ES2360597T3 - NEW DERIVATIVES OF PHENYLALANINE. - Google Patents

Abstract

Phenylalanine derivatives of the following general formula (1) and salts acceptable for pharmaceutical use thereof. where A represents one of the following general formulas (2), (3) or (3-1): where Arm represents a cyclic alkyl group or an aromatic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from the integrated group by atoms of oxygen, sulfur and nitrogen, U, V and X represent C (= O), S (= O) 2, C (-R5) (- R6), C (= C (R5) (R6)), C (= S), S (= O), P (= O) (- OH) or P (-H) (= O), W represents C (-R7) or a nitrogen atom, R1, R2, R3 , R4, R5, R6 and R7 may be the same or different from each other and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkenyl group, a substituted lower alkenyl group, a lower alkynyl group, a substituted lower alkynyl group, a cycloalkyl group which may contain a heteroatom or heteroatoms in the ring thereof, an aryl group, a heteroaryl group, a lower alkyl group substituted with a group or cycloalkyl groups that can den contain a heteroatom or heteroatoms in the ring thereof, a lower alkyl group substituted with an aryl group or groups, a lower alkyl group substituted with a heteroaryl group or groups, a lower alkoxy group, a lower alkylthio group, a lower alkoxy group and lower alkylthio group substituted with a cycloalkyl group or groups which may contain a heteroatom or heteroatoms in the ring thereof, a lower alkoxy group and a lower alkylthio group substituted with an aryl group or groups, a lower alkoxy group and a lower alkylthio group substituted with a heteroaryl group or groups, a cycloalkyloxy group which may contain a heteroatom or ring heteroatoms thereof, an aryloxy group, a heteroaryloxy group, a lower hydroxyalkyl group, a lower hydroxyalkenyl group, a lower hydroxyalkoxy group, a halogen group lower alkyl, a halogen group lower alkoxy, a halogen group lower alkylthio, a lower alkenyl halogen group, nitro group, cyano group, a substituted or unsubstituted amino group, carboxyl group, a lower alkoxycarbonyl group, a substituted or unsubstituted carbamoyl group, a lower alkanoyl group, an aroyl group, a lower alkylsulfonyl group, or a substituted or unsubstituted sulfamoyl group, or an ammonium group, R5 and R6 may be attached to form a ring that may contain one or two oxygen, nitrogen or sulfur atoms, B represents a hydroxyl group, a lower alkoxy group or a hydroxylamino group, C represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkyl group substituted with a cycloalkyl group or groups that may contain a heteroatom or heteroatoms in the ring thereof, a lower alkyl group substituted with an aryl group or groups or a lower alkyl group substituted with a heteroaryl group or groups, D represents a group aryl, or a heteroaryl group; or an optionally substituted cyclohexyl group. C and D may be joined to form a ring which may contain one or two oxygen, nitrogen or sulfur atoms, T represents an interatomic bond, C (= O), C (= S), S (= O), S (= O) 2, N (H) - C (= O), or N (H) -C (= S), J and J 'can be the same or different from each other and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkyloxy group or a nitro group, and the term "lower" as used above, indicates that the group qualified in this way has less than 6 carbons.

Description

Background of the invention

The present invention relates to new phenylalanine derivatives and to the use of phenylalanine derivatives in the form of medicaments. The present invention further relates to compounds that can be used as therapeutic agents or preventive agents for inflammatory diseases in which the adhesion process that depends on integrin participa4 participates in the pathology. It is reported that integr4 integrins participate in rheumatoid arthritis, inflammatory bowel diseases, systemic lupus erythematosus, multiple sclerosis, Sjögren's syndrome, asthma, psoriasis, allergy, diabetes, cardiovascular diseases, arterial sclerosis, restenosis, tumor proliferation, metastasis of tumor and transplant rejection. The compounds of the present invention that have an antagonistic effect on integr4 integrins can be used as therapeutic agents or prevention agents for the diseases described above.

In inflammatory reactions, it is generally understood that when a microorganism invades a tissue or when the tissue is damaged, leukocytes play an important role for the exclusion of the microorganism or for the repair of the injured tissue. It is also widely understood that in these cases, leukocytes that usually circulate in the blood must pass through the vascular wall and be provided again to the damaged tissue. It has been elucidated that the infiltration of leukocytes from the blood vessel to the tissue is carried out through the integrin molecules which are a group of heterodimeric proteins that are expressed on the leukocytes. Integrin molecules are classified into at least 8 subfamilies (subfamilies  1 to  8) that depend on their  chains. Typical known subfamilies are the  1 and  3 subfamilies involved in the adhesion of cellular components to the extracellular matrix such as collagen and fibronectin; the f 2 subfamily involved in cell-to-cell adhesion in the immune system; and the  7 subfamily that mainly participates in the infiltration of leukocytes into mucosal tissues (Shimizu et al., Adv. Immunol. 72: 325,380, 1999). With respect to the -4 integrins described above, 2 classes of molecules thereof are known. They are the VLA-4 molecule (very late antigen 4) that belongs to the subfamily 1 and which comprises the chain 4 1 and the molecule LPAM-1 (adhesion molecule-1 to VHE of the Peyer plate in lymphocytes ) that belongs to subfamily 7 and that comprises the chain 4 7. Usually most leukocytes that circulate in the blood have only low affinity for adhesion for vascular-endothelial cells and cannot move outside the blood vessel. However, lymphocytes that mainly comprise T cells and B cells are able to move out of the blood vessel through the so-called lymphocyte settlement phenomenon where they move from the blood into the lymphoid tissue through the blood vessel wall already They then return to the blood through the lymphatic vessel in physiological conditions. It is known that LPAM-1 molecules participate in lymphocyte settlement in the lymphoid tissue of the intestinal tract such as Peyer's plaque (Butcher et al., Adv. Immunol. 72: 209-253, 1999). On the other hand, when an inflammation occurs, the endothelial vascular cells are activated by the cytokine and chemokine released from the inflamed tissue, the expression of a group of cellular surface antigens (adhesion molecules) that participate in the adhesion of leukocytes to endothelial vascular cells, and many leukocytes infiltrate out of the blood vessel into inflamed tissue through adhesion molecules.

Since cell surface antigens in vascular endothelial cells participate in leukocyte adhesion, E-selectin (adhesion molecule that primarily participates in neutrophil adhesion), ICAM-1 and VCAM-1 have been known to participate mainly in lymphocyte adhesion, and the MAdCAM-1 that mainly participates in lymphocyte adhesion in the lymphoid tissue of the intestinal tract such as Peyer's plaque (Shimizu et al., Adv. Immunol. 72: 325-380, 1999 ). It was reported that in these adhesion molecules, VCAM-1 acts as a ligand for both VLA-4 and LPAM-1 and that MAdCAM-1 acts as the ligand for LPAM-1. As ligand of both VLA-4 and LPAM-1, fibronectin that is a kind of extracellular matrix is also known (Shimizu et al., Adv. Immunol. 72: 15 326-380, 1999). The f 1 integrin subfamily to which VLA-4 belongs comprises at least 6 integrins (VLA-1 to VLA-6) that use extracellular matrices such as fibronectin, collagen and laminin as ligands. Many of the integrins that use extracellular matrices such as ligands, such as VLA-5, subfamily 3 and subfamily  5, recognize the sequence of arginine - glycine - aspartic acid (RGD) in fibronectin, vitronectin, tenascin and osteopontin . On the other hand, in the interaction of VLA-4 and fibronectin, the RGD sequence does not participate but a CS-1 peptide segment that comprises the leucine - aspartic acid - valine (LDV) sequence as the central sequence (Pulido et al. ., J. Biol. Chem. 266: 10241-10245, 1991). Clements et al. found a sequence similar to LDV in the amino acid sequences of VCAM-1 and MAdCAM-1. It has been elucidated that a variant obtained by partially modifying the CS-1 type sequence of the VCAM-1 and MAdCAM-1 molecules cannot interact with VLA-4 or LPAM-1 (Clements et al., J. Cell Sci. 107: 2127-2135, 1994, Vonderheide et al., J. Cell. Biol. 125: 215-222, 1994, Renz et al., J. Cell. Biol. 125: 1395-1406, 1994, and Kilger et al. ., Int. Immunol. 9: 219-226, 1997). Thus, it was found that the CS-1 type sequence is important for the interaction of VLA-4 / LPAM-1 and VCAM-1 / MAdCAM-1.

It was also reported that the cyclic peptide having the structure of type CS-1 is antagonistic in both the interaction of VLA-4 or LPAM-1 with VCAM-1, MAdCAM-1 or CS-1 peptide (Vanderslice et aL, J Immunol. 158: 1710-1718, 1997). The facts described above indicate that all interactions of integr 4 integrin and VCAM-1, MAdCAM-1 or fibronectin can be blocked using a suitable  4 integrin antagonist (the term “integrin  4 antagonist” in The specification indicates an integrin antagonist substance  4  1 and / or  4  7).

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It is also known that the expression of VCAM-1 in vascular endothelial cells is caused by inflammatory factors such as LPS, TNF or IL-1 and that when inflammation occurs, the infiltration of leukocytes from the blood vessel in the tissue is carried out by the adhesion mechanism of VLA-4 / VCAM-1 (Elices, Cell 60: 577-584, 1990, Osborn et al., Cell 59: 1203-1211, 1989 and Issekutz et al ., J. Eex. Med. 183: 2175-2184, 1996). Since VLA-4 is expressed on the surfaces of activated lymphocytes, monocytes, eosinophils, mast cells and neutrophils, the adhesion mechanism of VLA-4 / VCAM-1 fulfills an important function for the infiltration of these cells into the inflamed tissue It was reported that VLA-4 is expressed in several sarcoma cells such as melanoma cells, and it was further elucidated that the mechanism of adhesion of VLA-4 / VCAM-1 participates in the metastasis of these tumors. When investigating the expression of VCAM-1 in several pathological tissues, it was evident that the mechanism of adhesion of this VLA-4 / VCAM-1 participates in several pathological stages. Namely, it was reported that in addition to activated endothelial vascular cells, VCAM-1 expression is increased in inflamed tissues in patients with autoimmune diseases such as rheumatoid synovial membrane (van Dinther-Janssen, J. Immunol. 147: 4207-4210, 1991 and Morales-Ducret et al., J. Immunol. 149: 1424-1431, 1992), lungs and respiratory tract epithelium in asthma (ten Hacken et al., Clin. Exp, Allergy 12: 1518- 1525, 1998) and allergic diseases (Randolph et al., J. Clin. Invest. 104: 1021-1029, 1999), systemic lupus erythematosus (Takeuchi et al., J. Clin. Invest. 92: 3008-3016, 1993 ), Sjögren's syndrome (Edwards et al., Ann. Rheum. Dis. 52: 806-811, 1993), multiple sclerosis (Steffen et al., Am. J. Pathol. 145: 189-201, 1994) and psoriasis (Groves et al., J. Am. Acad. Dermatol. 29: 67-72, 1993); atherosclerotic plaques (O'Brien et al., J. Clin. Invest. 92: 945-951, 1993), intestinal tissues of patients with inflammatory bowel diseases such as Crohn's disease and ulcerative colitis (Koizumi et al., Gastroenterol 103: 840-847, 1992 and Nakamura et al., Lab. Invest. 69: 77-85, 1993), inflamed tissue of the islets of Langerhans of patients with diabetes (Martin et al., J. Autoimmun. 9 : 637-643, 1996) and implants during heart or kidney transplant rejection (Herskowitz et al. Am. J. Pathol. 145: 1082-1094, 1994 and Hill et al., Kidney Int. 47: 1383-1391 , nineteen ninety five). The adhesion mechanism of VLA-4 / VCAM-1 participates in these various diseases.

There are many reports that show that in vivo administration of the VLA-4 or VCAM-1 antibody was effective in improving the diseases of animal models with those inflammatory diseases. Specifically, Yednock et al. and Baron et al. reported that in vivo administration of an antibody against -4 integrins was effective in controlling the incidence rate or in controlling encephalomyelitis in experimental autoimmune encephalomyelitis models, ie multiple sclerosis models (Yednock et al. ., Nature 356: 63-66, 1992 and Baron et al., J. Exp. Med. 177: 57-68, 1993). Zeidler et al. reported that in vivo administration of an antibody against integrin -4 was effective in controlling the incidence rate of collagen-induced arthritis in mice (rheumatoid models) (Zeidler et al., Autoimmunity 21: 245-252, 1995) . Abraham et al. and Sagara et. al reported on the therapeutic effect of an antibody against integrin  4 in asthma models (Abraham et al., J. Clin. Invest. 93: 776-787, 1994 and Sagara et al., Int. Arch. Allergy Immunol. 112: 287-294, 1997). Podolsky et al. reported on the effect of an antibody against integrin  4 in models of inflammatory bowel diseases (Podolsky et al., J. Clin. Invest. 92: 372-380, 1993). Baron et al reported the effect of an antibody against integrin -4 and the effect against the VCAM antibody in models of insulin-dependent diabetes. (Baron et al., J. Clin. Invest. 93: 1700-1708, 1994). It was evident with baboon models that restenosis of a blood vessel after an angioplasty carried out due to arteriosclerosis can be inhibited by administration of the antibody against integrin -4 (Lumsden et al., J. Vase. Surg. 26: 87.93, 1997). It was also reported that an antibody against ina-4 integrin or VCAM is effective in inhibiting the rejection of an implant or inhibiting the metastasis of a cancer (Isobe et al., J. Immunol. 153: 5810-5818, 1994 and Okahara et al. , Cancer Res. 54: 3233-3236, 1994).

As described above, unlike VCAM-1, MAdCAM-1 which is a ligand of LPAM-1 is constitutively expressed in the high endothelial venules (HEV) in the intestinal mucosa, mesenteric lymph nodes, plaque Peyer and spleen and participates in the settlement of mucosal lymphocytes. It is also known that the mechanism of adhesion of LPAM-1 / MAdCAM-1 not only has physiological functions in the settlement of lymphocytes but also participates in some pathological processes. Briskin et al reported an increase in the expression of MAdCAM-1 in inflamed regions in the intestinal tracts of patients with inflammatory bowel diseases such as Crohn's disease and ulcerative colitis (Briskin et al., Am. J. Pathol. 151: 97 -110, 1997). Hanninen et al reported that induction of expression in an inflamed tissue of the NOD mouse Langerhans islet is observed, which is a model of insulin-dependent diabetes (Hanninen et al., J. Immunol. 6018-6025, 1998). The fact that the mechanism of adhesion of LPAM- / MAdCAM-1 participates in the advancement of diseases is evident from the fact that the conditions of mouse models with inflammatory bowel disease (Picarella et al., J. Immunol 158: 2099-2106, 1997) and the NOD mouse models described above are enhanced by in vivo administration of the antibody against MAdCAM or the antibody against integrin  7 (Hanninen et al., J. Immunol. 160: 6018-6025, 1998 and Yang et al., Diabetes 46: 1542-1547, 1997).

The facts described above indicate the possibility that the use of the blockade of the adhesion mechanism of VLA-4 / VCAM-1, LPAM-1 / VCAM-1 or LPAM-1 / MAdCAM-1 by an appropriate antagonist is effective in treating chronic inflammatory diseases described above. The use of the antibody against VLA-4 as the antagonist of VLA-4 is described in WO 93/13798, WO 93/15764, WO 94/16094 and WO 95/19790. Peptide compounds as antagonists of VLA-4 are described in WO 94/15958., WO 95/15973, WO 96/00581 and WO 96/06108. The amino acid derivatives that can be used as antagonists of VLA-4 are described in WO 99/10312, WO 99/10313, WO 99/36393, WO 99/37618 and WO 99/43642. However, none of them is practically used for therapeutic treatment at present due to the lack of oral bioavailability and immunogenic properties during use for a long period of time.

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Description of the invention

An object of the present invention is to provide new compounds that have an antagonist effect of the -4 integrin.

Another objective of the present invention is to provide compounds that have antagonist effect of integr 4 integrin, which can be administered orally.

Even another objective of the present invention is to provide  4 integrin antagonists.

A further objective of the present invention is to provide a pharmaceutical composition containing these new compounds.

Another additional objective of the present invention is to provide therapeutic agents or prevention agents for diseases in which the adhesion process that depends on integrin  4 participates in the pathology, inflammatory diseases, rheumatoid arthritis, inflammatory bowel diseases, systemic lupus erythematosus,

15 Multiple sclerosis, Sjögren's syndrome, asthma, psoriasis, allergy, diabetes, cardiovascular diseases, arterial sclerosis, restenosis, tumor proliferation, tumor metastases and transplant rejection.

In order to solve the problems described above, the inventors have synthesized several phenylalanine derivatives and examined the antagonist activities of the -4 integrin thereof, and the inventors have found that the new phenylalanine derivatives specified have excellent antagonistic activity. of integrin  4. The

The present invention has been completed on the basis of this finding.

Namely, the present invention provides phenylalanine derivatives of the following general formula (1) and their salts acceptable for pharmaceutical use:

image3

where A represents one of the following general formulas (2), (3) or (3-1):

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where Arm represents a cyclic alkyl group or an aromatic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen atoms,

U, V and X represent C (= O), S (= O) 2, C (-R5) (- R6), C (= C (R5) (R6)), C (= S), S (= O), P (= O) (- OH) or P (-H) (= O),

W represents C (-R7) or a nitrogen atom,

image5

R1, R2, R3, R4 R5, R6 and R7 may be the same or different from each other and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkenyl group, a substituted lower alkenyl group, a lower alkynyl group, a substituted lower alkynyl group, a cycloalkyl group which may contain a heteroatom or ring heteroatoms thereof, an aryl group, a heteroaryl group, a substituted lower alkyl group with a cycloalkyl group or groups that may contain a heteroatom or heteroatoms in the ring thereof, a lower alkyl group substituted with an aryl group or groups, a lower alkyl group substituted with a heteroaryl group or groups, a lower alkoxy group, a group lower alkylthio, a lower alkoxy group and lower alkylthio group substituted with a cycloalkyl group or groups that may contain a heteroatom or heteroatoms in the ring thereof, a lower alkoxy group and a lower alkylthio group substituted with an aryl group or groups, a lower alkoxy group and a lower alkylthio group substituted with a heteroaryl group or groups, a cycloalkyloxy group which may contain a heteroatom or heteroatoms in the ring thereof, an aryloxy group, a heteroaryloxy group, a lower hydroxyalkyl group, a lower hydroxyalkenyl group, a lower hydroxyalkoxyl group, a lower alkyl halogen group, a lower alkoxy halogen group, a lower alkylthio halogen group, a lower alkenyl halogen group , nitro group, cyano group, a substituted or unsubstituted amino group, carboxyl group, a lower alkoxycarbonyl group, a substituted or unsubstituted carbamoyl group, a lower alkanoyl group, an aroyl group, a lower alkylsulfonyl group, a substituted sulfamoyl group or unsubstituted or an ammonium group, R5 and R6 can be attached to form a ring which can and contain one or two atoms of oxygen, nitrogen, or sulfur,

B represents a hydroxyl group, a lower alkoxy group or a hydroxylamino group,

C represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkyl group substituted with a cycloalkyl group or groups that may contain a heteroatom or heteroatoms in the ring thereof, a lower alkyl group substituted with an aryl group or groups or a lower alkyl group substituted with a heteroaryl group or groups,

D represents an aryl group, or a heteroaryl group; or an optionally substituted cyclohexyl group,

C and D may be joined to form a ring which may contain one or two oxygen, nitrogen or sulfur atoms,

T represents an interatomic bond, C (= O), C (= S), S (= O), S (= O) 2, N (H) - C (= O), or N (H) -C ( = S),

J and J 'can be the same or different from each other and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkyloxy group or nitro group.

The present invention provides a ina 4 integrin antagonist containing the phenylalanine derivative described above or its salt acceptable for pharmaceutical use as an active ingredient.

The present invention further provides a pharmaceutical composition containing the phenylalanine derivative described above or its salt acceptable for pharmaceutical use.

The present invention also provides a therapeutic agent or prevention agent, which contains the phenylalanine derivative or its salt acceptable for pharmaceutical use in the form of active ingredient, for diseases in which the adhesion process that depends on the integrin -4 participates in the pathology, such as inflammatory diseases, rheumatoid arthritis, inflammatory bowel diseases, systemic lupus erythematosus, multiple sclerosis, Sjögren's syndrome, asthma, psoriasis, allergy, diabetes, cardiovascular diseases, arterial sclerosis, restenosis, tumor proliferation, tumor metastases and transplant rejection.

Best way to carry out the invention

The term "lower", for example, in a lower alkyl group herein indicates that the group has 1 to 6 carbon atoms and preferably 1 to 4 carbon atoms. The alkyl groups, alkenyl groups and alkynyl groups in the alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkanoyl groups, alkylamino groups and the like can be linear or branched. Examples of these alkyl groups are the methyl group, ethyl group, propyl group, isopropyl group, butyl group, secondary butyl group, tertiary butyl group, pentyl group and hexyl group. It is preferable that the alkyl groups have 1 to 6 carbon atoms and more preferably that the groups have 1 to 4 carbon atoms. The alkenyl groups are, for example, the vinyl group propynyl group, butenyl group and pentenyl group. It is preferable that the alkynyl groups have 2 to 6 carbon atoms and more preferably that the groups have 2 to 4 carbon atoms. Alkynyl groups include the ethynyl group, propynyl group and butynyl group. It is preferable that the alkynyl groups have 2 to 8 carbon atoms and more preferably that the groups have 2 to 4 carbon atoms. Cycloalkyl groups indicate substituted or unsubstituted cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, norbornyl group, adamantyl group and cyclohexenyl group. It is preferable that the cycloalkyl groups have 3 to 8 carbon atoms and more preferably that the groups have 3 to 5 carbon atoms. Alkoxy groups include methoxy group, ethoxy group, propyloxy group, isopropyloxy group, etc. It is preferable that the alkoxy groups have 1 to 6 carbon atoms and more preferably that the groups have 1 to 4 carbon atoms. Heteroatoms include nitrogen, oxygen, sulfur, etc. Halogen atoms are fluorine, chlorine, bromine and iodine. The alkyl halogen groups include the chloromethyl group, trichloromethyl group, trifluoromethyl group, trifluoroethyl group, pentafluoromethyl group, etc.

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Haloxy alkoxy groups include the trichloromethoxy group, trifluoromethoxy group, etc. Hydroxyalkyl groups include the hydroxymethyl group, hydroxyethyl group, etc. Cycloalkyl groups that may contain a heteroatom or heteroatoms in the ring thereof may be either substituted or unsubstituted. Examples of these include the cyclopentyl group, cyclohexyl group, piperidyl group, piperazinyl group, morpholinyl group, pyrrolidinyl group, tetrahydrofuranyl group and uracil group, which are a cyclic group of 4 to 8 members, preferably a cyclic group of 5 to 7 members.

In the present specification, aryl groups are substituted and unsubstituted aryl groups such as the phenyl group, 1-naphthyl group and 2-naphthyl group. Preferably they are the phenyl group and the substituted phenyl group, and the substituents are in particular preferably halogen atoms, alkoxy groups, alkyl groups, hydroxyl groups, alkyl halogen groups and alkoxy halogen groups. Heteroaryl groups are substituted and unsubstituted heteroaryl groups such as pyridyl group, pyrazyl group, pyrimidinyl group, pyrazolyl group, pyrrolyl group, triazyl group, furyl group, thienyl group, isoxazolyl group, isothiazolyl group, indolyl group, quinolyl group, isoquinolyl group and benzimidazolyl group. Preferred heteroaryl groups are the pyridyl group, pyrazyl group, pyrimidinyl group, furyl group, thienyl group and substituted pyridyl, furyl and thienyl groups. Particularly preferred substituents are halogen atoms, alkoxy groups, alkyl groups, hydroxyl groups, halogen alkyl groups and halogen alkoxy groups. Lower alkyl groups substituted with an aryl group or aryl groups include, for example, substituted or unsubstituted benzyl groups and substituted or unsubstituted phenethyl groups. Particularly preferred substituents are halogen atoms, alkoxy groups, alkyl groups, hydroxyl groups, halogen alkyl groups and halogen alkoxy groups. Lower alkyl groups substituted with a heteroaryl group or groups include, for example, the pyridylmethyl group, and particularly preferred substituents thereof are halogen atoms, alkoxy groups, alkyl groups, hydroxyl groups, alkyl halogen groups and alkoxy halogen groups. Alkanoyl groups include, for example, formyl groups, acetyl groups, propanoyl groups, butanoyl groups and pivaloyl groups. The aroyl groups include, for example, the substituted or unsubstituted benzoyl group and the pyridylcarbonyl group, and the substituents thereof are in particular preferably halogen atoms, alkoxy groups, alkyl groups, hydroxyl groups, alkyl halogen groups and alkoxy halogen groups . The alkanoyl halogen groups include, for example, the trichloroacetyl group and the trifluoroacetyl group.

Alkylsulfonyl groups include, for example, the methanesulfonyl group, the ethanesulfonyl group, etc. Arylsulfonyl groups include, for example, the benzenesulfonyl group and the p-toluenesulfonyl group. Heteroarylsulfonyl groups include, for example, the pyridylsulfonyl group. The alkylsulfonyl halogen groups include, for example, the trifluoromethanesulfonyl group. Alkyloxycarbonyl groups include, for example, the methoxycarbonyl group, ethoxycarbonyl group and terbutoxycarbonyl group. The substituted alkoxycarbonyl groups include, for example, the benzyloxycarbonyl group and the 9-fluorenyl methoxycarbonyl group. The substituted carbamoyl groups include, for example, the methylcarbamoyl group, phenylcarbamoyl group and the substituted phenylcarbamoyl group, and the substituents thereof are in particular preferably halogen atoms, alkoxy groups, alkyl groups, hydroxyl groups, alkyl halogen groups and halogen groups alkoxy The substituted thiocarbamoyl groups include, for example, the methylthiocarbamoyl group, phenylthiocarbamoyl group and the substituted phenylthiocarbamoyl group, and the substituents thereof are in particular preferably halogen atoms, alkoxy groups, alkyl groups, hydroxyl groups, halogen alkyl groups and halogen groups alkoxy The substituted amino groups herein indicate substituted or di-substituted mono amino groups and the substituents thereof include lower alkyl groups, lower alkyl groups substituted with an aryl group, lower alkyl groups substituted with a heteroaryl group, lower alkanoyl groups , aroyl groups, lower alkanoyl halogen groups, lower alkylsulfonyl groups, arylsulfonyl groups, heteroarylsulfonyl groups, alkylsulfonyl halogen groups, lower alkyloxycarbonyl groups, substituted aryl lower alkoxycarbonyl groups, substituted or unsubstituted carbamoyl groups and substituted or unsubstituted thiocarbamoyl groups. Ammonium groups include trialkylammonium groups.

Since the phenylalanine derivatives of the general formula (1) of the present invention include asymmetric carbons, the phenylalanine derivatives of the present formula (1) of the present invention can be considered to be optical isomers and the compound indicated in the present invention They include the mentioned optical isomers. However, form L is preferred.

With respect to the compound in which there is a diastereomer, the diastereomer and the diastereomeric mixture are included in said phenylalanine derivatives. Since the phenylalanine derivatives of the general formula

(1) of the present invention include a movable hydrogen atom, the phenylalanine derivatives of the present formula (1) of the present invention can be considered to include a variety of tautomeric forms and the compounds indicated in the present invention include the aforementioned forms Tautomeric In addition, the carboxyl groups of the compound of the present invention can be substituted with the appropriate substituents which are converted into a carboxyl group in vivo. An example of these substituents is a lower alkoxycarbonyl group.

In the general formula (1) described above, it is preferable that the groups indicated as A are the general formulas (2) and (3), Arm in the general formulas (2) and (3) is preferably an aromatic ring and in particular a benzene ring and a substituted benzene ring are preferred. R1 in the general formula (2) is preferably a hydrogen atom, a lower alkyl group and a substituted lower alkyl group. The substituents thereof are preferably a phenyl group, cyano group and carboxyl group. It is preferable that R2 to R4 of the general formulas (2) and (3) are a hydrogen atom, a halogen, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a halogen lower alkyl group, a substituted amino group or unsubstituted and an ammonium group.

The group represented by B is preferably a hydroxyl group. A lower alkoxy group is also preferred.

image7

The group represented by C is preferably a lower alkyl group or a hydrogen atom and the hydrogen atom is most preferred.

The groups represented by D, ie the cyclohexyl group, the aryl group or the heteroaryl group, are either unsubstituted or substituted, and the substituents are those described above with reference to R1, R2, R3, R4, R5, R6 and R7. Among these, the groups represented by D are in particular preferably a substituted or unsubstituted cyclohexyl group or phenyl group. The substituents thereof are preferably 1 to 3 of, more preferably, 1 or 2 of the lower alkyl groups or lower alkoxy groups or halogen atoms.

The group represented by J and J 'is preferably a hydrogen atom.

The group represented by T is preferably C (= O).

It is preferred that U, V and X are C (= O) and C (= S), and C (= O) is particularly preferred. W is preferably C (-R7) and -R7 is preferably a lower alkyl group, a lower alkoxy group and a lower alkylthio group.

In the general formula (1) of the present invention, it is preferable that A represents one of the groups indicated as the general formula (2) or (3) and R1, R2, R3, R4, R5, R6 and R7 can be the same or different from each other, and each represents the groups shown below:

a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkenyl group, a substituted lower alkenyl group, a lower alkynyl group, a substituted lower alkynyl group, a cycloalkyl group which may contain a heteroatom or heteroatoms in the ring thereof, an aryl group, a heteroaryl group, a lower alkyl group substituted with a cycloalkyl group or groups which

or which may contain a heteroatom or heteroatoms in the ring thereof, a lower alkyl group substituted with an aryl group or groups, a lower alkyl group substituted with a heteroaryl group or groups, a lower alkoxy group, a lower alkylthio group, a lower alkoxy group and lower alkylthio group substituted with a cycloalkyl group or groups which may contain a heteroatom or heteroatoms in the ring thereof, a lower alkoxy group and a lower alkylthio group substituted with an aryl group or groups, a lower alkoxy group and a lower alkylthio group substituted with a heteroaryl group or groups, a cycloalkyloxy group which may contain a heteroatom or ring heteroatoms thereof, an aryloxy group, a heteroaryloxy group, a lower hydroxyalkyl group, a lower hydroxyalkenyl group, a lower hydroxyalkoxyl group, a lower alkyl halogen group, a lower alkoxy halogen group, an alkyl halogen group lower ilium, a lower alkenyl halogen group, nitro group, cyano group, a substituted or unsubstituted amino group, carboxyl group, a lower alkoxycarbonyl group, a substituted or unsubstituted carbamoyl group, a lower alkanoyl group, an aroyl group, a group lower alkylsulfonyl, or a substituted or unsubstituted sulfamoyl group, R5 and R6 may be attached to form a ring which may contain one or two atoms of oxygen, nitrogen, or sulfur.

It is preferred that, in the general formula (1) of the present invention, B represents a hydroxyl group or a lower alkoxy group, C represents a hydrogen atom or a lower alkyl group,

J and J 'represent a hydrogen group, and

In the general formulas (2) and (3), V and X represent any group of C = (O), S (= O) 2 or C (-R5) (- R6).

U represents any of the group of C = (O), S (= O) 2, C (-R5) (- R6), C (= C (R5) (R6)), C (= S), S (= O), P (= O) (- OH) or P (-H) (= O).

In addition, it is preferred that, in the general formula (1), B represents a hydroxyl group or a lower alkoxy group, C represents a hydrogen atom or a lower alkyl group,

J and J 'represent a hydrogen group, and

In the general formulas (2) and (3), Arm represents a benzene ring or an aromatic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen atoms.

In addition, it is preferred that, in the general formula (1), B represents a hydroxyl group or a lower alkoxy group,

C represents a hydrogen atom or a lower alkyl group,

J and J 'represent a hydrogen group, and

In the general formulas (2) and (3), Arm represents a benzene ring or an aromatic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen atoms.

V and X represent any of the group of C = (O), S (= O) 2 or C (-R5) (- R6),

U represents any of the group of C = (O), S (= O) 2, C (-R5) (- R6), C (= C (R5) (R6)), C (= S), S (= O), P (= O) (- OH) and P (-H) (= O).

image8

It is further preferred that, in the general formula (1), C represents a hydrogen atom and T represents C (= O). It is further preferred that, in the general formula (1), A represent the following formula (3-3):

image3

where Arm, U and R1 to R4 are the same as described above.

In the general formula (3-3), Arm is preferably an aromatic ring, and in particular preferably a benzene ring or a substituted benzene ring. R1 in the general formula (3-3) is preferably a hydrogen atom, a lower alkyl group or a lower alkyl group substituted with a phenyl group, cyano group or carboxyl group. R1 to R4 in the general formula (3-3) are preferably a hydrogen atom, halogen atom, hydroxyl group, lower alkyl group, lower alkoxy group, cyano group, nitro group, an unsubstituted amino group or group

10 amino substituted with a lower alkyl group or groups.

In the general formula (1), A preferably represents the following formulas (3-4)

image3

where Arm and R1 to R4 are the same as described above. In the general formula (1), D preferably represents the following formulas (4-1), (4-2), (4-3) or (4-4):

image9

where R13 represents a halogen atom or methyl group, R8 represents a halogen atom, methyl group, trifluoromethyl group, methoxy group or a hydrogen atom, R9 represents a hydrogen atom, halogen atom, hydroxyl group, lower alkyl group, cycloalkyl group which may contain a hetero atom or heteroatoms in the ring thereof, alkyl group substituted with a group or cycloalkyl group that may contain a heteroatom or heteroatoms in the ring thereof, lower alkoxy group, lower alkylthio group, halogen alkyl group lower, lower alkoxy halogen group, lower alkyl halide group, nitro group, cyano group, amino group, amino group substituted with a lower alkyl group or groups, trialkylammonium group, amino methanesulfonyl group and tetrazolyl group.

In the above formulas, formula (4-1) is preferred. In particular, it is preferable that in the formula (4-1), R13 and R8 represent a chlorine atom, and R9 represents a hydrogen atom, halogen atom, hydroxyl group, lower alkyl group, cycloalkyl group which may contain a heteroatom or ring heteroatoms thereof, lower alkoxy group, lower alkylthio group, lower alkyl halogen group, lower alkoxy halogen group, inner alkylthio halogen group, nitro group, cyano group, amino group, amino group substituted with a lower alkyl group or groups , trialkylammonium group.

It is further preferred that in the general formula (1), A represents the formula (3-4), Arm is a benzene ring, pyridine ring, pyrazole ring or cyclohexane ring, R1 is a lower alkyl group, R2, R3 and R4 they may be the same or different from each other and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a cycloalkyl group that may contain a heteroatom or heteroatoms in the ring thereof, an alkyl group lower substituted with a cycloalkyl group or groups which or which may contain a heteroatom or heteroatoms in the ring thereof, a lower alkoxy group, a lower alkylthio group, a lower alkyl halogen group, a lower alkoxy halogen group, a halogen group lower alkylthio, a nitro group, a cyano group, an amino group, an amino group substituted with a lower alkyl group or groups or a trialkylammonium group.

Furthermore, it is preferred that in the general formula (1), A represents the formula (3-4), D represents (4-1), (4-2), (4-3) or (4-4), B it is a hydroxyl group or a lower alkoxy group, C is a hydrogen atom, each of J and J 'is a hydrogen atom and T is C (= O).

In the present invention, it is preferable that in the general formula (1), A represents the formula (3-4) where Arm is a benzene ring, pyridine ring, pyrazole ring or cyclohexane ring, R1 is a lower alkyl group, R2 , R3 and R4 may be the same or different from each other and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a cycloalkyl group that may contain a heteroatom or heteroatoms in the ring thereof , a lower alkyl group substituted with a cycloalkyl group or groups which may contain a heteroatom or heteroatoms in the ring thereof, a lower alkoxy group, a lower alkylthio group, a lower alkyl halogen group, a lower alkoxy halogen group, a halogen group lower alkylthio, a nitro group, a cyano group, an amino group, an amino group substituted with a lower alkyl group or groups or a trialkylammonium group, D represents the formula (4-1) where R13 and R8 represents a chlorine atom, and R9 represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, cycloalkyl group that may contain a heteroatom or heteroatoms in the ring thereof, lower alkoxy group, alkylthio group lower, lower alkyl halogen group, lower alkoxy halogen group, inner alkylthio halogen group, nitro group, cyano group, amino group, amino group substituted with a lower alkyl group or groups, trialkylammonium group, B is a hydroxyl group or a lower alkoxy group , C is a hydrogen atom, each of J and J 'is a hydrogen atom and T is C (= O).

In the present invention, it is further preferred that in the general formula (1), A represents the formula (3-3), and in the formula (3-3), U represents C (= O) or C (= S) , R1 represents a lower alkyl group, R2, R3 and R4 may be the same or different from each other and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a cycloalkyl group which may contain a heteroatom or heteroatoms in the ring thereof, a lower alkyl group substituted with a cycloalkyl group or groups that may contain a heteroatom or heteroatoms in the ring thereof, a lower alkoxy group, a lower alkylthio group, a lower alkyl halogen group, a lower alkoxy halogen group, a lower alkylthio halogen group, a nitro group, a cyano group, an amino group, an amino group substituted with a lower alkyl group or groups or a trialkylammonium group, C represents a hydrogen atom, D represents the formula ( 4-1), (4-2), (4.3) or (4-4), T represents C (O).

Furthermore, in the present invention, it is preferred that A represents formula (3-3), and in formula (3-3), U represents C (= O) or C (= S), R1 represents a methyl group or an ethyl group, R2, R3 and R4 may be the same or different from each other and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a cycloalkyl group that may contain a heteroatom or heteroatoms in the ring thereof, a lower alkoxy group, a lower alkylthio group, a lower alkyl halogen group, a lower alkoxy halogen group, a lower alkylthio halogen group, a nitro group, a cyano group, an amino group, a substituted amino group with a group

or lower alkyl groups or a trialkylammonium group, B represents a hydroxyl group or a lower alkyl group, C represents a hydrogen atom, D represents formula (4-1), where R13 and R8 represent a chlorine atom, and R9 represents a hydrogen atom, halogen atom, hydroxyl group, lower alkyl group, cycloalkyl group which may contain a heteroatom or heteroatoms in the ring thereof, lower alkoxy group, lower alkylthio group, lower alkyl halogen group, lower alkoxy halogen group, group halogen inner alkylthio, nitro group, cyano group, amino group, amino group substituted with a lower alkyl group or groups, or trialkylammonium group, T is C (= O) and each of J and J 'is a hydrogen atom.

image10

In the present invention, phenylalanine derivatives of the following general formula and their salts acceptable for pharmaceutical use are preferred:

image3

where R1 represents a methyl group or an ethyl group, R8 represents a halogen atom or methyl group,

R10 represents a hydrogen atom or a lower alkyl group, R11 and R12 may be the same or different from each other and each represents a hydrogen atom, a methyl group, ethyl group or propyl group, R11 and R12 may be attached to each other. form a ring, and in that case, R11-R12 represents trimethylene, tetramethylene or pentamethylene. It is particularly preferred that R 10 represents a lower alkyl group.

Specifically, the compounds described in the examples are preferred although they are not particularly limited.

Especially, the compounds of the following formulas and their salts acceptable for pharmaceutical use are preferred:

image11

image3

image3

image12

image3

The phenylalanine derivatives (1) of the present invention can be synthesized, for example, by the methods described below when B is a hydroxyl group.

image3

image3

solid phase vehicle

image13

A protected carboxylic acid (4) is suitably loaded into a resin by a usual method. The substituent P of the carboxylic acid (4) has a C structure as described above with reference to the general formula (1), is a substituent that can be converted to C at any stage of the synthesis or is a suitably protected form of these substituents. The substituent Q of the carboxylic acid (4) has a structure of

5 D-T as described above with reference to the general formula (1), is a substituent that can be converted to D-T at any stage of the synthesis or is a suitably protected form of these substituents. In addition, the substituent R of the carboxylic acid (4) has a structure of a substituent that can be converted into NH2 or the suitably protected form of the NH2 group.

With respect to the reaction conditions of the load, the reaction can be carried out using, if it were

10, a suitable additive such as HOAt (1-hydroxy-7-azabenzotriazole), HOBt (1-hydroxybenzotriazole) or DMAP (dimethylaminopyridine) and a condensing agent such as DIC (diisopropylcarbodiimide), DCC (dicyclohexylcarbodiimide) or EDC -ethyl-3- (3-dimethylaminopropyl) carbodiimide) in an organic solvent such as dichloromethane, DMF (N, N-dimethylformamide) or NMP (N-methyl-2-pyrrolidone). For example, when Wang resin is used, the reaction is carried out in the presence of pyridine and 2,6-dichlorobenzoyl chloride in DMF to obtain a

15 ester (5). The ester (5) can be changed to an amine (6) under suitable conditions that depend on the R substituent. For example, when a nitro group is used as R, the ester (5) can be changed to the amine (6) in presence of a reducing agent such as SnCl2 or hydrates thereof in a solvent such as NMP, DMF or ethanol. In the case of an amine protected with an Fmoc group (9-fluorenylmethoxycarbonyl group) (FmocNH), the protecting group can be removed with a base such as piperidine in a solvent such as DMF to obtain the amine (6).

A quinazolindione (9) where A represents the general formula (2) and U and V are both C (= O) in the general formula (1) can be obtained by the following method. First, a urea (7) is obtained by reacting the amine (6) with an isocyanate having a carboxylate ester group in the ortho position. Next, a quinazolindione (8) can be obtained by a ring closure reaction with a base such as a piperidine in a solvent such as DMF or TMG (tetramethylguanidine). Subsequently, reagents such as alkyl halide and aryl halide are

They are reacted to obtain quinazolindione (9), or said compound can also be obtained by the reaction of Mitsunobu using alcohol.

image3

A quinazolindione (9) where A represents the general formula (2) and U and V are both C (= O) in the general formula (1) can also be synthesized by the following method. First, an amide (10) can be obtained by reacting the amine (6) with an aciol chloride having a nitro group in the ortho position under the existence of the 2,6-lutidine base in a solvent such as NMP, or by reacting it with a carboxylic acid having a nitro group in the ortho activated position using a condensing agent such as DIC and, if necessary, a suitable additive such as HOAt or HOBt in an organic solvent such as DMF, NMP or dichloromethane . TO

image14

Then, an amine (11) is obtained by reducing the nitro group with SnCl2 or hydrates thereof and cyclized by reagents such as CDT (carbonyldiimidazole), triphosgene or p-nitrophenylchloroformate to obtain quinazolindione (8).

Like the other methods of synthesis, quinazolindione (8) can also be obtained by the following method. First, an amide (11) can be obtained by reacting the amine (6) with a carboxylic acid having an amino group in the ortho activated position by using a condensing agent such as DIC and, if it were

10, a suitable additive such as HOAt or HOBt in an organic solvent such as DMF, NMP or dichloromethane. Next, an amide (11) is cyclized with reagents such as CDI, triphosgene or p-nitrophenylchloroformate to obtain quinazolindione (8). This method is applied to one of the synthesis methods in case A represents the general formula (3-1) and U and V are both C (: = O) in the general formula (1), when a variety of acids Salicylic is used instead of the above carboxylic acid and the resulting amide (11) is cyclized with reagents such as CDT,

15 triphosgene or p-nitrophenylchloroformate after adding a base such as ethanolamine.

image3

A quinazolindione (9) where A represents the general formula (2), U and V are both C (= O) and R2, R3 or R4 is an electron removal substituent such as a nitro group in the general formula (1) , can also be synthesized by the following method. First, an amide (42) can be obtained by reacting the amine (6) with an acid

A carboxylic group having a fluoro group in the ortho activated position through the use of a condensing agent such as DIC and, if necessary, a suitable additive such as HOAt or HOBt in an organic solvent such as DMF, NMP or dichloromethane. Then, after an amine (43) is obtained by replacing a fluoro group with an amine, the amine (43) is cyclized with reagents such as CDT, triphosgene or p-nitrophenylchloroformate to obtain the quinazolinedione (9).

image4

According to the example of the methods for synthesizing an ester (12) where A represents the general formula (2), U is C (= S) and V is C (= O) in the general formula (1), said ester can be obtained by reacting the amine (6) with an isothiocyanate having a carboxylate group in the ortho position.

image15

image3

According to the example of the methods for synthesizing an ester (44) where A represents the general formula (2), U is C (= S) and V is C (= O) in the general formula (1), said ester can be obtained by reacting the amine (43) with a thiocarbonyldiimidazole in a solvent such as decahydro-naphthalene and toluene.

image16

Among the ester (13) where A represents the general formula (3) and W is C (-R7) in the general formula (1), in particular those in which R7 is a lower alkylthio group, a lower alkylthio group substituted with a cycloalkyl group which may contain a heteroatom or heteroatoms in the ring thereof, a lower alkylthio group substituted with an aryl group or a lower alkylthio group substituted with a heteroaryl group can be obtained by reacting the ester

10 (12) with reagents such as alkyl halide and aryl halide.

image3

In addition, between the ester (14) where A represents the general formula (3) and W is C (-R7) in the general formula (1), particularly those in which R7 is a hydrogen atom, a lower alkyl group, a lower alkynyl group, a lower alkynyl group, a cycloalkyl group that may contain a heteroatom or ring heteroatoms thereof, an aryl group, a heteroaryl group, a lower alkyl group substituted with a cycloalkyl group or groups that can

5 containing a heteroatom or heteroatoms in the ring thereof, a lower alkyl group substituted with an aryl group or groups, a lower alkyl group substituted with a heteroaryl group or groups, a lower alkoxy group, a lower alkoxy group substituted with a group or cycloalkyl groups that may contain a heteroatom or heteroatoms in the ring thereof, a lower alkoxy group substituted with an aryl group or groups, a lower alkoxy group substituted with a heteroaryl group or groups, a cycloalkyloxy group that may contain a heteroatom or heteroatoms in the ring

10 thereof, an aryloxy group, a heteroaryloxy group, a lower hydroxyalkyl group, a lower hydroxyalkenyl group, a lower hydroxyalkoxy group, a lower alkyl halogen group, a lower alkoxy halogen group, a lower alkenyl halogen group, a nitro group, a cyano group, a substituted or unsubstituted amino group, carboxyl group, a lower alkyloxycarbonyl group, a substituted or unsubstituted carbamoyl group, a lower alkanoyl group, an aroyl group, a lower alkylthio group, a lower alkylsulfonyl group or a substituted sulfamoyl group or unsubstituted, can be obtained

15 by reacting the amine (11) with several orthoformates or equivalents thereof. Said ester can also be obtained by oxidation after reacting with aldehyde or acetal.

image3

Among the ester (14) where A represents the general formula (3) and W is C (-R7) in the general formula (1), particularly those in which R7 is a substituted amino group can be synthesized as follows: First , And 20 in an ester (15) is a group such as an azide group and an amino group and each can be changed to an iminophosphine (16) by reacting it with triphenylphosphine or triphenylphosphine under the existence of diisopropylazodicarboxylic acid respectively. Then, carbodiimide (17) (n is 0 to 4) is obtained by the Aza-Wittig reaction of the iminophosphine (16) with an isocyanate having a carboxylate group in the ortho position. After the nucleophilic attack on the carbodiimide of the amine and the closure of the ring subsequently, it is possible to synthesize the

25 ester (18).

image17

image3

According to the example of the methods for synthesizing an ester (45) where A represents the general formula (3), W is N and X is C (= O) in the general formula (1), said ester can be obtained by reacting the amine (11) with a sodium nitrite in a solvent such as acetic acid.

image16

According to the example of the methods for synthesizing an ester (46) where A represents the general formula (2), U is S (= O) and V is C (= O) in the general formula (1), said ester can be obtained by reacting the amine (43) with, for example, a thionyl chloride in a solvent such as dichloromethane.

image18

image3

According to the example of the methods for synthesizing an ester (50) where A represents the general formula (2), U is C (= O) and V is S (= O) 2 in the general formula (1), said ester is You can get it using the following method. First, a sulfonamide (47) can be obtained by reacting the amine (6) with a sulfonyl chloride having a nitro group in the ortho position under the existence of a base such as 2,6-lutidine in a solvent such as NMP and dichloromethane. Next, an amine (48) is obtained by reducing a nitro group with SnCl2 or hydrates thereof and cyclized with reagents such as CDI, triphosgene or p-nitrophenylchloroformate to obtain (49). Subsequently, the alkyl halide is reacted to obtain said ester.

image3

According to the example of the methods for synthesizing an ester (54) where A represents the general formula (2), U and V are both C (= O) and V R2, R3 or R4 is an amino group in the general formula ( 1), said ester can be obtained by the following method. First, an amide (51) can be obtained by reacting the amine (6) with a carboxylic acid having a nitro group as a substituent and an amino group in the ortho activated position through the use of a condensing agent such as DIC and, if necessary, a suitable additive such as HOAt or HOBt in a

Organic solvent such as DMF, NMP or dichloromethane. Then, it is obtained (52) when it is cycled by reagents such as CDI, triphosgene or p-nitrophenylchloroformate. After the reaction with alkyl halide, the amine (54) can be obtained by reducing a nitro group with SnCl2, hydrates thereof or the like.

image19

image3

According to the example of the methods for synthesizing an ester (55) where A represents the general formula (2), U and V are both C (= O) and R2, R3 or R4 is an acylamino group in the general formula (1) , said ester can be obtained by reacting (54) with acyl halide under the existence of a base such as pyridine in an organic solvent such as DMF, NMP and dichloromethane.

image3

According to the example of the methods for synthesizing an ester (61) where A represents the general formula (2), U and V are both C (= O) and R2, R3 or R4 is a substituted amino group in the general formula (1 ), said ester can be obtained by the following method. First, an amide (56) can be obtained by reacting the amine (6) with

10 a carboxylic acid having a fluoro group in the form of a substituent and a nitro group in the ortho position, activated by the use of a condensing agent such as DIC and, if necessary, a suitable additive such as HOAt or HOBt in an organic solvent such as DMF, NMP or dichloromethane. An amine (57) can then be obtained by reacting the amide (56) with a substituted amine in a solvent such as NMP and DMSO, and (58) is obtained by reducing the nitro group with SnCl2, hydrates thereof or the like. After obtaining (60) cycling (58) by

Reagents such as CDI, triphosgene and p-nitrophenylchloroformate, (61) can be obtained by the reaction of Mitsunobu using an alcohol, diisopropylazodicarboxylic acid and the like.

image20

image3

According to the example of the methods for synthesizing an ester (62) where A represents the general formula (2), U and V are both C (= O) and R2, R3 or R4 is an ammonium group in the general formula (1) , said ester can be obtained by reacting (61) with alkyl halide under the existence of a base such as pyridine in an organic solvent such as DMF, NMP and dichloromethane.

image3

According to the example of the methods for synthesizing an ester (68) where A represents the general formula (3-2) in the general formula (1), said ester can be obtained by the following method. First, an amide (63) can be obtained by reacting the amine (6) with a carboxylic acid having an amino group protected with Fmoc in the

10 position  activated by the use of a condensing agent such as DIC and, if necessary, a suitable additive such as HOAt or HOBt in an organic solvent such as DMF, NMP or dichloromethane. Next, an amine (64) can be obtained by removing Fmoc and subsequently a sulfonamide (65) can be obtained by reacting (64) with a sulfonyl chloride having a nitro group as a substituent under the existence of a base such as 2, 6-lutidine in a solvent such as NMP and dichloromethane. In addition, (66) can be obtained by reacting

15 (65) with alkyl halide under the existence of a base such as diisopropylethylamine, and subsequently an amine (67) can be obtained by reacting (66) with mercaptoethanol, diazabicycloundecene, etc. The compound is cyclized by reagents such as CDI, triphosgene and -nitrophenylchloroformate to obtain the ester (68).

image21

image22

image3

When A in the phenylalanine derivative (1) of the present invention represents the general formula (3-3) and Arm is a benzene ring, the ester can be synthesized according to the following method. The same method can be applied even when Arm is different from a benzene ring.

image23

image3

First, the amine (6) is reacted with a halogenated methylbenzene having a nitro group in the ortho position to obtain a benzylamine (69). After said benzylamine is reduced by tin chloride and the like to obtain an amine (70), an amine (71) can be obtained by converting the amine into the benzene ring of

5 the benzyl part introduced into the mono group R1 substituted by several methods. An ester (72) can be obtained by being finally cyclized by reagents such as CDI, triphosgene and p-nitrophenylchloroformate.

The D-T part in the general formula (1) can be constructed as follows. For example, when T is C (= O) and B is a hydroxyl group in the formula (1), if, in the ester (19), the substituent G has the structure C, the substituent or the substituents that can be converted at C at a certain point in the synthesis process or the substituent (s) that have a suitably protected structure, then substituent Z has the structure of (2), (3), (3-1), (3- 2) or the substituent (s) that can be converted to A at a certain point in the synthesis process or the

or the substituents have a suitably protected structure, the ester (19) can be converted into the amine

(20) by removing a protecting group or groups under the appropriate conditions that depend on the protective group E. For example, when the Fmoc group (9-fluorenylmethoxycarbonyl group) is used as E, the protecting groups can be

Remove with a base such as piperidine in a solvent such as DMF. The amine (20) can be converted into the amide (21) by condensation of the carboxylic acid using a condensing agent such as DIC and, if necessary, a suitable additive such as HOAt and HOEt into an organic solvent such as DMF, NMP and dichloromethane.

image3

In addition, the amine (20) is reacted with acyl halide, carboxylic anhydride, sulfonyl halide and sulfonyl anhydride under the existence of an organic base such as triethylamine, diisopropylethylamine, pyridine and N, N-dimethylaminopyridine or an inorganic base such as potassium and sodium carbonate in an organic solvent such as DMF, NMP and dichloromethane and can then form the corresponding amide structure and the sulfonamide structure.

image24

5

10

fifteen

twenty

25

30

35

40

In addition, the amine (20) is reacted with various isocyanate and isothiocyanate under the existence of an organic base, if necessary, such as triethylamine, diisopropylethylamine, pyridine and N, N-dimethylamino pyridine in an organic solvent such as DMF, toluene and dichloromethane and then can form the corresponding urea structure and the thiourea structure.

The esters synthesized by the methods described above such as (9), (12), (13), (14), (18), (21), (44), (45), (46), (50), (54), (55), (61), (62), (68) and (72) are separated from a resin under suitable conditions to obtain a carboxylic acid (87). For example, when Wang resin is used, if, in the ester (22), each of A1, C1, and D1 is A, C, and D respectively or a group that becomes A, C, and D respectively in the cleavage condition, the ester (22) is treated with an acid solution that includes TFA (trifluoroacetic acid) therein to obtain a solution of the carboxylic acid (87). In addition, pure carboxylic acid (87) can be obtained by applying well-known isolation and purification methods such as concentration, extraction, crystallization, column chromatography, HPLC and recrystallization to the carboxylic acid thus obtained (87).

The compound where B represents a lower alkoxy group in the general formula (1) can be obtained by condensing the carboxylic acid (87) with a suitable lower alcohol under the existence of a suitable condensing agent or acid catalyst.

The compound where B represents a lower hydroxylamino group in the general formula (1) can be obtained by condensing the carboxylic acid (87) with a hydroxylamine under the existence of a suitable condensing agent.

The phenylalanine derivative (1) can be synthesized by applying the solid phase methods shown above to the solution phase methods, selecting a suitable protecting group and using well known purification and isolation methods.

image3

When the compounds of the general formula (1) can form salts thereof, it is sufficient that the salts be acceptable for pharmaceutical use. When the compound has an acidic group such as a carboxylic group, the salts may be ammonium salts, or salts thereof with alkali metals, e.g., sodium and potassium, salts thereof with alkaline earth metals, e.g., calcium and magnesium, salts thereof with aluminum and zinc, salts thereof with organic amines, eg, triethylamine, ethanolamine, morpholine, piperidine and dicyclohexylamine, and salts thereof with basic amino acids, eg. arginine and lysine. When the compound has a basic group, the salts may be those with inorganic acids, eg, hydrochloric acid, sulfuric acid and phosphoric acid; those with organic acids, eg, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, and succinic acid; and those with organosulfonic acids, eg, methanesulfonic acid and p-toluenesulfonic acid. The salts can be formed by mixing a compound of the general formula (1) with a necessary acid or base in an appropriate ratio in a solvent or dispersant or by cation exchange or anion exchange reaction with another salt.

The compounds of the general formula (1) of the present invention further include solvates thereof such as hydrates and alcohol adducts thereof.

The compounds of the general formula (1) and the salts thereof are administered as they are or in the form of various pharmaceutical compositions to the patients. The dosage forms of the pharmaceutical compositions are, for example, tablets, powders, pills, granules, capsules, suppositories, solutions, sugar-coated tablets, depot preparations and syrups. They can be prepared with ordinary preparation assistants by an ordinary method.

For example, tablets are prepared by mixing the phenylalanine derivative, the active ingredient of the present invention, with any of the known adjuvants such as inert diluents, eg, lactose, calcium carbonate and calcium phosphate; binders, eg, acacia, corn starch and gelatin; spreading agents, eg alginic acid, corn starch and pregelatinized starch; sweetening agents, eg, sucrose, lactose and saccharin; flavorings, eg, mint, akamono oil (Gaultheria aderothrix) and cherry; lubricants, eg, magnesium stearate, talc and carboxymethyl cellulose; excipients for soft gelatin capsules and suppositories, eg, fats, waxes, semi-solid and liquid polyols, natural oils and hardened oils; and excipients for solutions, eg, water, alcohols, glycerols, polyols, sucrose, invert sugars, glucose and vegetable oils.

image25

The antagonist containing a compound or the compounds of the above general formula (1) or the salt or salts thereof as active ingredient is used as a therapeutic agent or prevention agent for diseases in which the adhesion process that depends on the integrin  4 participates in the pathology, inflammatory diseases, rheumatoid arthritis, inflammatory bowel diseases, systemic lupus erythematosus, multiple sclerosis, Sjögren's syndrome, asthma, psoriasis, allergy, diabetes, cardiovascular diseases, arterial sclerosis, restenosis, tumor proliferation, metastasis of tumors, transplant rejection, etc.

The dosage of the compound of the general formula (1) or a salt thereof that is used for the purposes described above varies depending on the desired therapeutic effect, the method of administration, the period of treatment, and the age and body weight of the patient. . The dosage is usually 1 µg at 5 g per day for adults in oral administration, and 0.01 µg up to 1 g per day for adults in parenteral administration.

(Examples)

The following examples will further illustrate the present invention, which are only preferred embodiments of the invention and in no way limit the invention.

Example 1. Synthesis of the compound of the following general formula (23) which has a substituent or substituents of Example 1 of Table 1.

Process 1. Resin preparation

Fmoc-Fe (4-nitro) -OH (2.5g), 2,6-dichlorobenzoyl chloride (0.745 ml) and pyridine (1.5 ml) in a solution of NMP (25 ml) were added to Wang resin ( 0.76 mmol / g, 2.3g) and stirred at room temperature for 16 hours. After removing excess solvent, the resin was washed with DMF three times, dichloromethane three times and NMP twice. In order to carry out the coverage of an unreacted hydroxyl group on the resin, the resin was treated with acetic anhydride (20 ml), pyridine (20 ml) and NMP (20 ml) for 2 hours. After removing excess solvent, the resin was washed with DMF three times, and dichloromethane three times, and dried under reduced pressure.

Process 2. Elimination of the Fmoc group

A DMF solution of 20% piperidine (25 ml) was added to the resin obtained in process 1 and reacted for 15 minutes. After removing excess solvent, the resin was washed with DMF and dichloromethane three times, and dried under reduced pressure.

Process 3. Acylation reaction

2,6-Dichlorobenzoyl chloride (1.1 ml), 2,6-lutidine (1.6 ml) and NMP (26 ml) were added to 2.0g of the resin obtained in process 2 and reacted during 6 hours. After removing excess solvent, the resin was washed with DMF and dichloromethane three times, and dried under reduced pressure.

Process 4. Reduction of the nitro group

Solution in NMP (30 ml) • EtOH (1.5 ml) of SnCl2 • 2H2O (15.0 g) was added to 1.5 g of the resin obtained in process 3 and reacted for 16 hours. After removing the solvent from the reaction, the resin was washed with DMF and dichloromethane three times.

Process 5. Construction of the quinazolin-2,4-dione ring

2g of the resin obtained in process 4 in NMP solution (32 ml) of methyl 2-isocyanatobenzoate (1.92 g) was reacted for 16 hours. After removing the solvent from the reaction, the resin was washed with DMF and dichloromethane three times. 20% piperidine DMF solution was added to the resin for 1 hour. After removing excess solvent, the resin was washed with DMF and dichloromethane three times, and dried under reduced pressure.

Process 6. Alkylation

Methyl iodide (0.75 mmol), 18-crown-6 (30 mg), NMP (1 ml) and K2CO3 (35 mg) were added to 20 mg of the resin obtained in process 5 and reacted for 3 days . After removing the reaction solvent, the resin was washed with DMF, water, DMF and dichloromethane three times, and dried under reduced pressure.

image26

Process 7. Resin excision

The resin obtained in process 6 was treated with trifluoroacetic acid containing 5% water for 1 hour. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified with high pressure liquid chromatography (water / acetonitrile) to obtain 8 mg of the desired compound.

5 MS (ESI MH +): 512 CHNO: C25H19C12N305

Examples 2 to 7

The compounds described below were synthesized by the same procedure as in Example 1 except that the corresponding alkylation reagents were used in the process 6 of Example 1. Meanwhile, R in Table 1 is a substituent or substituents in the following general formula (23) and the same procedure

10 which in Example 1 was repeated in Example 2 except that Process 6 of Example 1 was not carried out.

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Table 1

Example

R Experimental MS (MH +)

one

I- 512

2

H- 408

3

Et- 526

4

2,6-difluorobenzyl 624

5

4- (1 pyrrolidino) benzenecarbonylmethyl 685

6

NCCH2 537

7

HOC (= O) CH2- 556

Example 8. Synthesis of the compound of the following general formula (24) which has a substituent or substituents of Example 8 of Table 2

Process 1. Construction of the quinazolin-2,4-dione ring and elimination of the Fmoc group.

A nitro group of the resin (1 g) that was obtained in Process 1 of Example 1 was reduced according to Process 4 of Example 1, and the quinazolin-2,4.dione ring was constructed and the Fmoc group was removed according to Process 5 of Example 1.

20 Process 2. Acylation, alkylation and resin cleavage

Acylation was performed using the resin obtained in Process 1 of Example 8 (25 mg), 2,6-dimethyl benzoic acid (0.4 mmol), DIC (0.4 mmol), HOAt (0.4 mmol) and NMP (2 ml). Then, the alkylation was carried out in accordance with Process 6 of Example 1 and the cleavage of the resin and purification was performed by the same process as Process 7 of Example 1 to obtain the desired compound (9 mg).

25 MS (ESI MH-E): 472

CHNO: C27H25N305 Examples 9 to 13

image27

The compounds described below were synthesized by the same procedure as in Example 8 except that the corresponding carboxylic acid was used in Process 2 of Example 8. R in Table 2 is a substituent or substituents in the following general formula ( 24). In addition, twice as much as possible DIC and HOAt that were used in Process 2 of Example 8 were used in Example 13, to obtain the desired compound (7 mg).

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Table 2

Example

R Experimental MS (MH +)

8

2,6-dimethylbenzoyl 472

9

2,6-dimethoxybenzoyl 504

10

 2-ethoxybenzoyl 488

eleven

 3,4-dimethoxycinnamoyl 530

12

cyclohexylcarbonyl 450

13

 trans-4-carboxycyclohexanecarbonyl 494

Example 14. Synthesis of the compound of the following general formula (25) which has a substituent or substituents of Example 14 of Table 3 Process 1. Construction of the quinazolin-2-thioxo-4-one ring The resin obtained in the Process 4 of Example 1 (2.00g) was reacted in NMP solution (25 ml) of methyl 2-thiocyanatobenzoate (1.40 g) for 16 hours. After removing the excess solvent, the resin was washed with DMF and dichloromethane three times, and dried under reduced pressure. Process 2. Resin cleavage The resin obtained in Process 1 (25 mg) was treated according to Process 7 of Example 1 to obtain the desired compound (10 mg). MS (ESI MH +): 513 20 CHNO C24H17C12N304S Example 15. Synthesis of the compound of the following general formula (25) which has a substituent or substituents of Example 15 of Table 3 Process 1. Acylation The acylation was performed using the resin obtained in Process 2 of Example 1 (25 mg), 2,625 dimethylbenzoic acid (0.4 mmol), DIC (0.4 mmol), HOAt (0.4 mmol) and NMP (2 ml). Process 2. Construction of the quinazolin-2-thioxo-4-one ring The resin obtained in Process 1 (2.00 g) was reacted in NMP solution (25 ml) of 2

image28

methyl isothiocyanatobenzoate (1.40 g) for 16 hours. After removing excess solvent, the resin is

washed with DMF and dichloromethane three times, and dried under reduced pressure.

Process 3. Resin excision

The resin obtained in Process 1 (25 mg) was treated according to Process 7 of Example 1 to

obtain the desired compound (8mg).

MS (ESI MH +): 474 CHNO: C26H23N304S

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Table 3

Example

R Experimental MS (MH +)

14

 2,6-dichlorobenzoyl 513

fifteen

 2,6-dimethylbenzoyl 474

Example 16. Synthesis of the compound of the following general formula (26) having a substituent or substituents of Example 16 of Table 4 Process 1. Alkylation Allyl bromide (0.5 mmol), diisopropylethylamine (1.0 mmol) were added ) and NMP (2 ml) to the resin obtained in Process 1 of Example 14 (25 mg) and reacted for 16 hours. After removing the solvent in excess, the resin was washed with DMF and dichloromethane three times, and dried under reduced pressure. Process 2. Resin cleavage The resin obtained in Process 1 was treated according to Process 7 of Example 1 to obtain the desired compound (6 mg). MS (ESI MH +): 554 20 CHNO: C27H21C12N304S Examples 17 to 30

The compounds shown in Table 4 were synthesized by the same procedure as in Example 16 except that the resin obtained in Process 1 of Example 14 or Process 2 of Example 15 was used and the corresponding halide was used in Process 1 of Example 16. Meanwhile, R1 and R2 in Table 4 are a

25 substituent or substituents in the following general formula (26).

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image29

Table 4

Example

R1- R2- Experimental MS (MH +)

16

 2,6-dichlorobenzoyl ally 554

17

 2,6-dichlorobenzoyl ethyl 542

18

 2,6-dichlorobenzoyl methyl 542

19

 2,6-dichlorobenzoyl isoamyl 583

twenty

 2,6-dichlorobenzoyl 2,6-difluorobenzyl 640

twenty-one

 2,6-dichlorobenzoyl 2-methylbenzyl 618

22

 2,6-dichlorobenzoyl 1-phenylethyl 618

2. 3

 2,6-dichlorobenzoyl 4-methoxyphenacyl 662

24

 2,6-dimethylbenzoyl methyl 488

25

 2,6-dimethylbenzoyl ethyl 502

26

 2,6-dimethylbenzoyl ally 514

27

 2,6-dimethylbenzoyl isoamyl 544

28

 2,6-dimethylbenzoyl 2,6-difluorobenzyl  600

29

 2,6-dimethylbenzoyl 1-phenylethyl 578

NMR data of the compound of Example 18: 1H NMR (CDCl3)  = 2.53 (3H, s), 3.40 (2H, t, J = 5.3 Hz), 5.20 (1H, t, J = 5.3 Hz), 7.21-7.35 (6H, m), 7.41 (1H, t, J = 7.5 Hz), 7.50 (2H, d, J = 8.7 Hz ), 7.65 (1H, d, J = 8.4 Hz), 7.76 (1H, t, 5 J = 6.9 Hz), 8.19 (1H, d, J = 7.5 Hz)

Example 31. Synthesis of the compound of the following general formula (27) which has a substituent or substituents of Example 31 of Table 5

Process 1. Acylation

2-Nitrobenzoyl chloride (4 mmol), 2,6-lutidine (8 mmol) and NMP were added to the resin obtained in Process 4 of Example 1 (1.00 g) and stirred for 16 hours. After that, the resin was washed with DMF and dichloromethane three times, and dried under reduced pressure.

Process 2. Reduction of the nitro group

The resin obtained in Process 1 (25 mg) was treated in accordance with Process 4 of Example 1 to obtain the desired resin.

15 Process 3. Cyclisation with ortho ester and resin cleavage

Trimethyl orthoacetate (1 ml), AcOH (50 ml) and NMP (1 ml) were added to the resin obtained in Process 2 (25 mg) and stirred at 50 ° C for 16 hours. After washing it with DMF and dichloromethane three times and drying it under reduced pressure, the resin was treated according to Process 7 of Example 1 to obtain the desired compound (8 mg).

20 MS (ESI MH +): 496

CHNO: C25H19C12N30

Examples 32 to 44

The compounds shown in Table 5 were synthesized by the same procedure as in Example 31 except that the resin obtained in Process 4 of Example 1 or Process 1 of Example 15 was used in Process 1 of Example 31 and the corresponding ortho ester was used in Process 3 of Example 31. Meanwhile, R1

and R2 in Table 5 are a substituent or substituents in the following general formula (27).

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Table 5

Example

R1- R2- Experimental MS (MH +)

31

 2,6-dichlorobenzoyl methyl 496

32

 2,6-dichlorobenzoyl ethyl 510

33

 2,6-dichlorobenzoyl n-propyl 524

3. 4

 2,6-dichlorobenzoyl n-butyl 538

35

 2,6-dichlorobenzoyl phenyl 558

36

 2,6-dichlorobenzoyl methoxy 512

37

 2,6-dichlorobenzoyl ethoxy 526

38

 2,6-dichlorobenzoyl chloromethyl 530

39

 2,6-dimethylbenzoyl methyl 456

40

 2,6-dimethylbenzoyl n-propyl 484

41

 2,6-dimethylbenzoyl n-butyl 498

42

 2,6-dimethylbenzoyl phenyl 518

43

 2,6-dimethylbenzoyl ethoxy 486

44

 2,6-dimethylbenzoyl  chloromethyl 490

NMR data of the compound of Example 32: 1H-NMR (CDCl3)  = 1.21 (3H, t, J = 7.4 Hz), 2.47 (2H, q, J = 7.4 5 Hz), 3.32-3.42 (2H, m), 5.19 (1H, t, J = 5.4 Hz), 7.10-7.20 (2H, m), 7.22-7.35 ( 4H, m), 7.43-7.54 (3H, m), 7.70-7.83 (2H, m), 8.21 (1H, d, J = 7.8 Hz) Example 45. Synthesis of the compound of the following general formula (28) which has a substituent or substituents of Example 45 of Table 6 Process 1. Acylation 10 3-Chloro-2-nitrobenzoic acid (210 mg, 1,041 mmol), HOAt (141 mg, 1.04 mmol), DIC (161 ul, 1.04 mmol) and NMP (2 ml) to the resin obtained in Process 4 of Example 1 (200 mg) and stirred for 64 hours. After that, the resin was washed with DMF and dichloromethane three times, and dried under reduced pressure. Process 2. Reduction of the nitro group The resin obtained in Process 1 was treated in accordance with Process 4 of Example 1. 15 Process 3. Construction of the quinazolin-2,4-dione ring Carbonyl diimidazole (844 mg, 5.21 mmol) and NMP (2 ml) to the resin obtained in Process 2 and stirred at 80 ° C for 16 hours. After washing it with DMF and dichloromethane three times and drying it under reduced pressure, the resin was treated according to Process 7 of Example 1 to obtain the desired compound. MS (ESI MH +): 632 20 CHNO: C24H16C13N305

image31

Examples 46 to 54

The compounds shown in Table 6 were synthesized by the same procedure as in Example 45 except that the corresponding respective substituted 2-nitrobenzoic acid was used in Process 1 of Example 45. Meanwhile, R1, R2, R3 and R4 in Table 6 they are a substituent or substituents in the following general formula (28).

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Table 6

Example

R1 R2 R3 R4 Experimental MS (MH +)

Four. Five

 chlorine H- H- H- 532

46

 methoxy H- H- H- 528

47

 H- H- chlorine H- 532

48

 H- H- methoxy H- 528

49

 H- trifluoromethyl H- H- 566

fifty

 methyl H- H- H- 512

51

 H- methoxy methoxy H- 558

52

 H- H- fluoro H- 516

53

 H- H- H- methyl 512

54

 H- H- H- chlorine 532

Example 57. Synthesis of the compound of the following general formula (29) which has a substituent or 10 substituents of Example 57 of Table 8

Process 1. Acylation

2-Fluoro-5-nitrobenzoic acid (1.63g, 8.81 mmol), HOAt (1.2g, 8.81 mmol), DIC (6750 ul, 4.36 mmol) and NMP (25 ml) were added to the resin obtained in Process 4 of Example 1 (1 g) and stirred for 14 hours. After that, the resin was washed with DMF and dichloromethane three times, and dried under reduced pressure.

15 Process 2. Replacement of the fluoro group by amine

Isopropylamine (400 ul) and NMP (2 ml) were added to the resin obtained in Process 1 (200 mg) and stirred for 21 hours. After that, the resin was washed with DMF and dichloromethane three times, and dried under reduced pressure.

Process 3. Construction of the quinazolin-2,4-dione ring

20 Carbonyldiimidazole (200mg) and trans-decahydronaphthalene (2ml) were added to the resin obtained in Process 2 and stirred at 95 ° C for 15 hours. After washing it with DMF, methanol and dichloromethane three times and drying it under reduced pressure, the resin was treated according to Process 7 of Example 1 to obtain the desired compound.

MS (ESI MH +) 585

25 CHNO: C27H22C12N407

image32

Examples 58 to 65

The compounds shown in Table 8 were synthesized by the same procedure as in Example 57 except that the corresponding respective amine was used in Process 2 of Example 57. Meanwhile, R in Table 8 is a substituent in the following general formula (29).

image16

Table 8

Example

R Experimental MS (MH +)

57

 isopropyl 585

58

 sec-butyl 599

59

 cyclobutyl 597

60

 cyclopentyl 611

61

 isobutyl 599

62

 cyclohexylmethyl 639

63

 methyl 557

64

 cyclopropyl 583

65

 benzyl 633

Example 66. Synthesis of the compound of the following general formula (30) having a substituent of Example 66 of Table 9

10 Process 1. Replacement of the fluoro group by amine

Solution in THM of 2.0M methylamine (3 ml) and NMP (2 ml) was added to the resin obtained in Process 1 of Example 57 (150 mg) and stirred for 14 hours. After that, the resin was washed with DMF and dichloromethane three times, and dried under reduced pressure.

Process 2. Construction of quinazolin-2-thioxo-4-one

15 Thiocarbonyldiimidazole (200mg) and trans-decahydronaphthalene (2ml) were added to the resin obtained in Process 1 and stirred at 95 ° C for 15 hours. After washing it with DMF, methanol and dichloromethane three times and drying it under reduced pressure, the resin was treated according to Process 7 of Example 1 to obtain the desired compound.

MS (ESI MH +) 573

20 CHNO: C25H18C12N406S

Examples 67 to 69

The compounds shown in Table 9 were synthesized by the same procedure as in Example 66 except that the corresponding respective amine was used in Process 1 of Example 66. Meanwhile, R in Table 9 is a substituent in the following general formula (30).

image33

image3

Table 9

Example

R Experimental MS (MH +)

66

 methyl 573

67

 ethyl 587

68

 cyclopropyl 599

69

 benzyl 649

Example 70. Synthesis of the compound of the following general formula (31) having substituents of Example 5 70 of Table 10 Process 1. Acylation

2-Amino-3,6-dichlorobenzoic acid (845mg, 4.10 mmol), HOAt (558g, 4.10 mmol), DIC (317 ul, 2.05 mmol) and NMP (11.5 ml) were added to The resin obtained in Process 4 of Example 1 (500 mg) and stirred for 24 hours. After that, the resin was washed with DMF, methanol and dichloromethane three times, and dried under pressure.

10 reduced. Process 2. Construction of the quinazolin-2,4-dione ring Carbonyl diimidazole (200 mg) and trans-decahydronaphthalene (2 ml) were added to the resin obtained in the

Process 1 (200 mg) and stirred at 95 ° C for 15 hours. After that, the resin was washed with DMF, methanol and dichloromethane three times, and dried under reduced pressure. 15 Process 3. Alkylation The resin obtained in Process 2 was rented according to Process 6 of Example 1. Process 4. Excision of the resin The desired compound was obtained by being treated in accordance with Process 7 of Example 1 MS (ESI MH +): 580 20 C25H17C14N305 Examples 71 to 80

The compounds of Examples 71 to 75 were synthesized by the same procedure as in Example 70 except that the corresponding respective benzoic acid derivatives were used in Process 1 of Example 70. The same procedure as in Example 70 was repeated in the examples 76 to 80 except that alkylation in the Process

25 3 of Example 70 was not carried out. Meanwhile, R in Table 10 is a substituent in the following general formula (31).

image34

image3

Table 10

Example

R1 R2  R3 R4  R5 X1 X2 Experimental MS (MH +)

70

methyl chlorine H H chlorine C C 580

71

methyl chlorine  H chlorine  H C C 580

72

methyl H fluoro H H C C 530

73

methyl H H Br H C C 591

74

methyl - H H H N C 513

75

methyl - H H - N N 514

76

H chlorine H H chlorine C C 566

77

H chlorine  H chlorine  H C C 566

78

H H fluoro H H C C 516

79

H - H H H N C 499

80

H - H H - N N 500

Example 81. Synthesis of the compound of the following general formula (32) which has substituents of Example 5 81 of Table 11 Process 1. Acylation The resin obtained in Process 4 of Example 1 was acylated according to Process 1 of Example 70. Process 2. Construction of the triazene ring Sodium nitrite (150 mg) and acetic acid (4.5 ml) were added to the resin obtained in Process 1 (90 10 mg) and stirred for 24 hours. After washing it with DMF, methanol and dichloromethane three times and drying it under reduced pressure, the desired compound was obtained by being treated according to Process 7 of Example 1. MS (ESI MH +): 551 CHNO: C23H14C14N404 Examples 82 and 83

The compounds of Examples 82 and 83 shown in Table 11, were synthesized by the same procedure as in Example 81 except that the corresponding respective 2-aminobenzoic acid was used in Process 1 of Example 81. Meanwhile, R1, R2, R3 and R4 in Table 11 are substituents in the following general formulas (32).

image35

Example 84. Synthesis of the compound of the following general formula (32) which has substituents of Example 84 of Table 11. Process 1. Acylation, reduction of the nitro group Acylation was performed using the resin obtained in Process 4 of the Example 1 (1 g), 5-methoxy-25 nitrobenzoic acid (1.62g, 8.21 mmol), DIC (635 ul, 4.11 mmol), HOAt (1.12 g, 8.21 mmol) and NMP (23 ml). Next, the nitro group was reduced according to Process 2 of Example 31. Process 2. Construction of the triazeno ring, resin cleavage. The resin obtained in Process 1 was treated in accordance with Process 2 of Example 81 and then treated in accordance with Process 7 of Example 1 to obtain the desired compound. 10 MS (ESI MH +): 513 CHNO: C24H18C12N405 Examples 85 to 89

The compounds of Examples 85 to 89 shown in Table 11, were synthesized by the same procedure as in Example 84 except that the corresponding respective 2-nitrobenzoic acid was used in Process 1 of Example 84. Meanwhile, R1, R2, R3 and R4 in Table 11 are substituents in the following formulas

general (32). Example 90. Synthesis of the compound of the following general formula (32) which has substituents of Example 90 of Table 11 Process 1. Construction of the triazene ring, resin cleavage. The resin obtained in Process 2 of Example 31 was treated in accordance with Process 2 of Example 81 and then treated in accordance with Process 7 of Example 1 to obtain the desired compound. MS (ESI MH +) 483 CHNO: C23H16C12N404

image3

image36

Table 11

Example

 R1 R2 R3 R4 Experimental MS (MH +)

81

 chlorine H- H- chlorine 551

82

 chlorine H- chlorine H- 551

83

 H- fluorine H- H- 501

84

 H- H- methoxy H- 513

85

 H- H- fluorine H- 501

86

methyl H- H- H- 497

87

 H- H- chlorine H- 517

88

 chlorine H- H- H- 517

89

 H- H- H- methyl 497

90

 H- H- H- H- 483

Example 91. Synthesis of the compound of the following general formula (33) which has substituents of Example 91 of Table 12 5 Process 1. Acylation, reduction of the nitro group Acylation and reduction of a nitro group were carried out according with Process 1 of Example 84 using the resin obtained in Process 4 of Example 1. Process 2. Cyclisation by ortho ester and resin cleavage Tetraethoxymethane (800 ul), acetic acid (200 ul) and NMP ( 2 ml) to the resin obtained in the

Process 1 (150 mg) and stirred at 55 ° C for 15 hours. After washing it with DMF, methanol and dichloromethane three times and drying it under reduced pressure, the resin was treated according to Process 7 of Example 1 to obtain the desired compound.

MS (ESI MH +) 556 CHNO: C27H23C12N306 15 Examples 92 to 94 The compounds of Examples 92 to 94 shown in Table 12, were synthesized by the same procedure as in Example 91 except that 2-nitrobenzoic acid was used correspondingly in Process 1 of Example 91. Meanwhile, R1, R2, R3 and R4 in Table 12 are substituents in the following general formulas (33). Example 95. Synthesis of the compound of the following general formula (33) which has substituents of Example

95 of Table 12 Process 1. Acylation 2-amino-4-fluorobenzoic acid (636 mg, 4.10 mmol), HOAt (558g, 4.10 mmol), DIC (317 ul,

2.05 mmol) and NMP (11.5 ml) to the resin obtained in Process 4 of Example 1 (500 mg) and stirred for 24 hours. After that, the resin was washed with DMF, methanol and dichloromethane three times, and dried under reduced pressure. Process 2: Cyclisation with ortho ester and resin cleavage

image37

The resin obtained in Process 1 was cyclized according to Process 2 of Example 91 and a

The desired compound was then obtained by being treated according to Process 7 of Example 1. MS (ESI MH +): 544 CHNO:, C261120C12FN305

image16

Table 12

Example

 R1 R2 R3 R4 Experimental MS (MH +)

91

 H- H- methoxy H- 556

92

 H- H- fluoro H- 544

93

 H- H- chlorine H- 560

94

 H- H- H- methyl 540

95

 H- fluoro H- H- 544

Example 96. Synthesis of the compound of the following general formula (34) having a substituent of Example 96 of Table 13 10 Process 1. Acylation, reduction of the nitro group

Acylation was carried out by reacting the resin obtained in Process 4 of Example 1 (1 g) with 6-methoxy-2-nitrobenzoic acid (1.49g, 8.21 mmol), DIC (635 ul, 4, 11 mmol), HOAt (1.12 g, 8.21 mmol) and NMP (23 ml) for 18 hours. Next, the nitro group was reduced according to Process 2 of Example 31.

Process 2. Cyclization 15 Carbonyldiimidazole (400 ul) and NMP (2 ml) were added to the resin obtained in Process 1 (200 mg) and stirred at 95 ° C for 15 hours. After that, the resin was washed with DMF, methanol and dichloromethane three times, and was

dried under reduced pressure. Process 3. Alkylation Ethyl iodide (200 ul) and tetramethyl guanidine (200 ul) were added to the resin obtained in Process 2

20 (200 mg) and stirred for 24 hours. After washing it with water, DMF, methanol and dichloromethane three times and drying it under reduced pressure, the resin was treated according to Process 7 of Example 1 to obtain the desired compound. MS (ESI MH +): 540 CHNO C27H23C12N305 Example 97

The compounds of Example 97 shown in Table 13 were synthesized by the same procedure as in Example 96 except that the corresponding respective halide was used in Process 3 of Example 96. Meanwhile, R in Table 13 is a substituent in the following general formula (34).

image38

image3

Table 13

Example

R Experimental MS (MH +)

96

 ethyl 540

97

 benzyl 602

Example 98. Synthesis of the compound of the following general formula (35) having substituents of Example 5 98 of Table 14

Process 1: Sulfonamidation, reduction of nitro group

2-Nitrobenzenesulfonylp chloride (450 mg), 2,6-lutidine (450 ul) and dichloromethane (10 ml) were added to the resin obtained in Process 4 of Example 1 (400mg) and stirred for 14 hours. After washing it with DMF, methanol and dichloromethane three times and drying it under reduced pressure, the nitro group obtained was reduced according to the

10 Process 2 of Example 31.

Process 2. Cycling

Carbonyl diimidazole (400 ul) and NMP (2 ml) were added to the resin obtained in Process 1 (200 mg) and stirred at 95 ° C for 15 hours. After that, the resin was washed with DMF, methanol and dichloromethane three times, and dried under reduced pressure.

15 Process 3. Alkylation, resin cleavage

Methyl iodide (400 ul), diisopropylethylamine (400 ul) and NMP (2 ml) were added to the resin obtained in Process 2 (200 mg) and stirred for 17 hours. After washing it with water, DMF, methanol and dichloromethane three times and drying it under reduced pressure, the resin was treated according to Process 7 of Example 1 to obtain the desired compound.

20 MS (ESI MH +): 548

CHNO: C24 / 119C12N3068

Examples 99 to 103

The compounds shown in Table 14 were synthesized by the same procedure as in Example 98 unless the corresponding respective sulfonyl chlorides were used in Process 1 of Example

25 98. Meanwhile, R1, R2, R3, R4 and R5 in Table 14 are substituents in the following general formula (35) and the same procedure as in Example 98 was repeated in Examples 101 to 103 except that alkylation in Process 3 of Example 98 it was not carried out.

image39

image3

Table 14

Example

R1 R2 R3 R4 R5 Experimental MS (MH +)

98

H- H- H- H- methyl 548

99

H- methoxy H- H- methyl 578

100

H- trifluoromethyl H- H- methyl 616

101

H- H- H- H- H- 534

102

H- methoxy H- H- H- 564

103

H- trilfuoromethyl H- H- H- 602

Example 104. Synthesis of the compound of the following general formula (36) having a substituent or 5 substituents of Example 104 of Table 15

Process 1. Acylation, Construction of the quinazolin-2,4-dione ring.

Alkylation and reduction of the nitro group

Acylation was carried out using the resin obtained in Process 4 of Example 1 (500 mg), 2-amino-5-nitrobenzoic acid (746 mg, 4.10 mmol), DIC (317, ul, 2.05 mmol ) HOAt (558 mg, 4.10 mmol) and NMP (11.5

10 ml) Then the quinazolin-2,4-dione ring was constructed in accordance with Process 2 of Example 96 and alkylation was performed in accordance with Process 6 of Example 1. In addition, the nitro group was reduced in the same manner as in Process 4 of Example 1.

Process 2. Acylation

Acetic anhydride (600 ul), pyridine (600 ul) and NMP (3 ml) were added to the resin obtained in Process 1 and stirred for 19 hours. After washing it with water, DMF, methanol and dichloromethane three times and drying it under reduced pressure, the resin was treated according to Process 7 of Example 1 to obtain the desired compound.

MS (ESI MH +): 569 CHNO: C27H22C12N406

Examples 105 to 107

The compounds shown in Table 15 were synthesized by the same procedure as that of

Example 104 except that the corresponding acid chloride was used in Process 2 of Example 104. Meanwhile, R in Table 15 is a substituent in the following general formula (36) and the same procedure as in Example 104 was repeated in Example 107 except that the acylation in Process 2 of Example 104 was not carried out.

image40

image3

Table 15

Example

R Experimental MS (MH +)

104

 acetyl 569

105

 methoxyacetyl 599

106

 pivaloyl 611

107

 H 527

Example 108. Synthesis of the compound of the following general formula (37) having a substituent of Example 10 of Table 16 Process 1. Acylation The resin obtained in Process 4 of Example 1 (1 g) was acylated using acid 5-fluoro-2-nitrobenzoic acid (1.63g, 8.81 mmol), DIC (675 ul, 4.36 mmol), HOAt (1.2 g, 8.81 mmol) and NMP (25 ml). Process 2. Substitution of the fluoro group with amine. 10 Reduction of the nitro group

THM solution of 2.0M dimethylamine (3 ml) and NMP (2 ml) were added to the resin obtained in Process 1 (200mg) and stirred for 14 hours. After washing it with water, DMF and dichloromethane three times and drying it under reduced pressure, the nitro group obtained was reduced according to Process 2 of Example 31.

Process 3. Construction of the quinazolin-2,4-dione ring 15 The resin obtained in Process 2 was treated in accordance with Process 2 of Example 96 to construct the

quinazolin-2,4-dione ring. Process 4. Alkylation Triphenylphosphine (520mg), methanol (80 ul), toluene solution of diisopropylazodicarboxylic acid were added

40% (1 ml) and dichloromethane (2 ml) to the resin obtained in Process 3 and stirred for 7 hours. After washing it with water, DMF, methanol and dichloromethane three times and drying it under reduced pressure, the resin was treated according to Process 7 of Example 1 to obtain the desired compound. MS (ESI MH +): 555 CHNO: C27H24C12N405 Examples 109 to 111

The compounds of Examples 109 to 111 shown in Table 16 were synthesized by the same procedure as in Example 108 except that the corresponding amine was used in Process 2 of Example 108. Meanwhile, R in Table 16 It is a substituent in the following general formula (37).

Example 112. Synthesis of the compound of the following general formula (37) having a substituent of Example 112 of Table 16 30 Process 1. Substitution of the fluoro group by amine Reduction of the nitro group

image41

THM solution of 2.0M dimethylamine (3 ml) and NMP (2 ml) was added to the resin (200 mg) obtained in Process 1 of Example 108 and stirred for 14 hours. After washing it with water, DMF and dichloromethane three times and drying it under reduced pressure, the nitro group obtained was reduced according to Process 2 of Example 31.

Process 3. Construction of the quinazolin-2,4-dione ring

5 The resin obtained in Process 2 was treated according to Process 2 of Example 96 to construct the quinazolin-2,4-dione ring.

Process 4. Alkylation

Methyl iodide (400 ul), diisopropylethylamine (400 ul) and NMP (2 ml) were added to the resin obtained in Process 3 (200 mg) and stirred for 17 hours. After washing it with water, DMF, methanol and dichloromethane three 10 times and drying it under reduced pressure, the resin was treated according to Process 7 of Example 1 to obtain the

desired compound.

MS (ESI MH +): 569 CHNO: C281127C12N405

Example 113

The compound of Example 113 shown in Table 16 was synthesized by the same procedure as that of Example 112 except that the corresponding respective halide was used in Process 1 of Example 112. Meanwhile, R in Table 16 is a substituent in the following general formula (37).

image3

Table 16

Example

R Experimental MS (MH +)

108

 dimethylamino 555

109

 ethylmethylamino 569

110

 pyrrolidyl 581

111

 diethylamino 583

112

 Formula X1 569

113

 Formula X2 695

20 Formulas X1 and X2 are described below.

NMR data of the compound of Example 108: 1H-NMR (400 MHz, DMSO-d6)  2.94 (3H, m), 3.02 (1H, dd, J = 10.2, 14.1 Hz), 3.22 (1H, m, J = 4.4, 14.1 Hz), 3.49 (3H, s), 4.82 (1H, m), 7.17 (2H, d), 7.24 (1H, d), 7.30 (1H, m), 7.367.45 (5H, m), 9.15 (1H, d).

13C-NMR (100 Mhz, DMSO-d6)  30.90, 36.64, 40.77, 53.68, 109.21, 116.00, 116.22, 121.37, 128.26, 128, 93, 25 129.90, 131.23, 131.82, 132.10, 135.23, 136.56, 137.57, 146.72, 150.38, 161.88, 163.91, 172.72 .

Formula X1

image3

Formula X2

image42

image3

Example 114. Synthesis of the compound of the following general formula (38) having substituents of Example 114 of Table 17 Process 1. Alkylation

2,6-Dichlorobenzylicol alcohol (531 mg), triphenylphosphine (786 mg), dichloromethane (3ml) and toluene solution of 40% diisopropylazodicarboxylic acid (1.5 ml) were added to the resin obtained in Process 5 of Example 1 (150 mg) and stirred for 14 hours. After washing it with water, DMF, methanol and dichloromethane three times and drying it under reduced pressure, the resin was treated according to Process 7 of Example 1 to obtain the desired compound.

MS (ESI MH +): 656

CHNO: C31H21C14N305

Examples 115 to 123

The compounds of Examples 115 to 123 shown in Table 17 were synthesized by the same procedure as in Example 114 except that the corresponding respective alcohol was used in Process 1 of Example 114. Meanwhile, R1, R2, R3, R4, R5 and n in Table 17 are substituents in the following general formulas (38).

Example 124. Synthesis of the compound of the following general formula (38) which has substituents of Example 124 of Table 17

Process 1. Acylation

The resin obtained in Process 4 of Example 1 (150 mg) was acylated using N-phenylantranilic acid (437 mg, 2.05 mmol), HOAt (279 mg, 2.05 mmol), DIC (106 ul, 1 , 03 mmol) and NMP (6 ml).

Process 2. Construction of the quinazolin-2,4-dione ring

The resin obtained in Process 1 was treated in accordance with Process 2 of Example 96. After constructing the quinazolin-2,4-dione ring, the resin was treated in accordance with Process 7 of Example 1 to obtain the desired compound.

MS (ESI MH +): 574

CHNO: C30H21C12N305 Table 17

image3

image43

Example

R1 R2 R3 R4 R5 n = Experimental MS (MH +)

114

 chlorine H H H chlorine one 656

115

H chlorine chlorine  H H one 656

116

chlorine H chlorine  H H one 656

117

H H chlorine  H H one 622

118

H H methyl H H one 602

119

chlorine H H H H one 622

120

methyl H H H H one 602

121

 chlorine H H H fluoro one 640

122

H H H H H one 588

123

H H H H H 2 602

124

H H H H H 0 574

Example 125. Synthesis of the compound of the following general formula (39) having a substituent of Example 125 of Table 18

5 Process 1. Synthesis of iminophosphine

Triphenylphosphine (7.86g), toluene solution of 40% diisopropylazodicarboxylic acid (30 ml) and toluene (30 ml) were added to the resin obtained in Process 4 of Example 1 (1 g) and stirred for 16 hours . After that, the resin was washed with dichloromethane ten times, and dried under reduced pressure.

Process 2. Synthesis of carbodiimide, nucleophilic addition of amine and ring closure.

10 Methyl 2-isocyanatobenzoate (200 mg) and dichloromethane (1 ml) were added to the resin obtained in Process 1 (100 mg), and stirred for 1 hour and washed with DMF and dichloromethane three times. Cyclobutylamine (600 ul) and NMP (3 ml) were added to the obtained resin and stirred for 13 hours. After washing with DMF, methanol and dichloromethane and drying it under reduced pressure, the resin was treated according to Process 7 of Example 1 to obtain the desired compound.

15 MS (ESI MH +): 551

CHNO: C28H24C12N404

Examples 126 to 130

The compounds shown in Table 18 were synthesized by the same procedure as in Example 125 except that the corresponding respective amine was used in Process 2 of Example 125. Meanwhile, R 20 in Table 18 is a substituent in the following general formula (39).

image44

Table 18

Example

R Experimental MS (MH +)

125

 cyclobutylamino 551

126

 isobutylamino 553

127

 isopropylamino 539

128

 dimethylamino 525

129

 ethylmethylamino 539

130

 azetidino 537

Example 131. Synthesis of the compound of the following general formula (40) having a substituent of Example 131 of Table 18

5 Process 1. Replacement of the fluoro group by amine

Solution in THM of 2.0M methylamine (3 ml) and NMP (2 ml) was added to the resin obtained in Process 1 of Example 57 (150 mg) and stirred for 14 hours. The resin was then washed with DMF and dichloromethane three times, and dried under reduced pressure.

Process 2. Ring closure with thionyl chloride

10 Triazole (250 mg), thionyl chloride (80 ul), dichloromethane (1 ml) and diisopropylethylamine (400 ul) were added to the resin obtained in Process 1 and stirred for 15 hours. After washing it with DMF, methanol and dichloromethane three times and drying it under reduced pressure, the resin was treated according to Process 7 of Example 1 to obtain the desired compound.

MS (ESI MH +): 576

15 CHNO: C24H18C12N4075

Examples 132 and 133

The compounds shown in Table 18 were synthesized by the same procedure as in Example 131 except that the corresponding respective amine was used in Process 1 of Example 131. Meanwhile, R in Table 18 is a substituent in the following general formula (40).

image45

Example

R Experimental MS (MH +)

131

 methyl 577

132

 ethyl 591

133

 benzyl 653

Example 136. Synthesis of the compound of the following general formula (73) having substituents of Example 136 of Table 20

image46

Process 1. Acylation, reduction of the O-aryl group

Salicylic acid (74 mg, 0.535 mmol), PyBOP (278 mg, 0.535 mmol), HOBt (120 mg, 0.89 mmol), DIEA (0.186 ml, 1.068 mmol) and DMF (3.6 ml) were added thereto resin obtained in Process 4 of Example 1 and stirred for 19 hours. Then, the resin was washed with DMF, methanol and dichloromethane eight times and ethanolamine.

30% / DMF (5 ml) was added to the obtained resin and stirred for 4 hours. The resin was washed again with DMF, methanol and dichloromethane eight times.

Process 2. Ring closure with carbonyldiimidazole, resin cleavage.

Carbonyl diimidazole (98 mg) and DCM (6 ml) were added to the resin obtained in Process 1 (50 mg), stirred for 1 hour and washed with dichloromethane five times. In addition, dichloromethane (4 ml) was added to the resin

10 obtained, stirred at room temperature for 3 hours and washed with dichloromethane five times. Then, the desired compound was obtained by cleavage of the resin and purification by HPLC in the same manner as in Process 7 of Example 1 (3 mg).

MS (ESI MH +): 499

CHNO C24H16CL2N206

15 Examples 137 to 144

The compounds shown in Table 20 were synthesized by the same procedure as in Example 136 except that the corresponding salicylic acid was used in Process 1 of Example 136. Meanwhile, R1, R2 and R3 in Table 20 are substituents. in the following general formula (73).

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20 Table 20

Example

 R1 R2 R3 Experimental MS (MH +)

136

 H H H 499

137

 CH = CH-CH = CH- H 549

138

 H H CHO 527

139

 H OMe H 529

140

 OH H H 515

141

 H OH H 515

142

 H NH2 H 514

143

 H H Cl 533

144

 H H F 517

Example 145. Synthesis of the compound of the following general formula (74) Process 1. Ring closure with thiocarbonyldiimidazole. Thiocarbonyldiimidazole (500 mg) and dichloromethane (2.5 ml) were added to the resin obtained in Process 1

image47

5

10

fifteen

twenty

25

30

from Example 98 and stirred at room temperature for 16 hours. The resin was then washed with methanol, DMF and dichloromethane three times, and dried under reduced pressure.

Process 2. Resin excision

The resin obtained in Process 1 (100 mg) was treated according to Process 7 of Example 1 to obtain 1.2 mg of the desired compound.

MS (ESI MH +) 550

CHNO: C23H17C12N305S2

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Example 146. Synthesis of the compound of the following general formula (75) Methylation and resin cleavage Diisopropylethylamine (200 ul), methyl iodide (100 ul) and NMP (3 ml) were added to 100 mg of the resin to be

obtained in Process 1 of Example 145 and stirred at room temperature for 16 hours. After washing it with DMF, methanol and dichloromethane three times and drying it under reduced pressure, the resin was treated according to Process 7 of Example 1 to obtain 13 mg of the desired compound.

MS (ESI MH +): 564

CHNO: C24H19Cl2N3O5S2

image3

Example 147. Synthesis of the compound of the following general formula (76) having substituents of Example 147 of Table 21.

The resin obtained in Process 4 of Example 1 was prepared to be a starting material. 500 mg of 2-nitrobenzyl bromide, 500 ul of diisopropylethylamine and 5 ml of NMP were added to 100 mg of said resin and stirred at room temperature for 12 hours. After removing the solvent from the reaction, the resin was washed with dichloromethane, NMP and dichloromethane three times. Solution in NMP (0.5 ml) • EtOH (3 ml) of SnCl2 was added. 2H2O (1.5g) to the resin obtained and reacted for 16 hours. The reaction solvent was removed and the resin was washed with NMP and dichloromethane three times. In addition, 200 mg of 2-nitrobenzenesulfonyl chloride, 400 ul of 2,6-lutidine and 2 ml of dichloromethane were added to the resin obtained and reacted at 0 ° C for hours. After removing the solvent from the reaction, the resin was washed with dichloromethane, NMP and dichloromethane three times. 200 ul of methyl iodide, 0.5 g of potassium carbonate and 7.5 ml of NMP were added to the sulfonamide resin and stirred at 45 ° C for 24 hours.

After removing the solvent from the reaction, the resin was washed with dichloromethane, NMP and dichloromethane three times. 200 ul of diazabicycloundecene, 400 ul of 2-mercaptoethanol and 500 ul of NMP were added to the resin obtained, and stirred at room temperature for 24 hours. Then, the reaction solvent was removed and the resin was washed with dichloromethane, NMP and dichloromethane three times. Subsequently, 500 mg of carbonyldiimidazole and 4 ml of dichloromethane were added to the obtained resin and stirred at 50 ° C for 24 hours. Then, the reaction solvent was removed and the resin was washed with dichloromethane, NMP and dichloromethane three times, and dried under reduced pressure. The resin obtained was treated with 100% trifluoroacetic acid for 1 hour and the resin was filtered. The filtrate obtained was concentrated and purified by reverse phase HPLC (mobile phase SYMMETRY 19 * 50mm water: acetonitrile containing 0.1% TFA) to obtain 0.9 mg of the desired compound.

image48

MS (ESI MH +): 498,500

CHNO; C25H21C12N304

Example 148. Synthesis of the compound of the following general formula (76) which has substituents of Example 148 of Table 21.

The resin as a starting material was prepared in the same manner as in Example 147. Thiocarbonyldiimidazole was used instead of carbonyldiimidazole which was used in Example 147 to obtain 0.8 mg of the desired compound.

MS (ESI MH +): 514, 516

CHNO: C25H21Cl2N303S

Example 149. Synthesis of the compound of the following general formula (76) which has substituents of Example 149 of Table 21.

The resin obtained in Process 4 of Example 1 was prepared to be a starting material. 500 mg of 2-nitrobenzyl bromide, 500 ul of diisopropylethylamine and 5 ml of NMP were added to 100 mg of the resin and stirred at room temperature for 12 hours. After removing the solvent from the reaction, the resin was washed with dichloromethane, NMP and dichloromethane three times. Solution in NMP (0.5 ml) • EtOH (3 ml) of SnCl2 2H2O (1.5g) was added to the resin obtained and reacted for 16 hours. After removing the solvent from the reaction, the resin was washed with DMF and dichloromethane three times. Subsequently, 500 mg of carbonyldiimidazole and 4 ml of dichloromethane were added to the resin and stirred at 50 ° C for 24 hours. After removing the reaction solvent, the resin was washed with dichloromethane, NMP and dichloromethane three times, and dried under reduced pressure. The resin obtained was treated with 100% trifluoroacetic acid solution for 1 hour and the resin was filtered. The filtrate obtained was concentrated and purified by reverse phase HPLC (mobile phase SYMMETRY 19 * 50 mm water: acetonitrile containing 0.1% TFA) to obtain 0.9 mg of the desired compound.

MS (ESI MH +): 484, 486

CHNO C24H19C12N304

Example 150. Synthesis of the compound of the following general formula (76) having substituents of Example 150 of Table 21.

1.6 mg of the desired compound was synthesized in the same manner as in Example 149 using 2-fluoro-6-nitrobenzyl bromide.

MS. (ESI MH +) 502, 504

CHNO C24H18C12FN304

Examples 151 to 159

The compounds shown in Table 21 were synthesized by the same procedure as in Example 147 except that the corresponding respective alkylation reagent was used instead of methyl iodide used in the Synthesis Process of Example 147. Meanwhile, R1 , RA1, RA2, RA3 and RA4 in Table 21 are substituents in the following general formula (76).

image49

Table 21

Example U

R1 RA1 RA2 RA3 RA4 Experimental MS (MH +)

147

 CO I H H H H 498,500

148

 CS I H H H H 514,516

149

 CO H H H H H 484,486

150

 CO H H H H F 502,504

151.

 CO Et H H H H 512,514

152

 CO n-Pr H H H H 526,528

153

 CO n-Bu H H H H 540,542

154

 CO iso-Pr H H H H 526,528

155

 CO iso-Bu H H H H1 540,542

156

 CO sec-butyl H H H H 540,542

157

 CO 2-phenylethyl H H H H ' 588,590

158

 CO benzyl H H H H 574,576

159

 CO 2,6-difluorobenzyl H H H H 610,612

Example 160. Synthesis of (2S) -2-amino-3- [4- (1-methyl-2,4-dioxo-1,3-dihydroquinazolin-3-yl) phenyl] propionic acid methyl ester hydrochloride

5 Process 1. Synthesis of 4-nitrophenylalanine methyl ester hydrochloride

1.49 ml of thionyl chloride and 25 ml of methanol were mixed, cooled by a dry acetonitrile ice bath and 2 g of Boc-Phe (4-NO2) -OH was added thereto. After stirring for 1 hour and removing the bath, the solution was warmed to room temperature and subsequently stirred for 2.5 hours. The reaction solvent was concentrated under reduced pressure to obtain 1.83 g of the desired compound as a white powder.

10 MS (ESI MH +): 225

CHNO C10H12N204 HCI

Process 2. Synthesis of N-tertiary butyloxycarbonyl-4-nitrophenylalanine methyl ester

Five hundred twenty-one mg of 4-nitrophenylalanine methyl ester hydrochloride obtained in Process 1 was dissolved in the solution of 554 ul of triethylamine in 10 ml of tetrahydrofuran and 480 mg of (Boc) 2O were added thereto with cooling in ice. The ice bath was removed 5 minutes later and the solution was stirred for 4.5 hours. The ethyl acetate (15 ml) was added to the reaction solvent and washed with 10% aqueous citric acid solution, water and saturated NaCl aqueous solution respectively. After drying the ethyl acetate layer, the solution was concentrated under reduced pressure to obtain 735 mg of the desired compound.

MS (ESI MH +) 325

20 CHNO: C15H20N2O6

Process 3. Synthesis of methyl ester of (2S) -2-tertiary butyloxycarbonylamino-3- (4-azinophenyl) propionic acid.

image50

648 mg of N-tertiary butyloxycarbonyl-4-nitrophenylalanine methyl ester which was obtained in Process 2 was dissolved in 20 ml of ethanol and 150 mg of 5% Pd / C was added and the solution was stirred at room temperature for 18 hours in atmosphere of hydrogen (1 atm). After filtration with celite, the product obtained was purified by silica gel column (hexane: ethyl acetate; 4: 1 * 2: 1) to obtain 441 mg of the desired compound.

MS (ESI MH +): 295

CHNO: C15H22N204

Process 4. Synthesis of methyl ester of (2S) -2-tertiary butyloxycarbonylamino-3- [4- (2,4-dioxo-1,3-dihydroquinazolin-3-yl) phenylpropionic acid

683 mg of methyl ester of (2S) -2-tertiary butyloxycarbonylamino-3- (4-aminophenyl) propionic obtained in Process 3 were dissolved in 20 ml of acetonitrile and 412 mg of methyl 2-isocyanatobenzoate was added and stirred at 70 ° C for 16.5 hours. After cooling to room temperature, the powder produced was filtered off and dried to obtain 588 mg of the desired compound as a white powder.

MS (ESI MH +): 440

CHNO: C23H25N306

Process 5. Synthesis of methyl ester of (2S) -2-tertiary butyloxycarbonylamino-3- [4

(1-methyl-2,4-dioxo-1,3-dihydroquinazolin-3-yl) phenyl) propionic. 1.0 g of (2S) -2-tertiary butyloxycarbonylamino-3- [4- (2,4-dioxo-1,3-dihydroquinazolin-3-yl) phenyl] propionic was obtained which was obtained in Process 4 in 20 ml of N, N-dimethylformamide and 378 mg of potassium carbonate and 0.284 ml of iodomethane were added and stirred for 1 hour. Subsequently, 70 ml of ethyl acetate was added to the reaction solvent and washed with water and saturated NaCl solution. After drying the ethyl acetate layer the solvent was concentrated under reduced pressure to obtain 1.04 g of the desired compound as a yellow powder.

MS (ESI MH +): 454

CHNO: C24H27N306

Example 6. Synthesis of (2S) -2-amino-3- [4- (1-methyl-2,4-dioxo-1,3-dihydroquinazolin-3-yl) phenyl] propionic acid methyl ester hydrochloride

5.00 mg of methyl ester of (2S) -2-tertiary butyloxycarbonylamino-3- [4- (1-methyl-2,4-dioxo-1,3-dihydroquinazolin-3-yl) phenyl] propionic acid obtained in the Process 5 in 11 ml of 4N hydrochloric acid solution -dioxane and stir at room temperature for 1 hour. The reaction solvent was concentrated under reduced pressure to obtain 426 mg of the desired compound as a white powder.

MS (ESI MH +): 354

CHNO C19H19N304 HCl

Example 161. Synthesis of the compound of the following general formula (77) having substituents of Example 161 of Table 22.

The 88.2 mg mixture of 2-chloro-6-methyl benzoic acid, 99.1 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 79.1 mg of 1-hydroxybenzotriazole monohydrate, 107 ul of triethylamine, 100 mg of methyl ester hydrochloride (2S) -2-amino-3- [4- (1-methyl-2,4-dioxo-1,3-dihydroquinazolin-3-yl) phenyl propionic acid and 1 ml of dichloromethane stirred at 45 ° C overnight. The mixture was purified respectively by silica gel chromatography (ethyl hexane acetate) and reverse phase HPLC to obtain the desired compound.

MS (ESI MH +): 506

CHNO C27H24N305Cl

Example 162. Synthesis of the compound of the following general formula (77) having substituents of Example 162 of Table 22

The 20 mg mixture of the methyl ester compound obtained in Example 161, 2 mg of lithium hydroxide monohydrate, 1 ml of tetrahydrofuran and 0.2 ml of water was stirred at room temperature for 1 hour. After 1M hydrochloric acid was added and the solution was neutralized, the solvent was evaporated. The desired compound (6.0 mg) was obtained by purification by reverse phase HPLC.

MS (ESI MH +) 492

CHNO C26H22N305Cl

Examples 163, 166, 168, 170, 172, 174 and 176

image51

Synthesis of the compound of the following general formula (77) having substituents of the corresponding Example of Table 22

The desired compound was obtained in the same manner as in Example 161 except that 2-chloro-6-methyl benzoic acid was replaced with a corresponding carboxylic acid in the Synthesis Process of Example 161. See Table 5 22.

Examples 164, 165, 167, 169, 171, 173 and 175

Synthesis of the compound of the following general formula (77) having substituents of the corresponding Example of Table 22

The desired compound was obtained in the same manner as in Example 162 except that the corresponding methyl ester compound was used. See Table 22.

Example 177. Synthesis of the compound of the general formula (77) having substituents of the corresponding Example of Table 22.

A methyl ester compound was obtained in the same manner as in Example 161 except that the 2-chloro-6-methyl benzoic acid was replaced with a 2,6-dichlorocinnamic acid in the synthesis process of Example 161. Next, the desired compound it was obtained in the same way as in Example 162 unless the methyl was used

previous resulting ester. See Table 22.

image3

Table 22

Example

R1- R2- Experimental MS

161

 2-chloro-6-methylbenzoyl I 506 (MH +)

162

 2-chloro-6-methylbenzoyl H 492 (MH +)

163

 2-Chloro-6trifluoromethylbenzoyl I 560 (MH +)

164

 2-Chloro-6trifluoromethylbenzoyl H 544 (MH-)

165

 2-Chloro-6bromobenzoyl H 556 (MH +)

166

 2-Chloro-6bromobenzoyl I 570 (MH +)

167

 2-chloro-6-fluorobenzoyl H 496 (MH +)

168

 2-chloro-6-fluorobenzoyl I 510 (MH +)

169

 3,5-dichloroisonicotinoyl H 513 (MH +)

170

 3,5-dichloroisonicotinoyl I 527 (MH +)

171

2,6-dichloro-3-methylbenzoyl H 526 (MH +)

172

 2,6-dichloro-3-methylbenzoyl I 540 (MH +)

image52

173

 2,4,6-trichloro-3 methylbenzoyl H 546 (MH +)

174

2,4,6-trichloro-3 methylbenzoyl I 560 (MH +)

175

 2,6-dichloro-3-nitrobenzoyl H 557 (MH +)

176

 2,6-dichloro-3-nitrobenzoyl I 588 (M + NH4 +)

177

 2,6-dichlorocinamoyl h 538 (MH +)

Example 178. Synthesis of the compound of the following general formula (78) having a substituent of Example 178 of Table 23 Process 1. 2-nitrosulfonylation, methylation 5 The resin obtained in Process 1 of Example 104 was 2-nitrosulfonyl and methylated according to Process 4 of Example 112. Process 2. Removal of the 2-nitrosulfonyl group The resin obtained in Process 1 was treated according to Process 2 of Example 135 and the 2-nitrosulfonyl group was removed. The desired compound was obtained according to Process 7 of Example 1. 10 MS (ESI MH +): 541 CHNO: C261122C12N405 Example 179. Synthesis of the compound of the following general formula (78) having a substituent of Example 179 of the Table 23 The desired compound was obtained in the same manner as in Example 178 except that ethyl bromide was used in Process 1 of Example 178. MS (ESI MH +): 555 CHNO: C27H24C12N405 Meanwhile, R in Table 23 is a substituent in the following general formula (78).

image3

image53

Table 23

Example

R- Experimental MS (MH +)

178

 methyl 541

179

 ethyl 555

Examples 180 to 189

The compounds in Table 24 below were synthesized in the same manner as those in Example 45 except that the corresponding respective substituted 2-nitrobenzoic acid was used in Process 1 of Example 45, and Process 6 and 7 of Example 1. While both, R1, R2, R3 and R4 in Table 24 are substituents of the following general formula (19).

image3

image54

Table 24

Example

 R1 R2 R3 R4 Experimental MS (MH +)

180

methoxy H H H 542

181

 H H H methyl 526

182

 chlorine H H H 546

183

 eleven H chlorine eleven 546

184

 H H methoxy H 542

185

 H trifluoromethyl H H 580

186

methyl H H H 526

187

 H H H chlorine 546

188

 H methoxy methoxy H 572

189

 H H fluorine H 530

NMR data of the compound of Example 180: 1H-NMR (CDCl3)  = 3.22-3.48 (2H, m), 3.83 (3H, s), 3.93 (3H, s), 5, 16-5.23 (1H, m), 7.16 (2H, d, J = 7.8 Hz), 7.19-7.34 (611, m), 7.44 (211, d, J = 8.7 Hz), 7.84 (1H, dd, J = 2.4, 6.6 Hz)

5 Example 190. Synthesis of the compound of the following general formula (80) which has substituents of Example 190 of Table 25

The compound (3.2 mg) of the general formula (23) having a substituent of Example 1 in Table 1 was suspended in a mixture of methanol solution (73 ul) and toluene (224 ul) and a solution in hexane of 2M trimethylsilyldiazomethane (73 ul) was added thereto. After 30 minutes, the reaction solvent was concentrated.

10 under reduced pressure to obtain 3 mg of the desired compound.

MS (ESI MH +): 526 CHNO C26H21C12N305

Example 191. Synthesis of the compound of the following general formula (80) having substituents of Example 191 of Table 25

The compound (72.7 mg) of the general formula (79) having a substituent of Example 183 in Table 24 is

It dissolved in a mixture of dichloromethane solution (10 ml) and isopropanol (0.2 ml). 1- (3dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (26 mg) and 4-dimethylaminopyridine (26.2 mg) were added and stirred. After stirring for 18 hours, 1N hydrochloric acid was added and the solution was extracted with ethyl acetate. The aqueous layer was subsequently extracted with ethyl acetate and mixed with the previously extracted layer, and washed with saturated sodium hydrogen carbonate solution and saturated NaCl aqueous solution. Then the organic layer was dried with sulfate

20 anhydrous sodium and concentrated under reduced pressure. The product obtained was purified with high pressure liquid chromatography (water - acetonitrile) to obtain 10 mg of the desired compound.

MS (ESI MH +): 588

CHNO: C28H24C13N305

Example 192. Synthesis of the compound of the following general formula (80) which has substituents of Example 192 of Table 25.

The compound (12mg) of the general formula (37) having a substituent of Example 111 in Table 16 was dissolved in methanol (0.5 ml), cooled to -78 ° C and thionyl chloride (0.04 ml) was added ). After stirring at room temperature for 7.5 hours, the reaction solvent was concentrated under reduced pressure to obtain 12 mg of the desired compound.

image55

MS (ESI MH +): 597 CHNO: C30H30C12N405

5 Examples 193 to 202

The compounds shown below were synthesized using a carboxylic acid described in the corresponding respective Example as a starting material. In this connection, examples 193 to 195 and 201 were synthesized in the same manner as in Example 191 except that a suitable alcohol was used. Examples 196 to 200 and 202 were synthesized in the same manner as in Example 192. Meanwhile, R1, R2, and R3 in Table 25 are 10 substituents of the following general formula (80).

image3

Table 25

Example

 R1 R2 R3 Experimental MS (MH +)

190

 H methyl H 526

191

 chlorine isopropyl H 588

192

diethylamino  methyl H 597

193

 H ethyl H 540

194

 H isopropyl H 554

195

methoxy  ethyl H 570

196

dimethylamino methyl H 569

197

ethylamino  methyl H 569

198

methylamino methyl H 555

199

ethylmethylamino  methyl H 583

200

 Not me methyl H 541

201

 chlorine ethyl H 574

202

H methyl  fluorine 544

image56

NMR data of the compound of Example 196: 1H-NMR (400 MHz, DMS0-d6)  2.94 (3H, m), 3.02 (1H, m), 3.22 (1H, m), 3, 58 (3H, s), 3.70 (3H, s), 4.82 (1H, m), 7.18-7.47 (10H, m), 9.28 (1H, d). 13C-NMR (100 MHz, DMSO-d6)  30.88, 36.37, 40.75, 52.28, 53.66, 109.17, 116.00, 116.22, 121.35, 128.32, 128.99, 129.88, 131.36, 131.79, 132.07,

5 135.35, 136.36, 137.21, 146.74, 150.37, 161.89, 163.99, 171.72. Example 203 Synthesis of the compound of the following general formula (81). Process 1 Acylation The resin obtained in Process 4 of Example 1 was acylated using cis-2 - [(9

10-Fluorenylmethyloxycarbonyl) amino-1-cyclohexane carboxylic acid (274 mg), DIC (0.058 ml), HOAt (101 mg) and NMP (2.5 ml). Process 2. Elimination of the 9-fluorenylmethyloxycarbonyl group The resin obtained in Process 1 was stirred in 20% piperidine-NMP solution for ten minutes two

times and washed with NMP, methanol and dichloromethane four times. Process 3. Cyclization, resin cleavage 15 The resin obtained in Process 2 was treated the same as in Process 2 of Example 96 and, a

then according to Process 7 of Example 1 to obtain the desired compound. MS (ESI MH +): 504 CHNO: C24H23C12N305

image3

Examples 205 and 206

Compounds of the following general formula (82) having a substituent in Table 26 were synthesized

using the carboxylic acid obtained in Example 108 as a starting material and in the same manner as in

Example 191 except that a suitable alcohol was used.

Meanwhile, R in Table 26 is a substituent in the following general formula (82).

image4

image57

Table 26

Example

R Experimental MS (MH +)

205

 ethyl 583

206

 isopropyl 597

Examples 207 and 208

The compounds of the following general formula (83) having substituents in Table 27 were synthesized from

in the same manner as in Example 149 unless the corresponding 2-nitrobenzyl bromide was used

replaced. Meanwhile, R1 and R2 in Table 27 are substituents of the following general formula (83).

image3

Table 27

Example

R1 R2 Experimental MS (MH +)

207

-H methyl 512

208

 fluorine -H 516

10 Example 209

The compound of the following general formula (84) having a substituent of Example 209 in Table 28 was synthesized in the same manner as those of Example 45 except that 3-chloro-2-nitrobenzoic acid was replaced with acid 1- ethyl-4-nitro-1H-pyrazol-3-carboxylic in Process 1 of Example 45, and processes 6 and 7 of Example 1. Meanwhile, R in Table 28 is a substituent of the following general formula (84) .

15 Example 210

The compound of the following general formula (84) having a substituent of Example 210 in Table 28 was synthesized using the compound obtained in Example 209 as a starting material and in the same manner as Example 192. Meanwhile, R in Table 28 is a substituent of the following general formula (84).

image3

image58

5

10

fifteen

twenty

25

30

35

Table 28

Example

R Experimental MS (MH +)

209

 H 530

210

 methyl 544

Example 211

The compound of the following general formula (85) was synthesized as follows. The compound of the general formula (23) having a substituent or substituents of Example 1 in Table 1 (28.9 mg) was dissolved in DMF

(1ml) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (12.9mg), 1-hydroxy-7-azabenzotriazole (10.7mg), hydroxylamine hydrochloride (11.5mg) and N-methylmorpholine (9.1 mg) were added and stirred. Subsequently, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11.7 mg), 1-hydroxy-7-azabenzotriazole (8.2 mg), hydroxylamine hydrochloride (9.5 mg) were added and stirred. N-methylmorpholine (10.5 mg) and DMF (0.5 ml). Two hours later, water was added to the reaction solvent and the separated crystal was dried to 14.8 mg of the desired compound.

MS (ESI MH-): 525

CHNO: C25H20C12N405

image3

Reference Example 1. 2-Chloro-6-trifluoromethylbenzoic acid

The mixture of 500 mg of 3-chlorobenzotrifluoride and 3 ml of tetrahydrofuran was cooled to -50 ° C and 2 ml of 1.6M of n-butyllithium hexane solution was added and stirred for 1 hour. The mixture was placed on dry ice and diluted with a 1N aqueous solution of sodium hydroxide. After washing with toluene, the aqueous layer was made acidic by means of hydrochloric acid and extracted with ethyl acetate. The crude material that was obtained by removing the solvent was purified by reverse phase HPLC to said compound. Yield 244 mg

H-NMR (DMSO-d6)  7.68 (1H, t), 7.80 (1H, d), 7.88 (1H, d).

MS (ESI m / z) 223 (M-H).

Reference Example 2. 2-Bromo-6-Chlorobenzoic Acid

The mixture of 500 mg of 3-bromochlorobenzene and 3 ml of tetrahydrofuran was cooled to -78 ° C and 1.3 ml of 2.0M lithium diisopropylamide heptane / tetrahydrofuran / ethylbenzene were added. After stirring for 2 hours, the mixture was placed on dry ice and washed and extracted as described in Reference Example 1 to obtain a crude material. The crude material was washed with a solvent mixture of hexane-ethyl acetate to obtain said compound.

Yield 317mg

H-NMR (DMSO-d6)  7.40 (1H, t), 7.60 (1H, d), 7.70 (1H, d).

MS (ESI m / z) 233 (M-H)

Example 214. VCAM antagonist activity (VCAM-1 /  4  1 binding assay)

The ability of an antagonistic test substance to the binding of the Jurkat cell strain (ATCC TIB-152) of human T cells, known to express integrin  4  1, to VCAM-1 was determined.

100 ul / well of a solution (500 ng / ml) of recombinant human VCAM-1 solution (R&D Systems) diluted with buffer A (0.1 M NaHCO3, pH 9.6) was added to a microtiter plate which have 96 wells (Nunc Maxisorp). After incubation at 4 ° C overnight, unbound VCAM-1 was removed by washing once with PBS. After completion of the wash, a buffer (buffer B) that was obtained by diluting Block Ace (Dainippon Pharmaceutical Co., Ltd.) with PBS to 1/4 concentration was added in an amount of 150 ul / well. After incubation at room temperature for 1 hour, buffer B was removed and the plate was washed with PBS once.

image59

Jurkat cells were washed with Dulbecco-modified Eagle medium (SIGMA, hereinafter referred to as "DMEM") twice and then incubated in DMEM containing 10 g / ml calcein-AM (Wako Pure Chemical Industries, Ltd.) at 37 ° C in a dark place for 30 minutes to mark them with fluorescence. The cells were resuspended in a binding buffer (20 mM HEPES, DMEM containing 0.1% BSA).

50 ul of a test substance of various concentrations that was obtained by dilution with the binding buffer was added to the plate. Immediately afterwards, 50 ul, (final volume: 100 ul / well) of the fluorescent Jurkat cells (4 x 106 cells / ml) were added thereto, and incubated in a dark place at room temperature for 30 minutes. After stirring on a plate shaker (IKA MTS-4) at 800 rpm for 30 seconds, the solution was removed immediately to remove unbound cells. The amount of fluorescence of the remaining non-binding cells in the wells was determined with a fluorescent plate reader (multi-brand counter Wallac 1420 ARVO) (filter excitation wavelength: 485 nm, emission wavelength: 535 nm ). The fluorescent power obtained in this way is proportional to the number of Jurkat cells bound to the VCAM-1 and remaining on the plate. The binding rate of each test material was determined at various concentrations, while the fluorescent potency of the free well of test material was determined to be 100%. The IC50 concentration for 50% inhibition of binding was calculated.

The test results obtained are shown in Table 30.

Example 215. VCAM antagonist activity (VCAM-1 /  4  7 binding assay)

The ability of an antagonistic test substance to the binding of the human B-cell RPMI-8866 lymphoma cell strain, known to express integrin  4  7, to VCAM-1 was determined. 100 ul / well of a solution (500 ng / ml) of recombinant human VCAM-1 solution (R&D Systems) diluted with buffer A (0.1 M NaHCO3, pH 9.6) was added to a microtiter plate which have 96 wells (Nunc Maxisorp). After incubation at 4 ° C overnight, unbound VCAM-1 was removed by washing once with PBS. After completion of the wash, a buffer (buffer B) that was obtained by diluting Block Ace (Dainippon Pharmaceutical Co., Ltd.) with PBS to 1/4 concentration was added in an amount of 150 ul / well. After incubation at room temperature for 1 hour, buffer B was removed and the plate was washed with PBS once.

RPMI-8866 cells were washed with DMEM twice and incubated in Dulbecco-modified Eagle medium containing 10 g / ml calcein-AM (Wako Pure Chemical Industries, Ltd.) (SIGMA, hereinafter referred to as "DMEM") in a dark place at 37 ° C for 30 minutes to mark them with fluorescence. The cells were resuspended in assay buffer (20 mM HEPES, DMEM containing 0.1% BSA) containing 4 mM MnCl2.

50 ul of a test substance of various concentrations that was obtained by dilution with the test buffer was added to the plate. Immediately afterwards, 50 ul, (final volume: 100 ul / well) of the fluorescent RPMI-8866 cells (4 x 106 cells / ml) were added thereto, and incubated in a dark place at room temperature for 30 minutes. After stirring on a plate shaker (IKA MTS-4) at 800 rpm for 30 seconds, the solution immediately removed to remove unbound cells. The amount of fluorescence of the remaining non-binding cells in the wells was determined with a fluorescent plate reader (multi-brand counter Wallac 1420 ARVO) (filter excitation wavelength: 485 nm, emission wavelength: 535 nm ). The fluorescent power obtained in this way is proportional to the number of RPMI-8866 cells bound to the VCAM-1 and remaining on the plate. The binding rate of each test material was determined at various concentrations while the fluorescent potency of the free well of test material was determined to be 100%. The IC50 concentration for 50% inhibition of binding was calculated.

The test results obtained are shown in Table 30.

image60

Table 30 Results of the determination of the antagonistic activity of VCAM (IC50, nmol / l).

Example

4 7 4 1

one

1.0 18

2

9.2 240

3

3.5 66

4

2.8 26

5

14.0 46

6

3.3 80

7

22.0 110

8

3.9 94

9

94.0 440

eleven

 74.0 6200

12

 19.0 490

13

 4,5 220

14

 26.0 1260

16

 14.0 1700

17

 43.0 2100

18

 23.0 1900

2. 3

 18.0 7240

31

 50.0 630

32

 64.0 2420

3. 4

 42.0 2210

35

 68.0 1700

36

 6.6 490

37

 19.0 200

41

 86.0 3410

42

 92.0 6730

44

 79.0 4230

Four. Five

 10.2 340

46

 6.8 195

47

 76.0 1980

48

 28.0 1800

49

 62.1 1180

fifty

 7.9 1770

51

 30.0 1180

52

 55.3 1310

image61

53 66.1 2460 54 9.8 71 57 29.9 639 58 31.6 1070 59 35.8 540 60 36.1 780 61 42.0 1150 62 45.0 1450 63 1.3 28 65 7.0 330 66 1.3 170 67 2.2 370 68 1.6 350 69 2.5 5630 70 3.5 34 71 11.0 185 72 2.6 27 73 1.6 27 74 2.5 53 75 2.3 60 76 13.0 192 78 9.6 180 79 18.0 440 80 74.0 960 81 8.6 72 84 20.0 158 85 25.0 230 89 2.7 41 90 43.7 511 91 1.6 1200 92 5.7 1340 93 4.8 4030 94 6.0 1150 95 1.8 960 97 13.0 1500 99 2.0 12

100 2.4 11

104 1.4 16

105 0.8 14

image62

106

 2.8 44

107

 1.1 17

108

 3.3 57

109

 4.3 56

110

 4.1 55

111

 11.0 88

112

 1.1 37

113

 1.6 52

114

 27.0 190

115

 36.0 760

116

 35.0 450

117

 19.0 480

118

 16.0 385

119

 21.0 440

120

 24.0 500

121

 14.0 109

122

 0.6 310

123

 12.0 180

124

 20.0 840

126

 70.0 1580

129

 76.4 2023

131

 24.0 183

136

 3.0 565

137

 11.2 2120

139

 17.0 107

142

 9.0 210

147

 6.5 107

162

 0.2 3. 4

164

 7.1 120

165

 0.6 eleven

169

 0.5 6

180

 5.4 86

181

 1.0 fifteen

182

 6.2 113

183

 1.7 25

184

 8.3 31

185

 2.7 12

186

 4.3 59

187

 3.2 26

image63

188 2.7 11

189 1.1 18

211 20 250

Thus, it is evident that the new phenylalanine derivatives exhibited excellent inhibitory activity of -4 integrin.

Since the new phenylalanine derivatives of the present invention have excellent inhibitory activity

5 of integrin -4, the present invention provides a therapeutic agent or prevention agent for diseases in which the adhesion process that depends on integrin  4 participates in the pathology, such as inflammatory diseases, rheumatoid arthritis, inflammatory diseases intestinal, systemic lupus erythematosus, multiple sclerosis, Sjögren's syndrome, asthma, psoriasis, allergy, diabetes, cardiovascular diseases, arterial sclerosis, restenosis, tumor proliferation, tumor metastasis and transplant rejection. Inflammatory diseases

10 intestinal described above include Crohn's disease and ulcerative colitis.

For this purpose, the compound of the present invention has high bioavailability and / or high blood level when administered orally. Therefore, oral administration of a drug is effective.

The compound of the present invention also has high stability in acidic or alkaline solutions and is effective, for example, since it is possible to apply it to various dosage forms.

image64

10

fifteen

twenty

25

30

35

Claims (38)

one.

Derivatives from  phenylalanine of the  following general formula (1) Y you go out acceptable for use

pharmacist thereof.

image 1 where A represents one of the following general formulas (2), (3) or (3-1): image2 where Arm represents a cyclic alkyl group or an aromatic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen atoms, U, V and X represent C (= O), S (= O) 2, C (-R5) (- R6), C (= C (R5) (R6)), C (= S), S (= O), P (= O) (- OH) or P (-H) (= O), W represents C (-R7) or a nitrogen atom, R1, R2, R3, R4, R5, R6 and R7 can be the same or different from each other and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkenyl group, a substituted lower alkenyl group, a lower alkynyl group, a substituted lower alkynyl group, a cycloalkyl group which may contain a heteroatom or ring heteroatoms thereof, an aryl group, a heteroaryl group, a lower alkyl group substituted with a cycloalkyl group or groups which may contain a heteroatom or heteroatoms in the ring thereof, a lower alkyl group substituted with an aryl group or groups, a lower alkyl group substituted with a heteroaryl group or groups, a lower alkoxy group, a lower alkylthio group, a lower alkoxy group and lower alkylthio group substituted with a cycloalkyl group or groups that may contain a heteroatom or heteroatoms in the ring thereof, a lower alkoxy group and a lower alkylthio group substituted with an aryl group or groups, a lower alkoxy group and a lower alkylthio group substituted with a heteroaryl group or groups, a cycloalkyloxy group which may contain a heteroatom or heteroatoms in the ring thereof, an aryloxy group, a heteroaryloxy group, a lower hydroxyalkyl group, a lower hydroxyalkenyl group, a lower hydroxyalkoxy group, a lower alkyl halogen group, a lower alkoxy halogen group, a lower alkylthio halogen group, an alkenyl halogen group lower, nitro group, cyano group, a substituted or unsubstituted amino group, carboxyl group, a lower alkoxycarbonyl group, a substituted or unsubstituted carbamoyl group, a lower alkanoyl group, an aroyl group, a lower alkylsulfonyl group, or a sulfamoyl group substituted or unsubstituted, or an ammonium group, R5 and R6 can be attached to form a ring that can of containing one or two atoms of oxygen, nitrogen or sulfur, B represents a hydroxyl group, a lower alkoxy group or a hydroxylamino group, C represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkyl group substituted with a cycloalkyl group or groups that may contain a heteroatom or heteroatoms in the ring thereof, a lower alkyl group substituted with an aryl group or groups or a lower alkyl group substituted with a heteroaryl group or groups, D represents an aryl group, or a heteroaryl group; or an optionally substituted cyclohexyl group. C and D may be joined to form a ring which may contain one or two oxygen, nitrogen or sulfur atoms, T represents an interatomic bond, C (= O), C (= S), S (= O), S (= O) 2, N (H) - C (= O), or N (H) -C ( = S), J and J 'may be the same or different from each other and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkyloxy group or a nitro group, and the term "lower" as used above, it indicates that the group qualified in this way has less than 6 carbons. image3

2.

The phenylalanine derivatives or their salts acceptable for pharmaceutical use according to claim 1, wherein A represents one of the groups indicated as the general formula (2) or (3) and R1, R2, R3, R4, R5, R6 and R7 may be the same or different from each other, and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a substituted lower alkyl group, a lower alkenyl group, a substituted lower alkenyl group, a lower alkynyl group, a substituted lower alkynyl group, a cycloalkyl group which may contain a heteroatom or heteroatoms in the ring thereof, an aryl group, a heteroaryl group, a lower alkyl group substituted with a cycloalkyl group or groups that may contain a heteroatom or heteroatoms in the ring thereof, a lower alkyl group substituted with an aryl group or groups, a lower alkyl group substituted with a heteroaryl group or groups, an alkox group lower yl, a lower alkylthio group, a lower alkoxy group and lower alkylthio group substituted with a cycloalkyl group or groups which may contain a heteroatom or heteroatoms in the ring thereof, a lower alkoxy group and lower alkylthio group substituted with a group or groups aryl, a lower alkoxy group and lower alkylthio group substituted with a heteroaryl group or groups, a cycloalkyloxy group which may contain a heteroatom or ring heteroatoms thereof, an aryloxy group, a heteroaryloxy group, a lower hydroxyalkyl group, a hydroxyalkenyl group lower, a lower hydroxyalkoxy group, a lower alkyl halogen group, a lower alkoxy halogen group, a lower alkyl halogen group, a lower alkenyl halogen group, nitro group, a cyano group, a substituted or unsubstituted amino group, carboxyl group, a lower alkyloxycarbonyl group, a substituted or unsubstituted carbamoyl group, a group a The lower alkanoyl, an aroyl group, a lower alkylsulfonyl group or a substituted or unsubstituted sulfamoyl group, R5 and R6 may be joined to form a ring that may contain one or two oxygen, nitrogen or sulfur atoms.

3.

The phenylalanine derivatives or their salts acceptable for pharmaceutical use according to claim 2, wherein, in the general formula (1), B represents a hydroxyl group or a lower alkoxy group,

C represents a hydrogen atom or a lower alkyl group, J and J 'represent a hydrogen group, and in the general formulas (2) and (3), V and X represent any of the group of C = (O), S (= O) 2 or C (-R5) (- R6), U represents any of the group of C = (O), S (= O) 2, C (-R5) (- R6), C (= C (R5) (R6)), C (= S), S (= O), P (= O) (- OH) and P (-H) (= O). 4. Phenylalanine derivatives or their salts acceptable for pharmaceutical use according to claim 2, wherein, in the general formula (1), B represents a hydroxyl group or a lower alkoxy group, C represents a hydrogen atom or a lower alkyl group, J and J 'represent a hydrogen group, and In the general formulas (2) and (3), Arm represents a benzene ring or an aromatic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen atoms. 5. Phenylalanine derivatives or their salts acceptable for pharmaceutical use according to claim 2, wherein, in the general formula (1), B represents a hydroxyl group or a lower alkoxy group, C represents a hydrogen atom or a lower alkyl group, J and J 'represent a hydrogen group, and In the general formulas (2) and (3), Arm represents a benzene ring or an aromatic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen atoms. V and X represent any of the group of C = (O), S (= O) 2 or C (-R5) (- R6), U represents any of the group of C = (O), S (= O) 2, C (-R5) (- R6), C (= C (R5) (R6)), C (= S), S (= O), P (= O) (- OH) and P (-H) (= O).

6.

Phenylalanine derivatives or their salts acceptable for pharmaceutical use according to claim 1, wherein A represents the following formula (3-3):

wherein Arm, U and R1 to R4 are the same as described in claim 1.

7.

Phenylalanine derivatives or their salts acceptable for pharmaceutical use according to claim 1, wherein A represents the following formula (3-4)

image4 image 1 image2 wherein Arm and R1 to R4 are the same as described in claim 1. 8. Phenylalanine derivatives or their salts acceptable for pharmaceutical use according to claim 7, wherein A represents formula (3-4), Arm is a benzene ring, pyridine ring, pyrazole ring or cyclohexane ring, R1 is a lower alkyl group, R2, R3 and R4 may be the same or different from each other and each 10 represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a cycloalkyl group that may contain a heteroatom or heteroatoms in the ring thereof, a lower alkyl group substituted with a cycloalkyl group or groups that can containing a heteroatom or heteroatoms in the ring thereof, a lower alkoxy group, a lower alkylthio group, a lower alkyl halogen group, a lower alkoxy halogen group, a lower alkylthio halogen group, a nitro group, a cyano group, an amino group , an amino group 15 substituted with a lower alkyl group or groups or a trialkylammonium group. 9. Phenylalanine derivatives or their salts acceptable for pharmaceutical use according to claim 1, wherein, in the general formula (1), D represents the following formulas (4-1), (4-2), (4- 3) or (4-4): image 1 where R13 represents a halogen atom or methyl group, R8 represents a halogen atom, group Methyl, trifluoromethyl group, methoxy group or a hydrogen atom, R9 represents a hydrogen atom, halogen atom, hydroxyl group, lower alkyl group, cycloalkyl group which may contain a heteroatom or heteroatoms in the ring thereof, alkyl group lower substituted with a cycloalkyl group or group which may contain a heteroatom or heteroatoms in the ring thereof, lower alkoxy group, lower alkylthio group, lower alkyl halogen group, lower alkoxy halogen group, lower alkylthio halogen group, nitro group, cyano group, 25 amino group, amino group substituted with a lower alkyl group or groups, trialkylammonium group, methanesulfonyl amino group and tetrazolyl group. image5 10. Phenylalanine derivatives or their salts acceptable for pharmaceutical use according to claim 9, wherein, in the general formula (1), D represents the formula (4-1), and in formula (4-1), R13 and R8 represent a chlorine atom, and R9 represents a hydrogen atom, atom 5 of halogen, hydroxyl group, lower alkyl group, cycloalkyl group which may contain a heteroatom or heteroatoms in the ring thereof, lower alkoxy group, lower alkylthio group, halogen lower alkyl group, lower alkoxy halogen group, inner alkylthio halogen group, group nitro, cyano group, amino group, amino group substituted with a lower alkyl group or groups, or trialkylammonium group. 11. Phenylalanine derivatives or their salts acceptable for pharmaceutical use according to claim 1, wherein, in the general formula (1), C represents a hydrogen atom and T is C (O). 12. Phenylalanine derivatives or their salts acceptable for pharmaceutical use according to claim 1, wherein, in the general formula (1), A represents the following formula (3-4): image 1 wherein Arm and R1 to R4 are the same as those described in claim 1, D represents the following formulas (4-1), (4-2), (4-3) or (4-4): image 1 where R13 represents a halogen atom or methyl group, R8 represents a halogen atom, methyl group, trifluoromethyl group, methoxy group or a hydrogen atom, R9 represents a hydrogen atom, halogen atom, hydroxyl group, lower alkyl group, cycloalkyl group which may contain a heteroatom or 20 heteroatoms in the ring thereof, lower alkyl group substituted with a cycloalkyl group or group that may contain a heteroatom or heteroatoms in the ring thereof, lower alkoxy group, lower alkylthio group, lower alkyl halogen group, lower alkoxy halogen group, group halogen lower alkylthio, nitro group, cyano group, amino group, amino group substituted with a lower alkyl group or groups, trialkylammonium group, methanesulfonyl amino group and tetrazolyl group, B represents a hydroxyl group or a lower alkoxy group, C represents an atom of Hydrogen, J and J 'represent a hydrogen group and T is C (= O). 13. The phenylalanine derivatives or their salts acceptable for pharmaceutical use according to claim 12, wherein, in the general formula (1), A represents the formula (3-4), Arm is a benzene ring, pyridine ring, pyrazole ring or cyclohexane ring, R1 is a lower alkyl group, R2, R3 and R4 can be the same or different from each other and each represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group 30, a cycloalkyl group that may contain a heteroatom or heteroatoms in the ring thereof, a lower alkyl group substituted with a group or cycloalkyl groups that may contain a heteroatom or heteroatoms in the ring thereof, a lower alkoxy group, a group lower alkylthio, a halogen group lower alkyl, a halogen group lower alkoxy, a halogen group lower alkylthio, a nitro group, a cyano group, an amino group, an amino group substituted with a lower alkyl group or groups or a trialkylammonium group, D represents the following formula (4  35 1). image6 image 1 5 10 fifteen twenty 25 30 35 in the formula (4-1), R13 and R8 represent a chlorine atom, and R9 represents a hydrogen atom, halogen atom, hydroxyl group, lower alkyl group, cycloalkyl group which may contain a heteroatom or heteroatoms in the ring of the same, lower alkoxy group, lower alkylthio group, lower alkyl halogen group, lower alkoxy halogen group, inner alkyl halide group, nitro group, cyano group, amino group, amino group substituted with a lower alkyl group or groups, or trialkylammonium group. B represents a hydroxyl group or a lower alkoxy group, C represents a hydrogen atom, J and J 'represent a hydrogen group and T is C (= O). 14. Phenylalanine derivatives or their salts acceptable for pharmaceutical use according to claim 6, wherein, in the general formula (1), A represents the formula (3-3), and in the formula (3-3), U represents C (= O) or C (= S), R1 represents a lower alkyl group, R2, R3 and R4 can be the same or different from each other and each represents a hydrogen atom, a halogen atom, a group hydroxyl, a lower alkyl group, a cycloalkyl group which may contain a heteroatom or heteroatoms in the ring thereof, a lower alkyl group substituted with a group or cycloalkyl groups that may contain a heteroatom or heteroatoms in the ring thereof, an alkoxyl group lower, a lower alkylthio group, a lower alkyl halogen group, a lower alkoxy halogen group, a lower alkyl halogen group, a nitro group, a cyano group, an amino group, an amino group substituted with a lower alkyl group or groups or a trialquil group ammonium, C represents a hydrogen atom, D represents the formula (4-1), (4-2), (4-3) or (4-4), image 1 where R13 represents a halogen atom or methyl group, R8 represents a halogen atom, methyl group, trifluoromethyl group, methoxy group or a hydrogen atom, R9 represents a hydrogen atom, halogen atom, hydroxyl group, lower alkyl group, cycloalkyl group which may contain a hetero atom or heteroatoms in the ring thereof, alkyl group substituted with a group or cycloalkyl group that may contain a heteroatom or heteroatoms in the ring thereof, lower alkoxy group, lower alkylthio group, halogen alkyl group lower, lower alkoxy halogen group, lower alkyl halide group, nitro group, cyano group, amino group, amino group substituted with a lower alkyl group or groups, trialkylammonium group, amino methanesulfonyl group and tetrazolyl group, and T represents C (= O) . 15. Phenylalanine derivatives or their salts acceptable for pharmaceutical use according to claim 14, wherein, in the general formula (1), A represents the formula (3-3), and in the formula (3-3), U represents C (= O) or C (= S), R1 represents a methyl group or ethyl group, R2, R3 and R4 can be the same or different from each other and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a cycloalkyl group that may contain a heteroatom or ring heteroatoms thereof, a lower alkoxy group, a lower alkylthio group, a lower alkyl halogen group, a lower alkoxy halogen group, a halogen group lower alkylthio, a nitro group, a cyano group, an amino group, an amino group substituted with a lower alkyl group or groups or a trialkylammonium group, B represents a hydroxyl group or a lower alkoxy group, C represents a hydrogen atom, D represents formula (4-1), where R13 and R8 represent a chlorine atom, and R9 represents a hydrogen atom, a halogen atom , hydroxyl group, lower alkyl group, cycloalkyl group which may contain a heteroatom or heteroatoms in the ring thereof, lower alkoxy group, lower alkylthio group, lower alkyl halogen group, lower alkoxy halogen group, lower alkylthio halogen group, nitro group, group cyano, amino group, amino group substituted with a lower alkyl group or groups or trialkylammonium group, T is C (= O) and each of J and J 'is a hydrogen atom. image7 16. Phenylalanine derivatives of the following formula or their salts acceptable for pharmaceutical use according to claim 1: image 1 where R1 represents a methyl group or an ethyl group, R8 represents a halogen atom or methyl group, R10 represents a hydrogen atom or a lower alkyl group, R11 and R12 can be the same or different from each other and each represents an atom of hydrogen, a methyl group, ethyl group or propyl group, R11 and R12 may be 10 joined to form a ring, and in that case, R11-R12 represents trimethylene, tetramethylene or pentamethylene.

17.

The phenylalanine derivatives of the following formula or their salts acceptable for pharmaceutical use according to claim 1:

18.

The phenylalanine derivatives of the following formula or their salts acceptable for pharmaceutical use according to claim 1:

19.

The phenylalanine derivatives of the following formula or their salts acceptable for pharmaceutical use according to claim 1:

twenty.

The phenylalanine derivatives of the following formula or their salts acceptable for pharmaceutical use according to claim 1:

twenty-one.

The phenylalanine derivatives of the following formula or their salts acceptable for pharmaceutical use according to claim 1:

22

The phenylalanine derivatives of the following formula or their salts acceptable for pharmaceutical use according to claim 1:

2. 3.

The phenylalanine derivatives of the following formula or their salts acceptable for pharmaceutical use according to claim 1:

24.

The phenylalanine derivatives of the following formula or their salts acceptable for pharmaceutical use according to claim 1:

25.

The phenylalanine derivatives of the following formula or their salts acceptable for pharmaceutical use according to claim 1:

26.

The phenylalanine derivatives of the following formula or their salts acceptable for pharmaceutical use according to claim 1:

27.

The phenylalanine derivatives of the following formula or their salts acceptable for pharmaceutical use according to claim 1:

28.

The phenylalanine derivatives of the following formula or their salts acceptable for pharmaceutical use according to claim 1:

29.

The phenylalanine derivatives of the following formula or their salts acceptable for pharmaceutical use according to claim 1:

30

The phenylalanine derivatives of the following formula or their salts acceptable for pharmaceutical use according to claim 1:

31.

The phenylalanine derivatives of the following formula or their salts acceptable for pharmaceutical use according to claim 1:

32

The phenylalanine derivatives of the following formula or their salts acceptable for pharmaceutical use according to claim 1:

33.

The phenylalanine derivatives of the following formula or their salts acceptable for pharmaceutical use according to claim 1:

3. 4.

The phenylalanine derivatives of the following formula or their salts acceptable for pharmaceutical use according to claim 1:

35

The phenylalanine derivatives of the following formula or their salts acceptable for pharmaceutical use according to claim 1

image8 image 1 image9 image 1 image10 image 1 image 1 image11 image 1 image 1 image 1 image 1 image12 image 1 image 1 image 1 image 1 image13 image 1 image 1 image 1 image 1 image14 image 1 image 1 image 1 image 1 image15 image 1 36. An ina 4 integrin antagonist containing a phenylalanine derivative or a salt acceptable for pharmaceutical use thereof according to any of claims 1 to 35 as active ingredient. 37. A therapeutic agent or prevention agent for inflammatory diseases in which the Adhesion Process that depends on integrin -4 participates in the pathology, which contains a phenylalanine derivative or a salt acceptable for pharmaceutical use thereof according to any of claims 1 to 35 as active ingredient. A pharmaceutical composition containing a phenylalanine derivative or a salt acceptable for pharmaceutical use thereof according to any one of claims 1 to 35 as an active ingredient. 39. A therapeutic agent or prevention agent for rheumatoid arthritis, inflammatory bowel diseases, systemic lupus erythematosus, multiple sclerosis, Sjögren's syndrome, asthma, psoriasis, allergy, diabetes, cardiovascular diseases, arterial sclerosis, restenosis, tumor proliferation, metastasis of the tumor and rejection of A transplant, which contains a phenylalanine derivative or a salt acceptable for pharmaceutical use thereof according to any one of claims 1 to 35 as active ingredient.