Metalloproteinase Inhibitors

专利摘要:
The present invention discloses compounds of formula (I) wherein z is SO 2 or SO useful as metalloproteinase inhibitors, in particular inhibitors of MMP12.
公开号:KR20030082989A
申请号:KR10-2003-7011987
申请日:2002-03-13
公开日:2003-10-23
发明作者:앤더스 에릭손；마티 레피스퇴；미카엘 룬드크비스트；마그누스 문크아프로센쇨드；파볼 츠라토이드스키
申请人:아스트라제네카 아베；
IPC主号:

专利说明:

Metalloproteinase Inhibitors {Metalloproteinase Inhibitors}
[1] The present invention relates to compounds useful for the inhibition of metalloproteinases, in particular pharmaceutical compositions containing them and their use.
[2] Compounds of the invention are inhibitors of one or more metalloproteinase enzymes. Metalloproteinases are a superfamily of proteinases (enzymes) which have recently increased significantly in number. These enzymes are described in N.M. Hooper (1994) FEBS Letters 354: 1-6; Examples of metalloproteinases are matrix metalloproteinases (MMP), for example collagenase (MMP1, MMP8, MMP13), gelatinases (MMP2, MMP9), stromelysin (MMP3, MMP10, MMP11), Matrilysine (MMP7), Metalloelasease (MMP12), Enamellysine (MMP19), MT-MMP (MMP14, MMP15, MMP16, MMP17); Leprolysine or adamalisine or MDC, including secretases such as TNF converting enzymes (ADAM10 and TACE) and shadase; Astaxin, including enzymes such as procollagen processing proteinases (PCPs); And other metalloproteinases such as agrecanase, endothelin converting enzyme family, and angiotensin converting enzyme family.
[3] Metalloproteinases are thought to be important for many physiological disease processes involved in tissue remodeling such as embryonic development, bone formation and uterine remodeling during menstruation. It is based on the ability of metalloproteinases to degrade a wide range of substrates such as collagen, proteoglycans and fibronectin. Metalloproteinases also include the processing or secretion of biologically important cell mediators such as tumor necrosis factor (TNF); And post-translational proteolytic processing or shedding of biologically important membrane proteins, such as the low affinity IgE receptor CD23 (see NM Hooper et al., (1997) Biochem J. 321: 265-279 for a more complete list). I think it's important.
[4] Metalloproteinases are associated with many diseases or conditions. Inhibition of the activity of one or more metalloproteinases can affect these diseases or conditions, such as various inflammatory and allergic diseases, such as inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract ( In particular, inflammatory bowel disease, ulcerative colitis and gastritis), inflammation of the skin (especially psoriasis, eczema and dermatitis); Tumor metastasis or infiltration; Diseases associated with uncontrolled degradation of extracellular matrix, such as osteoarthritis; Bone resorption diseases (eg osteoporosis and Paget's disease); Diseases associated with abnormal angiogenesis; Enhanced collagen remodeling associated with diabetes mellitus, periodontal disease (eg gingivitis), corneal ulcers, skin ulcers, postoperative conditions (eg colon anastomosis) and skin wound healing; Demyelinating diseases of the central and peripheral nervous systems (eg, multiple sclerosis); Alzheimer's disease; Extracellular matrix remodeling observed in cardiovascular diseases such as restenosis and atherosclerosis; asthma; Rhinitis; And chronic obstructive pulmonary disease (COPD).
[5] MMP12, also known as macrophage elastase or metalloelastase, was initially cloned in mice by Shapiro et al. (1992, Journal of Biological Chemistry 267: 4664) and cloned in humans in 1995 by the same researchers. MMP-12 is preferentially expressed in activated macrophages and from alveolar macrophages in smokers (Shapiro et al., 1993, Journal of Biological Chemistry, 268: 23824) and in foam cells in arteriosclerosis lesions (Matsumoto et al., 1998, Am J Pathol 153: 109). The mouse model of COPD allowed mice to smoke two cigarettes per day for six months for six days a week. In wild-type mice, emphysema developed after this treatment. When MMP12-deficient mice were tested with this model, no significant emphysema occurred, clearly indicating that MMP-12 is a key enzyme in COPD pathogenesis. The role of MMPs such as MMP12 in COPD (pulmonary emphysema and bronchitis) is discussed in Anderson and Shinagawa, 1999, Current Opinion in Anti-inflammatory and Immunomodulatory Investigational Drugs 1 (1): 29-38. Recently, smoking has been shown to increase macrophage infiltration and macrophage derived MMP-12 expression in human carotid plaque Kangavari (Matetzky S, Fishbein MC et al., Circulation 102: (18), 36- 39 Suppl. S, Oct 31, 2000).
[6] MMP13, or collagenase 3, was initially cloned from a cDNA library derived from breast cancer [J.M.P. Freije et al. (1994) Journal of Biological Chemistry 269 (24): 16766-16773. PCR-RNA analysis of RNA from various tissues indicated that MMP13 expression was found in breast fibroadenoma, normal or stationary mammary gland, placenta, liver, ovary, uterus, prostate or parotid gland or breast cancer cell lines (T47-D, MCF-7 and ZR75-1). Not found), indicating that it is limited to breast carcinoma. After this observation, MMP13 was transformed into epidermal keratinocytes [N. Johansson et al., (1997) Cell Growth Differ. 8 (2): 243-250], squamous cell carcinoma [N. Johansson et al., (1997) Am. J. Pathol. 151 (2): 499-508] and epithelial tumors [K. Airola et al., (1997) J. Invest. Dermatol. 109 (2): 225-231. These results suggest that MMP13 is secreted by transformed epithelial cells and is particularly involved in extracellular matrix degradation and cell-substrate interactions associated with metastasis as observed in invasive breast cancer lesions and also in malignant epithelial cell proliferation in skin carcinogenesis. It is implied.
[7] Recently published data suggest that MMP13 plays a role in metabolic rotation of other connective tissues. For example, consistent with the substrate specificity and priority of MMP13 for degradation of type II collagen [P.G. Mitchell et al., (1996) J. Clin. Invest. 97 (3): 761-768; V. Knauper et al., (1996) The Biochemical Journal 271: 1544-1550], MMP13 was found in [M. Stahle-Backdahl et al., (1997) Lab. Invest. 76 (5): 717-728; N. Johansson et al., (1997) Dev. Dyn. 208 (3): 387-397], in destructive joint diseases such as rheumatoid and osteoarthritis [D. Wernicke et al., (1996) J. Rheumatol. 23: 590-595; P.G. Mitchell et al., (1996) J. Clin. Invest. 97 (3): 761-768; O. Lindy et al., (1997) Arthritis Rheum 40 (8): 1391-1399] and during aseptic dissociation of hip replacements [S. Imai et al., (1998) J. Bone Joint Surg. Br. 80 (4): 701-710]. MMP13 has also been described as chronic adult periodontitis localized to epithelial cells of chronic inflammatory mucosal human gingival tissues [V. J. Uitto et al., (1998) Am. J. Pathol 152 (6): 1489-1499] and remodeling of collagen matrix in chronic wounds [M. Vaalamo et al., (1997) J. Invest. Dermatol. 109 (1): 96-101.
[8] MMP9 (gelatinase B; 92 kDa type IV collagenase; 92 kDa gelatinase) is a secreted protein that was first purified in 1989 and then cloned and sequenced [S.M. Wilhelm et al. (1989) J. Biol Chem. 264 (29): 17213-17221; published erratum in J. Biol Chem. (1990) 265 (36): 22570. A recent survey of MMP9 (TH Vu & Z. Werb (1998)) provides excellent data for detailed information and references to these proteases (Matrix Metalloproteinases. 1998. Edited by WC Parks & RP Mecham. Pp 115-148 Academic Press.ISBN 0-12-545090-7). The following are excerpts from the study of Vu and Werb (T.H. Vu & Z. Werb (1998)).
[9] Expression of MMP9 is generally limited to several cell types, including trophoblasts, osteoclasts, neutrophils and macrophages. However, its expression can be induced in the same cells and other cell types by several mediators, including exposure of cells to growth factors or cytokines. These are often the same mediators involved in initiating the inflammatory response. Like other secreted MMPs, MMP9 is released as an inactive proenzyme that is subsequently degraded to form enzymatically active enzymes. The proteases required for such in vivo activation are not known. The balance of active MMP9 against inactive enzymes is further regulated in vivo by interaction with the native protein TIMP-1 (tissue inhibitor of metalloproteinase-1). TIMP-1 binds to the C-terminal region of MMP9 and induces inhibition of the catalytic domain of MMP9. The balance of induced expression of ProMMP9, degradation of Pro-MMP9 to active MMP9 and the presence of TIMP-1 determines the amount of catalytically active MMP9 present at the local site. Proteolytic activity MMP9 attacks substrates comprising gelatin, elastin and native type IV and V collagen; It has no activity against native type I collagen, proteoglycans or laminin.
[10] There is increasing data on the role of MMP9 in various physiological and pathological processes. Physiological roles include infiltration of embryonic germ layers through the uterine epithelium in the early stages of embryo implantation; Some roles in bone growth and development and migration of inflammatory cells from the vasculature to tissues.
[11] MMP-9 release, measured using enzyme immunoassay, was significantly improved in secretions and AM supernatants obtained from untreated asthma patients compared to those obtained in other populations [Am. J. Resp. Cell & Mol. Biol., (Nov 1997) 17 (5): 583-591]. In addition, increased MMP9 expression has been observed in certain other pathological conditions, so plaque rupture in atherosclerosis in which MMP9 leads to acute coronary artery disease such as COPD, arthritis, tumor metastasis, Alzheimer's disease, multiple sclerosis, and myocardial infarction It can be seen that it is associated with such disease process.
[12] MMP-8 (collagenase-2, neutrophil collagenase) is a 53 kD enzyme from the family of metalloproteinases preferentially expressed in neutrophils. Later studies show that MMP-8 is expressed in other cells, such as osteoarthritis chondrocytes (Shlopov et al., (1997) Arthritis Rheum, 40: 2065). MMPs produced by neutrophils can cause tissue remodeling, and blocking of MMP-8 should have a positive effect in degradable diseases such as, for example, fibrotic disease and emphysema of the lung. MMP-8 has also been found to be upregulated in osteoarthritis, indicating that blocking of MMP-8 may also be beneficial for this disease.
[13] MMP-3 (stromelisin-1) is a 53 kD enzyme from the matrix metalloproteinase enzyme family. MMP-3 activity has been demonstrated in fibroblasts isolated from inflammatory gingiva [Uitto V.J. et al., (1981) J. Periodontal Res., 16: 417-424], enzyme concentrations correlate with severity of gum disease [Overall C.M. et al., (1987) J. Periodontal Res., 22: 81-88. MMP-3 is also produced by basal keratinocytes in various chronic ulcers [Saarialho-Kere U.K. et al., (1994) J. Clin. Invest., 94: 79-88. MMP-3 mRNA and protein were detected in basal keratinocytes adjacent to the wound but distal, usually representing proliferative epidermal sites. Thus, MMP-3 may interfere with the healing of the epidermis. Several researchers have shown a consistent assessment of MMP-3 in synovial fluid in patients with rheumatoid arthritis and osteoarthritis compared to controls [Walakovits L.A. et al., (1992) Arthritis Rheum., 35: 35-42; Zafarullah M. et al., (1993) J. Rheumatol., 20: 693-697. These studies have convinced that inhibitors of MMP-3 will treat diseases including destruction of extracellular matrix that causes inflammation due to lymphocytic infiltration, or loss of structural integrity necessary for organ function.
[14] Many metalloproteinase inhibitors are known (see Review of MMP inhibitors by Beckett R. P. and Whittaker M., 1998, Exp. Opin. Ther. Patents, 8 (3): 259-282). Different kinds of compounds may have different degrees of efficacy and selectivity to inhibit various metalloproteinases.
[15] Whittaker M. et al., 1999, Chemical Reviews 99 (9): 2735-2776 investigated various known MMP inhibitor compounds. They suggest that effective MPP inhibitors are zinc bond groups or ZBGs (functional groups capable of complexing active site zinc (II) ions), one or more functional groups that provide hydrogen bond interactions with the enzyme backbone, and van der Baal effective with enzyme subsites. Note that it requires one or more side chains to interact with each other. Zinc bonding groups in known MPP inhibitors include carboxylic acid groups, hydroxamic acid groups, sulfhydryl or mercapto and the like. For example, Whittaker et al. Discuss the following MMP inhibitors:
[16]
[17] The compound is in clinical development. It has a mercaptoacyl zinc bonding group, a trimethylhydantoinylethyl group and a leucineyl-tert-butylglycinyl skeleton at the P1 position.
[18]
[19] The compound has a mercaptoacyl zinc bond group and an imide group at the P1 position.
[20]
[21] The compound has been developed for the treatment of arthritis. It has a non-peptidic succinyl hydroxysamate zinc binding group and a trimethylhydantoinylethyl group at the P1 position.
[22]
[23] The compound is a phthalimido derivative that inhibits collagenase. It has a non-peptidic succinyl hydroxysamate zinc binding group and a cyclic imide group at the P1 position. Witker et al. Discuss other MMP inhibitors having P1 cyclic imido groups and various zinc bond groups (succinyl hydroxyxamate, carboxylic acid, thiol group, phosphorus containing group).
[24]
[25] The compound is known to be a good inhibitor of MMP8 and MMP9 (PCT patent applications WO9858925, WO9858915). It has a pyrimidine-2,3,4-trione zinc bonding group.
[26] The following compounds are not known as MMP inhibitors:
[27] [1968, An. Quim 64 (6): 591-606, Lora-Tamayo, M et al., Describe the synthesis of the following compounds as potential anticancer agents.
[28]
[29] Czech Patent Nos. 151744 (19731119) and 152617 (1974022) describe the synthesis and anticonvulsive activity of the following compounds.
[30]
[31] US Patent No. 3529019 (19700915) describes the following compounds for use as intermediates.
[32]
[33] PCT Patent Application WO 00/09103 describes compounds useful for treating visual impairments, including the following compounds (pages 47, compounds 81 and 83 in Table A).
[34]
[35] We have discovered a new class of compounds that are inhibitors of metalloproteinases and are particularly important for inhibiting MMPs, such as MMP-12. This compound is a metalloproteinase inhibitor with metal bonding groups not found in known metalloproteinase inhibitors. In detail, the inventors have found compounds that are potent MMP12 inhibitors and have desirable activity profiles. Compounds of the present invention have advantageous potency, selectivity and / or pharmacokinetic properties.
[36] The metalloproteinase inhibitor compounds of the present invention comprise a metal bonding group and one or more other functional groups or side chains, wherein the metal bonding groups have the following formula k.
[37]
[38] Where
[39] X is selected from NR 1, O and S;
[40] Y ₁ and Y ₂ are independently selected from O and S;
[41] R 1 is selected from H, alkyl and haloalkyl;
[42] Any of the alkyl groups described above may be straight or branched, and the optional alkyl group is preferably (C 1-7) alkyl, most preferably (C 1-6) alkyl.
[43] Metalloproteinase inhibitor compounds are compounds that inhibit the activity of a metalloproteinase enzyme (eg, MMP). By way of non-limiting example, the inhibitor compound may exhibit an in vitro IC50 in the range of 0.1-10000 nanomolar, preferably 0.1-1000 nanomolar.
[44] Metal bond groups are functional groups capable of binding metal ions within the active site of the enzyme. For example, the metal bonding group will be a zinc bonding group in the MMP inhibitor that binds to the active site zinc (II) ions. The metal bonding group of formula k is based on a five-membered ring structure, preferably a hydantoin group, most preferably -5 substituted 1-H, 3-H-imidazolidine-2,4-dione.
[45] In a first aspect of the invention, the invention provides a compound of formula (I)
[46]
[47] Where
[48] X is selected from NR 1, O and S;
[49] Y ₁ and Y ₂ are independently selected from O and S;
[50] Z is selected from SO and SO ₂ ;
[51] m is 1 or 2;
[52] A contains a direct bond, (C 1-6) alkyl, (C 1-6) haloalkyl, and a hetero group selected from N, O, S, SO, SO ₂ or selected from N, O, S, SO and SO ₂ And (C 1-6) heteroalkyl containing two hetero groups separated by two or more carbon atoms;
[53] R 1 is selected from H, (C 1-3) alkyl and haloalkyl;
[54] R2 and R3 are each H, halogen (preferably fluorine), alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkyl-heteroaryl, heteroalkyl-aryl, heteroalkyl-heteroaryl , Aryl-alkyl, aryl-heteroalkyl, heteroaryl-alkyl, heteroaryl-heteroalkyl, aryl-aryl, aryl-heteroaryl, heteroaryl-aryl, heteroaryl-heteroaryl, cycloalkyl-alkyl, heterocycloalkyl- Independently selected from alkyl, alkyl-cycloalkyl and alkyl-heterocycloalkyl;
[55] Each R 4 is independently selected from H, halogen (preferably fluorine), (C 1-3) alkyl and haloalkyl;
[56] R2 and R3 radicals are each independently alkyl, heteroalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, thiol, alkylthiol, arylthiol, alkylsulphone, haloalkylsulphone, arylsulphone, amino Sulfone, N-alkylaminosulfone, N, N-dialkylaminosulfone, arylaminosulfone, amino, N-alkylamino, N, N-dialkylamino, amido, N-alkylamido, N, N-di Alkyl amido, cyano, sulfoneamino, alkylsulfonamino, arylsulfonamino, amidino, N-aminosulfon-amidino, guanidino, N-cyano-guanidino, thioguandino, 2-nitro Optionally substituted with one or more (preferably one) groups selected from ethene-1,1-diamine, carboxy, alkyl-carboxy, nitro and carbamate;
[57] Optionally R2 and R3 may combine to form a ring containing up to seven ring atoms, or R2 and R4 may combine to form a ring containing up to seven ring atoms, or R3 and R4 may be Combine to form a ring containing up to seven ring atoms;
[58] R 5 is a monocyclic, bicyclic or tricyclic group comprising from 1 to 3 ring structures each containing up to 7 ring atoms each independently selected from cycloalkyl, aryl, heterocycloalkyl and heteroaryl; The ring structure is optionally halogen, hydroxy, alkyl, alkoxy, haloalkoxy, amino, N-alkylamino, N, N-dialkylamino, alkylsulfonamino, alkylcarboxyamino, cyano, nitro, thiol, alkylthiol, At least one substituent independently selected from alkylsulfonyl, haloalkylsulfonyl, alkylaminosulfonyl, carboxylate, alkylcarboxylate, aminocarboxy, N-alkylamino-carboxy and N, N-dialkylamino-carboxy Are independently substituted, and any alkyl radical in any substituent is itself halogen, hydroxy, alkoxy, haloalkoxy, amino, N-alkylamino, N, N-dialkylami , N-alkylsulfonamino, N-alkylcarboxyamino, cyano, nitro, thiol, alkylthiol, alkylsulfonyl, N-alkylaminosulfonyl, carboxylate, alkylcarboxy, aminocarboxy, N-alkylaminocarboxy, Optionally substituted with one or more groups selected from N, N-dialkylaminocarboxy and carbamate;
[59] When R 5 is a bicyclic or tricyclic group, each of the ring structures is a direct bond, —O—, (C 1-6) alkyl, (C 1-6) haloalkyl, (C 1-6) heteroalkyl, (C 1-6) al Is bound to or conjugated to a neighboring ring structure by kenyl, (C 1-6) alkynyl, sulfone, CO, NCO, CON, NH, S or C (OH);
[60] Said any heteroalkyl group is a hetero atom substituted alkyl containing at least one hetero group independently selected from N, O, S, SO, SO ₂ (hetero group is a hetero atom or a group of atoms);
[61] Any of the heterocycloalkyl or heteroaryl groups contains one or more hetero groups independently selected from N, O, S, SO, SO ₂ ;
[62] Any of the alkyl, alkenyl or alkynyl groups may be straight or branched chain; Unless otherwise specified, any of the above alkyl groups are preferably (C 1-7) alkyl, most preferably (C 1-6) alkyl.
[63] Preferred compounds of formula (I) are those in which one or more of the following applies.
[64] X is NR 1;
[65] Z is SO ₂ or SO, in particular Z is SO ₂ ;
[66] At least one of Y ₁ and Y ₂ is O, in particular both Y ₁ and Y ₂ are O;
[67] m is 1;
[68] R 1 is H, (C 1-3) alkyl or (C 1-3) haloalkyl, in particular R 1 is H or (C 1-3) alkyl, most preferably R 1 is H;
[69] R2 is H, alkyl, hydroxyalkyl, alkoxyalkyl, aryloxy alkyl, aminoalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, arylalkyl, alkylaryl, alkyl-heteroaryl, heteroalkyl, heterocycloalkyl-alkyl, Alkyl-heterocycloalkyl, heteroaryl-alkyl or heteroalkyl-aryl, in particular R 2 is alkyl, aminoalkyl, alkyl-heteroaryl, alkyl-heterocycloalkyl or heteroaryl-alkyl;
[70] R 3 and / or R 4 is H;
[71] R 3 and / or R 4 is methyl;
[72] R5 comprises 1 to 3 optionally substituted 5 or 6 membered rings of aryl or heteroaryl;
[73] R 5 is a bicyclic or tricyclic group comprising two or three optionally substituted ring structures.
[74] Particularly preferred compounds of formula I are those in which R 5 is a bicyclic or tricyclic group comprising two or three optionally substituted ring structures.
[75] The present invention also provides a compound of formula II.
[76]
[77] Where
[78] G1, G2 and G4 are monocyclic ring structures each containing up to 7 ring atoms each independently selected from cycloalkyl, aryl, heterocycloalkyl and heteroaryl, each ring structure being optionally halogen, hydroxy, One or two independently selected from haloalkoxy, amino, N-alkylamino, N, N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, alkylcarbamate and alkylamide Independently substituted with a substituent, any alkyl radical in any substituent is itself halogen, hydroxy, amino, N-alkylamino, N, N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy, aryl Optionally substituted with one or more groups selected from oxy, heteroaryloxy and carbamate;
[79] Z is SO ₂ ;
[80] B and F are each independently selected from a direct bond, O, (C 1-6) alkyl, (C 1-6) heteroalkyl, alkynyl, CO, NCO, CON, NH and S;
[81] R2 is H, alkyl, hydroxyalkyl, alkoxyalkyl, aryloxy alkyl, aminoalkyl, (N-alkylamino) alkyl, (N, N-dialkylamino) alkyl, amidoalkyl, thioalkyl cycloalkyl-alkyl, Alkyl-cycloalkyl, arylalkyl, alkylaryl, alkyl-heteroaryl, heteroalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, heteroaryl-alkyl and heteroalkyl-aryl;
[82] R 3 and R 4 are independently selected from H and (C 1-3) alkyl;
[83] Optionally R2 and R3 may combine to form a ring containing up to seven ring atoms, or R2 and R4 may combine to form a ring containing up to seven ring atoms, or R3 and R4 may be Combine to form a ring containing up to seven ring atoms;
[84] Said any heteroalkyl group is a heteroatom substituted alkyl containing at least one hetero group independently selected from N, 0, S, SO, SO ₂ (hetero group is a heteroatom or a group of atoms);
[85] Any of the heterocycloalkyl or heteroaryl groups contains one or more hetero groups independently selected from N, 0, S, SO, SO ₂ ;
[86] Any of the alkyl, alkenyl or alkynyl groups may be straight or branched chain; Unless otherwise specified, any of the above alkyl groups are preferably (C 1-7) alkyl, most preferably (C 1-6) alkyl.
[87] Preferred compounds of formula II include those wherein R 2 is alkyl, aminoalkyl, alkyl-heteroaryl, alkyl-heterocycloalkyl or heteroaryl-alkyl.
[88] The present invention also provides a compound of formula IIa.
[89]
[90] Where
[91] G1 and G2 are monocyclic ring structures each containing up to 7 ring atoms each independently selected from cycloalkyl, aryl, heterocycloalkyl and heteroaryl, each ring structure being optionally halogen, hydroxy, haloalkoxy With one or two substituents independently selected from amino, N-alkylamino, N, N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, alkylcarbamate and alkylamide Independently substituted, any alkyl radical in any substituent is itself halogen, hydroxy, amino, N-alkylamino, N, N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy, aryloxy, Optionally substituted with one or more groups selected from heteroaryloxy and carbamate;
[92] Z is SO ₂ ;
[93] B is selected from a direct bond, O, (C 1-6) alkyl, (C 1-6) heteroalkyl, CO, NCO, CON, NH, S and alkynyl;
[94] R 2 is from H, (C 1-6) alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (N-alkylamino) alkyl, (N, N-dialkylamino) alkyl, amidoalkyl and thioalkyl Or is selected from the group of formula III
[95]
[96] C and D are one selected from direct bonds, H, (C 1 -C 6) alkyl, (C 1 -C 6) haloalkyl, and N, O or S when two heteroatoms are present separated by two or more carbon atoms Or (C1-C6) heteroalkyl containing two hetero atoms;
[97] G3 is a monocyclic ring structure containing up to 7 ring atoms independently selected from cycloalkyl, aryl, heterocycloalkyl and heteroaryl, each ring structure is optionally halogen, hydroxy, amino, N-alkylamino , N, N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, and halogen, hydroxy, amino, N-alkylamino, N, N-dialkylamino, cyano, nitro Is substituted with one or two substituents independently selected from alkyl substituted with one or more groups selected from alkoxy and haloalkoxy;
[98] Optionally R2 is halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, aminoalkyl, N-alkylamino, N, N-dialkylamino, (N-alkylamino) alkyl, (N, N-dialkylamino Alkyl, alkylsulfone, aminosulfone, N-alkylamino-sulfone, N, N-dialkylamino-sulfone, amido, N-alkylamido, N, N-dialkylamido, cyano, sulfoneamino, With alkyl-sulfonamino, amidino, N-aminosulfon-amidino, guanidino, N-cyano-guanidino, thioguandino, 2-nitroguanidino, carboxy, alkylcarboxy or carbamate Substituted;
[99] R 3 and R 4 are independently selected from H and (C 1-3) alkyl;
[100] Optionally R2 and R3 may combine to form a ring containing up to seven ring atoms, or R2 and R4 may combine to form a ring containing up to seven ring atoms, or R3 and R4 may be Combine to form a ring containing up to seven ring atoms;
[101] Said any heteroalkyl group is a hetero atom substituted alkyl containing at least one hetero group independently selected from N, 0, S, SO, S0 ₂ (hetero group being a heteroatom or a group of atoms);
[102] Wherein said optionally heterocycloalkyl or heteroaryl group is N, 0, S, Contains at least one hetero group independently selected from SO, S02;
[103] Any of the alkyl, alkenyl or alkynyl groups may be straight or branched chain; Unless otherwise specified, any of the above alkyl groups are preferably (C 1-7) alkyl, most preferably (C 1-6) alkyl.
[104] Preferred compounds of formula (IIa) are those in which one or more of the following applies:
[105] B is selected from direct bond, O, CO, S and alkynyl, in particular B is direct bond, 0, S or alkynyl;
[106] R2 is H, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, aminoalkyl, N-alkylamino, N, N-dialkylamino, (N-alkylamino) alkyl, (N, N-dialkyl Amino) alkyl, alkylsulfone, aminosulfone, N-alkylamino-sulfone, N, N-dialkylamino-sulfone, amido, N-alkylamido, N, N-dialkylamido, carbamate, sia No, sulfonamino, alkylsulfonamino, amidino, N-aminosulfon-amidino, guanidino, N-cyano-guanidino, thioguandino, 2-nitroguanidino, 2-nitro-ethene Is selected from (C1-6) alkyl, aryl- (C1-6) alkyl and heteroaryl- (C1-6) alkyl, optionally substituted with -1,1-diamino, carboxy, alkylcarboxy or carbamate;
[107] R3 and R4 are each H;
[108] G2 is nitrogen containing a 6 membered ring;
[109] G1 is para substituted.
[110] Particularly preferred compounds of formula (IIa) are those in which R 3 and R 4 are each H.
[111] For example, particular compounds of the present invention are those wherein B is a direct bond, 0, S or alkynyl; R2 is H, cycloalkyl, heterocycloalkyl, halo, haloalkyl, hydroxy, alkoxy, aryloxy, haloalkoxy, amino, aminoalkyl, N-alkylamino, N, N-dialkylamino, (N-alkylamino ) Alkyl, (N, N-dialkylamino) alkyl, alkylsulfonyl, aminosulfonyl, N-alkylamino-sulfonyl, N, N-dialkylamino-sulfonyl, amido, N-alkylamido, N, N-dialkylamido, cyano, sulfoneamino, alkyl-sulfonamino, amidino, N-aminosulfon-amidino, guanidino, N-cyano-guanidino, thioguandino, 2 -(C1-6) alkyl, aryl (C1-6) alkyl, and heteroaryl- (C1-6) alkyl, optionally substituted with nitroguanidino, carbamate, carboxy or alkylcarboxy; R 3 and R 4 include a compound of Formula IIa each being H.
[112] Particularly preferred compounds of the present invention are those of formula IIb.
[113]
[114] Wherein G 2 is optionally substituted piperidine or piperazine, and G 1, B and R 2 are as described in Formula IIa.
[115] In the compound of formula (IIb), preferably G2 is unsubstituted and G1 is optionally substituted, preferably G1 is para substituted.
[116] Suitable for R2 include the following.
[117]
[118] Suitable for R5 include the following.
[119]
[120] Particular substituents and the number of substituents in the compounds of the present invention will be selected to avoid steric unnecessary bonds.
[121] Each compound exemplified represents a particular independent aspect of the present invention.
[122] When optically active centers are present in the compounds of the present invention, the present invention discloses, as individual specific embodiments, all individual optically active forms and mixtures thereof, and their corresponding racemates. Racemates can be prepared using known methods (see Advanced Organic Chemistry: 3rd Edition: author J March, p104-107), including the formation of diastereomeric derivatives with suitable optically active auxiliary groups followed by separation and decomposition of the auxiliary groups. Can be separated into individual optically active forms.
[123] The compounds according to the invention may contain one or more asymmetrically substituted carbon atoms. The presence of one or more such asymmetric centers (chiral centers) in the compounds of the present invention can lead to stereoisomers, in which case the invention is intended to include all stereoisomers, including enantiomers and diastereomers, and racemic mixtures thereof. It is to be understood that it extends to the mixture, including.
[124] When tautomers are present in the compounds of the present invention, the present invention discloses all individual tautomeric forms and mixtures thereof as individual specific embodiments.
[125] As already outlined, the compounds of the invention are metalloproteinase inhibitors, in particular inhibitors of MMP12. Each of the above descriptions of a compound of the present invention represents an independent particular embodiment of the present invention.
[126] Certain compounds of the invention have particular use as inhibitors of MMP13 and / or MMP9 and / or MMP8 and / or MMP3.
[127] Compounds of the present invention exhibit a preferred selectivity profile. Without wishing to be bound by any particular theory, it is believed that the compounds of the present invention exhibit selective inhibition of any of the above for any MMP1 inhibitory activity, and by way of non-limiting example they are 100 compared to any MMP1 inhibitory activity. It can represent -1000 times selectivity.
[128] The compounds of the present invention may be provided as pharmaceutically acceptable salts. These include acid addition salts such as hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric acid and sulfuric acid. In another aspect, suitable salts are alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, or organic amine salts such as triethylamine.
[129] They may also be provided as in vivo hydrolyzable esters. These are pharmaceutically acceptable esters that hydrolyze in the human body to produce the parent compound. Such esters can be identified, for example, by intravenously administering a test compound to a test animal followed by examining the body fluids of the test animal. Suitable in vivo hydrolyzable esters for carboxy include methoxymethyl and for hydroxy include formyl and acetyl, especially acetyl.
[130] Metalloproteinase inhibitor compounds of the invention (compounds of Formula I, II, IIa or IIb) or pharmaceutically acceptable salts thereof or in vivo hydrolysable for therapeutic treatment (including prophylactic treatment) of mammals, including humans To use an ester, it is generally formulated as a pharmaceutical composition according to standard pharmaceutical guidelines.
[131] Therefore, in another aspect the invention provides a pharmaceutical composition comprising a compound of the invention (compound of Formula I, II, IIa or IIb) or a pharmaceutically acceptable salt or in vivo hydrolysable ester and a pharmaceutically acceptable carrier thereof. to provide.
[132] Pharmaceutical compositions of the invention may be administered by standard methods for the disease or condition to be treated, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation. To this end, the compounds of the invention can be prepared by means known in the art, for example tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, fine powders or inhalable aerosols. And, in the form of sterile aqueous or oily solutions or suspensions or sterile emulsions for parenteral use (including intravenous, intramuscular or infusion).
[133] The pharmaceutical compositions of the present invention may contain or co-administer (simultaneously or sequentially) in addition to the compounds of the present invention and also useful for treating one or more of the diseases or conditions mentioned above.
[134] Pharmaceutical compositions of the invention will generally be administered to humans such that the daily dose is between 0.5 and 75 mg / kg body weight (preferably between 0.5 and 30 mg / kg body weight). Such daily doses may be administered in divided doses as needed and the exact amount and route of administration of the compound administered will depend on the weight, age and sex of the patient to be treated and the particular disease or condition to be treated according to principles known in the art. do.
[135] Unit dosage forms will typically contain about 1 mg to 500 mg of a compound of the present invention.
[136] Therefore, in another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof for use in or as a therapeutic method for human or animal therapeutic treatment. The present invention discloses use in the treatment of diseases or conditions mediated by one or more metalloproteinase enzymes. Specifically, the present invention relates to the use in the treatment of a disease or condition mediated by MMP12 and / or MMP13 and / or MMP9 and / or MMP8 and / or MMP3, in particular a disease or mediated by MMP12 or MMP9. Use in the treatment of conditions, most preferably in the treatment of diseases or conditions mediated by MMP12.
[137] In particular, the invention relates to diseases mediated by (eg, MMP12 and / or MMP13 and / or MMP9 and / or MMP8 and / or MMP3) for use in or as therapeutic agents for therapeutic treatment in humans or animals. Or for use in treating a condition, especially for treating a disease or condition mediated by MMP12 or MMP9, most preferably for use in treating a disease or condition mediated by MMP12). Or its pharmaceutically acceptable Salts or in vivo hydrolysable esters are provided.
[138] In another aspect, the present invention provides a method of treating a metalloproteinase mediated disease or condition comprising administering to a warm blooded animal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. To provide. The inventors also find the use of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolyzable precursor thereof in the manufacture of a medicament for use in the treatment of a disease or condition mediated by one or more metalloproteinase enzymes. It starts.
[139] For example, we provide metalloproteinase mediated diseases comprising administering to a warm blooded animal a therapeutically effective amount of a compound of Formula (II), (IIa) or (IIb) (or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof). Or a method of treating the condition. In addition, the inventors have also provided compounds of Formula II, IIa or IIb (or pharmaceutically acceptable salts or in vivo singers thereof) in the manufacture of a medicament for use in the treatment of a disease or condition mediated by one or more metalloproteinase enzymes. Degradable precursors).
[140] Metalloproteinase mediated diseases or conditions include asthma, rhinitis, chronic obstructive pulmonary disease (COPD), arthritis (eg, rheumatoid arthritis and osteoarthritis), atherosclerosis and restenosis, cancer, infiltration and metastasis, tissue Diseases related to destruction, dissociation of hip replacement surgery, periodontal disease, fibrotic disease, infarction and heart disease, liver and kidney fibrosis, endometriosis, diseases associated with weakening of the extracellular matrix, heart failure, aortic aneurysms, Alzheimer's disease and multiple sclerosis ( CNS related diseases, such as MS), hematologic abnormalities.
[141] Preparation of Compounds of the Invention
[142] In another aspect, the present invention provides a process for preparing a compound of formula (I), (II), (IIa) or (IIb) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as described below in (a) to (d). . Many related starting materials are commercially available or otherwise available or can be synthesized by known methods or can be found in the scientific literature.
[143] (a) reacting a compound of formula IV, wherein R5 is as defined in formula I, with a known compound of formula V, wherein X and m are as defined in formula I, wherein Y ₁ and Y ₂ are each O, Z is SO ₂ , R ₂ is as defined in formula I, A is a direct bond, R 5 comprises a nitrogen directly bonded to Z, or A is (C 1-6 ) N-alkyl).
[144]
[145]
[146] Preferably, this reaction is carried out in a suitable solvent for 1 to 24 hours at ambient temperature to reflux, optionally in the presence of a base. Preferably, a solvent, for example pyridine, dimethylformamide, tetrahydrofuran, acetonitrile or dichloro, for a reaction time of 2 to 16 hours at ambient temperature or until completion of the reaction by chromatography or spectroscopic methods is confirmed. Methane is used with a base such as triethylamine, N-methylmorpholine, pyridine or alkali metal carbonate. The reaction of various primary and secondary amines with sulfonyl chlorides of formula V is described in the prior literature, and changes in conditions will be apparent to those skilled in the art.
[147] The synthesis of compounds of formula V is described in the literature and can be prepared, for example, from cysteine or homocysteine (see Mosher, J .: J. Org. Chem. 23, 1257 (1958)). Is an oxidative chlorination reaction of a compound of formula Va, wherein R 2 is as described in formula I, wherein sulfonylchloride of formula V, wherein m is 1, X is NR 1 (R 1 = H), and R 2 is described in formula I Can be conveniently prepared (see Griffith, O .: J. Biol. Chem., 1983, 258, 3, 1591).
[148]
[149] (b) a compound of formula VI, wherein K is a leaving group (e.g., chloride or sulfonate ester) and R5 is as described in formula I, wherein a compound of formula VII, wherein G is sulfhydryl (SH ) And X and m are as described in formula (I) to yield compounds of formula (I), wherein Y ₁ and Y ₂ are each O, Z is S, and X and R 5 are as described in formula (I). Can be prepared. Preferably, this reaction is carried out in the presence of a base such as diethyl isopropyl amine or cesium carbonate and a suitable solvent such as DMF.
[150]
[151]
[152] In addition, compounds of formulas VI and VII, wherein K in compound VI are sulfhydryl or hydroxy groups and G in formula VII represent leaving groups, are reacted to react the compounds under method (b) in the same manner as in method (b) It can manufacture.
[153] (c) When Z is S, the final product described in process (b) is oxidized using a peroxide reagent, preferably an oxidizing agent such as m-chloroperbenzoic acid or oxone, wherein the compounds of formula I (where Y ₁ and Y ₂ is each O, Z is SO ₂ or S (O), and X, A and R 5 are as described in formula (I).
[154] (d) in a sealed container for 4 to 24 hours at 40 to 80 ° C., preferably in the presence of excess ammonium carbonate and potassium cyanide in ethanol, compounds of formula (XI) wherein R 2, R 3, R 4, R 5 and A Reacted with ammonium and cyanide salts in a protic solvent, where Y ₁ and Y ₂ are each O, X is NR 1 (R 1 = H) and m is 1 , R2, R3, R4 and R5 are as described in formula (I).
[155]
[156] In an aprotic solvent, the sulfonamide of formula XII, wherein R3 is H and R5 is as described in formula I, is treated with an excess of strong base, followed by the ester of formula XIII, wherein R is an alkyl or aryl moiety R 2 is as described in Formula I) to conveniently prepare ketones of Formula XI. Preferred conditions are 2 to 3 equivalents of a lithium base, such as lithium diisopropylamide, lithium hexamethyldisilazane or butyl lithium in a dry ether type solvent such as tetrahydrofuran.
[157]
[158]
[159] Furthermore, sulfinates of formula XIV, wherein R 5 is aryl or heteroaryl as described in formula I, are treated with a base such as tetrabutylammonium bromide and a ketone of formula XV, wherein R 2 is alkyl or aryl, Ketones of formula XI can be prepared (where R 3 and R 4 are each alkyl or form a ring, R 5 is aryl or heteroaryl, and R 2 is alkyl or aryl) (Crandall et al. J. Org. Chem. 1985, (8) 50, 1327-1329). Thereafter, R3 and R4 are introduced by reaction with an alkyl halide or alkyl dihalide. Preferably, this reaction is carried out at 50 to 100 ° C. in the presence of a base such as potassium carbonate or cesium carbonate and in the presence of a suitable solvent, for example DMF or DMSO.
[160]
[161]
[162] Compounds of the invention can be assessed, for example, by the following assays:
[163] Separation Enzyme Analysis
[164] For example, matrix metalloproteinase families including MMP12, MMP13
[165] Recombinant human MMP12 catalytic domains can be expressed and purified as described in Parkar AA et al., (2000), Protein Expression and Purification, 20: 152. Purified enzymes can be used to monitor the activity of inhibitors as follows: MMP12 (50 ng / ml final concentration) was added to the synthetic substrate in the presence or absence of the inhibitor Mac-Pro-Cha-Gly-Nva-His-Ala-Dpa Incubate for 30 minutes at RT in assay buffer (0.1M Tris-HCl, pH 7.3 containing 0.1M NaCl, 20mM CaCl ₂ , 0.040 mM ZnCl and 0.05% (w / v) Brij 35) using -NH ₂ . Activity is determined by measuring fluorescence at λex 328 nm and λem 393 nm. The inhibition rate is calculated as follows:% inhibition is [fluorescence _{plus inhibitor} -fluorescence _background ] divided by [fluorescence _{minus inhibitor} -fluorescence _background ].
[166] The synthetic human proMMP13 is described in V. Knauper et al., (1996) The Biochemical Journal 271: 1544-1550 (1996). Purified enzymes can be used to monitor the activity of inhibitors as follows: Purified proMMP13 is activated using 1 mM amino phenyl mercuric acid (APMA) at 21 ° C. for 20 hours; Activated MMP13 (11.25 ng per assay) was added to the synthetic substrate 7-methoxycoumarin-4-yl-acetyl.Pro.Leu.Gly.Leu.N-3- (2,4-dinitrophenyl) in the presence or absence of an inhibitor. ) -L-2,3-diaminopropynyl. 0.1 containing Ala.Arg.NH ₂ as assay buffer (0.1 M NaCl, 20 mM CaCl ₂ , 0.02 mM ZnCl and 0.05% (w / v) Brij 35) Incubate at 35 ° C. for 4-5 hours in M Tris-HCl, pH 7.5). Activity is determined by measuring fluorescence at λex 328 nm and λem 393 nm. The inhibition rate is calculated as follows:% inhibition is [fluorescence _{plus inhibitor} -fluorescence _background ] divided by [fluorescence _{minus inhibitor} -fluorescence _background ].
[167] For example, as described in C. Graham Knight et al., (1992) FEBS Lett. 296 (3): 263-266), other expressed and purified using substrate and buffer conditions that are optimal for a particular MMP. Similar protocols can be used for proMMP.
[168] For example, the adamalicin family including TNF convertases
[169] The ability of a compound to inhibit proTNFα convertase enzyme can be assessed using partially purified and isolated enzyme assays, which are described in KM Mohler et al., (1994) Nature 370: 218-220. As obtained from the membrane of THP-1. Purified enzyme activity and its inhibition is determined by the presence or absence of the substrate 4 ', 5'-dimethoxy-fluoresinylSer.Pro.Leu.Ala.Gln.Ala.Val.Arg.Ser.Ser.Ser Analysis buffer (0.1% (w / v) Triton X-100 and 2 mM CaCl ₂ ) using Arg.Cys (4- (3-succinimid-1-yl) -fluorescein) -NH ₂ Confirmation is by incubation of partially purified enzyme in 26 mM Tris HCl, pH 7.4 for 18 hours at 26 ° C. The amount of inhibition is determined as for MMP13, except that [lambda] ex 490 nm and [lambda] em 530 nm are used. Substrates were synthesized as follows. The peptide moiety of the substrate is the coupling agent of Fmoc-amino acid and O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU) of Fmoc-amino acid and HBTU. The Fmoc-NH-Rink-MBHA-polystyrene resin was conjugated either manually or on an automated peptide synthesizer by standard methods including using at least 4- or 5-fold excess. Ser ¹ and Pro ² were double-coupled. The following side chain protection methods were used: Ser ¹ (But), Gln ⁵ (trityl), Arg ^8,12 (Pmc or Pbf), Ser ^9,10,11 (trityl), Cys ¹³ (trityl). After conjugation, the N-terminal Fmoc-protecting group was removed by treating the Fmoc-peptidyl-resin in DMF. The amino-peptidyl-resin so obtained was obtained 1.5-2 equivalents of 4 ', 5'-dimethoxy-fluorescein-4 (5) -carboxylic acid at 70 ° C. for 1.5-2 hours [diisopropylcarbine in DMF Pre-activated with bodyimide and 1-hydroxybenzotriazole (Khanna & Ullman, (1980) Anal Biochem. 108: 156-161). Thereafter, the dimethoxyfluoresinyl-peptide was treated with trifluoroacetic acid containing 5% each of water and triethylsilane to simultaneously deprotect and decompose from the resin. Dimethoxyfluoresinyl-peptide was isolated by evaporation, softening with diethyl ether and filtration. The isolated peptide was reacted with 4- (N-maleimido) -fluorescein in DMF containing diisopropylethylamine, and the product was purified by RP-HPLC and finally freeze dried from aqueous acetic acid solution. The product was characterized by MALDI-TOF MS and amino acid analysis.
[170] Natural substrate
[171] The activity of the compounds of the invention as inhibitors of aggrecan degradation is described, for example, in EC Arner et al., (1998) Osteoarthritis and Cartilage 6: 214-228; (1999) Journal of Biological Chemistry, 274 (10), 6594-6601) and methods based on the disclosure and the antibodies described therein. The efficacy of compounds acting as inhibitors to collagenase can be identified as described in T. Cawston and A. Barrett. (1979) Anal. Biochem. 99: 340-345.
[172] Inhibition of metalloproteinase activity in cell / tissue activity
[173] Tested as a medicament that inhibits membrane shadase, such as TNF convertase
[174] The ability of the compounds of the present invention to inhibit cell processing of TNFα production is essentially achieved by using ELISA to detect released TNF as described in KM Mohler et al., (1994 Nature 370: 218-220). Can be evaluated in THP-1 cells. In a similar manner, processing or shedding of other membrane molecules, such as those described in NM Hooper et al., (1997) Biochem. J. 321: 265-279, can be used to identify appropriate cell lines and appropriate antibodies for detecting shed proteins. Can be tested using.
[175] Tested as a drug that inhibits cell invasion
[176] The ability of compounds of the present invention to inhibit cell migration in invasion assays can be identified as described in A. Albini et al., (1987) Cancer Research 47: 3239-3245.
[177] Tested as a drug that inhibits whole blood TNF shedase activity
[178] The ability of the compounds of the invention to inhibit TNFα production is assessed by human whole blood assays that simulate the release of TNFα using LPS. Heparinized (10 units / ml) human blood obtained from volunteers were diluted 1: 5 in medium (RPMI1640 + bicarbonate, penicillin, streptomycin and glutamine) and 20 μL of LPS (E. coli 0111: B4; final concentration 10 Incubate with 20 μl of test compound in DMSO or appropriate vehicle for 30 min at 37 ° C. in a humidified (5% CO ₂ /95% air) incubator before addition of μg / ml). Each assay includes a control of diluted blood incubated with a known TNFα inhibitor or media alone (6 wells / plate) as reference material. The plates were then incubated for 6 hours at 37 ° C. (humidified incubator), centrifuged (2000 rpm for 10 minutes; 4 ° C.), plasma collected (50-100 μl) and stored in 96 well plates at −70 ° C. TNFα concentrations are then analyzed by ELISA.
[179] Tested as a drug that inhibits cartilage degradation in vitro
[180] The ability of the compounds of the invention to inhibit degradation of the aggrecan or collagen component of cartilage can be assessed essentially as described in KM Bottomley et al., (1997) Biochem J. 323: 483-488. .
[181] Pharmacodynamic test
[182] In order to assess the purification properties and bioavailability of the compounds of the present invention, in vitro pharmacodynamic tests using HPLC or mass spectroscopy as described above, or alternatively, are used. This is a common test that can be used to assess the purification rate of a compound for various species. Animals (eg, rats, marmoset monkeys) are administered intravenously (iv) or orally (po) with soluble preparations of the compounds (eg, 20% w / v DMSO, 60% w / v PEG400), At subsequent time points (eg, 5, 15, 30, 60, 120, 240, 480, 720, 1220 minutes), blood samples are taken from the appropriate vessels and placed in 10U heparin. After centrifugation plasma fractions are obtained and plasma proteins are precipitated with acetonitrile (80% w / v final concentration). After 30 minutes at −20 ° C., the plasma protein is precipitated by centrifugation and the supernatant fractions are evaporated to dryness using a rapid vacuum. The precipitate is reconstituted in assay buffer and then analyzed for compound content using synthetic substrate analysis. In short, a compound concentration-response curve is drawn for the compound being evaluated. Serial dilutions of the reconstituted plasma extracts are evaluated for activity and the amount of compound present in the original plasma sample is calculated using the concentration-response curve taking into account the total plasma dilution factor.
[183] In vivo evaluation
[184] Tested as an anti-TNF drug
[185] The ability of the compounds of the invention as ex vivo TNFα inhibitors is evaluated in rats. In short, a route suitable for male Wistar Alderley Park (AP) rat groups (180-210 g), such as the oral (po), intraperitoneal (ip) and subcutaneous (sc) routes, Compound (6 rats) or drug vehicle (10 rats). After 90 minutes, the rats are sacrificed using a rinse concentration of CO ₂ and blood is drawn through the posterior vena cava into 5 units / ml of sodium heparin. Blood samples are immediately placed on ice, centrifuged at 2000 rpm for 10 minutes at 4 ° C., and frozen plasma is collected at −20 ° C. for subsequent analysis of their effect on TNFα production by LPS-stimulated human blood. Rat plasma samples are thawed and 175 μL of each sample is added to a set format pattern in a 96U well plate. 50 μl of heparinized human blood is added to each well, mixed and the plates are incubated at 37 ° C. for 30 minutes (humidity incubator). LPS (25 μl; final concentration 10 μg / ml) is added to the wells and the incubation is continued for an additional 5.5 hours. Control wells are incubated with 25 μl of single medium. The plates are then centrifuged at 2000 rpm for 10 minutes and 200 μl of the supernatant is transferred to 96 well plates and frozen at −20 ° C. and then analyzed for TNF concentration by ELISA.
[186] Data analysis by dedicated software is calculated for each compound / dose:
[187]
[188] Tested as a treatment for arthritis
[189] The activity of compounds as arthritis therapeutics is tested in collagen-induced arthritis (CIA) as defined by D.E. Trentham et al., (1977) J. Exp. Med. 146: 857. In this model, acid soluble native type II collagen causes multiple arthritis in rats when administered with Freund's incomplete adjuvant. Similar conditions can be used to induce arthritis in mice and primates.
[190] Test as an anticancer agent
[191] The activity of the compound as an anticancer agent is essentially described using, for example, the B16 cell line (B. Hibner et al., Abstract 283 p75 10th NCI-EORTC Symposium, Amsterdam June 16-19 1998) (IJ Fidler (1978) Methods in Cancer Research 15: 399-439).
[192] Test as emphysema treatment
[193] The activity of the compound as an emphysema treatment can be assessed essentially as described in Hautamaki et al (1997) Science, 277: 2002.
[194] The invention is illustrated by, but not limited to, the following examples.
[195] General Analytical Methods: ¹ H-NMR spectra were measured with a Varian ^Unity Inova 400 MHz or Varian Mercury-VX 30OMHz instrument. Central solvent peaks of chloroform- d (δ _H 7.27 ppm), dimethylsulfoxide- d ₆ (δ _H 2.50 ppm) or methanol- d ₄ (δ _H 3.31 ppm) were used as internal reference. Low resolution mass spectra were obtained on an Agilent 1100 LC-MS system equipped with an APCI ionization chamber.
[196] <Example 1>
[197] 5- (2-{[4- (4'-fluoro [1,1'-biphenyl] -4-yl) -1-piperazinyl] sulfonyl} ethyl) -2,4-imidazolidine Dion
[198]
[199] To a solution of 1- (4-fluorophenyl) -phenylpiperazine (0.125 mg, 0.48 mmol) in 5 ml of dichloromethane, triethylamine (0.06 ml, 0.5 mmol) and 2- (2,5-dioxo-4 Imidazolidinyl) -1-ethanesulfonyl chloride (0.113 ml, 0.48 mol) was added. The mixture was stirred for 18 h, diluted to 25 ml with DMC, extracted with 1N HCl (5 ml) saturated NaHCO ₃ (5 ml), dried, evaporated and crystallized (EtOH-dioxane).
[200]
[201] Starting materials were prepared as follows:
[202] 2- (2,5-dioxo-4-imidazolidinyl) -1-ethanesulfonyl chloride
[203] 5- (2-{[2- (2,5-dioxo-) in a mixture of 25 ml of vigorously stirred AcOH and 2 ml of water in a three-necked flask with a gas inlet tube, thermometer and a short reflux condenser placed in an ice bath. A suspension of 4-imidazolidinyl) ethyl] disulfanyl} ethyl) -2,4-imidazolidinedione (6.9 mol) was bubbled with chlorine gas for 15 minutes at a maximum temperature of + 5 ° C (all precipitates Until dissolved). The suspension is then stirred for at least 15 minutes, evaporated to small volume in vacuo (maximum temperature 30 ° C.), dissolved in 50 ml of dichloromethane and carefully shaken with saturated NaHCO ₃ (about 25 ml) before 10% sodium thiosulfate Shake with fat, dry, evaporate and crystallize from THF-hexane (Lora-Tamayo, M. et al, 1968, An. Quim., 64 (6): 591-606).
[204]
[205] 5- (2-{[2- (2,5-dioxo-4-imidazolidinyl) ethyl] disulfanyl} ethyl) -2,4-imidazolidinedione
[206] Commercially available RS homocystine (0.18 ml) was suspended in 25 ml of water, 1.5 g (0.2 mol) of potassium cyanate were added and the mixture was stirred at 100 ° C. for 45 minutes. The mixture was then partially cooled and 10 ml of 10% HCl was added in one portion and the mixture was stirred again at 100 ° C. for 50 minutes. It was placed in the refrigerator overnight and the crystals were filtered off, washed with water and dried under vacuum.
[207]
[208] The generalized general scheme is shown below:
[209]
[210] <Example 2>
[211] (5R) -5-{[(4-phenyl-1-piperazinyl) sulfonyl] methyl} -2,4-imidazolidinedione
[212] The title compound was prepared according to the scheme shown in Example 1. To a solution of R- (2,5-dioxo-4-imidazolidinyl) methanesulfonyl chloride (100 mg, 0.47 mmol) in 2.5 ml of THF, 1-phenylpiperazine (85 mg, 0.52 mmol in 2.5 ml of THF) ) And 65 μl of triethylamine (0.52 mmol) were added at once via syringe. The mixture was stirred for 3 hours and the precipitated triethylammonium chloride was filtered off, washed with two small portions of THF, evaporated and recrystallized from EtOH and a small amount of AcOH.
[213]
[214] Starting materials were prepared as follows:
[215] R- (2,5-dioxo-4-imidazolidinyl) methanesulfonyl chloride
[216] R-5-({[(2,5-dioxo-4-) in a mixture of 25 ml of vigorously stirred AcOH and 2 ml of water in a three-necked flask with a gas inlet tube, thermometer and a short reflux condenser placed in an ice bath. In a suspension of imidazolidinyl) methyl] disulfanyl} methyl) -2,4-imidazolidinedione (6.9 mol), chlorine gas was bubbled at a maximum temperature of + 5 ° C. for 15 minutes (all precipitates would be dissolved). until). The suspension is then stirred for at least 15 minutes, evaporated to small volume in vacuo (maximum temperature 30 ° C.), dissolved in 50 ml of dichloromethane and carefully shaken with saturated NaHCO ₃ (about 25 ml) before 10% sodium thiosulfate Shake with fat, dry, evaporate and crystallize from THF-hexane (Lora-Tamayo, M. et al, 1968, An. Quim., 64 (6): 591-606).
[217]
[218] R-5-({[((2,5-dioxo-4-imidazolidinyl) methyl] disulfanyl} methyl) -2,4-imidazolidinedione
[219] Commercially available R cystine (0.18 ml) was suspended in 25 ml of water, 1.5 g (0.2 mol) of potassium cyanate were added and the mixture was stirred at 100 ° C. for 45 minutes. The mixture was then partially cooled and 10 ml of 10% HCl was added in one portion and the mixture was stirred again at 100 ° C. for 50 minutes. It was placed in the refrigerator overnight and the crystals were filtered off, washed with water and dried under vacuum.
[220]
[221] <Example 3>
[222] (5S) -5-{[(4-phenyl-1-piperazinyl) sulfonyl] methyl} -2,4-imidazolidinedione
[223] The title compound was prepared according to the scheme shown in Example 1. To a solution of S- (2,5-dioxo-4-imidazolidinyl) methanesulfonyl chloride (100 mg, 0.47 mmol) in 2.5 ml of THF, 1-phenylpiperazine (85 mg, 0.52 mmol in 2.5 ml of THF) ) And 65 μl of triethylamine (0.52 mmol) were added at once via syringe. The mixture was stirred for 3 hours and the precipitated triethylammonium chloride was filtered off, washed with two small portions of THF, evaporated and recrystallized from EtOH and a small amount of AcOH.
[224]
[225] Starting materials were prepared as follows:
[226] S- (2,5-dioxo-4-imidazolidinyl) methanesulfonyl chloride
[227] S-5-({[(2,5-dioxo-4- in a mixture of 25 ml of AcOH and 2 ml of water, stirred vigorously in a three-necked flask with a gas inlet tube, thermometer and a short reflux condenser placed in an ice bath. In a suspension of imidazolidinyl) methyl] disulfanyl} methyl) -2,4-imidazolidinedione (6.9 mol), chlorine gas was bubbled at a maximum temperature of + 5 ° C. for 15 minutes (all precipitates were dissolved). until). The suspension is then stirred for at least 15 minutes, evaporated to small volume in vacuo (maximum temperature 30 ° C.), dissolved in 50 ml of dichloromethane and carefully shaken with saturated NaHCO ₃ (about 25 ml) before 10% sodium thiosulfate Shake with fat, dry, evaporate and crystallize from THF-hexane (Lora-Tamayo, M. et al, 1968, An. Quim., 64 (6): 591-606).
[228]
[229] S-5-({[(2,5-dioxo-4-imidazolidinyl) methyl] disulfanyl} methyl) -2,4-imidazolidinedione
[230] Commercially available S cystine (0.18 ml) was suspended in 25 ml of water, 1.5 g (0.2 mol) of potassium cyanate were added and the mixture was stirred at 100 ° C. for 45 minutes. The mixture was then partially cooled and 10 ml of 10% HCl was added in one portion and the mixture was stirred again at 100 ° C. for 50 minutes. It was placed in the refrigerator overnight and the crystals were filtered off, washed with water and dried under vacuum.
[231]
[232] <Example 4>
[233] (R) -5-(([4- (4'-fluoro [1,1'-biphenyl] -4-yl) -1-piperazinyl] sulfonyl) methyl) -2,4-imida Zolidinedione
[234]
[235] [(R) -2,5-dioxoimidazolidinyl] methanesulfonyl chloride (0.0127 g, 0.060 mmol), 1- (4'-fluoro [1,1'-biphenyl] -4-yl) Piperazine (0.0154 g, 0.060 mmol), triethylamine (0.0084 ml, 0.060 mmol) and anhydrous tetrahydrofuran (0.70 ml) were stirred overnight at room temperature. Polystyrene methylisocyanate (0.025 g, 0.030 mmol) was added and the mixture was shaken overnight. The white suspension was carefully transferred to a round bottom flask, the resin washed with tetrahydrofuran (2 × 1 ml) and the wash was transferred to the bulk of the suspension. The solvent is evaporated and the white solid suspended in water (5 ml), collected on a filter, washed with water (2 × 1 ml), aspirated off water and dried overnight in vacuo at 45 ° C. to give the title compound Approximately 0.010 g were obtained.
[236]
[237] Starting materials were prepared as follows:
[238] [(R) -2,5-dioxoimidazolidinyl] methanesulfonyl chloride was prepared according to Mosher et al, 1958, J. Org. Chem 23: 1257.
[239] 1- (4'-fluoro [1,1'-biphenyl] -4-yl) piperazine
[240] 4-bromo-4'-fluorobiphenyl (4.46 g, 17.8 mmol), N-tert-butoxycarbonyl piperazine (3.97 g, 21.3 mmol), sodium tert-butoxide (2.39 g, 24.9 mmol), Racemic 2,2'-bis (diphenylphosphino) -1,1'-binafyl (rac-BINAP) (0.082 g, 0.131 mmol), bis- (dibenzylideneacetone) palladium (0) (0.041 g, 0.045 mmol) and anhydrous toluene (45 ml) were stirred at 80 ° C. for 6 hours under a nitrogen atmosphere. The warm mixture was filtered, the solid was washed twice with warm toluene and the filtrate was concentrated in vacuo to give an orange-red crude product which was stirred with ether (50 ml) for 2 hours. The solid was filtered off, washed with a small volume of ether and dried overnight under vacuum at 45 ° C. to tert-butyl 4- (4'-fluoro [1,1'-biphenyl] -4-yl) -1- 5.57 g (88% yield) of piperazinecarboxylate were obtained. This product (5.52 g, 15.5 mmol) was dissolved in dioxane (150 ml) and stirred with 4M hydrochloric acid (8.1 ml) overnight at room temperature. Concentrated hydrochloric acid (3.0 ml) was added and stirring was continued for 1.5 h at 45 ° C. and 1 h at 60 ° C. The solution was concentrated to dryness and the solids treated with ether (100 ml), filtered, washed with small volume of ether and dried under vacuum at 45 ° C. for 2 hours to give 1- (4′-fluoro [1,1 5.26 g (yield 103%) of '-biphenyl] -4-yl) piperazine dihydrochloride were obtained as a pale yellow salt.
[241]
[242] The salt was treated with aqueous sodium hydroxide solution and the base was dissolved in dichloro-methane. The organic phase was dried over Na ₂ S0 ₄ , filtered and concentrated to give the title compound as off white solid.
[243]
[244] Example 5
[245] Using a procedure analogous to that described in Example 4, [(4R) -2,5-dioxoimidazolidinyl] methanesulfonyl chloride is reacted with an appropriate primary or secondary amine to give the compounds listed below. It was. All amines used are commercially available.
[246]
[247] The table below provides amine groups for each compound of the above formula.
[248]
[249] <Example 6>
[250] (S) -5-(([4- (4'-fluoro [1,1'-biphenyl] -4-yl) -1-piperazinyl] sulfonyl) methyl) -2,4-imida Zolidinedione
[251]
[252] [(S) -2,5-dioxoimidazolidinyl] methanesulfonyl chloride (0.0127 g, 0.060 mmol), 1- (4'-fluoro [1,1'-biphenyl] -4-yl) Piperazine (0.0154 g, 0.060 mmol), triethylamine (0.0084 ml, 0.060 mmol) and anhydrous tetrahydrofuran (0.70 ml) were stirred overnight at room temperature. Polystyrene methylisocyanate (0.025 g, 0.030 mmol) was added and the mixture was shaken overnight. The white suspension was carefully transferred to a round bottom flask, the resin washed with tetrahydrofuran (2 × 1 ml) and the wash was transferred to the bulk of the suspension. The solvent is evaporated and the white solid suspended in water (5 ml), collected on a filter, washed with water (2 × 1 ml), aspirated off water and dried overnight in vacuo at 45 ° C. to give the title compound Approximately 0.010 g were obtained.
[253]
[254] Starting materials were prepared as follows:
[255] [(S) -2,5-dioxoimidazolidinyl] methanesulfonyl chloride was prepared according to Mosher et al, 1958, J. Org. Chem 23: 1257.
[256] 1- (4'-fluoro [1,1'-biphenyl] -4-yl) piperazine was prepared according to Example 4.
[257] <Example 7>
[258] Using a procedure similar to the procedure described in Example 6, [(4S) -2,5-dioxoimidazolidinyl] methanesulfonyl chloride is reacted with an appropriate primary or secondary amine to give the compounds listed below. It was. All amines used are commercially available.
[259]
[260] The table below provides amine groups for each compound of the above formula.
[261]
[262] <Example 8>
[263] Hydantoin (wherein E is a carbon or heteroatom) having the following structural formula was synthesized.
[264]
[265] Representative Synthetic Routes:
[266] (5R, S) -5- [4- (4-Fluoro-phenyl) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[267]
[268] Sulfonyl-amide intermediates
[269]
[270] 4- (4-Fluoro-phenyl) -1-methanesulfonyl-piperidine
[271] 4- (4-fluoro-phenyl) piperidine hydrochloride (2.16 g, 10 mmol) and diisopropylethylamine (4.35 ml, 25 mmol) are dissolved in DCM (60 ml) and ice / water under nitrogen Cool in ancestors. Methanesulfonyl chloride (1.56 ml, 10.1 mmol) was dissolved in DCM (5 ml) and added dropwise for 2 minutes. The reaction mixture was stirred for 2.5 h in an ice / water bath. The reaction mixture was washed with dilute HCl (aq), pH = 2, H ₂ O and 1M Na ₂ CO ₃ . The organic phase was dried (Na ₂ SO ₄ ), filtered and evaporated to afford crude product which was recrystallized from THF / n-heptane. Colorless crystals were removed by filtration and dried under vacuum at 45 ° C.
[272] 1.96 g (76% yield) of the title compound obtained
[273]
[274] 5-Chloro-2- (1-methanesulfonyl-piperidin-4-yloxy) -pyridine
[275] The title compound was prepared as described in the synthesis of 4- (4-fluoro-phenyl) -1-methanesulfonyl-piperidine.
[276] 5-chloro-2- (piperidin-4-yloxy) -pyridine (2.13 g, 10 mmol) (preparation of this compound is carried out as described in WO 99-GB2801), diisopropylethylamine (2.20 ml , 12.5 mmol) and methanesulfonyl chloride (1.56 ml, 10.1 mmol) gave 2.14 g (74%) of the title compound.
[277]
[278] 1- (methylsulfonyl) -4- [5- (trifluoromethyl) pyridin-2-yl] piperazine
[279] 1- [5- (trifluoromethyl) -pyridin-2-yl] -piperazine (1.0 g, 4.3 mmol) and diisopropylethylamine (0.9 ml, 5.4 mmol) were dissolved in DCM (10 ml). . Molecular sieve 4A was added and the solution cooled in an ice / water bath. Methanesulfonylchloride (0.9 ml, 12 mmol) was added and the resulting slurry was stirred for 15 minutes, the reaction mixture was allowed to reach room temperature and after 1 hour the reaction was quenched by addition of 5% KHCO ₃ . Solvent was evaporated and the residue was dissolved between DCM and 5% KHCO ₃ . Separate and extract the aqueous phase with DCM (1 ×). The combined organic phases were dried (MgSO ₄ ), filtered and evaporated to afford the crude product as a slightly yellow solid.
[280] Recrystallization (3 ×) from EtOAc / heptane gave the title compound as colorless crystals.
[281] 1.06 g (79% yield) of the title compound obtained
[282]
[283] The following compounds were prepared as described in the synthesis of 1- (methylsulfonyl) -4- [5- (trifluoromethyl) pyridin-2-yl] piperazine.
[284] 6- [4- (methylsulfonyl) piperazin-1-yl] pyridine-3-carbonitrile
[285] 6- (1-piperazino) -pyridine-3-carbonitrile (2.07 g, 11 mmol) in DCM (20 ml), diisopropylethylamine (2.4 ml, 13.8 mmol) and methanesulfonylchloride (0.86 ml , 11 mmol) gave 2.53 g (86%) of the title compound.
[286]
[287] 1- (4-fluorophenyl) -4- (methylsulfonyl) piperazine
[288] 1- (4-fluorophenyl) -piperazine (1.98 g, 11 mmol), diisopropylethylamine (2.4 ml, 13.8 mmol) and methanesulfonylchloride (0.86 ml, 11 mmol) in DCM (20 ml) Afforded 2.46 g (86%) of the title compound.
[289]
[290] 1-[(4-fluorophenyl) methyl] -4- (methylsulfonyl) piperazine
[291] 1- (4-Fluoro-benzyl) -piperazine (2.14 g, 11 mmol), diisopropylethylamine (2.4 ml, 13.8 mmol) and methanesulfonylchloride (0.86 ml, 11 mmol) in DCM (20 ml) Yielded 1.97 g (65%) of the title compound.
[292]
[293] 2- [4- (methylsulfonyl) piperazin-1-yl] pyrimidine
[294] 1- (2-pyrimidyl) -piperazine dihydrochloride (2.61 g, 11 mmol) and diisopropylethylamine (7.2 ml, 41.3 mmol) were dissolved in DCM (20 ml) for 30 minutes. The precipitated salt was removed by filtration and the solvent was evaporated and the residue was redissolved in DCM (20 ml). Diisopropylethylamine (2.4 ml, 11 mmol) and 4A molecular sieve were added, the yellow solution was cooled in an ice / water bath and methanesulfonylchloride (0.86 ml, 11 mmol) was added. The resulting red solution was stirred for 15 minutes, the reaction mixture was allowed to reach room temperature and after 1 hour the reaction was quenched by addition of 5% KHCO ₃ . Solvent was evaporated and the residue was dissolved between DCM and 5% KHCO ₃ . The foaming made it difficult to separate. The aqueous phase was saturated with NaCl and the pH adjusted to 10-11. Extracted with EtOAc (3 ×). The combined organic phases were dried (K ₂ CO ₃ ), filtered and evaporated to afford the crude product as a red solid. Recrystallization (3 ×) from EtOAc / heptanes gave the title compound as a red powder.
[295] 0.6 g (22% yield) of the title compound obtained
[296]
[297] 4- (4-chlorophenyl) -1- (methylsulfonyl) piperidine
[298] The title compound was prepared as described in the synthesis of 4- (4-fluoro-phenyl) -1-methanesulfonyl-piperidine.
[299] 4- (4-chlorophenyl) piperidine hydrochloride (0.9 g, 3.9 mmol), diisopropylethylamine (1.7 ml, 9.7 mmol) and methanesulfonylchloride (0.33 ml, 4.3 mmol) in DCM (30 ml) ) Gave 0.82 g (78%) of the title compound after recrystallization from EtOAc / heptane.
[300]
[301] Ester intermediates
[302]
[303] All other esters used are commercially available or have been described previously.
[304] 4-pyrimidin-2-yl-butyric acid ethyl ester
[305] 2-bromopyrimidine (1.0 g, 6.3 mmol) was slurried in anhydrous THF (8 ml). N ₂ (g) was bubbled through the slurry for 5 minutes. Pd (CH ₃ CN) ₂ Cl ₂ (8 mg, 0.03 mmol) and PPh ₃ (23.6 mg, 0.09 mmol) were added. Under N ₂ atmosphere, 4-ethoxy-4-oxo-butylzinc bromide (0.5 M / THF) (15 ml, 7.5 ml) was added in portions. The resulting brown solution was stirred at room temperature for 2 hours. H ₂ O (5 ml) was added and the mixture was stirred for 60 minutes before evaporation of the solvent. The residue was redissolved in DCM (150 ml), washed with 0.5 M trisodium citrate (100 ml), H ₂ O (100 ml) and brine (100 ml), dried (MgSO ₄ ), filtered, Evaporation gave 1.3 g of orange oil. The crude product was purified on 70 g of Si-60 gel using a gradient of 100% heptane to 100% EtOAc as eluent. Fractions containing the product were collected and the solvent was evaporated to yield a yellow oil. Purity> 95% by NMR was considered sufficient for our needs. 1.12 g (92% yield) of the title compound obtained
[306]
[307] 3-pyrimidin-2-yl propionic acid ethyl ester
[308] 2-bromopyrimidine (1.0 g, 6.3 mmol) was dissolved in THF (8 ml) and bubbled with nitrogen. Pd (MeCN) ₂ Cl ₂ (8 mg, 0.03 mmol) and PPh ₃ (23.6 mg, 0.09 mmol) were added, followed by 3-ethoxy-3-oxopropylzinc bromide (15 ml, 7.5 mmol). The reaction was stirred for several days at room temperature. The crude product was purified on silica with heptane: EtOAc 3: 1 as eluent to afford 0.60 g (52%) of the title compound.
[309]
[310] tert-butyl-4- (2-methoxy-2-oxoethyl) piperidine-1-carboxylate
[311] 10% Pd / C (0.8 g) moistened with tert-butyl 4- (2-methoxy-2-oxoethylidene) piperidine-1-carboxylate (3.6 g, 14 mmol) and water was dissolved in MeOH (75 ml) and stirred for 4 h under H ₂ (1 atm). The mixture was filtered through celite and concentrated to give the title compound (3.6 g, 99%).
[312]
[313] Ketone intermediates
[314]
[315]
[316]
[317]
[318] 1- [4-4 (Fluoro-phenyl) -piperidine-1-sulfonyl] -propan-2-one
[319] 4- (4-fluoro-phenyl) -1-methanesulfonyl-piperidine (100 mg, 0.39 mmol) was dissolved in anhydrous THF (3 ml) under protective nitrogen atmosphere. Lithium bis (trimethylsilyl) amide was added in portions as a 1.0 M solution (1.0 ml, 1.0 mmol) in THF at room temperature and the resulting yellow solution was stirred for 45 minutes. Methyl acetate (50 mg, 0.68 mmol) dissolved in anhydrous THF (0.5 ml) was added and the mixture was stirred at rt for 45 min. The reaction was quenched by adding NH ₄ Cl (saturated) (2 ml). The mixture was evaporated and the resulting solid was dissolved in a mixture of DCM and H ₂ O. The organic phase was separated, washed with brine, dried (MgSO ₄ ), filtered and evaporated. The crude product was purified on 20 g of Si-60 gel using a gradient of 100% heptane to 50% EtOAc, using flow rate 20 ml / min and UV = 254 nm used for detection. Fractions containing product were evaporated to afford the title compound as a colorless solid.
[320] 70 mg (59% yield) obtained
[321]
[322] The following compounds were prepared as described in the synthesis of 1- [4-4 (fluoro-phenyl) -piperidine-1-sulfonyl] -propan-2-one.
[323] 1- [4-4 (Fluoro-phenyl) -piperidin-1-sulfonyl] -4-phenyl-butan-2-one
[324] 4- (4-fluoro-phenyl) -1-methanesulfonyl-piperidine (100 mg, 0.39 mmol), methyl-3-phenylpropionate (112 mg, 0.68 mmol) and lithium bis (trimethylsilyl) Amide 1.0 M / THF (1.0 ml, 1.0 mmol) gave 93 mg (61%) of the title compound.
[325]
[326] 1- [4-4 (Fluoro-phenyl) -piperidine-1-sulfonyl] -5-imidazole-pentan-2-one
[327] 4- (4-fluoro-phenyl) -1-methanesulfonyl-piperidine (100 mg, 0.39 mmol), 4-imidazol-1yl-butyric acid ethyl ester (127 mg, 0.70 mmol) and lithium bis ( Trimethylsilyl) amide 1.0 M / THF (1.0 ml, 1.0 mmol) gave 75 mg (48%) of the title compound.
[328]
[329] 1- [4- (4-Fluoro-phenyl) -piperidin-1-sulfonyl] -5-pyrimidin-2-yl-pentan-2-one
[330] 4- (4-fluoro-phenyl) -1-methanesulfonyl-piperidine (150 mg, 0.39 mmol) was dissolved in anhydrous THF (3 ml) and cooled in an ice / brine mixture. Lithium bis (trimethylsilyl) amide was added as a 1.0 M solution (1.5 ml, 1.5 mmol) in THF and the mixture was stirred for 40 minutes. 4-pyrimidin-2-yl-butyric acid ethyl ester (169 mg, 0.87 mmol) in THF (0.5 ml) was added and the reaction stirred for 30 minutes before reaching room temperature. After 2 hours, LC / MS analysis of the reaction mixture showed> 98% conversion to the starting material and the reaction was quenched by adding NH ₄ Cl (saturated) (2 ml). The mixture was evaporated and the resulting solid was dissolved in a mixture of DCM and 5% KHCO ₃ . The organic phase was separated and the aqueous phase extracted once with DCM. The combined organic phases were washed with brine, dried (MgSO ₄ ), filtered and evaporated to yield a yellow oil. The oil was dissolved in EtOAc and isohexane was added until a solid formed. The solvent was evaporated to give a yellow solid crude product. This material was analyzed using LC / MS only and used for the next step without further purification.
[331] 234 mg of the crude title compound obtained
[332]
[333] The following compounds were prepared as described in the synthesis of 1- [4- (4-fluoro-phenyl) -piperidine-1-sulfonyl] -5-pyrimidin-2-yl-pentan-2-one. It was obtained as crude product and used without further purification.
[334] 1- [4- (5-Chloro-pyridin-2-yloxy) -piperidine-1-sulfonyl] -propan-2-one
[335] 5-Chloro-2- (1-methanesulfonyl-piperidin-4-yloxy) -pyridine (150 mg, 0.51 mmol), methyl acetate (61 mg, 0.82 mmol) and lithium bis (trimethylsilyl) amide 1.0 Starting from M / THF (1.3 ml, 1.3 mmol) 161 mg of crude title compound were obtained. Used without further purification.
[336]
[337] 1- [4- (5-Chloro-pyridin-2-yloxy) -piperidine-1-sulfonyl] -4-phenyl-butan-2-one
[338] 5-Chloro-2- (1-methanesulfonyl-piperidin-4-yloxy) -pyridine (150 mg, 0.51 mmol), methyl-3-phenylpropionate (126 mg, 0.77 mmol) and lithium bis Starting with 1.0 M / THF (1.3 ml, 1.3 mmol) of (trimethylsilyl) amide, 258 mg of crude title compound were obtained. Used without further purification.
[339]
[340] 1- [4- (5-Chloro-pyridin-2-yloxy) -piperidin-1-sulfonyl] -5-imidazol-1-yl-pentan-2-one
[341] 5-Chloro-2- (1-methanesulfonyl-piperidin-4-yloxy) -pyridine (150 mg, 0.51 mmol), 4-imidazol-1yl-butyric acid ethyl ester (140 mg, 0.77 mmol) And 268 mg of crude title compound were obtained starting from 1.0 M / THF (1.3 ml, 1.3 mmol) of lithium bis (trimethylsilyl) amide. Used without further purification.
[342] LC-MS (APCI) m / z 427.2 (MH &lt; + &gt;).
[343] 1- [4- (5-Chloro-pyridin-2-yloxy) -piperidine-1-sulfonyl] -5-pyrimidin-2-yl-pentan-2-one
[344] 5-Chloro-2- (1-methanesulfonyl-piperidin-4-yloxy) -pyridine (150 mg, 0.51 mmol), 4-pyrimidin-2-yl-butyric acid ethyl ester (147 mg, 0.76 mmol ) And lithium bis (trimethylsilyl) amide 1.0 M / THF (1.3 ml, 1.3 mmol) to give 244 mg of the crude title compound. Used without further purification.
[345] LC-MS (APCI) m / z 439.2 (MH &lt; + &gt;).
[346] 1- [4- (5-Chloro-pyridin-2-yloxy) -piperidine-1-sulfonyl] -butan-2-one
[347] LC-MS (APCI) m / z 347 (MH &lt; + &gt;)
[348] 1- [4- (5-Chloro-pyridin-2-yloxy) -piperidine-1-sulfonyl] -pentan-2-one
[349] LC-MS (APCI) m / z 361 (MH &lt; + &gt;)
[350] 1- [4- (5-Chloro-pyridin-2-yloxy) -piperidine-1-sulfonyl] -4-methyl-pentan-2-one
[351] LC-MS (APCI) m / z 375 (MH &lt; + &gt;)
[352] 1- [4- (5-Chloro-pyridin-2-yloxy) -piperidine-1-sulfonyl] -4-pyrimidin-2-yl-butan-2-one
[353] LC-MS (APCI) m / z 425 (MH +)
[354] 1-({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) -3- (3-methylphenyl) propan-2-one
[355] LC-MS (APCI) m / z 423 (MH &lt; + &gt;)
[356] 1-({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) -3-tetrahydro-2H-pyran-4-ylpropan-2-one
[357] LC-MS (APCI) m / z 417 (MH +)
[358] 1-({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) -5-morpholin-4-ylpentan-2-one
[359] LC-MS (APCI) m / z 446 (MH &lt; + &gt;)
[360] 5-({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) -4-oxopentannitrile
[361] LC-MS (APCI) m / z 372 (MH &lt; + &gt;)
[362] 1,1-dimethylethyl 5-({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) -4-oxopentylcarbamate
[363] LC-MS (APCI) m / z 476 (MH &lt; + &gt;)
[364] 1-({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) -4-morpholin-4-ylbutan-2-one
[365] LC-MS (APCI) m / z 432 (MH &lt; + &gt;)
[366] 2-({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) -1-phenylethanone
[367] LC-MS (APCI) m / z 395 (MH &lt; + &gt;)
[368] 2-({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) -1- (4-fluorophenyl) ethanone
[369] LC-MS (APCI) m / z 413 (MH &lt; + &gt;)
[370] 2-({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) -1- (1H-imidazol-4-yl) ethanone
[371] LC-MS (APCI) m / z 385 (MH &lt; + &gt;)
[372] 4-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) acetyl] benzamide
[373] n.d
[374] 1-({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) -4- (1H-1,2,4-triazol-1-yl) butane 2-on
[375] LC-MS (APCI) m / z 414 (MH &lt; + &gt;)
[376] 1-{[4- (4-fluorophenyl) piperidin-1-yl] sulfonyl} -4-pyrimidin-2-ylbutan-2-one
[377] LC-MS (APCI) m / z 392 (MH &lt; + &gt;)
[378] 1-{[4- (4-fluorophenyl) piperidin-1-yl] sulfonyl} -3-tetrahydro-2H-pyran-4-ylpropan-2-one
[379] LC-MS (APCI) m / z 384 (MH &lt; + &gt;)
[380] 4-({[4- (4-fluorophenyl) piperidin-1-yl] sulfonyl} acetyl) benzamide
[381] LC-MS (APCI) m / z 405 (MH +)
[382] 2-{[4- (4-fluorophenyl) piperidin-1-yl] sulfonyl} -1- (1H-imidazol-4-yl) ethanone
[383] LC-MS (APCI) m / z 352 (MH &lt; + &gt;)
[384] 1-{[4- (4-chlorophenyl) piperidin-1-yl] sulfonyl} -3-tetrahydro-2H-pyran-4-ylpropan-2-one
[385] LC-MS (APCI) m / z 400 (MH +)
[386] 1-{[4- (4-chlorophenyl) piperidin-1-yl] sulfonyl} -5-morpholin-4-ylpentan-2-one
[387] LC-MS (APCI) m / z 429 (MH &lt; + &gt;)
[388] 1-({4- [5- (trifluoromethyl) pyridin-2-yl] piperazin-1-yl} sulfonyl) propan-2-one
[389] LC-MS (APCI) m / z 352.1 (MH &lt; + &gt;)
[390] 6- {4-[(2-oxopropyl) sulfonyl] piperazin-1-yl} pyridine-3-carbonitrile
[391] LC-MS (APCI) m / z 309.1 (MH &lt; + &gt;)
[392] 1-{[4- (4-fluorophenyl) piperazin-1-yl] sulfonyl} propan-2-one
[393] LC-MS (APCI) m / z 301.1 (MH &lt; + &gt;)
[394] 1-({4-[(4-fluorophenyl) methyl] piperazin-1-yl} sulfonyl) propan-2-one
[395] LC-MS (APCI) m / z 315.1 (MH &lt; + &gt;)
[396] 1-[(4-pyrimidin-2-ylpiperazin-1-yl) sulfonyl] propan-2-one
[397] LC-MS (APCI) m / z 285.1 (MH &lt; + &gt;)
[398] 1,1-dimethylethyl 4- [3-({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) -2-oxopropyl] piperidine-1 Carboxylate
[399] LC-MS (APCI) m / z 517 (MH &lt; + &gt;).
[400] Hydantoin of Formula (I)
[401]
[402]
[403]
[404]
[405] (5R, S) -5- [4- (4-Fluoro-phenyl) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[406] Ketone 1- [4-4 (fluorophenyl) -piperidine-1-sulfonyl] -propan-2-one (68 mg, 0.23 mmol), KCN (30 mg, 0.46 mmol) and (NH ₄ ) ₂ CO ₃ (111 mg, 1.16 mmol) was suspended in 50% EtOH / H ₂ O (8 ml) in a 22 ml sealed tube and heated to 70 ° C. to form a solution. The mixture is stirred at 70 ° C. for 17 hours to form a solid in the tube, the mixture is cooled to room temperature and the solvent is evaporated, the residue is suspended in water, the pH is adjusted to 6 with 1.0 M HCl and the precipitated product Was removed by filtration and washed with water. The aqueous phase was saturated with NaCl and extracted with MeCN. The solid material and MeCN solution were combined and evaporated. The crude product was purified using a semipreparative HPLC system and C-18 column with MeCN / H ₂ O + 0.1% TFA as eluent. Fractions containing product were combined and solvent removed by evaporation to afford the title compound as a colorless solid.
[407] 53 mg (62% yield) obtained
[408]
[409] (5R, S) -5- [4- (4-Fluoro-phenyl) -piperidine-1-sulfonylmethyl] -5-phenethyl-imidazolidine-2,4-dione
[410] Synthesis of (5R, S) -5- [4- (4-fluoro-phenyl) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione with the title compound Prepared as described in. 1- [4-4 (fluorophenyl) -piperidin-1-sulfonyl] -4-phenyl-butan-2-one (93 mg, 0.24 mmol), KCN (40 mg, 0.61 mmol) and (NH ₄ ) ₂ CO ₃ (117 mg, 1.22 mmol) gave 37 mg (33%) of the title compound.
[411]
[412] (5R, S) -5- [4- (4-Fluoro-phenyl) -piperidine-1-sulfonylmethyl] -5- (3-imidazol-1-yl-propyl) -imidazolidine -2,4-dione
[413] 1- [4-4 (fluorophenyl) -piperidine-1-sulfonyl] -5-imidazole-butan-2-one (75 mg, 0.19 mmol), KCN (30 mg, 0.46 mmol) and ( NH ₄ ) ₂ CO ₃ (91 mg, 0.95 mmol) was dissolved in EtOH / H ₂ O (l / l) (10 ml) in a 22 ml sealed tube and stirred at 70 ° C. for 17.5 h. Another portion of KCN (40 mg, 0.61 mmol) and (NH ₄ ) CO ₃ (250 mg, 2.60 mmol) was added and the mixture was stirred at 70 ° C. for another 16 hours. The solvent was evaporated, the residue suspended in H ₂ O, the precipitated product was removed by filtration and using a semi-preparative HPLC system and C-18 column with MeCN / H ₂ O + 0.1% TFA as eluent Purified. Fractions containing product were combined, evaporated to remove MeCN, the acidic aqueous phase was made basic to pH = 8-9 with 5% KHCO ₃ and the precipitated product was extracted using EtOAc. The organic phase was dried (Na ₂ SO ₄ ), filtered and evaporated to afford the title compound as a colorless solid.
[414] 60 mg (68% yield) obtained
[415]
[416] (5R, S) -5- [4- (4-Fluoro-phenyl) -piperidine-1-sulfonylmethyl] -5- (3-pyrimidin-2-yl-propyl) -imidazolidine -2,4-dione
[417] Crude 1- [4- (4-fluoro-phenyl) -piperidine-1-sulfonyl] -5-pyrimidin-2-yl-pentan-2-one (234 mg, up to 0.58 mmol), KCN ( 151 mg, 2.3 mmol) and (NH ₄ ) ₂ CO ₃ (557 mg, 5.8 mmol) were suspended in EtOH / H ₂ O (l / l) (26 ml) in a 40 ml sealed tube. The mixture was heated to 70 ° C. and the resulting yellow solution was stirred for 16 h. LC / MS analysis showed 15% unreacted ketones remained, adding another portion of KCN (65 mg, 1 mmol) and (NH ₄ ) ₂ CO ₃ (245 mg, 2.55 mmol) and adding the mixture to Heated to 70 ° C. for another 16 hours. The solvent was removed by evaporation and the residue was treated with H ₂ O (25 ml). The precipitated product was removed by filtration and purified using a semi-preparative HPLC system and C-18 column with MeCN / H ₂ O + 0.1% TFA as eluent. Fractions containing product were combined, evaporated to remove MeCN, acidic aqueous phase was made basic to pH = 8-9 with 5% KHCO ₃ , precipitated product was filtered off, washed with water and under reduced pressure Dried overnight at 40 ° C. in a drier. This gave the title compound as a colorless solid. Purity by NMR> 98%
[418] 120 mg (43% yield, 2 steps) obtained
[419]
[420] The following compound is (5R, S) -5- [4- (4-fluoro-phenyl) -piperidine-1-sulfonylmethyl] -5- (3-pyrimidin-2-yl-propyl) -imide Prepared as described in the synthesis of dazolidine-2,4-dione.
[421] (5R, S) -5- [4- (5-Chloro-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[422] No purification was necessary after evaporation of the reaction mixture and addition of water, and the precipitated product was sufficiently pure to> 98% by HPLC (220 nm, 254 nm) and NMR. 147 mg (71% yield, 2 steps) of the title compound were obtained as a colorless solid.
[423]
[424] (5S) -5- [4- (5-Chloro-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione and (5R ) -5- [4- (5-chloro-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[425] The corresponding racemic material (74 mg) was dissolved in 36 ml of isohexane / EtOH (25/75) and separated into pure enantiomers using the following Gilson HPLC system.
[426] Column: CHIRALCEL OD, 2.0 × 25 cm, flow rate = 6.0 ml / min, eluent = isohexane / EtOH (25/75), temperature = ambient, detector UV = 220 nm.
[427] Enantiomers were collected and analyzed at chiralcel OD-H, 0.46 × 25 cm, 0.5 ml / min, isohexane / EtOH (25/75), ambient temperature, 220 nm.
[428] Rt = 9.88 min, ee> 99%, 29 mg (39%) for rapidly eluting enantiomers
[429] Rt = 11.45 min, ee = 98.7%, 27 mg (36%) for slow eluting enantiomer
[430] LC-MS (APCI) m / z 403.1 (MH &lt; + &gt;).
[431] (5R, S) -5- [4- (5-Chloro-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -5-phenethyl-imidazolidine-2,4-dione
[432] Starting from crude 1- [4- (5-chloro-pyridin-2-yloxy) -piperidine-1-sulfonyl] -4-phenyl-butan-2-one (258 mg, up to 0.51 mmol). Purification of the crude product was carried out on a 70 g Si-60 gel using DCM + 5% MeOH as eluent.
[433] Purity> 96% by NMR and HPLC (220 nm, 254 nm).
[434] 201 mg (80% yield, 2 steps) of the title compound as a colorless solid
[435]
[436] (5R, S) -5- [4- (5-Chloro-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -5- (3-imidazol-1 yl-propyl) -imi Dazolidine-2,4-dione
[437] Crude 1- [4- (5-chloro-pyridin-2-yloxy) -piperidin-1-sulfonyl] -5-imidazol-1-yl-pentan-2-one (268 mg, up to 0.51 mmol ). 151 mg (59% yield, 2 steps) of the title compound were obtained as a colorless solid.
[438]
[439] (5R, S) -5- [4- (5-Chloro-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -5- (3-pyrimidin-2-yl-propyl)- Imidazolidine-2,4-dione
[440] Crude 1- [4- (5-chloro-pyridin-2-yloxy) -piperidine-1-sulfonyl] -5-pyrimidin-2-yl-pentan-2-one (244 mg, up to 0.51 mmol ). 105 mg (49% yield, 2 steps) of the title compound were obtained as a colorless solid.
[441]
[442] (5S) -5- [4- (5-Chloro-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -5- (3-pyrimidin-2-yl-propyl) -imida Zolidine-2,4-dione and (5R) -5- [4- (5-chloro-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -5- (3-pyrimidine- 2-yl-propyl) -imidazolidine-2,4-dione
[443] The corresponding racemic material (40 mg) is dissolved in 26 ml of isohexane / EtOH (25/75) and (5R, S) -5- [4- (5-chloro-pyridin-2-yloxy) -pi Separation into pure enantiomers was carried out using the same conditions as described for the separation of ferridine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione.
[444] Rt = 17.6 min, ee> 99%, 17 mg (42%) for rapidly eluting enantiomers
[445] Rt = 21.0 min, ee = 98.9%, 15 mg (37%) for slow eluting enantiomers
[446] LC-MS (APCI) m / z 509 (MH &lt; + &gt;).
[447] 5-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -5-ethylimidazolidine-2,4-dione
[448]
[449] 5-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -5-propylimidazolidine-2,4-dione
[450]
[451] 5-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -5- (2-methylpropyl) imidazolidine-2,4 Dion
[452]
[453] 5-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -5- (2-pyrimidin-2-ylethyl) imidazoli Dean-2,4-dione
[454]
[455] 5-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -5-[(3-methylphenyl) methyl] imidazolidine-2 , 4-dione
[456]
[457] 5-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -5- (tetrahydro-2H-pyran-4-ylmethyl) Dazolidine-2,4-dione
[458]
[459] 5-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -5- (3-morpholin-4-ylpropyl) imidazoli Dean-2,4-dione trifluoroacetic acid
[460]
[461] 3- {4-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -2,5-dioxoimidazolidine-4- Propane Nitrile
[462]
[463] 1,1-dimethylethyl 3- {4-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -2,5-dioxoimi Dazolidin-4-yl} propylcarbamate
[464]
[465] 5-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -5- (2-morpholin-4-ylethyl) imidazoli Dean-2,4-dione
[466] Not refined
[467] LC-MS (APCI) m / z 502 (MH &lt; + &gt;).
[468] 5-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -5-phenylimidazolidine-2,4-dione
[469] Not refined
[470] LC-MS (APCI) m / z 465 (MH &lt; + &gt;).
[471] 5-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -5- (4-fluorophenyl) imidazolidine-2, 4-dion
[472] Not refined
[473] LC-MS (APCI) m / z 483 (MH &lt; + &gt;).
[474] 5-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -5- (1H-imidazol-4-yl) imidazolidine -2,4-dione
[475] Not refined
[476] LC-MS (APCI) m / z 455 (MH &lt; + &gt;).
[477] 4- {4-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -2,5-dioxoimidazolidine-4- Benzamide
[478] Not refined
[479] LC-MS (APCI) m / z 508 (MH &lt; + &gt;).
[480] 5-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -5- [2- (1H-1,2,4-triazole -1-yl) ethyl] imidazolidine-2,4-dione
[481] Not refined
[482] LC-MS (APCI) m / z 484 (MH &lt; + &gt;).
[483] 5-({[4- (4-fluorophenyl) piperidin-1-yl] sulfonyl} methyl) -5- (2-pyrimidin-2-ylethyl) imidazolidine-2,4- Dion
[484]
[485] 5-({[4- (4-fluorophenyl) piperidin-1-yl] sulfonyl} methyl) -5- (tetrahydro-2H-pyran-4-ylmethyl) imidazolidine-2, 4-dion
[486]
[487] 4- [4-({[4- (4-fluorophenyl) piperidin-1-yl] sulfonyl} methyl) -2,5-dioxoimidazolidin-4-yl] benzamide
[488]
[489] 5-({[4- (4-fluorophenyl) piperidin-1-yl] sulfonyl} methyl) -5- (1H-imidazol-4-yl) imidazolidine-2,4-dione
[490] Not refined
[491] LC-MS (APCI) m / z 422 (MH &lt; + &gt;).
[492] 5-({[4- (4-chlorophenyl) piperidin-1-yl] sulfonyl} methyl) -5- (tetrahydro-2H-pyran-4-ylmethyl) imidazolidine-2,4 Dion
[493]
[494] 5-({[4- (4-chlorophenyl) piperidin-1-yl] sulfonyl} methyl) -5- (3-morpholin-4-ylpropyl) imidazolidine-2,4-dione Trifluoroacetic acid
[495]
[496] (5R, S) -5-methyl-5-[({4- [5- (trifluoromethyl) pyridin-2-yl] piperazin-1-yl} sulfonyl) methyl] imidazolidine-2 , 4-dione
[497]
[498] 6- (4-{[({4R, S} -4-methyl-2,5-dioxoimidazolidin-4-yl) methyl] sulfonyl} piperazin-1-yl) pyridine-3-carboni Trill
[499]
[500] (5R, S) -5-({[4- (4-fluorophenyl) piperazin-1-yl] sulfonyl} methyl) -5-methylimidazolidine-2,4-dione
[501]
[502] (5R, S) -5-[({4-[(4-fluorophenyl) methyl] piperazin-1-yl} sulfonyl) methyl] -5-methylimidazolidine-2,4-dione
[503]
[504] (5R, S) -5-methyl-5-{[(4-pyrimidin-2-ylpiperazin-1-yl) sulfonyl] methyl} imidazolidine-2,4-dione
[505]
[506] 5- (3-aminopropyl) -5-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] imidazolidine-2,4 -Dione trifluoroacetic acid
[507] 1,1-dimethylethyl 3- {4-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -2,5-dioxoimi Dazolidin-4-yl} propylcarbamate (426 mg, 0.78 mmol) was dissolved in 10 ml of CH ₂ Cl ₂ and 4 ml of TFA was added. The reaction was stirred at rt for 1 h. Removal of the solvent gave 408 mg (93%) of the title compound as a white solid.
[508]
[509] 5- [4- (5-Chloro-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -5-piperidin-4-yl-imidazolidine-2,4-dione hydro Chloride
[510] 4- {4- [4- (5-Chloro-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -2,5-dioxo-imidazolidin-4-yl} -pi Ferridine-1-carboxylic acid tert-butyl ester (100 mg, 0.16 mmol) was dissolved in 2M hydrogen chloride (ethyl acetate, 30 ml) and methanol (5 ml). The solution was stirred at 50 ° C. for 1 hour. Evaporation was carried out to give the title compound 5- [4- (5-chloro-pyridin-2-yloxy) -piperidin-1-sulfonylmethyl] -5-piperidin-4-yl-imidazolidine- 90.5 mg (0.16 mmol) of 2,4-dione hydrochloride were obtained in quantitative yield.
[511]
[512] 4- {4- [4- (5-Chloro-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -2,5-dioxo-imidazolidin-4-yl} -pi Ferridine-1-carboxylic acid tert-butyl ester
[513] For the preparation of reactive esters, piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl esters, see Albert A Carr et al., Journal of Organic Chemistry (1990), 55 (4). , 1399-401.
[514] LC-MS (APCI) m / z 472.3 (MH &lt; + &gt; -Boc).
[515] 5- [4- (5-Chloro-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -5- (tetrahydro-pyran-4-yl) -2,4-dione
[516]
[517] 5- [4- (5-Chloro-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -5-pyridin-4-yl-imidazolidine-2,4-dione trifluoro Acetic acid
[518]
[519] 1,1-dimethylethyl 4-({4-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -2,5-dioxo Imidazolidin-4-yl} methyl) piperidine-1-carboxylate
[520] The title compound is essentially (5R, S) -5- [4- (4-fluoro-phenyl) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione Prepared as described in the synthesis.
[521]
[522] 5-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -5- (piperidin-4-ylmethyl) imidazolidine -2,4-dione trifluoroacetate
[523] The title compound is essentially 5- (3-aminopropyl) -5-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] imidazoli Prepared as described in the synthesis of dean-2,4-dione trifluoroacetic acid.
[524]
[525] N- (3- {4-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl} methyl] -2,5-dioxoimidazolidine -4-yl} propyl) methanesulfonamide
[526] 5- (3-aminopropyl) -5-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl} methyl] imidazolidine-2,4 -Dione trifluoroacetic acid (100 mg, 0.18 mmol) was slurried in 2 ml DCM DIPEA (62 μl, 0.36 ml) was added and the slurry was stirred for several minutes Sulfonylchloride (16 μl, 0.18 mmol). The reaction was stirred overnight at rt The crude product was purified by preparative HPLC.
[527]
[528] Example 9
[529] (5R, S) -5- [4- (5-Chloro-pyridin-2-yl) -piperazin-1-sulfonylmethyl] -5- (3-pyrimidin-2-yl-propyl) -imida Zolidine-2,4-dione
[530]
[531] 1-([4- (5-chloro-2-pyridinyl) -1-piperazinyl] sulfonyl) -5- (2-pyrimidinyl) -2-pentanone (0.397 g, 0.936 mmol), cyan Potassium acid (0.122 g, 1.87 mmol), ammonium carbonate (0.500 g, 4.68 mmol) and 50% ethanol (4 ml) were stirred for 17 h in a sealed tube at 75 ° C. (oil temperature). Ethanol was removed by rotary evaporation, the pH was adjusted to 6 with 1M HCl, the suspension was filtered, the solid was washed with a small amount of water, collected and dried under vacuum at 45 ° C. Saturated by addition of solid sodium chloride and the mixture was extracted with acetonitrile (2 × 10 ml) to recover slightly more product from the aqueous filtrate. Dry over Na ₂ SO ₄ , filter the organic phase and concentrate to give a second crop. The combined extracts were dissolved in tetrahydrofuran (5-10 ml), adsorbed onto silica (3 g) and applied onto a short silica column. After eluting with EtOAc, eluting with EtOAc-MeCN (1: 1) gave 0.30 g (65% yield) of the title compound as a white crystalline solid.
[532]
[533] Starting materials were prepared as follows.
[534] 1-([4- (5-chloro-2-pyridinyl) -1-piperazinyl] sulfonyl) -5- (2-pyrimidinyl) -2-pentanone
[535]
[536] A stirred solution of 1- (5-chloro-2-pyridinyl) -1-methylsulfonyl-piperazine (0.64 g, 2.32 mmol) in dry THF (25 ml, 40 rel vol) was brought to -10 ° C under nitrogen. By cooling the sulfonamide precipitated out of solution. LHMDS 1M (4.64 ml, 4.64 mmol) in THF was added dropwise to the suspension of sulfonamide over 4 minutes, then the mixture was stirred for 40 minutes. 4- (2-pyrimidinyl) -butyric acid ethyl ester (0.68 g, 3.48 mmol) (Example 8) in anhydrous THF (6.4 ml, 10 rel vol) was added dropwise over 4 minutes and the mixture was stirred for 30 minutes It was. The mixture was quenched with saturated NH ₄ Cl (0.64 ml, 1 rel vol) and evaporated to a semisolid residue. The residue was dissolved in DCM (20 rel vol) and the organic layer was washed with water (15 ml, 24 rel vol), brine (15 ml, 24 rel vol) and dried over MgSO ₄ . Removal of the solvent by rotary evaporation gave the crude product as an off-white solid (0.84 g, 85%). The crude product was purified by Biotage FLASH chromatography using ethyl acetate / isohexane (90:10) as eluent to afford pure ketone as a white amorphous solid.
[537] 1- (5-chloro-2-pyridinyl) -1-methylsulfonyl piperazine
[538] Triethylamine (1.1 eq) was added to a solution containing 1- (5-chloro-2-pyridinyl) -piperazine (1 eq.) In toluene (25 vol) and the mixture was cooled to 5 ° C. in an ice bath. I was. Methanesulfonyl chloride diluted with toluene (0.5 vol) was added to the slowly cooled solution and the temperature was maintained below 10 ° C. Upon complete addition, the reaction was allowed to warm to room temperature. Water (6.6 vol) was added, the mixture was filtered and the cake slurried in toluene (2 vol). The cake was then washed with toluene (2 vol) and dried overnight at 40 ° C. under vacuum.
[539] 1- (5-chloro-2-pyridinyl) -piperazine
[540]
[541] Piperazine (4 eq) was charged to the reaction vessel as a solid. Pyridine (1.43 vol) was added to the vessel at room temperature followed by toluene (2.14 vol). The final slurry was stirred and heated to reflux at 120 ° C. to obtain a complete solution. After filling 2,5-dichloropyridine (DCP) in a separate vessel, toluene (1.43 vol) was added to dissolve the solids. Dissolution was endothermic and it was necessary to warm the solution to ˜30 ° C. to obtain a solution completely. The solution containing DCP was then slowly discharged into the reaction vessel over 5 hours. At this point, the residual amount of DCP should be about 20%. The reaction was left to reflux overnight to complete.
[542] The reaction mixture was cooled slowly to room temperature and then water was added (6 vol). The two layers were separated and the aqueous phase was reextracted with toluene (5 vol). The two organic layers were combined and rewashed with H ₂ O (6 vol). Finally, the organic layer was washed with brine (6 vol).
[543] (5S) -5- [4- (5-Chloro-pyridin-2-yl) -piperazin-1-sulfonylmethyl] -5- (3-pyrimidin-2-yl-propyl) -imidazolidine -2,4-dione and (5R) -5- [4- (5-chloro-pyridin-2-yl) -piperazin-1-sulfonylmethyl] -5- (3-pyrimidin-2-yl- Propyl) -imidazolidine-2,4-dione
[544] The corresponding racemic material (23 mg) was dissolved in 8 ml of isohexane / EtOH (25/75) and separated into pure enantiomers using the following Gilson HPLC system.
[545] Column: chiralcel OD, 2.0 × 25 cm, flow rate = 6.0 ml / min, eluent = isohexane / EtOH (25/75), temperature = ambient, detector UV = 230 nm.
[546] Enantiomers were collected and analyzed at chiralcel OD-H, 0.46 × 25 cm, 0.5 ml / min, isohexane / EtOH (25/75), ambient temperature, 220 nm.
[547] Rt = 11.5 min, ee> 99%, 8.7 mg (37%) for rapidly eluting enantiomers
[548] LC-MS (APCI) m / z 494.1 (MH &lt; + &gt;).
[549] [α] _D = -26.4 ° (c = 0.0022 g / ml, EtOH, t = 20 ° C)
[550] Rt = 14.5 min, ee = 98%, 9 mg (39%) for slow eluting enantiomer
[551] LC-MS (APCI) m / z 494.1 (MH &lt; + &gt;).
[552] [a] _D = + 24.5 ° (c = 0.0026 g / ml, EtOH, t = 20 ° C)
[553] <Example 10>
[554] The following compounds were prepared using methods analogous to those described in Examples 8 or 9.
[555] 5- [4- (4-Chloro-phenyl) -piperazine-1-sulfonylmethyl] -5- (3-pyrimidin-2-yl-propyl] -imidazolidine-2,4-dione 5- [4- (4-Fluoro-phenyl) -piperazine-1-sulfonylmethyl] -5- [2- (5-fluoro-pyrimidin-2-yl) -ethyl] -imidazolidine -2,4-dione 5- [4- (5-Chloro-pyridin-2-yl) -piperazin-1-sulfonylmethyl] -5- [2- (5-fluoro-pyrimidin-2-yl) -ethyl] -already Dazolidine-2,4-dione 5- [4- (3,4-Dichloro-phenyl) -piperazin-1-sulfonylmethyl] -5- (3-pyrimidin-2-yl-propyl] -imidazolidine-2,4-dione
[556] <Example 11>
[557] Compounds of the following formula were synthesized according to the method described in Example 8.
[558]
[559] Ketone intermediates
[560]
[561] 1- (1,1'-biphenyl-4-ylthio) propan-2-one
[562] 1-[(4-bromophenyl) thio] propan-2-one (357 mg, 1.46 mmol) was dissolved in phenyl boronic acid (231 mg, 1.89 mmol), dichloromethane and [1,1'-bis (diphenylphosph). Pino) ferrocene] dichloro palladium (II) complex (1: 1) (36 mg), toluene (20 ml), methanol (7.5 ml), saturated sodium carbonate solution (3.5 ml) and treated together at 80 ° C. for 18 hours Was stirred. After cooling, the reaction mixture was treated with dilute hydrochloric acid and extracted with ethyl acetate. The product was purified by flash chromatography on silica eluting with 25% ethyl acetate: iso-hexane to give 277 mg of product.
[563]
[564] The following compounds were prepared as described in the synthesis of 1- (1,1'-biphenyl-4-ylthio) propan-2-one.
[565] 4 '-[(2-oxopropyl) thio] -1,1'-biphenyl-4-carbonitrile
[566]
[567] 1-({4 '-[(trifluoromethyl) oxy] -1,1'-biphenyl-4-yl} thio) propan-2-one
[568]
[569] 1- (1,1'-biphenyl-4-ylsulfonyl) propan-2-one
[570] 1- (1,1'-biphenyl-4-ylthio) propan-2-one (69 mg, 0.28 mmol) was added sodium bicarbonate (72 mg, 0.85 mmol) oxone (525 mg, 0.85 mmol), water at room temperature. (5 ml) and methanol (10 ml) were stirred for 3 hours. Water (50 ml) was added and the product extracted into ethyl acetate (3 × 25 ml). The extract was washed with brine, dried over sodium sulfate and evaporated to give 78 mg (99%) of product with sufficient purity for use without further purification.
[571]
[572] 4 '-[(2-oxopropyl) sulfonyl] -1,1'-biphenyl-4-carbonitrile
[573] The title compound was prepared as described in the synthesis of 1- (1,1'-biphenyl-4-ylsulfonyl) propan-2-one.
[574]
[575] Hydantoin of Formula (I)
[576] The following compound was carried out (5R, S) -5- [4- (4-fluoro-phenyl) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione Prepared as described in the synthesis of Example 8).
[577]
[578] (5R, S)-[4- (5-Chloro-pyridin-2-yloxy) -benzenesulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[579]
[580] 5-chloro-2-{[4- (methylsulfonyl) phenyl] oxy} pyridine
[581] 2,5-dichloropyridine (1.48 g, 10 mmol), 4-methylsulfonylphenol (1.89 g, 11 mmol) and Cs ₂ CO ₃ (4.24 g, 13 mmol) were slurried in 75 ml of NMP. The slurry was heated to approximately 170 ° C. overnight. After cooling, Cs ₂ CO ₃ was filtered off and the solvent was extracted between H ₂ O and EtOAc. The organic phase was dried over Na ₂ SO ₄ and evaporated. Heptane: EtOAc 2: 1 was added to the residue and the crystals were filtered off. 1.42 g (50%).
[582]
[583] 5-methyl-5-[({4 '-[(trifluoromethyl) oxy] -1,1'-biphenyl-4-yl} sulfinyl) methyl] imidazolidine-2,4-dione
[584] 5-methyl-5-[({4 '-[(trifluoromethyl) oxy] -1,1'-biphenyl-4-yl} thio) methyl] imidazolidine-2,4-dione (48 mg, 0.112 mmol) was stirred for 18 hours with oxone (50 mg), sodium bicarbonate (50 mg), water (5 ml) and methanol (10 ml) at room temperature. The solid was filtered off and crystallized from ethanol to give 20 mg of the title compound.
[585]
[586] 5-methyl-5-[({4 '-[(trifluoromethyl) oxy] -1,1'-biphenyl-4-yl} thio) methyl] imidazolidine-2,4-dione
[587]
[588] 5-[(1,1'-biphenyl-4-ylsulfonyl) methyl] -5-methylimidazolidine-2,4-dione
[589]
[590] 4 '-{[(4-methyl-2,5-dioxoimidazolidin-4-yl) methyl] sulfonyl} -1,1'-biphenyl-4-carbonitrile
[591]
[592] <Example 12>
[593] Synthesis of Enantiomeric Pure Hydantoin
[594]
[595] Representative synthetic routes are shown below.
[596]
[597] Experiment process
[598] (5S) -5-({[4- (4-fluorophenyl) piperidin-1-yl] sulfonyl} methyl) -5-methylimidazolidine-2,4-dione
[599] 4- (4-fluorophenyl) piperidine hydrochloride (63 mg, 0.29 mmol) was dissolved in 3 ml of anhydrous THF, neutralized with diisopropylethylamine (50 μl, 0.29 mmol) and on an ice-water bath Cooled. [(4S) -4-methyl-2,5-dioxo-imidazolodin-4-yl] methanesulfonyl chloride (80 mg, 0.35 mmol) was added, stirred for 10 minutes, and then diisopropylethylamine (50 μl, 0.29 mmol) was added and the reaction mixture was stirred at ambient temperature until LC-MS (APCI) indicated consumption of amines. The reaction mixture was evaporated and the residue was dissolved in EtOH and heated to 50 ° C. and cooled before adding water. The precipitated product was collected, washed with EtOH / water and dried in vacuo to give 87 mg.
[600]
[601] Starting materials were prepared as follows:
[602] 5-methyl-5-{[(phenylmethyl) thio] methyl} imidazolidine-2,4-dione
[603] The steel vessel was filled with ethanol and water (315 ml / 135 ml). 31.7 g (0.175 mol) of benzylthioacetone, 22.9 g (0.351 mol) of potassium cyanate and 84.5 g (0.879 mol) of ammonium carbonate were added. The sealed reaction vessel was kept in an oil bath (bath temperature 90 ° C.) for 3 hours under vigorous stirring. The reaction vessel was cooled with ice-water (0.5 h), the yellow slurry was evaporated to dryness, and the solid residue was partitioned between 400 ml water and 700 ml ethyl acetate and separated. The water-phase was extracted with ethyl acetate (300 ml). The combined organic phases were washed with saturated brine (150 ml), dried (Na ₂ SO ₄ ), filtered and evaporated to dryness. If the product did not crystallize, 300 ml of dichloromethane were added to the oil. Evaporation gave 43.8 g (90%) of the product as a pale yellow powder.
[604]
[605] (5S) -5-methyl-5-{[(phenylmethyl) thio] methyl} imidazolidine-2,4-dione
[606] The title compound was prepared by chiral separation of racemic material using a 250 mm x 50 mm column on a Dynamic Axial Compression Preparative HPLC system. The stationary phase used was CHIRALPAK AD, eluent = methanol, flow rate = 89 ml / min, temperature = ambient temperature, UV = 220 nm, sample concentration = 150 mg / ml, injection volume = 20 ml.
[607] Retention time for the title compound = 6 minutes
[608] Analysis of chiral purity was performed using a 250 mm × 4.6 mm chiralpak-AD column, flow rate = 0.5 ml / min, eluent = ethanol, UV = 220 nm, temperature = ambient temperature available from Daicel. .
[609] Retention time for the title compound = 9.27 min
[610] Expected Purity> 99% ee.
[611]
[612] (5R) -5-methyl-5-{[(phenylmethyl) thio] methyl} imidazolidine-2,4-dione
[613] The title compound was prepared by chiral separation of racemic material using a 250 mm x 50 mm column on a dynamic axial compression preparative HPLC system. The stationary phase used was chiralpak AD, eluent = methanol, flow rate = 89 ml / min, temperature = ambient temperature, UV = 220 nm, sample concentration = 150 mg / ml, injection volume = 20 ml.
[614] Retention time for the title compound = 10 minutes
[615] Analysis of chiral purity was carried out using a 250 mm × 4.6 mm chiralpak-AD column, flow rate = 0.5 ml / min, eluent = ethanol, UV = 220 nm, temperature = ambient temperature available from Daicel.
[616] Retention time for the title compound = 17.81 minutes
[617] Expected chiral purity> 99% ee.
[618]
[619] [(4S) -4-methyl-2,5-dioxoimidazolidin-4-yl] methanesulfonyl chloride
[620] (5S) -5-methyl-5-{[(phenylmethyl) thio] methyl} imidazolidine-2,4-dione (42.6 g, 0.17 mol) was dissolved in AcOH (450 ml) and H ₂ O (50 ml). In a mixture). The mixture was immersed in an ice / water bath, Cl ₂ (g) was bubbled through the solution and the gas flow rate was adjusted to maintain the temperature below + 15 ° C. After 25 minutes, the solution became sulfur-green and samples were taken for LC / MS and HPLC analysis. It was shown that the starting material was consumed. The yellow clear solution was stirred for 30 minutes and an opaque solution / slurry formed. Solvent was removed on a rotary evaporator using a water bath having a temperature maintained at +37 ° C. The yellow solid was suspended in toluene (400 ml) and the solvent was removed on the same rotary evaporator. This was repeated one more time. The crude product is then suspended in iso-hexane (400 ml), warmed to + 40 ° C. with stirring, the slurry is cooled to room temperature and the insoluble product is removed by filtration and iso-hexane (6 × 100 ml) ) And dried overnight at +50 ° C under reduced pressure. This gave the product as a pale yellow powder. 36.9 g (95%) of the title compound obtained
[621] Purity by HPLC = 99%, NMR supports this purity.
[622] [a] _D = -12.4 ° (c = 0.01 g / ml, THF, T = 20 ° C).
[623]
[624] [(4R) -4-methyl-2,5-dioxoimidazolidin-4-yl] methanesulfonyl chloride
[625] According to the procedure described for [(4S) -4-methyl-2,5-dioxoimidazolidin-4-yl] methanesulfonyl chloride, (5R) -5-methyl-5-{[(phenylmethyl 8.78 g (yield 96%) of the title compound were obtained starting from) thio] methyl} imidazolidine-2,4-dione (10.0 g, 40 mmol).
[626]
[627] Example 13
[628] According to the method described in Example 12, a compound of the general formula
[629]
[630] Amine intermediates
[631]
[632]
[633]
[634]
[635] All other amines used are commercially available or have been described previously.
[636] 4- {4-[(trifluoromethyl) oxy] phenyl} piperidine trifluoroacetic acid
[637] Pd (PPh ₃ ) ₄ (87 mg, 0.0075 mmol), LiCl (190 mg, 4.5 mmol), tert-butyl 4-{[(trifluoromethyl) sulfonyl] oxy) -3,6-dihydropyridine- 5.2 mL of 1 (2H) -carboxylate (0.50 g, 1.5 mmol), 4- (trifluoromethoxy) phenylboronic acid (0.43 g, 2.1 mmol) and aqueous Na ₂ CO ₃ solution (2 mL, 2N solution) Mixed in DME, heated at 85 ° C. for 3 h, cooled to rt and concentrated under reduced pressure. The residue was partitioned between DCM (10 mL), Na ₂ CO ₃ aqueous solution (10 mL, 2N solution) and concentrated NH ₄ 0H (0.6 mL). The layers were separated and the aqueous layer was extracted with DCM (3 × 10 mL). The combined organic layers were dried (Na ₂ SO ₄ ) and concentrated. Purification by column chromatography (Si0 ₂ , heptane / ethylacetate / DCM 5: 1: 1) tert-butyl 4- [4- (trifluoromethoxy) phenyl] -3,6-dihydropyridine-1 (2H ) -Carboxylate was obtained (0.27 g, 52%). The product and 5% Pd / C (30 mg) were mixed in MeOH (3 mL) and stirred for 24 h under H ₂ (1 atm). The mixture was filtered through celite and concentrated to afford tert-butyl 4- [4- (trifluoromethoxy) phenyl] piperidine-1-carboxylate (0.23 g, 86%). The crude product was dissolved in a mixture of TFA (2 mL) and DCM (4 mL) and stirred at rt for 2 h. The reaction mixture was concentrated and purified by preparative HPLC to give the title compound (0.14 g, 58%, 3 steps 26%).
[638]
[639] 4-[(4-chlorophenyl) ethynyl] -1,2,3,6-tetrahydropyridine hydrochloride
[640] PdCl ₂ (PPh ₃ ) ₂ (47 mg, 0,07 mmol) and CuI (13 mg, 0.07 mmol) were dissolved in Et ₃ N (2.7 mL) and THF (8.4 mL) under an argon stream and stirred for 10 minutes. . Tert-butyl 4-{[(trifluoromethyl) sulfonyl] oxy) -3,6-dihydropyridine-1 (2H) -carboxylate (0.46 g, 1.4 mmol) and 2-in 3.5 mL THF Tinylpyridine (152 μl , 1.5 mmol) solution was added. The reaction mixture was stirred at rt for 2 h, diethyl ether was added and the precipitate was filtered off. The clear solution was washed with saturated NH ₄ Cl, water and brine and dried (Na ₂ SO ₄ ). Concentrated and purified by column chromatography (SiO ₂ , heptane / diethyl ether 1: 2) to give tert-butyl 4-[(4-chlorophenyl) ethynyl] -3,6-dihydropyridine-1 (2H)- Carboxylate was obtained (0.26 g, 58%). The product was dissolved in THF (3 mL) and concentrated HCl (3 mL) and stirred at room temperature for 30 minutes. Concentration several times with toluene and EtOH gave the title compound (0.20 g, 98%, two steps 57%).
[641]
[642] The following amines were prepared in a similar manner as described for 4-[(4-chlorophenyl) ethynyl] -1,2,3,6-tetrahydropyridine hydrochloride.
[643] 2- (1,2,3,6-tetrahydropyridin-4-ylethynyl) pyridine
[644]
[645] 4-[(4-methylphenyl) ethynyl] -1,2,3,6-tetrahydropyridine
[646]
[647] 2- (piperidin-4-yloxy) -5-trifluoromethyl-pyridine
[648] Sodium hydride (0.52 g, 12 mmol, 55% in oil) was washed twice in hexane and suspended in dry dimethoxyethane (30 mL). 4-hydroxypiperidine (1.21 g, 12 mmol) and 2-chloro-5-trifluoromethylpyridine were dissolved in dry dimethoxyethane (30 mL). This solution was added dropwise to the sodium hydride suspension. The reaction was stirred overnight at 80 ° C. under nitrogen. After cooling, water was carefully added to the mixture and the solvent was removed by rotary evaporation. The residue was dissolved in water and extracted with ethyl acetate. The organic layer was dried over Na ₂ SO ₄ and evaporated. The residue was chromatographed on silica gel, eluting with 80: 20: 2 EtOAc / MeOH / Et ₃ N to give 1.7 g (63%) of the title compound as a yellow oil which crystallized after several hours.
[649]
[650] The following amines were prepared in a similar manner as described for the synthesis of 2- (piperidin-4-yloxy) -5-trifluoromethyl-pyridine.
[651] 6- (piperidin-4-yloxy) -nicotinonitrile
[652]
[653] 5-Methyl-2- (piperidin-4-yloxy) -pyridine
[654]
[655] 2-methoxy-6- (piperidin-4-yloxy) -pyridine
[656]
[657] 2-Chloro-6- (piperidin-4-yloxy) -pyridine
[658]
[659] 5-fluoro-2- (piperidin-4-yloxy) -pyrimidine
[660]
[661] 2- (piperidin-4-yloxy) -4-trifluoromethyl-pyrimidine
[662]
[663] 5-ethyl-2- (piperidin-4-yloxy) -pyrimidine
[664]
[665] 5-methoxy-2- (piperidin-4-yloxy) -pyridine; Hydrochloride
[666] 4- (5-methoxy-pyridin-2-yloxy) -piperidine-1-carboxylic acid tert-butyl ester (45 mg, 0.14 mmol) was dissolved in THF (3 mL) and concentrated HCl (2 mL ) Was added. The reaction was stirred at room temperature for 2 hours, then the solvent was removed in vacuo and the remaining water was removed by azeotropic evaporation using EtOH / toluene to give 35 mg (97%) of the title compound as oily crystals.
[667]
[668] Starting materials were prepared as follows.
[669] 2-Chloro-5-methoxy-pyridine 1-oxide
[670] 2-Chloro-5-methoxy-pyridine (200 mg, 1.39 mmol) and mCPBA (360 mg, 2.09 mmol) were dissolved in CH ₂ Cl ₂ (10 mL). The mixture was stirred at rt for 2 days. The mixture was then diluted with CH ₂ Cl ₂ , washed with 10% K ₂ CO ₃ aqueous solution and brine and dried over Na ₂ SO ₄ . Removal of solvent in vacuo gave 140 mg (63%) of the title compound as white crystals.
[671]
[672] 4- (5-methoxy-1-oxy-pyridin-2-yloxy) -piperidine-1-carboxylic acid tert-butyl ester
[673] Potassium tert-butoxide (128 mg, 1.14 mmol) is dissolved in dry THF (10 mL) and hydroxy-piperidine-1-carboxylic acid tert-butyl ester (dissolved in dry THF (5 mL) under nitrogen) 177 mg, 0.88 mmol) was added. The mixture was stirred at rt for 10 min before 2-chloro-5-methoxy-pyridine 1-oxide (140 mg, 0.88 mmol) dissolved in dry THF (5 mL). The reaction was stirred at rt for 3 days. Solvent was removed and the residue was partitioned between H ₂ O and CHCl ₃ . The organic phase was washed with brine and dried over Na ₂ SO ₄ . Removal of solvent in vacuo gave 245 mg (86%) of the title compound as a brown oil.
[674]
[675] 4- (5-methoxy-pyridin-2-yloxy) -piperidine-1-carboxylic acid tert-butyl ester
[676] 4- (5-methoxy-1-oxy-pyridin-2-yloxy) -piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.62 mmol) was dissolved in EtOH (5 mL). To this solution was added indium (498 mg, 4.34 mmol) and saturated aqueous NH ₄ Cl solution (4 mL) and the reaction was refluxed for 4 hours. After cooling the mixture, it was filtered through celite and the solvent was removed in vacuo. The residue was chromatographed on silica gel, eluting with 5: 1 heptane / EtOAc to give 50 mg (26%) of the title compound as a yellow oil.
[677]
[678] 4- (4-pyridin-3-yl-phenyl) piperazine; Hydrochloride
[679] Stir 4- (4-pyridin-3-yl-phenyl) piperazin-1-carboxylic acid tert-butyl ester (60 mg, 0.18 mmol) in THF (3 mL) and concentrated HCl (3 mL) for 1 h. It was. The solvent was removed in vacuo and the remaining water was removed by azeotropic evaporation using EtOH / toluene to give 50 mg (100%) of the title compound as a yellow powder.
[680]
[681] Starting materials were prepared as follows.
[682] 4- (4-iodophenyl) piperazine-1-carboxylic acid tert-butyl ester
[683] Starting from N-phenylpiperazine (19 mmol), La Clair in Angew. Chem. Int. Ed. 1998, 37 (3), 325-329 to give the title compound in 55% overall yield.
[684] 4- (4-Pyridin-3-yl-phenyl) piperazine-1-carboxylic acid tert-butyl ester
[685] (See Wellmar et al. J. Heterocycl. Chem. 32 (4), 1995, 1159-1164)
[686] 4- (4-iodophenyl) piperazin-1-carboxylic acid tert-butyl ester (0.272 g, 0.70 mmol), 3-pyridylboronic acid (0.078 g, 0.64 mmol), tetrakis (triphenylphosphine Palladium (0.024 g, 0.02 mmol), 1 M sodium bicarbonate (1.0 mL) and 1,2-dimethoxyethane (1.5 mL) were stirred for 3 h at 84 ° C. under nitrogen, collected in ethyl acetate, Washed with brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation with silica (1 g) to give a solid and applied on a short silica column. Elution with dichloromethane, dichloromethane / ethyl acetate (4: 1) and ethyl acetate without solvent gave 0.06O g (yield 32%) of the title compound as a white solid and 0.060 g of the starting material (iodide), respectively. . The yield was calculated from the amount of iodide converted.
[687]
[688] N- [3- (piperidin-4-yloxy) -phenyl] -acetamide; Hydrochloride
[689] 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (300 mg, 1.5 mmol mmol)₂Cl₂In water and cooled to -10 ° C. Polymer bound triphenylphosphine (750 mg, 2.25 mmol) was added and swelled. N- (3-hydroxy-phenyl) -acetamide (340 mg, 2.25 mmol) dissolved in dry THF was added and the reaction was stirred at −10 ° C. for 10 minutes and then DEAD (0.35 mL, 2.25) was added to the mixture. mmol) was added dropwise. The reaction was stirred overnight while raising the temperature to room temperature. The polymer was filtered off using eluent toluene / EtOAc (5: 1) and a short silica plug. Rotary evaporation reduced the volume of the combined fractions and the solution was washed with 5% aqueous KOH solution and water,₂SO₄And dried in vacuo. The resulting white powder was dissolved in THF (10 mL) and concentrated HCl (10 mL) and stirred at ambient temperature for 1 hour. The solvent was removed in vacuo and the remaining water was removed by azeotropic evaporation using EtOH / toluene to give 230 mg (57%) of the title compound as a white powder.
[690]
[691] The following amines were prepared in a similar manner to that described for N- [3- (piperidin-4-yloxy) -phenyl] -acetamide synthesis.
[692] 3- (piperidin-4-yloxy) -benzonitrile
[693]
[694] 4- (3-methoxy-phenoxy) -piperidine
[695]
[696] 4- (3-Trifluoromethoxy-phenoxy) -piperidine
[697]
[698] 4- (2,4-Difluoro-phenoxy) -piperidine
[699]
[700] 4- (4-Chloro-phenoxy) -piperidine
[701]
[702] 4- (piperidin-4-yloxy) -benzonitrile
[703]
[704] 4- (4-methoxy-phenoxy) -piperidine
[705]
[706] 4- (3,4-Dichloro-phenoxy) -piperidine
[707]
[708] 4- (3,4-Difluoro-phenoxy) -piperidine
[709]
[710] N- [4- (piperidin-4-yloxy) -phenyl] -acetamide
[711]
[712] 4-{[(3,4-dimethylphenyl) methyl] oxy} piperidine hydrochloride
[713]
[714] 4-{[(2,5-dimethylphenyl) methyl] oxy} piperidine hydrochloride
[715]
[716] 5-chloro-2-piperidin-4-ylpyridine hydrochloride
[717] Zn dust (225 mg, 3.5 mmol) was stirred in THF (1 mL) under argon and 1,2-dibromoethane (50 μl) was added at room temperature. The mixture was heated to 65 ° C. for 3 minutes and cooled to room temperature, then trimethylsilyl chloride (70 μl) was added and the mixture was stirred at room temperature for 30 minutes. A 4-iodo-N-Boc-piperidine solution (840 mg, 2.7 mmol) in THF (1.5 mL) was added slowly and the reaction mixture was stirred at 40 ° C for 2 h. Pd ₂ (dba) ₃ (22 mg, 0.024 mmol) and P (2-furyl) ₃ (23 mg, 0.1O mmol) are mixed in THF (0.5 mL) and the mixture is stirred at rt for 10 min. , To an organozinc reagent solution, then 2-bromo-5-chloropyridine (624 mg, 3.24 mmol) in THF (1 mL) and DMA (4 mL). The reaction mixture was heated at 80 ° C. for 3 h, cooled to rt, filtered through celite and diluted with EtOAc. The filtrate was washed with saturated aqueous NaHCO ₃ and brine, dried over Na ₂ SO ₄ and concentrated. Purification on SiO ₂ eluting with heptane / EtOAc 95: 5 to 2: 1 gave tert-butyl-4- (5-chloropyridin-2-yl) piperidine-1-carboxylate as a yellow oil ( 128 mg, 16%). This oil was dissolved in THF (1.5 mL) and concentrated HCl (1.5 mL) and stirred at room temperature for 30 minutes. Concentration several times with toluene and EtOH gave the title compound (89 mg, 89%).
[718]
[719] 5-benzyloxy-2- (piperidin-4-yloxy) -pyridine; Hydrochloride
[720] Amines were prepared in the same manner as described for the synthesis of 5-methoxy-2- (piperidin-4-yloxy) -pyridine.
[721]
[722] Starting materials were prepared as follows.
[723] 2-chloro-5-benzyloxypyridine
[724] Sodium hydride (55% in oil, 236 mg, 5.40 mmol) washed in hexane and 2-chloro-5-hydroxypyridine (350 mg, 2.70 mmol) were suspended in dry DMF (20 mL). Benzylbromide (0.32 mL) after 10 min at room temperature,2.70 mmol) was added and the mixture was stirred for another 2 hours. Dilute the reaction with water and add EtOAc (3 x 50 mL). The combined organic layers were washed with water and brine, Na₂SO₄Dried over. The solvent was removed by rotary evaporation to give 520 mg (88%) of the title compound as a yellow oil.
[725]
[726] 2-Chloro-5-benzyloxy-pyridine 1-oxide
[727] Amines were prepared in the same manner as described for the synthesis of 2-chloro-5-methoxy-pyridine 1-oxide.
[728]
[729] 4- (5-Benzyloxy-1-oxy-pyridin-2-yloxy) -piperidine-1-carboxylic acid tert-butyl ester
[730] Compounds were prepared as described for the synthesis of 4- (5-methoxy-1-oxy-pyridin-2-yloxy) -piperidine-1-carboxylic acid tert-butyl ester.
[731]
[732] 4- (5-Benzyloxy-pyridin-2-yloxy) -piperidine-1-carboxylic acid tert-butyl ester
[733] Compounds were prepared as described for the synthesis of 4- (5-methoxy-pyridin-2-yloxy) -piperidine-1-carboxylic acid tert-butyl ester.
[734]
[735] 5-hydroxy-2- (piperidin-4-yloxy) -pyridine trifluoroacetic acid
[736] 4- (5-benzyloxy-1-oxy-pyridin-2-yloxy) -piperidine-1-carboxylic acid tert-butyl ester (476 mg, 1.19 mmol) was dissolved in methanol (20 mL) and Pd (OH) ₂ (30 mg) was added. This mixture was hydrogenated at 1 atm and room temperature for 24 hours. The catalyst was filtered off and the mixture was purified using preparative HPLC and lyophilized to give 110 mg (30%) of the title compound as a TFA-salt and 34 mg (10%) of neutral Boc protected intermediate. It was.
[737]
[738] 5-Bromo-2- (piperidin-4-yloxy) -pyridine hydrochloride
[739] Amines were prepared in the same manner as described for the synthesis of 5-methoxy-2- (piperidin-4-yloxy) -pyridine.
[740]
[741] Starting materials were prepared as described for the synthesis of 4- (5-methoxy-pyridin-2-yloxy) -piperidine-1-carboxylic acid tert-butyl ester.
[742] 4- (5-Bromo-pyridin-2-yloxy) -piperidine-1-carboxylic acid tert-butyl ester
[743]
[744] 4- (5- (4-Fluoro-phenyl) -pyridin-2-yl) -piperazine hydrochloride
[745] 4- (5- (4-Fluoro-phenyl) -pyridin-2-yl) -piperazin-1-carbaldehyde (98 mg, 0.34 mmol) was dissolved in MeOH (5 mL) and concentrated HCl (12 M , 5 mL) was added. The mixture was stirred at rt overnight. The solvent was removed in vacuo and the remaining water was removed by azeotropic evaporation using EtOH / toluene to give 102 mg (100%) of the title compound as a yellow powder.
[746]
[747] Starting materials were prepared as follows.
[748] 4- (5- (4-Fluoro-phenyl) -pyridin-2-yl) -piperazine-1-carbaldehyde
[749] 4- (5-Bromo-pyridin-2-yl) -piperazine-1-carbaldehyde (100 mg, 0.37 mmol), 4-fluorobenzeneboronic acid (55 mg, 0.39 mmol), (1,1 '-Bis (diphenylphosphino) ferrocene) dichloropalladium (II) (10 mg, 0.01 mmol), toluene (2 mL), EtOH (0.5 ml) and 2 M Na ₂ CO ₃ solution (0.5 mL, 1 mmol) Heated at 80 ° C. overnight under N ₂ . After cooling, the mixture was diluted with toluene and separated. The organic phase was washed with water and brine, filtered through a pad of celite and dried over Na ₂ SO ₄ . Removal of solvent in vacuo gave 100 mg (94%) of the title product as a beige powder.
[750]
[751] The following compounds were synthesized as described for the synthesis of 4- (5- (4-fluorophenyl) -pyridin-2-yl) -piperazine hydrochloride.
[752] 4- (5- (4-methoxy-phenyl) -pyridin-2-yl) -piperazine hydrochloride
[753]
[754] 4- (5- (4-Chloro-phenyl) -pyridin-2-yl) -piperazine hydrochloride
[755]
[756] 4- (5- (4-Trifluoromethoxy-phenyl) -pyridin-2-yl) -piperazine hydrochloride
[757]
[758] 4- (5-Furan-2-yl-pyridin-2-yl) -piperazine hydrochloride
[759]
[760] 4- (5- (1H-Pyrrole-2-yl) -pyridin-2-yl) -piperazine dihydrochloride
[761] The title compound was prepared from 2- (6- (4-formyl-piperazin-1-yl) -pyridin-3-yl) -pyrrole-1-carboxylic acid tert-butyl ester.
[762]
[763] 4- [3,3 ']-bipyridinyl-6-yl-piperazine hydrochloride
[764]
[765] 4- (6-Piperazin-1-yl-pyridin-3-yl) -benzonitrile hydrochloride
[766]
[767] Hydantoin of Formula (I)
[768]
[769]
[770]
[771]
[772]
[773]
[774]
[775] (5S) -5-({[4- (4-fluorophenyl) piperidin-1-yl] sulfonyl} methyl) -5-methylimidazolidine-2,4-dione (Example 12) The following compounds were prepared in the same manner as, precipitated and washed with EtOH / water or purified using preparative HPLC.
[776] (5S) -5-methyl-5-({[4- [4- (methyloxy) phenyl] -3,6-dihydropyridin-1 (2H) -yl] sulfonyl} methyl) imidazolidine- 2,4-dione
[777]
[778] (5S) -5-methyl-5-[({4- [4- (methyloxy) phenyl] piperidin-1-yl} sulfonyl) methyl] imidazolidine-2,4-dione
[779]
[780] (5S) -5-({[4- (4-chlorophenyl) -4-hydroxypiperidin-1-yl] sulfonyl} methyl) -5-methylimidazolidine-2,4-dione
[781]
[782] (5S) -5-methyl-5-[({4- [2- (methyloxy) phenyl] piperidin-1-yl} sulfonyl) methyl] imidazolidine-2,4-dione
[783]
[784] (5S) -5-methyl-5-[({4- [4- (trifluoromethyl) phenyl] piperidin-1-yl} sulfonyl) methyl] imidazolidine-2,4-dione
[785]
[786] (5S) -5-methyl-5-[({4- [3- (trifluoromethyl) phenyl] piperidin-1-yl} sulfonyl) methyl] imidazolidine-2,4-dione
[787]
[788] (5S) -5-[({4- [3,5-bis (trifluoromethyl) phenyl] piperidin-1-yl} sulfonyl) methyl] -5-methylimidazolidine-2,4 Dion
[789]
[790] (5S) -5-({[4- [4-chlorophenyl) -3,6-dihydropyridin-1 (2H) -yl] sulfonyl} methyl) -5-methylimidazolidine-2,4 Dion
[791]
[792] (5S) -5-({[4- (3-fluorophenyl) piperidin-1-yl] sulfonyl} methyl) -5-methylimidazolidine-2,4-dione
[793]
[794] (5S) -5-({[4- (2-fluorophenyl) piperidin-1-yl] sulfonyl} methyl) -5-methylimidazolidine-2,4-dione
[795]
[796] (5S) -5-methyl-5-({[4- (4-methylphenyl) piperidin-1-yl] sulfonyl} methyl) imidazolidine-2,4-dione
[797]
[798] (5S) -5-methyl-5-({[4- (phenylmethyl) piperidin-1-yl] sulfonyl} methyl) imidazolidine-2,4-dione
[799]
[800] (5S) -5-[(1,4'-bipiperidine-1'-ylsulfonyl) methyl] -5-methylimidazolidine-2,4-dione Trifluoroacetic acid
[801]
[802] (5S) -5-({[4- (3-furan-2-yl-1H-pyrazol-5-yl) piperidin-1-yl] sulfonyl} methyl) -5-methylimidazolidine -2,4-dione
[803]
[804] (5S) -5-methyl-5-{[(4- {4-[(trifluoromethyl) oxy] phenyl} piperidin-1-yl) sulfonyl] methyl} imidazolidine-2,4 Dion
[805]
[806] (5S) -5-({[4- (4-chlorophenyl) piperidin-1-yl] sulfonyl} methyl) -5-methylimidazolidine-2,4-dione
[807]
[808] (5S) -5-methyl-5-{[(4-pyrrolidin-1-ylpiperidin-1-yl) sulfonyl] methyl} imidazolidine-2,4-dione trifluoroacetic acid
[809]
[810] (5S) -5-methyl-5-({[4- (tetrahydrofuran-2-ylcarbonyl) piperazin-1-yl] sulfonyl} methyl) imidazolidine-2,4-dione
[811]
[812] N- [1-({[(4S) -4-methyl-2,5-dioxoimidazolidin-4-yl] methyl} sulfonyl) piperidin-4-yl] benzamide
[813]
[814] (5S) -5-{[(4-{[2- (1,1-dimethylethyl) -1H-indol-5-yl] amino} piperidin-1-yl) sulfonyl] methyl} -5- Methylimidazolidine-2,4-dione
[815]
[816] (5S) -5-methyl-5-[(piperidin-1-ylsulfonyl) methyl] imidazolidine-2,4-dione
[817]
[818] (5S) -5-[(3,6-dihydropyridine-1 (2H) -ylsulfonyl) methyl] -5-methylimidazolidine-2,4-dione
[819]
[820] (5S) -5-methyl-5-({[4- (2-oxo-2,3-dihydro-1H-benzimidazol-1-yl) piperidin-1-yl] sulfonyl} methyl) Imidazolidine-2,4-dione
[821]
[822] (5S) -5-({[4- (1H-1,2,3-benzotriazol-1-yl) piperidin-1-yl] sulfonyl} methyl) -5-methylimidazolidine- 2,4-dione
[823]
[824] (5S) -5-methyl-5-({[4- (pyridin-2-ylethynyl) -3,6-dihydropyridin-1 (2H) -yl} sulfonyl} methyl) imidazolidine- 2,4-dione trifluoroacetic acid
[825]
[826] (5S) -5-methyl-5-({[4-[(4-methylphenyl) ethynyl] -3,6-dihydropyridin-1 (2H) -yl] sulfonyl} methyl) imidazolidine- 2,4-dione
[827]
[828] (5S) -5-({[4-[(4-chlorophenyl) ethynyl] -3,6-dihydropyridin-1 (2H) -yl] sulfonyl} methyl) -5-methylimidazolidine -2,4-dione
[829]
[830] (5S) -5- [4- (3,4-Dichloro-phenoxy) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[831]
[832] (5S) -5- [4- (5-Chloro-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[833]
[834] (5S) -5-Methyl-5- [4- (5-trifluoromethyl-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -imidazolidine-2,4-dione
[835]
[836] 6- [1-((4S) -4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl) -piperidin-4-yloxy] -nicotinonitrile
[837]
[838] (5S) -5-Methyl-5- (4-p-tolyloxy-piperidine-1-sulfonylmethyl) -imidazolidine-2,4-dione
[839]
[840] (5S) -5-Methyl-5- [4- (4-trifluoromethyl-phenoxy) -piperidine-1-sulfonylmethyl] -imidazolidine-2,4-dione
[841]
[842] 4- [1- (4S) -4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl) -piperidin-4-yloxy] -benzonitrile
[843]
[844] (5S) -5- [4- (4-Methoxy-phenoxy) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[845]
[846] (5S) -5- [4- (3,4-Difluoro-phenoxy) -piperidine-1-sulfonylmethyl-5-methyl-imidazolidine-2,4-dione
[847]
[848] (5S) -5- [4- (4-Chloro-phenoxy) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[849]
[850] (5S) -5- [4- (5-ethyl-pyrimidin-2-yloxy) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[851]
[852] (5S) -5-Methyl-5- [4- (4-trifluoromethyl-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -imidazolidine-2,4-dione
[853]
[854] (5S) -5-Methyl-5- [4- (5-methyl-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -imidazolidine-2,4-dione
[855]
[856] (5S) -5- [4- (4-Fluoro-benzoyl) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[857]
[858] (5S) -5- [4- (5-Fluoro-piperidin-2-yloxy) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[859]
[860] (5S) -5- [4- (6-methoxy-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[861]
[862] (5S) -5- [4- (6-Chloro-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[863]
[864] 3- [1-((4S) -Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl) -piperidin-4-yloxy] -benzonitrile
[865]
[866] (5S) -5- [4- (3-methoxy-phenoxy) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[867]
[868] N- {4- [1-((4S) -4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl) -piperidin-4-yloxy] -phenyl}- Acetamide
[869]
[870] (5S) -5- [4- (3-Chloro-phenoxy) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[871]
[872] (5S) -5-Methyl-5- [4- (4-trifluoromethoxy-phenoxy) -piperidine-1-sulfonylmethyl] -imidazolidine-2,4-dione
[873]
[874] (5S) -5-Methyl-5- [4- (3-trifluoromethoxy-phenoxy) -piperidine-1-sulfonylmethyl] -imidazolidine-2,4-dione
[875]
[876] (5S) -5- [4- (2,4-Difluoro-phenoxy) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[877]
[878] (5S) -5- [4- (4-Fluoro-phenoxy) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[879]
[880] (5S) -5- [4- (3-Fluoro-phenoxy) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[881]
[882] (5S) -5- [4- (2-Fluoro-phenoxy) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[883]
[884] (5S) -5- [4- (5-methoxy-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -5-methyl- Imidazolidine-2,4-dione
[885]
[886] (5S) -5-Methyl-5- [4- (4-pyridin-3-yl-phenyl) -piperidine-1-sulfonylmethyl] -imidazolidine-2,4-dione
[887]
[888] (5S) -5-methyl-5-({[4- (pyridin-2-yloxy) piperidin-1-yl] sulfonyl} methyl) imidazolidine-2,4-dione
[889]
[890] (5S) -5-[({4-[(3,4-dimethylbenzyl) oxy] piperidin-1-yl} sulfonyl) methyl] -5-methylimidazolidine-2,4-dione
[891] (NB. Contained 30% of the 2,3-dimethyl isomer that was present in the starting material)
[892]
[893] (5S) -5-methyl-5-{[(4-phenoxypiperidin-1-yl) sulfonyl] methyl} imidazolidine-2,4-dione
[894]
[895] 4-Fluoro-N- [1-((4S) -4-methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl) -piperidin-4-yl] -benzamide
[896]
[897] (5S) -5-[({4-[(2,5-dimethylbenzyl) oxy] piperidin-1-yl} sulfonyl) methyl] -5-methylimidazolidine-2,4-dione
[898]
[899] (5S) -5-{[4- (5-chloropyridin-2-yl) piperidin-1-yl] sulfonyl} -5-methylimidazolidine-2,4-dione
[900]
[901] (5S) -5- [4- (5-benzyloxy-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[902]
[903] (5S) -5- [4- (6-Chloro-pyridin-3-yloxy) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[904]
[905] (5S) -5- [4- (5-hydroxy-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[906]
[907] (5S) -5- [4- (4-Chloro-phenylsulfanyl) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[908]
[909] (5S) -5- [4- (4-Chloro-benzenesulfonyl) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[910]
[911] (5S) -5- [4- (4-Fluoro-phenylamino) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[912]
[913] N- {3- [1-((4S) -4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl) -piperidin-4-yloxy] -phenyl}- Acetamide
[914]
[915] (5S) -5- [4- (4-Chloro-benzoyl) -piperazine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[916]
[917] 1-((4S) -4-Methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl) -piperidine-4-carboxylic acid (4-fluoro-phenyl) -amide
[918]
[919] (5S) -5- [4- (5-Bromo-pyridin-2-yloxy) -piperidine-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[920]
[921] (5S) -5- [4- (5- (4-Fluoro-phenyl) -pyridin-2-yl) -piperazin-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4 Dion
[922]
[923] (5S) -5- [4- (5- (4-Methoxy-phenyl) -pyridin-2-yl) -piperazin-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4 Dion
[924]
[925] (5S) -5- [4- (5- (4-Chloro-phenyl) -pyridin-2-yl) -piperazin-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4- Dion
[926]
[927] (5S) -5- [4- (5- (4-Trifluoromethoxy-phenyl) -pyridin-2-yl) -piperazin-1-sulfonylmethyl] -5-methyl-imidazolidine-2 , 4-dione
[928]
[929] (5S) -5- [4- (5-Furan-2-yl-pyridin-2-yl) -piperazin-1-sulfonylmethyl] -5-methyl-imidazolidine-2,4-dione
[930]
[931] (5S) -5-Methyl-5- (4- [5- (1H-pyrrole-2-yl) -pyridin-2-yl] -piperazin-1-sulfonylmethyl) -imidazolidine-2, 4-dion
[932]
[933] (5S) -5- (4- [3,3 ']-bipyridinyl-6-yl-piperazine-1-sulfonylmethyl) -5-methyl-imidazolidine-2,4-dione
[934]
[935] (4S) -4- (6- [4- (4-methyl-2,5-dioxo-imidazolidin-4-ylmethanesulfonyl) -piperazin-1-yl] -pyridin-3-yl ) -Benzonitrile
[936]
[937] <Example 14>
[938] According to the method described in Example 12, a compound of the general formula
[939]
[940]
[941]
[942] 5-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -5-[(3,4,4-trimethyl-2,5- Dioxoimidazolidin-1-yl) methyl] imidazolidine-2,4-dione
[943] Racemic {2,5-dioxo-4-[(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) methyl] imidazolidine as described in Example 12 The title compound was prepared from 4-yl} methanesulfonyl chloride and 5-chloro-2- (piperidin-4-yloxy) -pyridine.
[944]
[945] Starting materials were prepared as follows.
[946] 3- [3- (benzylthio) -2-oxopropyl] -1,5,5-trimethylimidazolidine-2,4-dione
[947] Benzyl mercaptan (256 μL in dimethyl formamide (5 mL), 2.2 mmol) and cesium carbonate (712 mg, 2.2 mmol) were stirred at room temperature for 1 hour. 3- (3-bromo-2-oxopropyl) -1,5,5-trimethylimidazolidine-2,4-dione (552 mg, 1.99 mmol) prepared as in WO99 / 06361 was added and The mixture was stirred at rt for 18 h. The reaction mixture was treated with water, extracted with ethyl acetate (3 × 25 mL), the organic phases combined, washed with brine and dried. The product was eluted with 50% ethyl acetate / iso-hexane and purified by silica chromatography to give 300 mg of product.
[948]
[949] 5-[(benzylthio) methyl] -5-[(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) methyl] imidazolidine-2,4-dione
[950] The title compound was prepared as described for the synthesis of 5-methyl-5-{[(phenylmethyl) thio] methyl} imidazolidine-2,4-dione of Example 12.
[951]
[952] {2,5-dioxo-4-[(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) methyl] imidazolidin-4-yl} methanesulfonyl chloride
[953] The title compound was prepared as described for the synthesis of [(4S) and (4R) -4-methyl-2,5-dioxoimidazolidin-4-yl] methanesulfonyl chloride of Example 12.
[954]
[955] 5-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -5-[(3,4,4-trimethyl-2,5- The following compounds were prepared as described for the synthesis of dioxoimidazolidin-1-yl) methyl] imidazolidine-2,4-dione.
[956] 5-[({4- [5- (trifluoromethyl) pyridin-2-yl] piperazin-1-yl} sulfonyl) methyl] -5-[(3,4,4-trimethyl-2,5 -Dioxoimidazolidin-1-yl) methyl] imidazolidine-2,4-dione
[957]
[958] 5- [4- (4-fluoro-phenyl-piperazine-1-sulfonylmethyl] -5-[(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) Methyl] imidazolidine-2,4-dione
[959]
[960] 5-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -5- {2-[(phenylmethyl) oxy] ethyl} imida Zolidine-2,4-dione
[961] 5-[({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) methyl] -5-[(3,4,4-trimethyl-2,5- 5-Chloro-2- (piperidin-4-yloxy) -pyridine hydrochloride as described for the synthesis of dioxoimidazolidin-1-yl) methyl] imidazolidine-2,4-dione And (2,5-dioxo-4- {2-[(phenylmethyl) oxy] ethyl} imidazolidin-4-yl) methanesulfonyl chloride to prepare the title compound.
[962]
[963] 6-({4-[(5-chloropyridin-2-yl) oxy] piperidin-1-yl} sulfonyl) -1,3-diazaspiro [4.5] decane-2,4-dione
[964]
[965] Starting materials were prepared as follows.
[966] 6-[(phenylmethyl) thio] -1,3-diazaspiro [4.5] decane-2,4-dione
[967] Benzylmercaptan (937 mg, 7.5 mmol) was dissolved in 70 mL of THF. NaH (362 mg, 60%, 9.O mmol) was added and the slurry stirred for several minutes. 2-chlorocyclohexanone (1.0 g, 7.5 mmol) was added and the reaction was stirred at rt overnight. The solid was filtered off and the solvent was removed by rotary evaporation. Potassium cyanide (4 eq), (NH ₄ ) ₂ CO ₃ (8 eq) and 25 mL of ethanol were added. The reaction was stirred at 80 ° C overnight in a sealed vial. The suspension was filtered and the solid was recrystallized from DMSO and water to give the title compound as white solid.
[968]
[969] <Example 15>
[970]
[971] 5-Methyl-5- (1- (toluene-4-sulfonyl) -cyclopentyl) -imidazolidine-2,4-dione
[972] 1- (1- (Toluene-4-sulfonyl) -cyclopentyl))-ethanone (0.10 g, 0.38 mmol) in water (1.6 mL), potassium cyanide (0.049 g, 0.75 mmol), ammonium carbonate (0.18 g , 1.9 mmol) and 50% ethanol were stirred at 90 ° C. in a sealed tube (volume 2 mL) for 70 hours. The solution was acidified to pH 6 with 10% acetic acid and concentrated to half of the original volume by rotary evaporation and the product portion dropped. The solution and its solid phase contents were collected in ethyl acetate, the aqueous phase was separated and washed twice with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to give 0.74 g of a white solid. The crude product was dissolved in methanol (5 mL), concentrated using silica (1 g) by rotary evaporation and applied on a short silica column. Elution with ethyl acetate / n-heptane (1: 2 and 2: 1) gave 0.060 g (48%) of the title product as a colorless needle.
[973]
[974]
[975] Starting materials were prepared as follows.
[976] 1- (toluene-4-sulfonyl) -propan-2-one
[977] J. Org. Chem. Sodium p-toluenesulfinate dihydrate (4.2 g, 18 mmol), chloroacetone (1.0 mL, 12 mmol), n-tetrabutylammonium bromide according to 1985, (8) 50, 1327-1329, Crandall et al. (0.30 g) and water-benzene-acetone 4: 3: 3 (10 mL) prepared the title compound. Work up and chromatograph the crude product on silica using ethyl acetate / n-heptane (1: 3 to 1: 2) as eluent to afford 2.4 g (95%) of the title product as an oil which crystallizes as such in a refrigerator. .
[978]
[979] 1- (1- (Toluene-4-sulfonyl) -cyclopentyl))-ethanone
[980] 1- (toluene-4-sulfonyl) -propan-2-one (0.10 g, 0.47 mmol), 1,4-diiobutane (0.068 mL, 0.52 mmol), finely ground potassium carbonate (0.14 g, 1.0 mmol ) And dry dimethylsulfoxide (0.80 mL) were stirred at 50 ° C. (bath temperature) for 22 hours. The heating was stopped and stirring continued at 22 ° C. for 22 hours. The crude product was collected in ethyl acetate, washed with water (5 x 50 mL) and brine (1 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The oily residue was chromatographed on silica using ethyl acetate / n-heptane (1: 4 to 1: 3) to afford 0.1O g (80%) of the title product as a colorless oil.
[981]

权利要求:
Claims (16)
[1" claim-type="Currently amended] A compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
<Formula I>

Where
X is selected from NR 1, O and S;
Y ₁ and Y ₂ are independently selected from O and S;
Z is selected from SO and SO ₂ ;
m is 1 or 2;
A is a direct bond, (C1-6) alkyl, (C1-6) haloalkyl, and N, O, S, SO, S0 ₂ containing a heteroatom selected from, or N, O, S, selected from SO, S0 ₂ And (C 1-6) heteroalkyl containing two hetero groups separated by two or more carbon atoms;
R 1 is selected from H, (C 1-3) alkyl and haloalkyl;
R2 and R3 are each H, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, alkyl-heteroaryl, heteroalkyl-aryl, heteroalkyl-heteroaryl, aryl-alkyl, aryl -Heteroalkyl, heteroaryl-alkyl, heteroaryl-heteroalkyl, aryl-aryl, aryl-heteroaryl, heteroaryl-aryl, heteroaryl-heteroaryl, cycloalkyl-alkyl, heterocycloalkyl-alkyl, alkyl-cycloalkyl And alkyl-heterocycloalkyl;
Each R 4 is independently selected from H, halogen, (C 1-3) alkyl and haloalkyl;
R2 and R3 radicals are each independently alkyl, heteroalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, thiol, alkylthiol, aryl thiol, alkylsulfone, haloalkylsulfone, arylsulfone, amino Sulfone, N-alkylaminosulfone, N, N-dialkylaminosulfone, arylaminosulfone, amino, N-alkylamino, N, N-dialkylamino, amido, N-alkylamido, N, N-di Alkyl amido, cyano, sulfoneamino, alkylsulfonamino, arylsulfonamino, amidino, N-aminosulfon-amidino, guanidino, N-cyano-guanidino, thioguandino, 2-nitro Optionally substituted with one or more groups selected from ethene-1,1-diamine, carboxy, alkyl-carboxy, nitro and carbamate;
Optionally R2 and R3 may combine to form a ring containing up to seven ring atoms, or R2 and R4 may combine to form a ring containing up to seven ring atoms, or R3 and R4 may be Combine to form a ring containing up to seven ring atoms;
R 5 is a monocyclic, bicyclic or tricyclic group containing from 1 to 3 ring structures each containing up to 7 ring atoms each independently selected from cycloalkyl, aryl, heterocycloalkyl and heteroaryl; The ring structure is optionally halogen, hydroxy, alkyl, alkoxy, haloalkoxy, amino, N-alkylamino, N, N-dialkylamino, alkylsulfonamino, alkylcarboxyamino, cyano, nitro, thiol, alkylthiol, At least one substituent independently selected from alkylsulfonyl, haloalkylsulfonyl, alkylaminosulfonyl, carboxylate, alkylcarboxylate, aminocarboxy, N-alkylamino-carboxy and N, N-dialkylamino-carboxy Are independently substituted, and any alkyl radical in any substituent is itself halogen, hydroxy, alkoxy, haloalkoxy, amino, N-alkylamino, N, N-dialkylami , N-alkylsulfonamino, N-alkylcarboxyamino, cyano, nitro, thiol, alkylthiol, alkylsulfonyl, N-alkylaminosulfonyl, carboxylate, alkylcarboxy, aminocarboxy, N-alkylaminocarboxy, Optionally substituted with one or more groups selected from N, N-dialkylaminocarboxy and carbamate;
When R 5 is a bicyclic or tricyclic group, each of the ring structures is a direct bond, —O—, (C 1-6) alkyl, (C 1-6) haloalkyl, (C 1-6) heteroalkyl, (C 1-6) al Is bound to or conjugated to a neighboring ring structure by kenyl, (C 1-6) alkynyl, sulfone, CO, NCO, CON, NH, S or C (OH).
[2" claim-type="Currently amended] The compound of claim 1, wherein X is NR 1, Z is SO ₂ or SO, at least one of Y ₁ and Y ₂ is O, m is 1, and R 1 is H, (C 1-3) alkyl or (C 1 -1). 3) A compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, which is haloalkyl.
[3" claim-type="Currently amended] 3. The compound of claim 1, wherein R 2 is H, alkyl, hydroxyalkyl, alkoxyalkyl, aryloxy alkyl, aminoalkyl, cycloalkyl-alkyl, alkyl-cycloalkyl, arylalkyl, alkylaryl, alkyl-heteroaryl, A compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, which is heteroalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, heteroaryl-alkyl or heteroalkyl-aryl.
[4" claim-type="Currently amended] 4. A compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof according to any one of claims 1 to 3, wherein R3 and R4 are each independently selected from H or methyl.
[5" claim-type="Currently amended] The compound of formula (I) or a pharmaceutically acceptable thereof according to any one of claims 1 to 4, wherein R 5 comprises one to three optionally substituted 5 or 6 membered aryl or heteroaryl. Salts or in vivo hydrolysable esters.
[6" claim-type="Currently amended] The compound of formula (I) or a pharmaceutically acceptable salt thereof or in vivo according to any one of claims 1 to 5, wherein R 5 is a bicyclic or tricyclic group comprising two or three optionally substituted ring structures. Hydrolysable esters.
[7" claim-type="Currently amended] A compound of formula II: or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
<Formula II>

Where
G1, G2 and G4 are monocyclic ring structures each containing up to 7 ring atoms each independently selected from cycloalkyl, aryl, heterocycloalkyl and heteroaryl, each ring structure being optionally halogen, hydroxy, One or two independently selected from haloalkoxy, amino, N-alkylamino, N, N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, alkylcarbamate and alkylamide Independently substituted with a substituent, any alkyl radical in any substituent is itself halogen, hydroxy, amino, N-alkylamino, N, N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy, aryl Optionally substituted with one or more groups selected from oxy, heteroaryloxy and carbamate;
Z is SO ₂ ;
B and F are each independently selected from a direct bond, 0, (C 1-6) alkyl, (C 1-6) heteroalkyl, alkynyl, CO, NCO, CON, NH and S;
R2 is H, alkyl, hydroxyalkyl, alkoxyalkyl, aryloxy alkyl, aminoalkyl, (N-alkylamino) alkyl, (N, N-dialkylamino) alkyl, amidoalkyl, thioalkyl cycloalkyl-alkyl, Alkyl-cycloalkyl, arylalkyl, alkylaryl, alkyl-heteroaryl, heteroalkyl, heterocycloalkyl-alkyl, alkyl-heterocycloalkyl, heteroaryl-alkyl and heteroalkyl-aryl;
R 3 and R 4 are independently selected from H and (C 1-3) alkyl;
Optionally R2 and R3 may combine to form a ring containing up to seven ring atoms, or R2 and R4 may combine to form a ring containing up to seven ring atoms, or R3 and R4 may be Can be joined to form a ring containing up to seven ring atoms.
[8" claim-type="Currently amended] 8. A compound of formula (II) or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof according to claim 7, wherein R2 is alkyl, aminoalkyl, alkyl-heteroaryl, alkyl-heterocycloalkyl or heteroaryl-alkyl.
[9" claim-type="Currently amended] A compound of formula (IIa) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof.
<Formula IIa>

Where
G1 and G2 are monocyclic ring structures each containing up to 7 ring atoms each independently selected from cycloalkyl, aryl, heterocycloalkyl and heteroaryl, each ring structure being optionally halogen, hydroxy, haloalkoxy With one or two substituents independently selected from amino, N-alkylamino, N, N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, alkylcarbamate and alkylamide Independently substituted, any alkyl radical in any substituent is itself halogen, hydroxy, amino, N-alkylamino, N, N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy, aryloxy, Optionally substituted with one or more groups selected from heteroaryloxy and carbamate;
Z is SO ₂ ;
B is selected from a direct bond, O, (C 1-6) alkyl, (C 1-6) heteroalkyl, CO, NCO, CON, NH, S and alkynyl;
R 2 is from H, (C 1-6) alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (N-alkylamino) alkyl, (N, N-dialkylamino) alkyl, amidoalkyl and thioalkyl Or is selected from the group of formula III
<Formula III>

C and D may be a direct bond, H, (C 1 -C 6) alkyl, (C 1 -C 6) haloalkyl, and one or two hetero atoms selected from N, O or S (if two hetero atoms are present they are two Independently selected from (C1-C6) heteroalkyl containing a carbon atom);
G3 is a monocyclic ring structure containing up to 7 ring atoms independently selected from cycloalkyl, aryl, heterocycloalkyl and heteroaryl, each ring structure is optionally halogen, hydroxy, amino, N-alkylamino , N, N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, and halogen, hydroxy, amino, N-alkylamino, N, N-dialkylamino, cyano, nitro Is substituted with one or two substituents independently selected from alkyl substituted with one or more groups selected from alkoxy or haloalkoxy;
Optionally R2 is halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, aminoalkyl, N-alkylamino, N, N-dialkylamino, (N-alkylamino) alkyl, (N, N-dialkylamino Alkyl, alkylsulfone, aminosulfone, N-alkylamino-sulfone, N, N-dialkylaminosulfone, amido, N-alkylamido, N, N-dialkylamido, cyano, sulfoneamino, alkyl Substituted by sulfonamino, amidino, N-aminosulfon-amidino, guanidino, N-cyano-guanidino, thioguandino, 2-nitroguanidino, carboxy, alkylcarboxy or carbamate Become;
R 3 and R 4 are independently selected from H and (C 1-3) alkyl;
Optionally R2 and R3 may combine to form a ring containing up to seven ring atoms, or R2 and R4 may combine to form a ring containing up to seven ring atoms, or R3 and R4 may be Can be joined to form a ring containing up to seven ring atoms.
[10" claim-type="Currently amended] The compound of formula (IIa) or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof according to claim 9, wherein B is selected from direct bonds, O, CO, S and alkynyl.
[11" claim-type="Currently amended] A compound according to claim 9 or 10, wherein R 2 is H, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, aminoalkyl, N-alkylamino, N, N-dialkylamino, (N-alkylamino) Alkyl, (N, N-dialkylamino) alkyl, alkylsulfone, aminosulfone, N-alkylamino-sulfone, N, N-dialkylamino-sulfone, amido, N-alkylamido, N, N-di Alkylamido, carbamate, cyano, sulfoneamino, alkylsulfonamino, amidino, N-aminosulfone-amidino, guanidino, N-cyano-guanidino, thioguandino, 2-nitro (C1-6) alkyl, aryl- (C1-6) alkyl and heteroaryl- (optionally substituted with guanidino, 2-nitro-ethene-1,1-diamino, carboxy, alkylcarboxy or carbamate A compound of formula (IIa) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, selected from C1-6) alkyl.
[12" claim-type="Currently amended] 12. A compound of formula (IIa) or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof according to any one of claims 9 to 11, wherein R3 and R4 are each H.
[13" claim-type="Currently amended] A compound of formula (IIb) or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof.
<Formula IIb>

Where
G 1 is a monocyclic ring structure each containing up to 7 ring atoms each independently selected from cycloalkyl, aryl, heterocycloalkyl and heteroaryl, each ring structure being optionally halogen, hydroxy, haloalkoxy, amino Independently with one or two substituents independently selected from N-alkylamino, N, N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, alkylcarbamate and alkylamide And any alkyl radical in any substituent is itself halogen, hydroxy, amino, N-alkylamino, N, N-dialkylamino, cyano, nitro, alkoxy, haloalkoxy, aryloxy, heteroaryl Optionally substituted with one or more groups selected from oxy or carbamate;
G2 is optionally substituted piperidine or piperazine;
B is selected from a direct bond, O, (C 1-6) alkyl, (C 1-6) heteroalkyl, CO, NCO, CON, NH, S and alkynyl;
R 2 is from H, (C 1-6) alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (N-alkylamino) alkyl, (N, N-dialkylamino) alkyl, amidoalkyl and thioalkyl Or is selected from the group of formula III
<Formula III>

C and D may be a direct bond, H, (C 1 -C 6) alkyl, (C 1 -C 6) haloalkyl, and one or two hetero atoms selected from N, O or S (if two hetero atoms are present they are two Independently selected from (C1-C6) heteroalkyl containing a carbon atom);
G3 is a monocyclic ring structure containing up to 7 ring atoms independently selected from cycloalkyl, aryl, heterocycloalkyl or heteroaryl, each ring structure is optionally halogen, hydroxy, amino, N-alkylamino , N, N-dialkylamino, cyano, nitro, alkyl, alkoxy, alkyl sulfone, haloalkyl sulfone, or halogen, hydroxy, amino, N-alkylamino, N, N-dialkylamino, cyano, nitro Is substituted with one or two substituents independently selected from alkyl substituted with one or more groups selected from alkoxy and haloalkoxy;
Optionally R2 is halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino, aminoalkyl, N-alkylamino, N, N-dialkylamino, (N-alkylamino) alkyl, (N, N-dialkylamino Alkyl, alkylsulfone, aminosulfone, N-alkylamino-sulfone, N, N-dialkylaminosulfone, amido, N-alkylamido, N, N-dialkylamido, cyano, sulfoneamino, alkyl Substituted by sulfonamino, amidino, N-aminosulfon-amidino, guanidino, N-cyano-guanidino, thioguandino, 2-nitroguanidino, carboxy, alkylcarboxy or carbamate Become;
R 3 and R 4 are independently selected from H and (C 1-3) alkyl;
Optionally R2 and R3 may combine to form a ring containing up to seven ring atoms, or R2 and R4 may combine to form a ring containing up to seven ring atoms, or R3 and R4 may be Can be joined to form a ring containing up to seven ring atoms.
[14" claim-type="Currently amended] A compound of formula (I) of claim 1, a compound of formula (II) of claim 7, a compound of formula (IIa) of claim 9, a compound of formula (IIb) of claim 13, or a pharmaceutically acceptable salt or in vivo hydrolysable ester and pharmaceutically acceptable thereof A pharmaceutical composition comprising a carrier.
[15" claim-type="Currently amended] A method of treating a metalloproteinase mediated disease or condition comprising administering to a warm blooded animal a therapeutically effective amount of a compound of Formula (I), (II), (IIa) or (IIb), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. .
[16" claim-type="Currently amended] Compounds of Formula (I), (II), (IIa) or (IIb), or a pharmaceutically acceptable salt or in vivo hydrolyzable precursor thereof, in the manufacture of a medicament for use in the treatment of a disease or condition mediated by one or more metalloproteinase enzymes Use of

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2001-03-15|Priority to SE0100902-6

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2001-03-15|Priority to SE0100902A

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2002-03-13|Application filed by 아스트라제네카 아베

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2002-03-13|Priority to PCT/SE2002/000472

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2003-10-23|Publication of KR20030082989A

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2009-03-04|Application granted

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2009-03-04|Publication of KR100886315B1

优先权:

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申请号 | 申请日 | 专利标题

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SE0100902-6|2001-03-15|

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SE0100902A|SE0100902D0|2001-03-15|2001-03-15|Compounds|

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PCT/SE2002/000472|WO2002074767A1|2001-03-15|2002-03-13|Metalloproteinase inhibitors|