Nitrogen-containing heterocyclic compounds and medicinal use thereof   

Abstract: (wherein ring A represents a nitrogen-containing heterocyclic group which may have a substituent(s); ring B represents a homocyclic group which may have a substituent(s) or a heterocyclic group which may have a substituent(s); and Y represents a hydrocarbon group which may have a substituent(s), a heterocyclic group which may have a substituent(s), an amino group which may be protected, a hydroxyl group which may be protected or a mercapto group which may be protected; T represents ring A or an amino group which may be protected.) The compound represented by formulae (I) and (II), the salt thereof, the N-oxide thereof or the solvate thereof, or the prodrug thereof and the pharmaceutical composition comprising thereof have a CXCR4-regulating effect, and they are effective in treatment and prevention of various inflammatory disease, various allergic disease, acquired immunodeficiency syndrome infection with human immunodeficiency virus, or agents for regeneration therapy.

This is a Continuation of application Ser. No. 12/776,989 filed May 10, 2010 which is a Continuation of application Ser. No. 10/538,758 filed Jun. 10, 2005, now U.S. Pat. No. 7,759,336 issued Jul. 20, 2010, which is the National Stage of Entry of PCT/JP03/15718, filed on Dec. 9, 2003, which claims priority from Japanese Patent Application Nos. 2002-357446 and 2003-162706 filed on Dec. 10, 2002 and Jun. 6, 2003, respectively. The entire disclosures of the prior applications are hereby incorporated by reference.

TECHNICAL FIELD

The present invention relates to CXCR4 regulators that are useful as medicament.

More particularly, it relates to

(1) compounds of formula (I)

(wherein all the symbols have the same meanings as defined hereinafter), salts thereof, N-oxides thereof or solvates thereof, or prodrugs of the same, (2) pharmaceutical compositions comprising compounds of formula (I)

(wherein all the symbols have the same meanings as defined hereinafter), salts thereof, N-oxides thereof or solvates thereof, or prodrugs of the same, (3) CXCR4 regulator comprising compounds of formula (II)

(wherein all the symbols have the same meanings as defined hereinafter), salts thereof, N-oxides thereof or solvates thereof, or prodrugs of the same, as an active ingredient, and (4) methods for preparation thereof.

Chemokine is known as a basic protein having endogeneous leukocyte chemotactic and activating abilities and strong heparin-binding abilities. At present, it is considered that chemokine is related to not only the control of infiltration of specific leukocyte at the time of inflammations and immune responses but also the development and homing of lymphocyte under physiological conditions and migration of hemocyte precursor cells and somatic cells.

Differentiation, proliferation and cell death of hemocytes are controlled by various types of cytokine In the living body, inflammations are found topically and differentiation, maturation and the like of lymphocytes are carried out at certain specified sites. That is, various necessary cells migrate into certain specified sites and accumulate therein to cause a series of inflammations and immune responses. Accordingly, migration of cells is also an indispensable phenomenon in addition to differentiation, proliferation and death of cells.

Migration of hemocytes in the living body starts firstly in the development stage by the shift of hematopoiesis started in the AGM region into permanent hematopoiesis in bone marrow via fetal liver. Furthermore, precursor cells of T cells and thymus dendritic cells migrate from the fetal liver into the bone marrow and then into the thymus gland and cytodifferentiate under thymus environment. The T cell which received clone selection migrates into secondary lymphoid tissues and takes part in an immune response in the periphery. The Langerhans\' cell of the skin activated and differentiated by capturing an antigen migrates into the T cell region of a topical lymph node and activates naive T cell therein as a dendritic cell. The memory T cell performs its homing again into the lymph node via lymphatic and blood vessels. Also, B cell, T cell in the intestinal epithelium, γδ T cell, NKT cell and dendritic cell migrate from bone marrow without passing through the thymus gland and differentiate to take part in an immune response.

Chemokines are deeply involved in these various cell migration. For example, an SDF-1 (stromal cell derived factor-1) and its receptor CXCR4 act on various immunological and inflammatory reactions. They are reported to be involved in accumulation and activation of CD4+T cells in a synovial membrane derived from a human patient having a rheumatoid arthritis (J. Immunol., 165, 6590-6598 (2000)). In addition, a CXCR4 inhibitor suppressed recruitment of leukocytes into a joint also in CIA model mice and reduces the arthritis score dramatically (J. Immunol., 167, 4648-4692 (2001)). In a mouse OVA-induced airway hypersensitivity model, an anti-CXCR4 antibody reduced the number of eosinophiles recruited into a pulmonary interstice to suppress the airway hypersensitivity (J. Immunol., 165, 499-508 (2000)).

SDF-1 and its receptor CXCR4 are also reported to play an important role in maintaining hemopoietic stem cells in a bone marrow (J. Exp. Med., 185, 111-120 (1997), Blood, 97, 3354-3360 (2001)). Accordingly, the inhibition of SDF-1 and CXCR4 is expected to regulate the recruitment of the hemopoietic stem cells into a peripheral blood and to be useful in a peripheral blood stem cell transplantation and this also in a regeneration transplantation therapy.

SDF-1 and CXCR4 are involved in an infiltration of cells of various cancers such as mammary cancer, prostate cancer and ovarian cancer (Nature, 410, 50-56 (2001), Cancer Res., 62, 1832-1837 (2002), Cancer Res., 62, 5930-5938 (2002)), and an anti-CXCR4 antibody inhibited metastasis of a mammary cancer cell into a lung in a human mammary cancer cell line transfusion model in SCID mice. Also, since SDF-1 is highly expressed in a human ovarian epithelial tumor, it promotes accumulation of a plasmocytic dendric cell to inhibit the action of a bone marrow dendric cell involved in a tumor immune, resulting in an inhibition of the tumor immune (Nat. Med., 12, 1339 (2001)). In addition, it is involved also in proliferation and movement of a non-hodgkin lymphoma cell, and an anti-CXCR4 antibody inhibits proliferation of tumor cells in a human non-hodgkin lymphoma cell transfusion model in BID/SCID mice, resulting in an improvement in the mortality in mice (Cancer Res., 62, 3106-3112 (2002)).

SDF-1 and CXCR4 play important roles in formation of a hippocampal dentate gyrus granulocyte essential for memory and learning, and are involved in progression of an adult disease associated with plasticity and hippocampal pathology such as Alzheimer\'s disease, cerebral stroke, epilepsy and the like (Development, 129, 4249-4260 (2002), Trends Neuroscience, 25, 548-549 (2002)).

SDF-1 and CXCR4 are essential for a function of an auto-reactive B cell involved in progression of a diabetes, and an anti-SDF-1 antibody reduced the blood sugar level in NOD mice and reduced the mature IgM+B cell count in a peripheral tissue (Immunology, 107, 222-232 (2002)). SDF-1 was highly expressed in a human arteriosclerotic plaque, resulting in an activation of platelets (Circ. Res., 86, 131-138 (2000)).

Results observed in SDF-1/CXCR4 knockout mice also indicated that SDF-1 is essential for functions of the blood vessels in central nervous tissues, heart and gastrointestinal tracts in addition to lymphocytes (Nature, 382, 635-639 (1996), Nature, 393, 591-594 (1998), Nature, 393, 595-599 (1998)). Accordingly, it is believed to be involved in diseases of such tissues.

Thus, chemokine receptors are greatly related to the control of inflammation and immune responses through a mechanism in which they are expressed at certain specified periods in variously specific cells and the effector cells are accumulated in a region where chemokine is produced.

Acquired immunodeficiency syndrome (called AIDS) which is induced by human immunodeficiency virus (hereinafter referred to as “HIV”) is one of the diseases of which their therapeutic methods are most earnestly desired in recent years. Once infection with HIV is completed in a CD4-positive cell which is a principal target cell, HIV repeats its proliferation in the body of the patient and, sooner or later, completely destroys T cell which takes charge of the immunological function. During this process, the immunological function is gradually reduced to cause fever, diarrhea, lymph node enlargement and the like various immunodeficiency conditions which are apt to cause complications with pneumocystis carinii pneumonia and the like various opportunistic infections. Such conditions are the onset of AIDS, and it is well known that they induce and worsen Kaposi sarcoma and the like malignant tumors.

As the recent preventive and therapeutic methods for AIDS, attempts have been made to, e.g., (1) inhibit growth of HIV by the administration of a reverse transcriptase inhibitor or a protease inhibitor and (2) prevent or alleviate opportunistic infections by the administration of a drug having immunopotentiation activity.

Helper T cells which take charge of the central of immune system are mainly infected with HIV. It is known since 1985 that HIV uses the membrane protein CD4 expressing on the membrane of T cells in the infection (Cell, 52, 631 (1985)). The CD4 molecule is composed of 433 amino acid residues, and its expression can be found in macrophages, some B cells, vascular endothelial cells, Langerhans\' cells in skin tissues, dendritic cells in lymphoid tissues, glia cells of the central nervous system and the like, in addition to the mature helper T cells. However, since it has been revealed that the infection with HIV is not completed by the CD4 molecule alone, a possibility has been suggested on the presence of factors other than the CD4 molecule, which are related to the infection of cells with HIV.

In 1996, a cell membrane protein called Fusin was identified as a factor other than the CD4 molecule, which is related to the HIV infection (Science, 272, 872 (1996)). It was confirmed that this Fusin molecule is a receptor (namely, CXCR4) of SDF-1. In addition, it was confirmed also in vitro that the SDF-1 specifically inhibits infection of T cell tropic (X4) HIV (Nature, 382, 829 (1996), Nature, 382, 833 (1996)). That is, it is considered that the HIV infection was inhibited by the binding of SDF-1 to CXCR4 preceding HIV, thereby depriving HIV of a foothold for infecting cells.

Also at that time, it was discovered that another chemokine receptor CCR5, which is a receptor of RANTES, MIP-1α and MIP-β, is also used at the time of the infection with a macrophage tropic (R5) HIV (Science, 272, 1955 (1996)).

Accordingly, substances which can compete with CXCR4 and CCR5 for HIV, or which can bind to HIV virus thus causing the virus unable to bind to CXCR4 and CCR5, could become HIV infection inhibitors. Also, there is a case in which a low molecular compound initially discovered as an HIV infection inhibitor was actually a CXCR4 antagonist (Nature Medicine, 4, 72 (1998)).

Based on the above, a chemokine and a chemokine receptor are deeply involved in inflammation, immune disease or HIV infection. A compound having an ability of regulating CXCR4 is effective in treatment and prevention, for example, of an inflammatory/immune disease, allergic disease, infectious disease, especially HIV infection and accompanying diseases, psychoneurotic disease, cerebral disease, cardiovascular disease, metabolic disease and cancerous disease. In addition, it is also useful in cell medicine and regeneration medicine. The cell medicine includes peripheral blood stem cell recruitment and in vitro and in vivo proliferation of a stem cell for the purpose of a gene therapy. The regeneration medicine includes transplantation medicine such as various organ transplantations including bone marrow transplantation, peripheral blood stem cell transplantation and tissue repair. The transplantation medicine agent is an agent used in the bone marrow transplantation, peripheral blood stem cell transplantation or various organ transplantation. The transplantation medicine agent includes, for example, an infection-preventing agent or immunosuppressant. Those included also are agents intended to supplement and/or enhance the therapeutic effect in the regeneration medicine. An transplantation medicine agent has an effect, for example, of migrating a stem cell from a bone marrow into a peripheral blood or to increase leukocyte rapidly to a normal level.

The inflammatory/immune diseases include, for example, rheumatoid arthritis, arthritis, gout, transplanted organ rejection, graft versus host disease (GVHD), nephritis, psoriasis, rhinitis, conjunctivitis, multiple sclerosis, ulcerative colitis, Crohn\'s disease, shock accompanied with bacterial infection, pulmonary fibrosis, systemic response syndrome (SIRS), acute pulmonary disorder, diabetes and the like.

The allergic diseases include, for example, asthma, atopic dermatitis, rhinitis, conjunctivitis and the like.

The infectious diseases, especially HIV infection and accompanying diseases, include, for example, acquired immunodeficiency syndrome (AIDS), candidosis, carinii pneumonia, cytomegalovirus retinitis, Kaposi\'s sarcoma, malignant lymphoma, AIDS encephalopathy, bacterial sepsis and the like.

The psychoneurotic diseases and the cerebral diseases include, for example, dementia such as Alzheimer\'s disease, Parkinson\'s disease, cerebral stroke, cerebral infarction, cerebral hemorrhage, epilepsy, schizophrenia, peripheral nervous disorder and the like.

The cardiovascular diseases include, for example, arteriosclorosis, ischemic reperfusion injury, hypertension, myocardial infarction, angina pectoris, cardiac insufficiency and the like.

The metabolic diseases include, for example, diabetes, osteoporosis, prostatic hypertrophy, pollakiuia and the like.

The cancerous diseases include, for example, mammary cancer, malignant tumor such as malignant lymphoma, cancer metastasis, post-radiotherapy/chemotherapy bone marrow suppression or thrombocytopenia and the like.

BACKGROUND ART

In specification of WO01/14333, it is described that piperazine or piperidine derivates of formula (A)

are chemokine receptor (specifically CCR1 or CCR3) regulator, and they are useful as treatment for inflammatory diseases, autoimmune diseases, gastrointestinal discomforts, HIV diseases and systemic diseases etc.

In specification of WO00/58305, it is described that 1,4-piperidine derivatives of formula (B)

are useful for diseases related to chemokine receptor.

In specification of JP-A-6-192235, it is described that quinazoline derivatives of formula (C)

having an effect of inhibiting cGMP phosphodiesterase and TXA2.

In specification of U.S. Pat. No. 3,956,495, it is described that N-[4-(4-morpholinyl)-2-quinazolinyl]-1,2-ethanediamine dihydrochloride (CAS No. 59870-53-0), N,N-diethyl-N′-[2-(1-pyrrolidinyl)-4-quinazolinyl]-1,2-ethanediamine (CAS No. 59870-50-70) and N,N-diethyl-N′-[2-(1-pyrrolidinyl)-4-quinazolinyl]-1,2-ethanediamine dihydrochloride (CAS No. 59870-51-8) are having an effect of inhibiting platelet aggregation.

In specification of JP-A-3-14568, N,N-diethyl-N′-[2-(4-phenyl-1-piperidinyl)-4-pyrimidinyl]-1,2-ethylenediamine (CAS No. 131039-38-8) is described as nervous system drugs.

In specification of WO95/05383, N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N′-[2-(1-piperidinyl)-4-pyrimidinyl]-1,3-propanediamine oxalate (CAS No. 169747-23-3) is having an effect of vasoconstriction.

In specification of DE1794396, it is described that 7-[4-[4,6-bis(hexahydro-1H-azepin-1-yl)-1,3,5-triazin-2-yl]amino-2H-1,2,3-triazol-2-yl]-3-phenyl-2H-1-benzopyran-2-one (CAS No. 19695-38-6) is useful as fluorescent brightening agent.

In specification of JP-A-51-9759, N-[4-(hexahydro-1H-azepin-1-yl)thieno[3,2-d]pyrimidin-2-yl-1,4-butanediamine (CAS No. 31895-98-4) is described.

Other than those above, N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N′-[2-(1-piperidinyl)-4-pyrimidinyl]-1,3-propanediamine (CAS No. 169747-22-2), 4-ethoxy-6-(hexahydro-1H-azepin-1-yl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-amine (CAS No. 295344-71-7), 4-(hexahydro-1H-azepin-1-yl)-6-methyl-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-amine (CAS No. 332167-02-9), 4-chloro-6-(hexahydro-1H)-azepin-1-yl)-N-[2-(4-morpholinyl)ethyl]-1,3,5-triazin-2-amine (CAS No. 337484-66-9), 4-(hexahydro-1H-azepin-1-yl)-6-methoxy-N-[3-(4-morpholinyl)propyl-1,3,5-triazin-2-amine (CAS No. 384845-62-9) are known.

DISCLOSURE OF THE INVENTION

It is desired that safety CXCR4 regulators that are useful as preventives and/or treatments for various inflammatory diseases, various allergic diseases, acquired immunodeficiency syndrome, infection with human immunodeficiency virus, or agents for regeneration therapy are developed.

In order to find a compound binding CXCR4, the present inventors have conducted intensive studies and found that the compounds represented by formulae (I) and (II), salts thereof, N-oxides thereof or solvates thereof, or prodrugs of the same regulate CXCR4 and they are useful as preventing and/or treatment for various diseases, and thus the present invention has been accomplished.

The present invention relates to

[1] a compound represented by formula (I):

wherein ring A represents a nitrogen-containing heterocyclic group which may have a substituent(s); ring B represents a homocyclic group which may have a substituent(s) or a heterocyclic group which may have a substituent(s); and Y represents a hydrocarbon group which may have a substituent(s), a heterocyclic group which may have a substituent(s), an amino group which may be protected, a hydroxyl group which may be protected or a mercapto group which may be protected,

a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof,

[2] the compound according to the above-described [1], wherein ring A is a 5- to 10-membered nitrogen-containing heterocyclic group which may have a substituent(s), [3] the compound according to the above-described [1], wherein ring B is a nitrogen-containing heterocyclic group which may have a substituent(s), [4] the compound according to the above-described [1], wherein Y is

wherein G represents a bond or a spacer containing 1 to 3 atoms as a main chain; ring J represents a 4- to 7-membered nitrogen-containing heterocyclic group; and W represents hydrogen, a hydrocarbon group which may have a substituent(s) or a heterocyclic group which may have a substituent(s),

[5] the compound according to the above-described [1], which is represented by formula (I-1):

wherein ring A1 represents a 5- to 10-membered nitrogen-containing saturated heterocyclic group which may have a substituent(s), or a 5- to 10-membered nitrogen-containing heterocyclic group which has one double bond and which may have a substituent(s); ring B1 represents a 6- to 11-membered nitrogen-containing monocyclic or bicyclic heterocyclic group which may have a substituent(s); and other symbols have the same meanings as those described in the above-described [4],

[6] the compound according to the above-described [1], which is represented by formula (I-2):

wherein all symbols have the same meanings as those described in the above-described [1] or [4],

[7] a compound represented by formula (I-A):

wherein ring AA represents a 4- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic group which is saturated or has one double bond and which contains at least one nitrogen atom and may further contain 1 to 3 nitrogen atoms, 1 or 2 oxygen atoms and/or one sulfur atom;

ring BA represents BA1 or BA2;

BA1 represents:

BA2 represents:

R4 represents (i) hydrogen, (ii) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which may be substituted with 1 to 5 of R10, (iii) a C3-8 carbocyclic group which may be substituted with 1 to 5 of R3, (iv) a 5- to 15-membered heterocyclic group which contains 1 or 2 nitrogen atoms, 1 or 2 oxygen atoms and/or one sulfur atom and which may be substituted with 1 to 5 of R3, (v) COR5 wherein R5 represents C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl or phenyl, or (vi) COOR6 wherein R6 represents C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl or phenyl; the upward arrow represents a binding position to ring AA; and the right-downward arrow represents a binding position to the nitrogen atom bound to L;

L represents (1) a bond, (2) C1-8 alkylene, C2-8 alkenylene or C2-8 alkynylene, wherein the alkylene, alkenylene and alkynylene each may be substituted with 1 to 5 of R10, or (3) a C3-8 carbocyclic group which may be substituted with R3;

Q represents (1) NR1R2 wherein R1 and R2 each independently represents (i) hydrogen, (ii) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which may be substituted with 1 to 5 of R10, (iii) a C3-8 carbocyclic group which may be substituted with 1 to 5 of R3, or (iv) a 5- to 15-membered heterocyclic group which contains 1 or 2 nitrogen atoms, 1 or 2 oxygen atoms and/or one sulfur atom and which may be substituted 1 to 5 of R3, or (2) ring C;

ring C represents a 4- to 15-membered heterocyclic group which contains at least one nitrogen atom and may further contain 1 or 2 nitrogen atoms, 1 or 2 oxygen atoms and/or one sulfur atom and which may be substituted with 1 to 5 of R3;

plural R3\'s each independently represents (1) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl, wherein the alkyl, alkenyl and alkynyl may be substituted with 1 to 5 of R10, (2) oxo, or (3)R10;

plural R10\'s each independently represents (1) OR11, (2) OCOR12, (3) OCOOR13, (4) NR14R15, (5) NR16COR12, (6) NR16CONR14R15, (7) NR16COOR13, (8) COOR13, (9) COR12, (10) CONR14R15, (11) SO2R12, (12) SOR22, (13) SO2NR24R25, (14) NR16SO2R12, (15) B(OH)2, (16) SR11, (17) halogen, (18) nitro, (19) cyano, or (20) ring D;

R11 represents (i) hydrogen, (ii) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl, wherein the alkyl, alkenyl and alkynyl may be substituted with 1 to 5 of halogen, NR14R15, OR21, SR21, COOR13, or ring D, or (iii) ring D;

R12, R13, R14, R15 and R16 each independently represents (i) hydrogen, (ii) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which may be substituted with ring D, or (iii) ring D;

ring D represents a C3-15 monocyclic, bicyclic or tricyclic carbocyclic group, or a 5- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic group which contains 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms and/or one sulfur atom; and

ring D may be substituted with 1 to 5 of the groups selected from the following (1) to (22):

(1) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl, wherein the alkyl, alkenyl or alkynyl may be substituted with 1 to 5 of OR21, OCOR22, OCOOR23, NR24R25, NR26COR22, NR26CONR24R25, NR26COOR23, COOR23, COR22, CONR24R25, SO2R22, SOR22, SO2NR24R25, NR26SO2R22, B(OH)2, SR21, halogen, nitro or cyano, (2) oxo, (3) OR21, (4) OCOR22, (5) OCOOR23, (6) NR24R25, (7) NR26COR22, (8) NR26CONR24R25, (9) NR26COOR23, (10) COOR23, (11) COR22, (12) CONR24R25, (13) SO2R22, (14) SOR22, (15) SO2NR24R25, (16) NR26SO2R22, (17) B(OH)2, (18) SR21, (19) halogen, (20) nitro, (21) cyano or (22) ring E;

R21 represents (i) hydrogen, (ii) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which may be substituted with COR22, NR24R25 or ring E, or (iii) ring E;

R22, R23, R24, R25 and R26 each independently represents (i) hydrogen, (ii) C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl which may be substituted with ring E, or (iii) ring E;

ring E represents a C3-15 monocyclic, bicyclic or tricyclic carbocyclic group, or a 5- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic group which contains 1 to 4 nitrogen atoms, 1 or 2 oxygen atoms and/or one sulfur atom, and

ring E may be substituted with 1 to 5 of (i) C1-15 alkyl which may be substituted with phenyl, (ii) halogen, (iii) phenyl, (iv) C1-15 alkoxy, (v) hydroxyl, (vi) amino, (vii) mono(C1-8 alkyl)amino, or (viii) di(C1-8 alkyl)amino;

ring AA may be substituted with 1-5 of Ra;

ring BA may be substituted with 1-5 of Rb);

Ra and Rb) each independently represents a group which has the same meaning as the group represented by R3; and

wherein the following compounds (1) to (6) are excluded: (1) N-[4-(4-morpholinyl)-2-quinazolinyl]-1,2-ethanediamine dihydrochloride, (2) N,N-dimethyl-N′-[2-(4-phenyl-1-piperidinyl)-4-pyrimidinyl]-1,2-ethylenediamine, (3) N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N′-[2-(1-piperidinyl)-4-pyrimidinyl]-1,3-propanediamine, (4) N-[(3,4-dihydro-2H-1-benzopyrane-2-yl)methyl]-N′-[2-(1-piperidinyl)-4-pyrimidinyl]-1,3-propanediamine oxalate, (5) N,N-diethyl-N′-[2-(1-pyrrolidinyl)-4-quinazolinyl-1,2-ethanediamine, and (6) N,N-diethyl-N′-[2-(1-pyrrolidinyl)-4-quinazolinyl-1,2-ethanediamine dihydrochloride,

a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof,

[8] a compound represented by formula (I-B):

wherein ring AB represents a 7- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic group which is saturated or contains one double bond and which contains at least one nitrogen atom and may further contain 1 to 3 nitrogen atoms, 1 or 2 oxygen atoms and/or one sulfur atom;

ring BB represents:

wherein ring Z represents a C5-10 monocyclic or bicyclic carbocyclic group, or a 5- to 10-membered monocyclic or bicyclic heterocyclic group which may contain 1 or 2 nitrogen atoms, one oxygen atom and/or one sulfur atom; the upward arrow represents a binding position to ring AB; and the right-downward arrow represents a binding position to the nitrogen atom bound to L;

ring AB may be substituted with 1 to 5 of Ra; ring BB may be substituted with 1 to 5 of Rb; and Ra, Rb and other symbols have the same meanings as those described in the above-described [7], and

wherein the following compounds (1) to (7) are excluded: (1) N-[4-(hexahydro-1H-azepin-1-yl)thieno[3,2-d]pyrimidin-2-yl]-1,4-butandiamine dihydrochloride, (2) 7-[4-[4,6-bis(hexahydro-1H-azepin-1-yl)-1,3,5-triazin-2-yl]amino-2H-1,2,3-triazol-2-yl]-3-phenyl-2H-1-benzopyran-2-one, (3) 4-ethoxy-6-(hexahydro-1H-azepin-1-yl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-amine, (4) 4-(hexahydro-1H-azepin-1-yl)-6-methyl-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-amine, (5) 4-chloro-6-(hexahydro-1H)-azepin-1-yl)-N-[2-(4-morpholinyl)ethyl]-1,3,5-triazin-2-amine, (6) 4-(hexahydro-1H-azepin-1-yl)-6-methoxy-N-[3-(4-morpholinyl)propyl-1,3,5-triazin-2-amine, and (7) N-[4-(hexahydro-1H-azepin-1-yl)thieno[3,2-d]pyrimidin-2-yl-1,4-butanediamine, or

a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof,

[9] the compound according to any one of the above-described [1], [7] and [8], which is (1) N-(4-azepan-1-ylpyrimidin-2-yl)ethane-1,2-diamine, (2) N1-(4-azepan-1-ylpyrimidin-2-yl)-N2,N2-dimethylethane-1,2-diamine, (3) 4-azepan-1-yl-N-((3S)-1-cyclohexylpyrrolidin-3-yl)pyrimidin-2-amine, (4) 4-azepan-1-yl-N-((3S)-1-benzylpyrrolidin-3-yl)pyrimidin-2-amine, (5) 4-azepan-1-yl-N-((3S)-1-(2-ethylbutyl)piperidin-3-yl)pyrimidin-2-amine, (6) 4-azepan-1-yl-N-[(3S)-1-cyclohexylpiperidin-3-yl]pyrimidin-2-amine, (7) 4-azepan-1-yl-N-[(3S)-1-tetrahydro-2H-pyran-4-ylpiperidin-3-yl]pyrimidin-2-amine, (8) 4-(3S)-3-[(4-azepan-1-ylpyrimidin-2-yk)amino]piperidin-1-ylcyclohexanol, or (9) (3S)-N-(4-azepan-1-ylpyrimidin-2-yl)-1′-(cyclohexylcarbonyl)-1,4′-bipiperidin-3-amine, [10] a pharmaceutical composition, which comprises a compound represented by formula (I):

wherein all symbols have the same meanings as those described in the above-described [1],

a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof,

[11] the pharmaceutical composition according to the above-described [10], which is a CXCR4 regulating agent, [12] the pharmaceutical composition according to the above-described [11], wherein the CXCR4 regulating agent is a CXCR4 antagonist, [13] the pharmaceutical composition according to the above-described [12], which is a preventive and/or therapeutic agent for human immunodeficiency virus infection, [14] the pharmaceutical composition according to the above-described [13], which is a preventive and/or therapeutic agent for acquired immunodeficiency syndrome, [15] the pharmaceutical composition according to the above-described [10], which is an agent for regeneration medicine, [16] the pharmaceutical composition according to the above-described [15], wherein the agent for regeneration medicine is an agent for transplantation medicine, [17] a CXCR4 regulating agent, which comprises a compound represented by formula (II):

wherein T represents

wherein R101 and R102 each independently represents hydrogen or a hydrocarbon group which may have a substituent(s); ring A has the same meaning as that described in the above-described [1]; and other symbols have the same meanings as those described in the above-described [1],

a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, as an active ingredient,

[18] the agent according to the above-described [17], wherein the CXCR4 regulating agent is a CXCR4 antagonist, [19] a CXCR4 regulating agent, which comprises a compound represented by formula (I-3):

wherein ring A2 represents a 4- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic group which contains at least one nitrogen atom and may further contain 1 to 3 nitrogen atoms, 1 or 2 oxygen atoms and/or one sulfur atom; ring B2 represents a 5- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic group which contains at least one nitrogen atom and may further contain 1 to 3 nitrogen atoms, 1 or 2 oxygen atoms and/or one sulfur atom; ring A2 may be substituted with 1 to 5 of Ra; ring B2 may be substituted with 1 to 5 of Rb; and Ra, Rb and other symbols have the same meanings as those described in the above-described [7],

a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, as an active ingredient,

[20] the CXCR4 regulating agent according to the above-described [19], which is a CXCR4 antagonist,

[21] a CXCR4 regulating agent, which comprises the compound represented by formula (I-A) according to the above-described [7], a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, as an active ingredient,

[22] the CXCR4 regulating agent according to the above-described [21], which is a CXCR4 antagonist, [23] a CXCR4 regulating agent, which comprises the compound represented by formula (I-B) according to the above-described [8], a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, as an active ingredient,

Download full PDF for full patent description/claims.




You can also Monitor Keywords and Search for tracking patents relating to this Nitrogen-containing heterocyclic compounds and medicinal use thereof patent application.
###


Other recent patent applications listed under the agent Ono Pharmaceutical Co., Ltd.: