H).

B) 1- [3- (N- {3- (4-methylphenyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane.pentahydrochloride Salt 5-amino-3- (4-methylphenyl) pyrazole (217 mg, 1.25 m
mol), 1- [3- (bromomethyl) phenylmethyl] -4,8,11-tri- (t
-Butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane (77
A mixture of 9 mg, 1.14 mmol), potassium carbonate (473 mg, 3.42 mmol) and acetonitrile (11 mL) was stirred at 60 ° C. for 2.5 hours, then cooled and partitioned between water and ethyl acetate. . The extract was washed with water, saturated aqueous NaCl, and then dried (MgSO ₄ ). The solvent was removed under reduced pressure and the residue was chromatographed (silica gel, ethyl acetate, then 10% methanol / dichloromethane + 0.5% aqueous ammonia). 30 mg of the resulting protected intermediate in 4 M HCl / dioxane (1 mL, 4 mmol) and dichloromethane (2 mL)
) Was allowed to stand for 18 hours and then filtered. The residue was washed with dichloromethane and ether, then dried under high vacuum to give the title compound as a solid (25mg, 26%). MS (ES +) m / e 476 [M + H] ^< +>.

Example 52 1- [3- (N- {1-Methyl-3-phenylpyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane 5-amino -1-methyl-3-phenylpyrazole (51 mg, 0.292 m
mol) and 1- [3- (bromomethyl) phenylmethyl] -4,8,11-tri-
(t-butoxycarbonyl) -1,4,8,11-tetraazacyclotetradecane (
A solution of 100 mg (0.146 mmol) in dimethylformamide (0.5 mL) was shaken for 18 hours and then partitioned between 0.1 M aqueous potassium carbonate and ethyl acetate. The organic extract was evaporated under reduced pressure, and the residue was separated by RP preparative HPLC (ODS, 1
(0-90% acetonitrile / water + 0.1% TFA). A solution of the resulting protected intermediate in 4M HCl / dioxane (1 mL, 4 mmol) and dichloromethane (3 mL) was allowed to stand for 72 hours, then diluted with dichloromethane and water. The aqueous layer was partitioned between 1M aqueous NaOH and dichloromethane. The organic layer was dried (sodium sulfate) and evaporated under reduced pressure to give the title compound as an amorphous solid (3mg, 4%). LCMS m / z 476 [M + H] ^< +>.

Examples 53-55 The following compounds were prepared according to the method described in Example 52 using the appropriate amine. 1- [3- (N- {3- (4-chlorophenyl) -1-methylpyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane. LCMS m / z 510, 512 [M + H] ^< +>. 1- [3- (N- {1,3-diphenylpyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane. LCMS m /
z 538 [M + H] ^< +>. 1- [3- (N- {3- (4-t-butylphenyl) -1-methylpyrazole-5
-Yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane. LCMS m / z 532 [M + H] ^< +>.

Pharmaceutical formulations incorporating the compounds of the present invention can be prepared in a variety of dosage forms using numerous excipients. Examples of such formulations are described below.

Example 56 Inhalation Formulation A compound of Formula I or II (1-100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.

Example 57 Tablet Formulation

[Table 1]

Preparation of Tablet Formulations Components 1, 2, 3 and 4 are blended in a suitable mixer / blender. The blend is converted to wet granules by dropping enough water (with careful mixing after each addition) until the mass of the blend has consistency. No. 8
Convert to granules by passing through a vibrating granulator using a 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 component 5 and the lubricated granules are compressed with a suitable tablet press.

Example 58 Parenteral Formulation A pharmaceutical composition for parenteral administration is prepared by dissolving a suitable amount of a compound of formula I or II in polyethylene glycol while heating. Then
This solution is diluted with injection solution (European Pharmacopoeia) (up to 100 ml). The solution is then sterilized by filtration through a 0.22 micron membrane filter and sealed in a sterile container.

Detailed examples of pharmaceutical formulations incorporating the compounds of the present invention are described below.

Example 59-Capsule Composition An oral dosage form for administering a compound of the present invention is prepared by filling a standard two-piece hard gelatin capsule with the ingredients in the proportions shown in Table 2 below.

[Table 2]

Example 60 Parenteral Composition for Injection An injectable formulation for administering a TPO receptor agonist of the present invention was prepared using 1.5% by weight of 1- [3- () in 10% by volume propylene glycol in water. N- {3- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) -5-nitrophenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride (compound of Example 39 Is prepared by stirring.

Example 61 Tablet Composition Sucrose, calcium sulfate dihydrate and TPO of the present invention shown in Table 3 below
The receptor agonist is mixed and granulated in a predetermined ratio with a 10% gelatin solution. The wet granules are sieved, dried, mixed with starch, talc and stearic acid, sieved and compressed into tablets.

[Table 3]

Among the compounds of the present invention, the compounds of the following examples are preferred: Example 2-CX
CR4, Example 7-CXCR4, Example 34-TPO, Example 39-TP
O, Example 40-TPO, Example 44-TPO and Example 51-TPO
.

Among the compounds of the present invention, the compounds of the following examples are more preferred: Example 13
-CXCR4, Example 33-TPO, Example 35-TPO, Example 43-TPO, Example 46-TPO and Example 49-TPO, Example 53-
TPO.

Although the preferred embodiments of the present invention have been illustrated, the present invention is not limited to the teachings described herein, but reserves the right to all modifications falling within the scope of the claims. I should understand.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/4427 A61K 31/4427 31/4439 31/4439 31/4523 31/4523 31/4709 31/4709 31 / 496 31/496 31/506 31/506 31/5377 31/5377 31/5415 31/5415 31/551 31/551 A61P 1/08 A61P 1/08 1/14 1/14 3/04 3/04 3 / 10 3/10 7/04 7/04 9/02 9/02 9/04 9/04 9/10 9/10 9/12 9/12 11/06 11/06 13/02 13/02 13/08 13/08 17/02 17/02 19/10 19/10 25/00 25/00 25/06 25/06 25/14 25/14 25/16 25/16 25/18 25/18 25/22 25 / 22 25/24 25/24 29/00 29/00 31/12 31/12 35/00 35/00 37/00 37/00 43/00 105 43/00 105 C07D 401/12 C07D 401/12 401/14 401/14 403/10 403/10 403/12 403/12 405/12 405/12 405/14 405/14 409/14 409/14 413/10 413/10 417/12 417/12 (31) Claim number 60 / 132,185 (32) Priority date May 1999 3rd (1999.5.3) (33) Priority country United States (US) (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE , IT, LU, MC, NL, PT, SE), AU, CA, JP, US (72) Inventor Alan Thomas Price 2201 Eland Down 2201 in Phoenix Building, Pennsylvania, USA 19460 (72) Inventor Antony Shaw United States 19425 Jester Circle, Pennsylvania, Jack Circle 713 (72) Inventor Kenneth Wigor United States 19355 Malvern, Pennsylvania, Brookmont Circle 910 F-term (reference) 4C063 AA01 AA03 AA05 BB01 BB03 BB09 CC47 CC54 CC59 CC62 CC92 DD10 DD12 DD14 DD22 DD26 DD29 DD34 DD36 DD47 EE01 4C086 AA01 AA02 AA03 BC58 BC73 BC76 BC82 GA04 GA07 GA08 GA09 GA10 GA12 MA01 MA04 NA14 ZA02 Z A05 ZA08 ZA12 ZA15 ZA18 ZA36 ZA42 ZA43 ZA45 ZA59 ZA66 ZA70 ZA71 ZA83 ZA97 ZB11 ZB13 ZB26 ZB35 ZC33 ZC35 ZC55

Claims (23)

[Claims] 1. A compound of formula (I): Wherein, -CH 2 _-Z substituent is in the meta or para position with respect tetraazacyclotetradecane substituent; Z is nitrogen binding heteroaryl, substituted nitrogen linked heteroaryl, cyclic amine groups, substituted cyclic amine or represents ^NY 1 ^{Y 2} (where,, ^{Y 1} and ^{Y 2} are each independently hydrogen, alkyl, substituted _alkyl, C 3 _{-C 1 2} aryl, substituted X is hydrogen, alkyl, C ₃ -C ₁₂ aryl, substituted C ₃ -C ₁₂ aryl, amino, alkylamino, nitro, C ₃ -C ₁₂ aryl, cycloalkyl and substituted cycloalkyl). , Hydroxy, alkoxy, halogen,
Selected from the group consisting of carboxyl and carboxamide], and further pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes thereof. 2. Formula (II): Y′CH ₂ ACH ₂ Y ′ Formula (II) wherein Y ′ is And Wherein Y 'is optionally substituted by a substituent selected from the group consisting of alkyl, alkoxy, halogen and carboxy, wherein A is X'-substituted Represents an aryl or heteroaryl ring (where X ′
Is selected from the group consisting of hydrogen, alkyl, aryl, amino, alkylamino, nitro, hydroxy, alkoxy, halogen, carboxyl, and carboxamide) with the proviso that the Y′CH ₂ groups are mutually meta or para And further pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes thereof. 3. The compound according to claim 1, which is selected from the group consisting of: 1- [4- (4-acetyl-1-piperazinomethyl) phenylmethyl] -1,4,8.
, 11-Tetraazacyclotetradecane pentahydrochloride; 1- [4- (1,4-diazacycloheptan-1-ylmethyl) phenylmethyl]
-1,4,8,11-tetraazacyclotetradecane hexahydrochloride; 1- [4- (azacycloheptane-1-ylmethyl) phenylmethyl] -1,4,8
1,11-Tetraazacyclotetradecane pentahydrochloride; 1- [4- (1-piperidinomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (1 -Morpholinomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (azacyclotridecane-1-ylmethyl) phenylmethyl] -1,4,
8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (5,6,14,15-dibenzo-1,4-dioxa-8,12-diazacyclopentadeca-5,14-diene -8-ylmethyl) phenylmethyl] -1,4
1,8,11-Tetraazacyclotetradecane hexahydrochloride; 1- [4- (1,4,7-trioxa-10-azacyclododecane-10-ylmethyl) phenylmethyl] -1,4,8,11- Tetraazacyclotetradecane pentahydrochloride; 1- [4- (1,4,7,10-tetraoxa-13-azacyclopentadecane-
13-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (1,4,10-trioxa-7,13-diazacyclopentadecane-
7-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane hexahydrochloride; 1- {4- [4- (2-pyridyl) -1-piperazinomethyl] phenylmethyl} -1
, 4,8,11-Tetraazacyclotetradecane hexahydrochloride; 1- {4- [4- (2-pyrimidyl) -1-piperazinomethyl] phenylmethyl}-
1,4,8,11-tetraazacyclotetradecane hexahydrochloride; 1- [4- (2-guanidinobenzimidazol-1-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane Pentahydrochloride; 1- [4- (1-piperazinomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane hexahydrochloride; 1,4-bis- [4- (1,4,8 , 11-Tetraazacyclotetradecane-1-ylmethyl) phenylmethyl] piperazine decahydrate; 1- [4- (1,5-diazacyclooctane-1-ylmethyl) phenylmethyl]
-1,4,8,11-tetraazacyclotetradecane hexahydrochloride; 1- (4- {bis [2- (diethylamino) ethyl] aminomethyl} phenylmethyl)
-1,4,8,11-tetraazacyclotetradecane heptahydrochloride; 1- (4-{[(2-aminoethyl) (3-aminopropyl) amino] methyl]} phenylmethyl) -1,4, 8,11-tetraazacyclotetradecane heptahydrochloride; 1- {4- [di- (2-pyridyl) aminomethyl] phenylmethyl} -1,4,8,1
1-tetraazacyclotetradecane pentahydrochloride; 1- [4- (2-thiazolylaminomethyl) phenylmethyl] -1,4,8,11-
1- [3- (2-guanidinobenzimidazol-1-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4 -(2-aminobenzimidazol-1-ylmethyl) phenylmethyl]
-1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1,8-bis- [4- (1,4,8,11-tetraazacyclotetradecane-1-ylmethyl) phenylmethyl] -1 , 4,8,11-tetraazacyclotetradecane
Dihydrobromide; 1,11-bis- [4- (1,4,8,11-tetraazacyclotetradecane-1-
1- [4- (N- {3- (methylamino) propyl} -N-methylaminomethyl; ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane dihydrobromide ) Phenylmethyl] -1,4,8,11-tetraazacyclotetradecane hexahydrochloride; 1- [4- (N- {3,4-methylenedioxyphenylmethyl} aminomethyl) phenylmethyl] -1, 4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (N- {3,5-difluorophenylmethyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclo Tetradecane pentahydrochloride; 1- [4- (phenothiazin-10-ylmethyl) phenylmethyl] -1,4,8,
11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (N- {4-amino-2-methylquinolin-6-yl} aminomethyl)
Phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (N- {4- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (N- {3- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) phenylmethyl] -1, 4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [5-nitro-3- (N- {3- (2-thienyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1, 4,8,11-tetraazacyclotetradecane
Pentahydrochloride; 1- [5-nitro-3- (phenothiazin-10-ylmethyl) phenylmethyl]
-1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {4-amino-2-methylquinolin-6-yl} aminomethyl)
-5-nitrophenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {4- (2-guanidinothiazol-4-yl) phenyl} aminomethyl ) -5-Nitrophenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {3- (2-guanidinothiazol-4-yl) phenyl} amino Methyl) -5-nitrophenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [5-bromo-3- (N- {3- (2-thienyl) pyrazole-5 -Yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane.
Pentahydrochloride; 1- [5-bromo-3- (phenothiazin-10-ylmethyl) phenylmethyl]
-1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {4-amino-2-methylquinolin-6-yl} aminomethyl)
-5-bromophenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [5-bromo-3- (N- {4- (2-guanidinothiazol-4-yl) Phenyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [5-bromo-3- (N- {3- (2-guanidinothiazol-4-yl) ) Phenyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {6-methyl-2-nitrophenyl} aminomethyl) phenylmethyl ] -1,4,8,11-Tetraazacyclotetradecane pentahydrochloride; and 1- [3- (N- {3- (2-thienyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1 , 4,8,11-Tetraazacyclotetradecane / pentahydrochloride ; 1- [4- (N- {1- methyl-3- (2-thienyl) pyrazol-5-yl} amino) phenyl methyl] -1,4,8,11- tetraazacyclotetradecane-
1- [4- (N- {3-methylpyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4 -(N- {3- (4-methylphenyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (N -{3- (2-furyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {3- (4-methylphenyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {1-methyl-3 -Phenylpyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetra 1- [3- (N- {3- (4-chlorophenyl) -1-methylpyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane; 1- [3- (N- {1,3-diphenylpyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane; and 1- [3- (N- { 3- (4-t-butylphenyl) -1-methylpyrazole-5
-Yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane; and their further pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes. 4. The compound according to claim 3, which is selected from the group consisting of the following compounds: 1,8-bis- [4- (1,4,8,11-tetraazacyclotetradecane-1-ylmethyl) phenyl Methyl] -1,4,8,11-tetraazacyclotetradecane
Dihydrobromide; 1,11-bis- [4- (1,4,8,11-tetraazacyclotetradecane-1-
Ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane / 12 hydrobromide; 1- [4- (N- {4-amino-2-methylquinolin-6-yl} amino Methyl)
Phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (N- {4- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (N- {3- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) phenylmethyl] -1, 4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [5-nitro-3- (N- {3- (2-thienyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1, 4,8,11-tetraazacyclotetradecane
Pentahydrochloride; 1- [5-nitro-3- (phenothiazin-10-ylmethyl) phenylmethyl]
-1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {4- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) -5-nitrophenylmethyl ] -1,4,8,11-Tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {3- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) -5-nitrophenyl Methyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [5-bromo-3- (N- {3- (2-thienyl) pyrazol-5-yl} aminomethyl) phenyl Methyl] -1,4,8,11-tetraazacyclotetradecane
Pentahydrochloride; 1- [3- (N- {4-amino-2-methylquinolin-6-yl} aminomethyl)
-5-bromophenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [5-bromo-3- (N- {4- (2-guanidinothiazol-4-yl) Phenyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [5-bromo-3- (N- {3- (2-guanidinothiazol-4-yl) ) Phenyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {3- (2-thienyl) pyrazol-5-yl} amino Methyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [4- (N- {3-methylpyrazol-5-yl} aminomethyl) phenylmethyl] -1, 4,8,11-tetraazacyclotetradecane pentahydrochloride; 1 [4- (N- {3- (4-methylphenyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {3- (4-methylphenyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; 1- [3- (N- {3- (4-chlorophenyl) -1-methylpyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane; and 1- [3- (N- {1, 3-diphenylpyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane; and their further pharmaceutically acceptable salts, hydrates, solvates, esters and Metal complex. 5. The compound according to claim 2, which is selected from the group consisting of the following compounds: 1,4-bis [2- (2-benzimidazolylamino) -5,5-di (2-pyridyl)
) -4-oxo-5H-imidazolin-3-ylmethyl] benzene, bis-trifluoroacetate; 2,6-bis [2- (2-benzimidazolylamino) -5,5-di (2-pyridyl)
) -4-oxo-5H-imidazolin-3-ylmethyl] pyridine, bis-trifluoroacetate; and 1,4-bis {[1- (2-benzimidazolyl) -1-guanidino] methyl} benzene; Further pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes. 6. The compound according to claim 3, which is selected from the group consisting of the following compounds: 1- [4- (N- {4- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) phenylmethyl ] -1,4,8,11-Tetraazacyclotetradecane pentahydrochloride; 1- [4- (N- {3- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) phenylmethyl] -1 , 4,8,11-Tetraazacyclotetradecane pentahydrochloride; 1- [5-nitro-3- (N- {3- (2-thienyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1 , 4,8,11-tetraazacyclotetradecane
Pentahydrochloride; 1- [5-bromo-3- (N- {3- (2-thienyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane.
Pentahydrochloride; 1- [5-bromo-3- (N- {4- (2-guanidinothiazol-4-yl) phenyl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane Pentahydrochloride; 1- [3- (N- {3- (2-thienyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride 1- [4- (N- {3- (4-methylphenyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; [3- (N- {3- (4-methylphenyl) pyrazol-5-yl} aminomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane pentahydrochloride; and 1- [3 -(N- {3- (4-chlorophenyl) -1-methylpyrazol-5-yl} a Minomethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane; and further pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes thereof. 7. The compound according to claim 6, which is selected from the group consisting of the following compounds: 1- [4- (1,5-diazacyclooctan-1-ylmethyl) phenylmethyl]
-1,4,8,11-tetraazacyclotetradecane hexahydrochloride; 1- [4- (2-guanidinobenzimidazol-1-ylmethyl) phenylmethyl] -1,4,8,11-tetraazacyclotetradecane Pentahydrochloride; 1- [4- (5,6,14,15-dibenzo-1,4-dioxa-8,12-diazacyclopentadeca-5,14-dien-8-ylmethyl) phenylmethyl] -1,4
, 8,11-Tetraazacyclotetradecane hexahydrochloride; 1- [4- (azacyclotridecane-1-ylmethyl) phenylmethyl] -1,4,
8,11-tetraazacyclotetradecane pentahydrochloride; and 1- [4- (1,4-diazacycloheptan-1-ylmethyl) phenylmethyl]
-1,4,8,11-tetraazacyclotetradecane hexahydrochloride; and their further pharmaceutically acceptable salts, hydrates, solvates, esters and metal complexes. 8. A method of antagonizing a CXCR-4 receptor by administering a compound according to claim 1. 9. A method of antagonizing a CXCR-4 receptor by administering a compound according to claim 2. 10. A pharmaceutical composition comprising a suitable pharmaceutical carrier and a compound according to claim 1. 11. A pharmaceutical composition comprising a suitable pharmaceutical carrier and a compound according to claim 2. 12. A compound according to any one of claims 1 to 7 for use as an active therapeutic substance. 13. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment of thrombocytopenia. 14. Use of a compound according to claim 2 in the manufacture of a medicament for the treatment of thrombocytopenia. 15. A method of agonizing a TPO receptor in a subject, comprising administering an effective amount of a compound according to claim 1. 16. A method of agonizing a TPO receptor in a subject, comprising administering an effective amount of a compound according to claim 2. 17. Use of a compound according to claim 1 in the manufacture of a medicament for use in antagonizing a CXCR-4 receptor. 18. Use of a compound according to claim 2 in the manufacture of a medicament for use in antagonizing the CXCR-4 receptor. 19. A method of treating a CXCR-4 mediated disease comprising administering to a patient in need of such treatment a safe and effective amount of the compound of claim 1 or 2. 20. The disease is a bacterial, fungal or protozoal infection, pain, cancer, thrombocytopenia, diabetes, obesity, anorexia, morbid hunger, asthma, allergy, Parkinson's disease, acute heart failure, hypotension, Hypertension, nerve damage, atherosclerosis, urinary retention, osteoporosis, angina, myocardial infarction, stroke, ulcer, benign prostatic hyperplasia, migraine, angiogenesis, vomiting, psychotic and neurological disorders, The method according to claim 8 or 9, wherein the method is selected from the group consisting of dyskinesia, viral infection, and spinal cord-related injury. 21. The disease is a neurological disease selected from the group consisting of anxiety, schizophrenia, manic depression, depression, delirium, dementia, mental retardation, Huntington's disease and Jill de la Tourette syndrome. The method according to claim 19. 22. The method according to claim 19, wherein the disease is a viral infection selected from HIV infection showing clinical signs of AIDS and asymptomatic HIV infection. 23. The method of claim 19, wherein the disease is an injury to the spinal cord.